Stapled peptides and methods thereof

Abstract

Among other things, the present disclosure provides technologies including 1-66 formulations, compositions, methods, etc. for treating various cancers.

Description

Attorney Docket No.: 2012675-0415STAPLED PEPTIDES AND METHODS THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to United States Provisional Application Nos. 63 / 733412, filed December 12, 2024, 63 / 733414, filed December 12, 2024, 63 / 830309, filed June 25, 2025, 63 / 895909, filed October 8. 2025, 63 / 898451, filed October 13. 2025, 63 / 903831, filed October 22, 2025, and 63 / 922935, filed November 21, 2025, the entirety of each of which is incorporated herein by reference.BACKGROUND

[0002] Stapled peptides are useful for various applications. For example, as biologically active agents, they can be utilized to modulate various biological functions.SUMMARY

[0003] 1-66 is a synthetic, helically constrained polypeptide. Various technologies have confirmed that it binds directly to an oncogenic protein, beta-catenin, and its binding to beta-catenin leads to blockade of beta-catenin: TCF (T-cell factor) complex formation, which has been confirmed in various in vitro and in vivo assays, including PDX mouse models, to inhibit downstream transcriptional program driven by the complex and dramatically inhibiting tumor growth.

[0004] Among other things, the present disclosure provides technologies, e.g., formulations, doses, dosage regimen, etc., for treating conditions, disorders or diseases particularly certain types of cancer. In some embodiments, the present disclosure provides high purity 1-66 drug substance. In some embodiments, the present disclosure provides 1-66 drug products. In some embodiments, the present disclosure provides 1-66 formulations which are liquid compositions in which 1-66 has sufficiently high solubility and stability for clinical applications.

[0005] The present disclosure also encompasses description of useful clinical development programs for 1-66 to demonstrate and confirm that it can be utilized as described herein to treat conditions, disorders or diseases including cancer. In some embodiments, clinical programs include an open-label, in-human phase 1 / 2, multi-center study to evaluate and confirm the safety, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of 1-66. Among other things, objectives of clinical studies include to demonstrate the safety and tolerability profile of 1-66 and to assess the antitumor activity of 1-66 in cancer patients.

[0006] In some embodiments, the present disclosure provides methods comprising administering or delivering 1-66 to a subject suffering from cancer. Various technologies, e.g., 1-66 doses and dosing regimens, combinations of 1-66 and other therapies or therapeutic agents, etc., are described herein. In some embodiments, 1-66 is administered or delivered as a pharmaceutically acceptable salt. In some embodiments, 1-66 is administered or delivered via a pharmaceutical composition described herein. In some embodiments, 1-66 is administered or delivered via a formulation as described herein. In some embodiments, a subject is a Page 1 of 27013160427vlAttorney Docket No.: 2012675-0415patient with a locally advanced and / or metastatic solid tumor. In some embodiments, a cancer is microsatellite stable (MSS) colorectal cancer (CRC). In some embodiments, a subject is a patient with a solid tumor with a Wnt-pathway activating mutation (WPAM). In some embodiments, a cancer is hepatocellular carcinoma (HCC). In some embodiments, a cancer is HCC with a WPAM. In some embodiments, a subject has desmoid tumors. In some embodiments, a subject has desmoid tumors with a WPAM. In some embodiments, 1-66 is administered intravenously. In some embodiments, 1-66 is administered about weekly. In some embodiments.1-66 is administered about every two weeks. In some embodiments, 1-66 is administered about weekly for 3 doses followed by a rest week (e.g., IV on days 1, 8 and 15 followed by a rest week). In some embodiments, 1-66 is utilized as a monotherapy for cancer. In some embodiments, 1-66 is combined with another cancer therapy (e.g., immunotherapy, chemotherapy, etc.) or therapeutic agent (e.g., a checkpoint inhibitor (c.g., an anti-PD-1 antibody, an anti-PD-Ll antibody, a chemotherapy agent, etc.). In some embodiments, 1-66 is combined with one or more additional therapeutic agents. In some embodiments, a combination is 1-66 with mF0LF0X-6 and bevacizumab. In some embodiments, a combination is 1-66 with mF0LF0X-6 and bevacizumab and is administered as IL for MSS CRC. In some embodiments, a combination is 1-66 with an anti-PD-1 antibody, e.g., nivolumab. In some embodiments, a combination is 1-66 with nivolumab and is administered as 3L for MSS CRC (e.g., with and without liver metastases). In some embodiments, a combination is 1-66 with trifluridine / tipiracil + bevacizumab. In some embodiments, a combination is 1-66 with trifluridine / tipiracil + bevacizumab and is administered as 3L MSS CRC.

[0007] In some embodiments, the present disclosure provides pharmaceutical compositions comprising or delivering 1-66 and a pharmaceutical acceptable carrier. In some embodiments, 1-66 is in a pharmaceutically acceptable salt form. In some embodiments, a provided composition comprises a pharmaceutically acceptable salt form of 1-66. In some embodiments, in various compositions and methods, I-66 is provided as one or more pharmaceutically acceptable salt forms.

[0008] In some embodiments, the present disclosure provides methods for modulating a property, activity and / or function of beta-catenin, comprising contacting beta-catenin with 1-66. In some embodiments, the present disclosure provides methods for modulating a property, activity and / or function of beta-catenin in a system comprising beta-catenin, comprising administering or delivering to a system an effective amount of 1-66. In some embodiments, the present disclosure provides methods for modulating a property, activity and / or function of beta-catenin in a system expressing beta-catenin, comprising administering or delivering to a system an effective amount of 1-66. In some embodiments, an activity of beta-catenin is inhibited or reduced. In some embodiments, a function of beta-catenin is inhibited or reduced. In some embodiments, a property, activity and / or function is associated with beta-catenin / TCF interaction.

[0009] In some embodiments, the present disclosure provides methods for modulating beta-catenin / TCF interaction. In some embodiments, the present disclosure provides methods for modulating beta-catenin / TCF interaction, comprising contacting beta-catenin with 1-66. In some embodiments, the present disclosure provides methods for modulating beta-catenin / TCF interaction in a system comprising beta-catenin and TCF,Page 2 of 27013160427vlAttorney Docket No.: 2012675-0415comprising administering or delivering to the system an effective amount of 1-66. In some embodiments, the present disclosure provides methods for modulating beta-catenin / TCF interaction in a system expressing beta-catenin and TCF, comprising administering or delivering to the system an effective amount of 1-66. In some embodiments, interactions between bcta-catcnin and TCF is reduced. In some embodiments, interactions between beta-catenin and TCF is inhibited.

[0010] In some embodiments, the present disclosure provides methods for inhibiting cell proliferation, comprising administering or delivering to a population of cells an effective amount of 1-66. In some embodiments, the present disclosure provides methods for inhibiting cell proliferation in a system, comprising administering or delivering to the system an effective amount of 1-66. In some embodiments, the present disclosure provides methods for inhibiting cell growth, comprising administering or delivering to a population of cells an effective amount of 1-66. In some embodiments, tire present disclosure provides methods for inhibiting cell growth in a system, comprising administering or delivering to tire system an effective amount of 1-66. In some embodiments, such cell proliferation is beta-catenin dependent. In some embodiments, such cell growth is beta-catenin dependent. In some embodiments, such proliferation or growth is dependent on beta-catenin interactions with TCF.

[0011] In some embodiments, the present disclosure provides methods for reducing or preventing activation of a Wnt pathway. In some embodiments, the present disclosure provides methods for reducing or preventing activation of a Wnt pathway in a system, comprising administering or delivering to the system an effective amount of 1-66.

[0012] In some embodiments, the present disclosure provides technologies for modulating level of expression and / or activity of a nucleic acid, e.g., a gene, a transcript, a polypeptide, and / or a product thereof in a system, comprising administering or delivering to tire system an effective amount of 1-66. In some embodiments, level of expression of a nucleic acid, e.g., a gene, or a product thereof (e.g.. a transcript, a polypeptide, etc.) is modulated. In some embodiments, level of activity of a nucleic acid, e.g.. a gene, or a product thereof (e.g., a transcript, a polypeptide, etc.) is modulated. In some embodiments, level of a transcript and / or a product thereof (e.g., a polypeptide) is modulated. In some embodiments, level of activity of a transcript and / or a product thereof (e.g., a polypeptide) is modulated. In some embodiments, a transcript is a transcript of a nucleic acid, e.g., gene, described herein. In some embodiments, level of a polypeptide is modulated. In some embodiments, level of activity of a polypeptide is modulated. In some embodiments, a polypeptide is a encoded by a nucleic acid or a transcript described herein. In some embodiments, a level is increased. In some embodiments, a level is decreased. As described herein, in some embodiments, a system is an in vitro system. In some embodiments, a system is an in vivo system. In some embodiments, a system is or comprises a cell, tissue or organ. In some embodiments, a system is or comprises one or more cancer cells. In some embodiments, a system is or comprises tumor. In some embodiments, a system is or comprises an organism. In some embodiments, a system is a subject. In some embodiments, a system is a human. In some embodiments, a system comprises beta-catenin. In some embodiments, a system expresses beta-catenin. In Page 3 of 27013160427vlAttorney Docket No.: 2012675-0415some embodiments, a system comprises beta-catenin and a partner. In some embodiments, a system expresses beta-catenin and a partner. Tn some embodiments, a level is regulated by beta-catenin. Tn some embodiments, a level is regulated by Wnt activation. In some embodiments, a level is regulated by beta-catenin / Wnt signaling. In some embodiments, a level is regulated by interaction ofbcta-catcnin and a partner. In some embodiments, interaction of beta-catenin and a partner is modulated, e.g., reduced, prevented, etc., by an agent, e.g., a stapled peptide, as described herein. For example, in some embodiments, a partner is TCF. In some embodiments, level of expression and / or activity of a nucleic acid and / or a product thereof is modulated. In some embodiments, a nucleic acid is AXIN2. In some embodiments, level of an AXIN2 transcript, e.g., mRNA, is reduced. In some embodiments, level of an AXIN2 polypeptide is reduced. In some embodiments, a nucleic acid is NKD1. In some embodiments, level of an NKD1 transcript, e.g., mRNA, is reduced. In some embodiments, level ofanNKDl polypeptide is reduced. In some embodiments, a nucleic acid is a member of a negatively enriched gene set observed in, or can be identified using technologies in. e.g., WO 2022 / 261257, WO 2024 / 130218, WO 2024 / 130217, and / or WO 2024 / 254017. In some embodiments, a nucleic acid is a member of BCAT GDS748 UP gene set. In some embodiments, a nucleic acid is a member of BOAT.100 UP. V 1_UP gene set. In some embodiments, a nucleic acid is a member of HALLMARK Wnt BETA CATENIN SIGNALING gene set. In some embodiments, a nucleic acid is a member of HALLMARK_MYC_TARGETS_V2 gene set. In some embodiments, a nucleic acid is a member of HALLMARK E2F TARGETS gene set. In some embodiments, a nucleic acid is a member of HALLMARK G2M CHECKPOINT gene set.

[0013] In some embodiments, a system is in vitro. In some embodiments, a system is ex vivo. In some embodiments, a system is in vivo. In some embodiments, a system is or comprise a cell. In some embodiments, a system is or comprises a tissue. In some embodiments, a system is or comprises an organ. In some embodiments, a system is or comprises an organism. In some embodiments, a system is an animal. In some embodiments, a system is human. In some embodiments, a system is or comprises cells, tissues or organs associated with a condition, disorder or disease. In some embodiments, a system is or comprises cancer cells, e.g., colorectal cancer cells.

[0014] In some embodiments, 1-66 is administered as pharmaceutically compositions that comprise or deliver 1-66. In some embodiments, 1-66 is provided and / or delivered in one or more pharmaceutically acceptable salt fonns. In some embodiments, in a composition (e.g., a liquid composition of certain pH) 1-66 may exist in various forms including various pharmaceutically acceptable salt forms.

[0015] Further description of certain embodiments of provided technologies is presented below.BRIEF DESCRIPTION OF THE DRAWING

[0016] Figure 1. ’HNMRof a preparation ofI-66 (DMSO-d6, 373K).

[0017] Figure 2. Integration of peaks in a1H NMR spectrum of a preparation of 1-66 prepared as described in Example 9 (DMSO-d6, 373K). Those skilled in the art appreciate that integration may be further Page 4 of 27013160427vlAttorney Docket No.: 2012675-0415adjusted and / or optimized.

[0018] Figure 3. ’HNMR of a preparation of T-66. Solvent: methanol-d4. About 10 mg / 750 uL.Temperature: 298 K. Number of scans: 8. Receiver gain: 30.1. Relaxation Delay: 2.5000. Acquisition Time: 1.5139. Spectrometer Frequency: 900.30 MHz. Spectra Width: 10822.5. Lowest Frequency: -927.2. Acquired Size: 16384. Spectral Size: 65536. Digital Resolution: 0.17.

[0019] Figure 4. A region of 'H NMR of a preparation of 1-66. Top: 900 MHz H of a preparation of 1-66 in methanol-d4, 298 K, about 10 mg / 750 uL. Bottom: 500 MHz 'H of a preparation of 1-66 in methanol-d4, 298 K, about 10 mg / 500 uL. As shown here, the top spectra can provide improved resolution for various peaks.

[0020] Figure 5. A region of 'H NMR of a preparation of 1-66. Top: 900 MHz H of a preparation of 1-66 in methanol-d4, 298 K, about 10 mg / 750 uL. Bottom: 500 MHz H of a preparation of 1-66 in metlianol-d4, 298 K, about 10 mg / 500 uL. As shown here, the top spectra can provide improved resolution for various peaks; certain NH peaks at about 7.7ppm that were observed in the 500 MHz data were absent in the 900 MHz data. As those skilled in the art appreciate, NH peaks may change depending on sample environments.

[0021] Figure 6.13C NMR of a preparation of 1-66. Solvent: methanol-d4. About 10 mg / 750 uL.Temperature: 298 K. Number of scans: 8108. Receiver gain: 177.2. Relaxation Delay: 1.5000. Acquisition Time: 0.3277. Spectrometer Frequency: 226.40 MHz. Spectra Width: 50000.0. Lowest Frequency: -911.8. Acquired Size: 16384. Spectral Size: 65536. Digital Resolution: 0.76.

[0022] Figure 7. COSY of a preparation of 1-66. Solvent: methanol-d4. About 10 mg / 750 uL.Temperature: 298 K. Number of scans: 4. Receiver gain: 30.1. Relaxation Delay: 2.0000. Acquisition Time: 0.2272. Spectrometer Frequency: (900.30, 900.30). Spectra Width: (9014.4, 9009.0). Lowest Frequency: (- 22.7, -23.3). Nucleus: (’H, 'H). Acquired Size: (2048, 1024). Spectral Size: (2048, 1024). Digital Resolution: (4.40, 8.80).

[0023] Figure 8. ’H-13C HSQC of a preparation of 1-66. Solvent: methanol-d4. About 10 mg / 750 uL. Temperature: 298 K. Number of scans: 8. Receiver gain: 177.2. Relaxation Delay: 1.5000. Acquisition Time: 0.1137. Spectrometer Frequency: (900.30, 226.40). Spectra Width: (9009.0, 34013.6). Lowest Frequency: (-22.0, 288.5). Nucleus: (’H,BC). Acquired Size: (1024, 512). Spectral Size: (1024, 1024). Digital Resolution: (8.80, 33.22).

[0024] Figure 9. ’H-BC HMBC of a preparation of 1-66. Solvent: methanol-d4. About 10 mg / 750 uL. Temperature: 298 K.

[0025] Figure 10. 'H-'H TOCSY of a preparation of 1-66. Solvent: methanol-d4. About 10 mg / 750 uL. Temperature: 298 K. Number of scans: 8. Receiver gain: 57.7. Relaxation Delay: 2.0000. Acquisition Time: 0.2272. Spectrometer Frequency: (900.30, 900.30). Spectra Width: (9014.4, 9009.0). Lowest Frequency: (- 21.8, -23.3). Acquired Size: (2048, 800). Spectral Size: (2048, 1024). Digital Resolution: (4.40, 8.80).

[0026] Figure 11. 'H-’H NOESY of a preparation of 1-66. Solvent: methanol-d4. About 10 mg / 750 uL. Temperature: 298 K. Number of scans: 8. Receiver gain: 57.7. Relaxation Delay: 2.0000. Acquisition Time:Page 5 of 27013160427vlAttorney Docket No.: 2012675-04150.2272. Spectrometer Frequency: (900.30, 900.30). Spectra Width: (9014.4, 9009.0). Lowest Frequency: (-5.7, -3.0). Acquired Size: (2048, 1024). Spectral Size: (2048, 1024). Digital Resolution: (4.40, 8.80).

[0027] Figure 12. Expansion of 'H-'H NOESY of a preparation of 1-66. Solvent: methanol-d4. About 10 mg / 750 uL. Temperature: 298 K. Number of scans: 8. Receiver gain: 57.7. Relaxation Delay: 2.0000.Acquisition Time: 0.2272. Spectrometer Frequency: (900.30, 900.30). Spectra Width: (9014.4, 9009.0). Lowest Frequency: (-5.7, -3.0). Acquired Size: (2048, 1024). Spectral Size: (2048, 1024). Digital Resolution: (4.40, 8.80). As shown herein, NOE peak between the olefin protons of the PL3-B5 staple (111 and 112) was observed. In some embodiments, this peak was stronger than the NOE peak between neighboring aromatic protons of 3Thi (20 and 21), and / or of the p and m protons in the phenyl group of Phe (48 and 47 / 49).

[0028] Figure 13. Microfluidic Modulation Spectroscopy (MMS) data of an 1-66 preparation. (A) Absolute absorbance spectrum of 1-66 at 20 mg / mL in the Amide I band (shown 1588-1712 cm1). This spectrum was averaged from triplicate measurements. (B) Second derivative plot of the absolute absorbance spectrum. The four peaks highlighted represent the main secondary structural motifs in this peptide molecule. (C) Relative abundance of each secondary' structural motif in 1-66.

[0029] Figure 14. An 1-66 monotherapy dose escalation and expansion design. CRC = colorectal cancer; HCC = hepatocellular carcinoma; mCRPC = metastatic castration-resistant prostate cancer; MSS = microsatellite stable; MTD = maximum tolerated dose; PD= pharmacodynamics; pRP2D = preliminary recommended Phase 2 dose: WPAM = Wnt pathway activating mutation..

[0030] Figure 15. Certain 1-66 combination therapies. CRC = colorectal cancer; MSLH = microsatellite instability-high; MSS = microsatellite stable; MTD = maximum tolerated dose; pRP2D = preliminary recommended Phase 2 dose; PD-1 = programmed cell death- 1; PD-L1 = programmed cell death-ligand 1.

[0031] Figure 16. An 1-66 trial design. In some embodiments, (e.g., Parts la and lb), 1-66 is administered on days 1, 8, 15, and 22 of each 28-day cycle to cohorts of e g., 3-6 patients per cohort. In some embodiments, cohorts 1 to 7 receive 1-66 doses of 36-600 mg / m2weekly in a standard 3+3 design with, e.g., >3 (or 6) DLT-evaluable patients. In some embodiments, additional cohorts of 6 patients may be dosed (e.g., in Part 2) to evaluate PD effects.

[0032] Figure 17. Tumor responses from two patients with desmoid tumors.

[0033] Figure 18. 1-66 PK in certain patients.

[0034] Figure 19. 1-66 can modulate Wnt, sternness and differentiation transcription signatures. Shown are certain data for NKD1 (A) and ASCL2 (B). Empty circles are patient 2 and patient 3. Patient 5 is the 4thcircle from the top at 360 mg / m2in A, and the 2ndcircle from the top at 360 mg / m2in B. See also Table E-19 for additional data.

[0035] Figure 20. 1-66 + 5-FU exhibits robust anti-tumor activity in KRAS-mutant CRC PDX models. The lines from top to bottom: Vehicle (circle, top line), 5-FU (inverted triangle), 1-66 (triangle), and 1-66 + 5-FU (larger circle, lowest line). Tire PDX model was PDX Model 7.

[0036] Figure 21. 1-66 + a-PDl exhibits robust anti-tumor activity in MC38 APC+ / - CRC syngeneic Page 6 of 27013160427vlAttorney Docket No.: 2012675-0415model. The lines from top to bottom: Vehicle (circle), 1-66 (triangle), a-PDl (square), and 1-66 + a-PDl (inverted triangle).

[0037] Figure 22. 1-66 provides efficacy in patients with desmoid tumor. Dose levels of 1-66 for the respective patient numbers arc as described in Table E-20.

[0038] Figure 23. 1-66 provides efficacy in patients with desmoid tumor. Dose levels of 1-66 for tire respective patient numbers are as described in Table E-20. PR: partial response. GSI: gamma secretase inhibitor.

[0039] Figure 24. 1-66 PK in certain patients.

[0040] Figure 25. 1-66 provides efficacy in patients with WPAM+ tumors. PD is progressive disease; SD is stable disease; and PR is partial response. The tumor types arc as follows from left to right: jejunal, vaginal, pancreatic ACC, EICC, NSCLC, uterine, desmoid, desmoid, endometrial, desmoid, ACP, desmoid, desmoid, desmoid, ameloblastoma, desmoid, desmoid, ACP, salivary gland, desmoid, desmoid. ACP. and SPN.

[0041] Figure 26. 1-66 has been administered to a number of patients with WPAM+ tumors. The tumor types are as follows from top to bottom: desmoid, desmoid, desmoid, desmoid, desmoid, desmoid, desmoid, desmoid, desmoid, desmoid, desmoid, desmoid, ACP, ACP, ACP, endometrial, salivary gland, SPN, ameloblastoma, NSCLC, jejunal, vaginal, uterine, pancreatic ACC, HCC, HCC, and esophageal.

[0042] Figure 27. 1-66 provides dose-dependent efficacy in patients with CRC tumors. Dose levels 1-3 are 36 mg / m2, 72 mg / m2, and 144 mg / m2. Dose levels 4-6 are. 240 mg / m2. 360 mg / m2, 420 mg / m2, and 480 mg / m2.

[0043] Figure 28. 1-66 can provide reduction in ctDNA levels (e.g., ctDNA tumor fraction (TF)) in patients with CRC tumors. MR is ctDNA molecular response (defined as >50% reduction in ctDNA tumor fraction compared to baseline). Dose levels 1-3 are 36 mg / m2, 72 mg / m2, and 144 mg / m2.Aindicates a patient with a TCF7L2(TCF4) loss of function mutation. # indicates a patient with a WPAM negative tumor.

[0044] Figure 29. 1-66 can provide reduction in ctDNA levels (e.g., ctDNA tumor fraction (TF)) in patients with CRC tumors. MR is ctDNA molecular response (defined as >50% reduction in ctDNA tumor fraction compared to baseline). Results are not shown for patients for whom baseline ctDNA TF was below 0.1%. Dose levels 4-6 are 240 mg / m2, 360 mg / m2, 420 mg / m2, and 480 mg / m2.Aindicates a patient with a TCF7L2(TCF4) loss of function mutation. * indicates a patient for whom baseline TF was below 0.25%.

[0045] Figure 30A. 1-66 can provide reduction in ctDNA levels (e.g.. ctDNA tumor fraction (TF)) in patients with CRC tumors.

[0046] Figure 30B. 1-66 can provide reduction in ctDNA levels (e.g., ctDNA tumor fraction (TF)) in patients with CRC tumors.

[0047] Figure 31. Administration of 1-66 can provide reduced expression of genes belonging to a Wnt-target genes (e.g., AXIN2, NKD1, RNF43, and ZNRF3).

[0048] Figure 32. 1-66 in combination with a-PDl exhibits anti-tumor activity in a MC38 CRC syngeneic model. The lines from top to bottom: Vehicle (circle), 1-66 (triangle), a-PDl (square), and 1-66 + a- Page 7 of 27013160427vlAttorney Docket No.: 2012675-0415PD1 (inverted triangle).

[0049] Figure 33. 1-66 can modulate Wnt-target gene and KRAS-target gene expression in PDX models and provide tumor growth inhibition. Each point represents a particular PDX model.

[0050] Figure 34. 1-66 in combination with RMC-6236 exhibits anti-tumor activity in a KRAS-mutant CRC PDX model. Hie lines from top to bottom: Vehicle (filled circle), RMC-6236 (25 mg / kg, empty circle), 1-66 (60 mg / kg, filled circle), and 1-66 + RMC-6236 (60 mg / kg and 25 mg / kg, respectively, half-filled circle). The PDX model was PDX Model 3.

[0051] Figure 35. 1-66 in combination with RMC-6236 exhibits anti-tumor activity in a KRAS-mutant CRC PDX model. The lines from top to bottom: Vehicle (filled circle), RMC-6236 (25 mg / kg, empty circle), 1-66 (60 mg / kg, filled circle), and 1-66 + RMC-6236 (half-filled circle). Hie PDX model was PDX Model 1.

[0052] Figure 36. 1-66 in combination with RMC-6236 exhibits anti -tumor activity in a KRAS-mutant CRC PDX model. Hie lines from top to bottom: Vehicle (filled circle), Vehicle (filled circle). RMC-6236 (25 mg / kg, empty circle), 1-66 (60 mg / kg, filled circle), and 1-66 + RMC-6236 (20 mg / kg and 25 mg / kg, respectively, half-filled circle). The PDX model was PDX Model 6.

[0053] Figure 37. 1-66 in combination with RMC-6236 exhibits anti-tumor activity in a KRAS-mutant CRC PDX model. The lines from top to bottom: Vehicle (filled circle), Vehicle (filled circle), 1-66 (60 mg / kg, filled circle), RMC-6236 (empty circle), and 1-66 + RMC-6236 (60 mg / kg and 25 mg / kg, respectively, halffilled circle). The PDX model was PDX Model 2.

[0054] Figure 38. 1-66 in combination with bevacizumab exhibits robust anti -tumor activity in KRAS-mutant CRC PDX models. The lines from top to bottom: Vehicle (circle, top line), bevacizumab (inverted triangle), 1-66 (triangle), and 1-66 + bevacizumab (larger circle, lowest line). The PDX model was PDX Model 7.

[0055] Figure 39. 1-66 in combination with bevacizumab exhibits robust anti-tumor activity in KRAS-mutant CRC PDX models. The lines from top to bottom: Vehicle (circle, top line), bevacizumab (inverted triangle), 1-66 (triangle), and 1-66 + bevacizumab (larger circle, lowest line). The PDX model was PDX Model 8.

[0056] Figure 40. 1-66 in combination with 5-FU exhibits robust anti-tumor activity in KRAS-mutant CRC PDX models. Hie lines from top to bottom: Vehicle (circle, top line), 5-FU (inverted triangle), 1-66 (triangle), and 1-66 + 5-FU (larger circle, lowest line). Hie PDX model was PDX Model 7.

[0057] Figure 41. Nonclinical evaluation of 1-66 combinations across lines of treatment in mCRC.Various treatments were illustrated.

[0058] Figure 42. Certain clinical trial designs.

[0059] Figure 43. 1-66 provides efficacy in patients with desmoid tumor. Initial dose levels of 1-66 for the respective patient numbers are as described in Table E-20. Circles and squares represent evaluation, wherein circles represent observation of stable disease and squares represent observation of partial response. Dose levels administered over the preceding interval are noted in circles and squares as follows: 2: 72 mg / nr:Page 8 of 27013160427vlAttorney Docket No.: 2012675-04153: 144 mg / m2; 4: 240 mg / m2; 6: 480 mg / m2. Solid bars represent QW administration of 1-66. Dashed bars represent Q2W administration of 1-66.

[0060] Figure 44. 1-66 provides efficacy in patients with desmoid tumor. Initial dose levels of 1-66 for the respective patient numbers arc as described in Table E-20. Patient numbers correspond to those in Figure 43. SD: Stable Disease. PR: partial response. PD: Progressive Disease.

[0061] Figure 45A. 1-66 provides efficacy in patients with desmoid tumor. Efficacy was evaluated by RECIST 1.1. Dose levels of 1-66 administered from left to right are as follows: 240 mg / m2; 240 mg / m2; 240 mg / m2; 240 mg / m2; 72 mg / m2; 480 mg / m2; 480 mg / m2; and 240 mg / m2.

[0062] Figure 45B. 1-66 provides efficacy in patients with desmoid tumor. Efficacy was evaluated by RECIST 1.1. Dose levels of 1-66 administered arc as follows: filled circle: 72 mg / m2; filled square, filled triangle, filled inverted triangle, filled diamond, and filled hexagon: 240 mg / m2; empty circle and empty square: 480 mg / m2.

[0063] Figure 46A. 1-66 provides efficacy in patients with desmoid tumor. Efficacy was evaluated by volumetric analysis. Dose levels of 1-66 administered from left to right are as follows: 240 mg / m2; 240 mg / m2; 240 mg / m2; 480 mg / m2; 72 mg / m2; 240 mg / m2; 480 mg / m2; and 240 mg / m2.

[0064] Figure 46B. 1-66 provides efficacy in patients with desmoid tumor. Efficacy was evaluated by volumetric analysis. Dose levels of 1-66 administered are as follows: filled circle: 72 mg / m2; filled square, filled triangle, filled inverted triangle, filled diamond, and filled hexagon: 240 mg / m2; empty circle and empty square: 480 mg / m2.

[0065] Figure 47. 1-66 provides efficacy in patients with various Wnt / beta-catenin-driven tumor types. PD is progressive disease; SD is stable disease; and PR is partial response. The tumor types are as follows from left to right: jejunal, HCC, desmoid, desmoid, endometrial, desmoid, desmoid, desmoid, ACP, desmoid, desmoid, desmoid, desmoid, HCC, ameloblastoma, desmoid, desmoid, ACP, salivary gland, desmoid, desmoid, ACP, desmoid, desmoid, and SPN.

[0066] Figure 48. 1-66 has been administered to a number of patients with Wnt / beta-catenin-driven tumor types. The tumor types are as follows from top to bottom: desmoid, desmoid, desmoid, desmoid, desmoid, desmoid, desmoid, desmoid, desmoid, desmoid, desmoid, desmoid, desmoid, desmoid, desmoid, desmoid, desmoid, desmoid, desmoid, ACP, ACP, ACP, salivary gland, endometrial, ameloblastoma, SPN, HCC, jejunal, HCC, synovial sarcoma, and esophageal. * Ended treatment: radiographic disease progression. + ended treatment: other (e.g.. worsening symptoms, physician decision, etc.). — on treatment.

[0067] Figure 49. Tumor response of a desmoid tumor in a patient with familial adenomatous polyposis. Dosing level at the time of each measurement from left to right are 480 mg / m2QW, 480 mg / m2QW, 240 mg / m2QW, 144 mg / m2QW, 72 mg / m2Q2W, 72 mg / m2Q2W, 72 mg / m2Q2W, and 72 mg / m2Q2W.

[0068] Figure 50. 1-66 in combination with RAS inhibition can provide improved anti -tumor activity in a KRAS-mutant CRC PDX model. The lines from top to bottom at Day 20: 1-66 vehicle (n=l); 1-66, 60 mg / kg (n=l); RMC-6236 vehicle; RMC-6236, 25 mg / kg; 1-66. 60 mg / kg + RMC-6236, 25 mg / kg. The CRC PDX Page 9 of 27013160427vlAttorney Docket No.: 2012675-0415has KRAS G12A and APC ¥1414* mutations. Error bars: + / - STD.

[0069] Figure 51. 1-66 in combination with RAS inhibition is tolerated in a PDX CRC model. The lines from top to bottom: at Day 40: RMC-6236 vehicle; RMC-6236, 25 mg / kg; 1-66, 60 mg / kg + RMC-6236, 25 mg / kg. The CRC PDX has KRAS G12A and APC ¥1414* mutations. Error bars: + / - STD.

[0070] Figure 52. 1-66 can provide reduction in ctDNA levels (e.g. APC D849fs, PBRM1 c. 1087+ Idel, etc.). The reduction was observed in a patient with ameloblastoma. 1-66 was administered at a dose of 480 mg / m2. ctDNA was collected at C1D1 and C3D1 at 8 weeks of 1-66 administration. ¥AF = ¥ariant Allele Frequency. (A) Median ¥AF of APC D849fs and PBRM1 c.1087+ldel; (B) ¥AF of APC D849fs (squares) and PBRM1 c.1087+ldel (triangles).

[0071] Figure 53. 1-66 can provide reduction in ctDNA levels. Tire reduction was observed in patients with heavily pre-treated CRC. Patients were administered 1-66 at dose levels of 240 mg / m2, 360 mg / m2, and 480 mg / m2.

[0072] Figure 54. Reduction in ctDNA levels was observed to be associated with stable disease in patients with heavily pre-treated CRC administered 1-66 at dose levels of 240 mg / m2, 360 mg / m2, and 480 mg / m2.

[0073] Figure 55. 1-66 can provide reduction in ctDNA levels (e.g. PEILPP1 c.4570+2T> A, CTNNB1 p. S45P, CREBBP p. Y226*, TSC2 p. L764fs, etc.). Tire reduction was observed in a patient with HCC. 1-66 was administered at a dose of 240 mg / m2. ctDNA was collected at CID 1 and C2D1 at 4 weeks of 1-66 administration. ctFE = circulating tumor Fraction Estimate. ¥AF = ¥ariant Allele Frequency. (A) ctFE; (B) ¥AF of PHLPP1 c.4570+2T> A (squares), CTNNB1 p. S45P (diamonds), CREBBP p. Y226* (inverted triangles), and TSC2 p. L764fs (circles).DETAILED DESCRIPTION OF CERTAIN EMBODIMENTSDefinitions

[0074] As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M. B. and March, I., lohn Wiley & Sons, New York: 2001.

[0075] Administration: As used herein, the term “administration” typically refers to the administration of a composition to a subject or system. Those of ordinary skill in the art will be aware of a variety of routes that may, in appropriate circumstances, be utilized for administration to a subject, for example a human. For example, in some embodiments, administration may be ocular, oral, parenteral, topical, etc. In some particular embodiments, administration may be bronchial (e.g., by bronchial instillation), buccal, dermal (which may be or comprise, for example, one or more of topical to the dermis, intradermal, interdermal, transdermal, etc), Page 10 of 27013160427vlAttorney Docket No.: 2012675-0415enteral, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, within a specific organ (e. g., intrahepatic), mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., by intratracheal instillation), vaginal, vitreal, etc. In some embodiments, administration may involve dosing that is intermittent (e.g., a plurality of doses separated in time) and / or periodic (e.g., individual doses separated by a common period of time) dosing. In some embodiments, administration may involve continuous dosing (e.g., perfusion) for at least a selected period of time.

[0076] Affinity. As is known in the art, '‘affinity” is a measure of the tightness with a particular ligand (e.g., an agent) binds to its partner (e.g., beta-catenin or a portion thereof). Affinities can be measured in different ways. In some embodiments, affinity is measured by a quantitative assay. In some such embodiments, binding partner concentration may be fixed to be in excess of ligand concentration so as to mimic physiological conditions. Alternatively or additionally, in some embodiments, binding partner concentration and / or ligand concentration may be varied. In some such embodiments, affinity may be compared to a reference under comparable conditions (e.g., concentrations).

[0077] Agent: In general, the term “agent”, as used herein, may be used to refer to a compound or entity of any chemical class including, for example, a polypeptide, nucleic acid, saccharide, lipid, small molecule, metal, or combination or complex thereof. In appropriate circumstances, as will be clear from context to those skilled in the art, the term may be utilized to refer to an entity that is or comprises a cell or organism, or a fraction, extract, or component thereof. Alternatively or additionally, as context will make clear, the term may be used to refer to a natural product in that it is found in and / or is obtained from nature. In some instances, again as will be clear from context, the term may be used to refer to one or more entities that is man-made in that it is designed, engineered, and / or produced through action of the hand of man and / or is not found in nature. In some embodiments, an agent may be utilized in isolated or pure form: in some embodiments, an agent may be utilized in crude form. In some embodiments, potential agents may be provided as collections or libraries, for example that may be screened to identify or characterize active agents within them. In some cases, the term “agent” may refer to a compound or entity that is or comprises a polymer; in some cases, the term may refer to a compound or entity that comprises one or more polymeric moieties. In some embodiments, the term “agent” may refer to a compound or entity that is not a polymer and / or is substantially free of any polymer and / or of one or more particular polymeric moieties. In some embodiments, the term may refer to a compound or entity that lacks or is substantially free of any polymeric moiety. In some embodiments, an agent is a compound. In some embodiments, an agent is a stapled peptide.

[0078] Amino acid: In its broadest sense, as used herein, refers to any compound and / or substance that can be incorporated into a polypeptide chain, e.g., through formation of one or more peptide bonds. In some embodiments, an amino acid comprising an amino group and an a carboxylic acid group. In some embodiments, an amino acid has the structure of NH(Ral)-Lal-C(Ra2)(Ra3)-La2-COOH, wherein each variable is independently as described in the present disclosure. In some embodiments, an amino acid has the Page 11 of 27013160427vlAttorney Docket No.: 2012675-0415general structure NH(R’)-C(R’)2-COOH, wherein each R’ is independently as described in the present disclosure. In some embodiments, an amino acid has the general structure H2N-C(R’)2-COOH, wherein R’ is as described in the present disclosure. In some embodiments, an amino acid has the general structure H2N-C(H)(R’)-COOH, wherein R’ is as described in the present disclosure. In some embodiments, an amino acid is a naturally -occurring amino acid. In some embodiments, an amino acid is a non-natural amino acid; in some embodiments, an amino acid is a D-amino acid; in some embodiments, an amino acid is an L-amino acid. “Standard amino acid” refers to any of the twenty standard L-amino acids commonly found in naturally occurring peptides. “Nonstandard amino acid” refers to any amino acid, other than the standard amino acids, regardless of whether it is prepared synthetically or obtained from a natural source. In some embodiments, an amino acid, including a carboxy - and / or amino-terminal amino acid in a polypeptide, can contain a structural modification as compared with the general structure above. For example, in some embodiments, an amino acid may be modified by methylation, amidation, acetylation, pegylation, glycosylation, phosphorylation, and / or substitution (e.g., of the amino group, the carboxylic acid group, one or more protons, one or more hydrogens, and / or the hydroxyl group) as compared with the general structure. In some embodiments, such modification may, for example, alter the circulating half-life of a polypeptide containing the modified amino acid as compared with one containing an otherwise identical unmodified amino acid. In some embodiments, such modification does not significantly alter a relevant activity of a polypeptide containing the modified amino acid, as compared with one containing an otherwise identical unmodified amino acid. As will be clear from context, in some embodiments, the term “amino acid” may be used to refer to a free amino acid; in some embodiments it may be used to refer to an amino acid residue of a polypeptide.

[0079] Analog: As used herein, the term “analog” refers to a substance that shares one or more particular structural features, elements, components, or moieties with a reference substance. Typically, an “analog” shows significant structural similarity with the reference substance, for example sharing a core or consensus structure, but also differs in certain discrete ways. In some embodiments, an analog is a substance that can be generated from the reference substance, e.g., by chemical manipulation of the reference substance. In some embodiments, an analog is a substance that can be generated through performance of a synthetic process substantially similar to (e.g., sharing a plurality of steps with) one that generates the reference substance. In some embodiments, an analog is or can be generated through performance of a synthetic process different from that used to generate the reference substance.

[0080] Animal'. As used herein refers to any member of the animal kingdom. In some embodiments, "animal" refers to humans, of either sex and at any stage of development. In some embodiments, "animal" refers to non-human animals, at any stage of development. In certain embodiments, the non-human animal is a mammal e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, and / or a pig). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, insects, and / or worms. In some embodiments, an animal may be a transgenic animal, genetically engineered animal, and / or a clone.Page 12 of 27013160427vlAttorney Docket No.: 2012675-0415

[0081] Approximately: As used herein, the term ‘‘approximately” or “about,” as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In certain embodiments, the term “approximately” or “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in cither direction (greater than or less than) of the stated reference value unless otherwise stated or otherw ise evident from the context (except where such number would exceed 100% of a possible value).

[0082] Associated with: Two events or entities are “associated” with one another, as that term is used herein, if the presence, level and / or form of one is correlated with that of the other. For example, a particular entity (e.g., nucleic acid (e.g., genomic DNA, transcripts, mRNA, etc.), polypeptide, genetic signature, metabolite, microbe, etc..) is considered to be associated with a particular disease, disorder, or condition, if its presence, level and / or form correlates with incidence of and / or susceptibility to the disease, disorder, or condition (e.g., across a relevant population).

[0083] Binding'. It will be understood that the term “binding”, as used herein, typically refers to a non-covalent association between or among agents. In many embodiments herein, binding is addressed with respect to particular agents and beta-catenin. It will be appreciated by those of ordinary skill in the art that such binding may be assessed in any of a variety of contexts. In some embodiments, binding is assessed with respect to beta-catenin. In some embodiments, binding is assessed with respect to one or more amino acid residues of beta-catenin. In some embodiments, binding is assessed with respect to one or more amino acid residues corresponding to (e.g., similarly positioned in three dimensional space and / or having certain similar properties and / or functions) those of beta-catenin.

[0084] Binding site. The term “binding site”, as used herein, refers to a region of a target polypeptide, formed in three-dimensional space, that includes one or more or all interaction residues of the target polypeptide. In some embodiments, “binding site” may refer to one or more amino acid residues which comprise or are one or more or all interaction amino acid residues of a target polypeptide. As will be understood by those of ordinary skill in the art, a binding site may include residues that are adjacent to one another on a linear chain, and / or that are distal to one another on a linear chain but near to one another in three-dimensional space when a target polypeptide is folded. A binding site may comprise amino acid residues and / or saccharide residues.

[0085] Carrier: as used herein, refers to a diluent, adjuvant, excipient, or vehicle with which a composition is administered. In some exemplary embodiments, carriers can include sterile liquids, such as, for example, water and oils, including oils of petroleum, animal, vegetable or synthetic origin, such as, for example, peanut oil, soybean oil, mineral oil, sesame oil and the like. In some embodiments, carriers are or include one or more solid components.

[0086] Comparable: As used herein, the term “comparable” refers to two or more agents, entities, situations, sets of conditions, etc., that may not be identical to one another but that are sufficiently similar to permit comparison there between so that one skilled in the art will appreciate that conclusions may reasonably Page 13 of 27013160427vlAttorney Docket No.: 2012675-0415be drawn based on differences or similarities observed. In some embodiments, comparable sets of conditions, circumstances, individuals, or populations are characterized by a plurality of substantially identical features and one or a small number of varied features. Those of ordinary skill in the art will understand, in context, what degree of identity’ is required in any given circumstance for two or more such agents, entities, situations, sets of conditions, etc. to be considered comparable. For example, those of ordinary skill in the art will appreciate that sets of circumstances, individuals, or populations are comparable to one another when characterized by a sufficient number and type of substantially identical features to warrant a reasonable conclusion that differences in results obtained or phenomena observed under or with different sets of circumstances, individuals, or populations are caused by or indicative of the variation in those features that are varied.

[0087] Derivative: As used herein, the term “derivative” refers to a structural analogue of a reference substance. That is. a “derivative” is a substance that shows significant structural similarity with the reference substance, for example sharing a core or consensus structure, but also differs in certain discrete ways. In some embodiments, a derivative is a substance that can be generated from the reference substance by chemical manipulation. In some embodiments, a derivative is a substance that can be generated through performance of a synthetic process substantially similar to (e.g., sharing a plurality of steps with) one that generates the reference substance.

[0088] Dosage form or unit dosage form: Those skilled in the art will appreciate that the term “dosage form” may be used to refer to a physically discrete unit of an active agent (e.g., a therapeutic or diagnostic agent) for administration to a subject. Typically, each such unit contains a predetermined quantity’ of active agent. In some embodiments, such quantity is a unit dosage amount (or a whole fraction thereof) appropriate for administration in accordance with a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e.. with a therapeutic dosing regimen). Those of ordinary skill in the art appreciate that the total amount of a therapeutic composition or agent administered to a particular subject is determined by one or more attending physicians and may involve administration of multiple dosage forms.

[0089] Dosing regimen: Those skilled in the art will appreciate that the term “dosing regimen” may be used to refer to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, a dosing regimen comprises a plurality of doses each of which is separated in time from other doses. In some embodiments, individual doses are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses. In some embodiments, all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose Page 14 of 27013160427vlAttorney Docket No.: 2012675-0415amount different from the first dose amount. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount same as the first dose amount. In some embodiments, a dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population (i.e., is a therapeutic dosing regimen).

[0090] “Improved, ' "increased' or “reduced”: As used herein, these terms, or grammatically comparable comparative terms, indicate values that are relative to a comparable reference measurement. For example, in some embodiments, an assessed value achieved with an agent of interest may be ‘’improved7’ relative to that obtained with a comparable reference agent. Alternatively or additionally, in some embodiments, an assessed value achieved in a subject or system of interest may be ‘’improved” relative to that obtained in the same subject or system under different conditions (e.g., prior to or after an event such as administration of an agent of interest), or in a different, comparable subject (e.g., in a comparable subject or system that differs from the subject or system of interest in presence of one or more indicators of a particular disease, disorder or condition of interest, or in prior exposure to a condition or agent, etc). In some embodiments, comparative terms refer to statistically relevant differences (e.g., that are of a prevalence and / or magnitude sufficient to achieve statistical relevance). Those skilled in the art will be aware, or will readily be able to determine, in a given context, a degree and / or prevalence of difference that is required or sufficient to achieve such statistical significance.

[0091] Peptide: The term “peptide” as used herein refers to a polypeptide. In some embodiments, a peptide is a polypeptide that is relatively short, for example having a length of less than about 100 amino acids, less than about 50 amino acids, less than about 40 amino acids less than about 30 amino acids, less than about 25 amino acids, less than about 20 amino acids, less than about 15 amino acids, or less than 10 amino acids. In some embodiments, a length is about 5-20, 5-19, 5-18, 5-17, 5-16, 5-15, 10-20, 10-19, 10-18, 10-17, 10-16. 10-15, 11-20. 11-19, 11-18, 11-17, 11-16, 11-15, 12-20, 12-19. 12-18, 12-17, 12-16, 12-15, 13-20, 13-19, 13-18. 13-17, 13-16. 13-15, 14-20, 14-19, 14-18, 14-17. 14-16, 14-15. or about 2, 3. 4, 5, 6, 7. 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids.

[0092] Pharmaceutical composition: As used herein, the term “pharmaceutical composition” refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, active agent is present in unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, Page 15 of 27013160427vlAttorney Docket No.: 2012675-0415lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.

[0093] Pharmaceutically acceptable: As used herein, tire phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which arc, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0094] Pharmaceutically acceptable carrier: As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil. cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; RingeR’s solution; ethyl alcohol; pH buffered solutions; polyesters, polycarbonates and / or polyanhydrides; and other non-toxic compatible substances employed in pharmaceutical formulations.

[0095] Pharmaceutically acceptable salt: The term “pharmaceutically acceptable salt”, as used herein, refers to salts of such compounds that are appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). In some embodiments, pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts, which are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other known methods such as ion exchange. In some embodiments, pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethane sulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2 -hydroxy- Page 16 of 27013160427vlAttorney Docket No.: 2012675-0415ethanesulfonate, lactobionate. lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. In some embodiments, pharmaceutically acceptable salts include, but are not limited to, nontoxic base addition salts, such as those formed by acidic groups of provided compounds with bases. Representative alkali or alkaline earth metal salts include salts of sodium, lithium, potassium, calcium, magnesium, and the like. In some embodiments, pharmaceutically acceptable salts are ammonium salts (e.g., -N(R)3+). In some embodiments, pharmaceutically acceptable salts are sodium salts. In some embodiments, pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.

[0096] Polypeptide: As used herein refers to any polymeric chain of amino acids. In some embodiments, a polypeptide has an amino acid sequence that occurs in nature. In some embodiments, a polypeptide has an amino acid sequence that does not occur in nature. In some embodiments, a polypeptide has an amino acid sequence that is engineered in that it is designed and / or produced through action of the hand of man. In some embodiments, a polypeptide may comprise or consist of natural amino acids, non-natural amino acids, or both. In some embodiments, a polypeptide may comprise or consist of only natural amino acids or only nonnatural amino acids. In some embodiments, a polypeptide may comprise D-amino acids, L-amino acids, or both. In some embodiments, a polypeptide may comprise only D-amino acids. In some embodiments, a polypeptide may comprise only L-amino acids. In some embodiments, a polypeptide may include one or more pendant groups or other modifications, e.g., modifying or attached to one or more amino acid side chains, at the polypeptide’s N-terminus, at tire polypeptide’s C-terminus, or any combination thereof. In some embodiments, such pendant groups or modifications may be selected from the group consisting of acetylation, amidation, lipidation, methylation, pegylation, etc., including combinations thereof. In some embodiments, a polypeptide may be cyclic, and / or may comprise a cyclic portion. In some embodiments, a polypeptide is not cyclic and / or does not comprise any cyclic portion. In some embodiments, a polypeptide is linear. In some embodiments, a polypeptide may be or comprise a stapled polypeptide. In some embodiments, the term “polypeptide” may be appended to a name of a reference polypeptide, activity, or structure; in such instances it is used herein to refer to polypeptides that share the relevant activity or structure and thus can be considered to be members of the same class or family of polypeptides. For each such class, the present specification provides and / or those skilled in the art will be aware of exemplary polypeptides within the class whose amino acid sequences and / or functions are known; in some embodiments, such exemplary polypeptides are reference polypeptides for the polypeptide class or family. In some embodiments, a member of a polypeptide class or family shows significant sequence homology or identity with, shares a common sequence motif (e.g., a characteristic sequence element) with, and / or shares a common activity (in some embodiments at a comparable level or within a designated range) with a reference polypeptide of the class; in somePage 17 of 27013160427vlAttorney Docket No.: 2012675-0415embodiments with all polypeptides within the class). For example, in some embodiments, a member polypeptide shows an overall degree of sequence homology or identity with a reference polypeptide that is at least about 30-40%, and is often greater than about 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more and / or includes at least one region (e.g., a conserved region that may in some embodiments be or comprise a characteristic sequence element) that shows very high sequence identity, often greater than 90% or even 95%, 96%, 97%, 98%, or 99%. Such a conserved region usually encompasses at least 3-4 and often up to 20 or more amino acids; in some embodiments, a conserved region encompasses at least one stretch of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more contiguous amino acids. In some embodiments, a relevant polypeptide may comprise or consist of a fragment of a parent polypeptide. In some embodiments, a useful polypeptide as may comprise or consist of a plurality of fragments, each of which is found in the same parent polypeptide in a different spatial arrangement relative to one another than is found in the polypeptide of interest (e.g., fragments that are directly linked in the parent may be spatially separated in the polypeptide of interest or vice versa, and / or fragments may be present in a different order in the polypeptide of interest than in the parent), so that the polypeptide of interest is a derivative of its parent polypeptide.

[0097] Prevent or prevention: as used herein when used in connection with the occurrence of a disease, disorder, and / or condition, refers to reducing the risk of developing the disease, disorder and / or condition and / or to delaying onset of one or more characteristics or symptoms of the disease, disorder or condition. Prevention may be considered complete when onset of a disease, disorder or condition has been delayed for a predefined period of time.

[0098] Protecting group: The term “protecting group,” as used herein, is well known in the art and includes those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999. the entirety of which is incorporated herein by reference. Also included are those protecting groups specially adapted for nucleoside and nucleotide chemistry described in Current Protocols in Nucleic Acid Chemistry, edited by Serge L. Beaucage et al. 06 / 2012, the entirety of Chapter 2 is incorporated herein by reference. Suitable amino-protecting groups include methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-( 10,10-dioxo- 10,10,10,10— tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc). 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ). 1-(l-adamantyl)-l-methylethyl carbamate (Adpoc), l,l-dimethyl-2-haloethyl carbamate, 1, 1-dimethy 1—2,2— dibromoethyl carbamate (DB-t-BOC), l,l-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1 -methyl- 1-(4-biphenylyl)ethyl carbamate (Bpoc), l-(3,5-di-t-butylphenyl)-l-methylethyl carbamate (t-Bumeoc), 2-( - and 4’-pyridyl)etliyl carbamate (Pyoc), 2-(N, N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC). 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl Page 18 of 27013160427vlAttorney Docket No.: 2012675-0415carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(l,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc). 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), l,l-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, phenothiazinyl-(10)-carbonyl derivative, N'-p-toluenesulfonylaminocarbonyl derivative, N’-phenylaminothiocarbonyl derivative, t-amyl carbamate. S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxycarbonylvinyl carbamate, o-(N, N-dimethylcarboxamido)benzyl carbamate, l,l-dimethyl-3-(N, N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p’-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1 -methylcyclohexyl carbamate, 1 -methyl- 1 -cyclopropylmethyl carbamate. l-methyl-l-(3,5-dimethoxyphenyl)ethyl carbamate, l-methyl-l-(p-phenylazophenyl)ethyl carbamate, 1 -methyl- 1-phenylethyl carbamate, l-methyl-l-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, 2,4,6-trimethylbenzyl carbamate, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide. o-nitrophenylacetamide, o-nitrophenoxyacetamide. acetoacetamide, (N’-dithiobenzyloxycarbonylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivative, o-nitrobenzamide, o-(benzoyloxymethyl)benzamide, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2.3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1.3-dimethyl- 1,3,5— triazacyclohexan-2-one, 5-substituted l,3-dibenzyl-l,3,5-triazacyclohexan-2-one, 1 -substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(l-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr). N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2.7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fem), N-2-picolylamino N’-oxide, N- Page 19 of 27013160427vlAttorney Docket No.: 2012675-04151,1-dimethylthiomethyleneamine, N-benzylideneamine, N-p-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N’, N’-dimethylaminomethylene)amine, N, N’-isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-l-cyclohexenyl)amine, N-borane derivative, N-diphenylborinic acid derivative, N-[phenyl(pentacarbonylchromium- or tungsten)carbonyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, 3-nitropyridinesulfenamide (Npys), p-toluene sulfonamide (Ts), benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2.4.6-trimethoxybenzenesulfonamide (Mtb), 2, 6-dimethyl-4-methoxybenzene sulfonamide (Pme), 2,3, 5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2, 2, 5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), P-trimethylsilylethanesulfonamide (SES). 9-anthracenesulfonamide, 4-(4’,8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0099] In some embodiments, suitable mono-protected amines include, but are not limited to, aralkylamines, carbamates, allyl amines, amides, and the like. Examples of suitable mono-protected amino moieties include t-butyloxycarbonylamino (-NHBOC), ethyloxycarbonylamino, methyloxycarbonylamino, trichloroethyloxycarbonylamino, allyloxycarbonylamino (-NHAlloc), benzyloxocarbonylamino (-NHCBZ), allylamino, benzylamino (-NHBn), fluorenylmethylcarbonyl (-NHFmoc), formamido, acetamido, chloroacetamido, dichloroacetamido, trichloroacetamido, phenylacetamido, trifluoroacetamido, benzamido. t-butyldiphenylsilyl, and the like. In some embodiments, suitable di -protected amines include amines that are substituted with two substituents independently selected from those described above as mono-protected amines, and further include cyclic imides, such as phthalimide, maleimide, succinimide, and the like. In some embodiments, suitable di-protected amines include pyrroles and the like, 2,2,5,5-tetramethyl-[1.2.5]azadisilolidine and the like, and azide.

[0100] Suitably protected carboxylic acids further include, but are not limited to. silyl-, alkyl-, alkenyl-, aryl-, and arylalkyl-protected carboxylic acids. Examples of suitable silyl groups include trimethyl silyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and the like. Examples of suitable alkyl groups include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, tetrahydropyran-2-yl. Examples of suitable alkenyl groups include allyl. Examples of suitable ary l groups include optionally substituted phenyl, biphenyl, or naphthyl. Examples of suitable arylalkyl groups include optionally substituted benzyl (e.g., p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p- Page 20 of 27013160427vlAttorney Docket No.: 2012675-0415nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl), and 2- and 4-picolyl. In some embodiments, suitable protected carboxylic acids include, but are not limited to, optionally substituted Ci-e aliphatic esters, optionally substituted aryl esters, silyl esters, activated esters, amides, hydrazides, and the like. Examples of such ester groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, benzyl, and phenyl ester, wherein each group is optionally substituted. Additional suitable protected carboxylic acids include oxazolines and ortho esters.

[0101] Suitable hydroxyl protecting groups include methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymcthyl, 4-pcntcnyloxymcthyl (POM), siloxymcthyl, 2-mcthoxycthoxymcthyl (MEM), 2,2,2-trichloroetlioxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-mctho.xytctrahydropyranyl (MTHP), 4-mcthoxytctrahydrothiopyranyl. 4-methoxytetrahydrothiopyranyl S, S-dioxide, l-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofiiranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1 -ethoxy ethyl, l-(2-chloroethoxy)ethyl, 1 -methyl- 1 -methoxy ethyl, 1 -methyl- 1-benzyloxyethyl, l-methyl-l-benzyloxy-2-fluoroethyl, 2.2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl. p-methoxyphenyl, 2.4-dinitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p.p’-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, a-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4’-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4”-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4’,4"’-tris(levulinoyloxyphenyl)methyl, 4,4 ’.4 ’ '-tris(benzoyloxyphenyl)methyl, 3-(imidazol- 1 — y 1) bis (4 ',4 ’ ’-dimethoxyphenyl)methyl, 1, l-bis(4-methoxyphenyl)- 1 ’-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, l,3-benzodithiolan-2-yl, benzisothiazolyl S, S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2- (triphenylphosphonio) ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate alkyl allyl Page 21 of 27013160427vlAttorney Docket No.: 2012675-0415carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate, 4-ethoxy-l-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-mcthylpcntanoatc, o-(dibromomcthyl)bcnzoatc, 2-formylbcnzcncsulfonatc, 2-(methyltliiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-( 1, 1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis( 1, 1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxycarbonyl)benzoate, a-naphthoate, nitrate, alkyl N, N, N’, N’-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophcnylsulfcnatc, sulfate, methane sulfonate (mesylate), bcnzylsulfonatc, andtosylatc (Ts). For protecting 1.2- or 1,3-diols, the protecting groups include methylene acetal, ethylidene acetal, 1-t-butylethylidene ketal, 1-phenylethylidene ketal. (4-methoxyphenyl)ethylidene acetal. 2,2,2-trichloroethylidene acetal, acetonide, cyclopentylidene ketal, cyclohexylidene ketal, cycloheptylidene ketal, benzylidene acetal, p-methoxybenzylidene acetal, 2,4-dimethoxybenzylidene ketal, 3,4-dimethoxybenzylidene acetal, 2-nitrobenzylidene acetal, methoxymethylene acetal, ethoxymethylene acetal, dimethoxymethylene ortho ester, 1 -methoxy ethylidene ortho ester, 1 -ethoxy ethylidine ortho ester, 1,2— dimethoxyethylidene ortho ester, a-methoxybenzylidene ortho ester, l-(N, N-dimethylamino)etlrylidene derivative. a-(N, N’-dimethylamino)benzylidene derivative. 2-oxacyclopentylidene ortho ester, di— t— butylsilylene group (DTBS), l,3-(l,l,3,3-tetraisopropyldisiloxanylidene) derivative (TIPDS), tetra-t-butoxydisiloxane-l,3-diylidene derivative (TBDS), cyclic carbonates, cyclic boronates, ethyl boronate, and phenyl boronate.

[0102] In some embodiments, a hydroxyl protecting group is acetyl, t-butyl, tbutoxymethyl, methoxymethyl, tetrahydropyranyl, 1 -ethoxyethyl, 1 -(2-chloroethoxy)ethyl, 2- trimethylsilylethyl, p-chlorophenyl, 2.4-dinitrophenyl. benzyl, benzoyl, p-phenylbenzoyl, 2.6- dichlorobenzyl, diphenylmethyl, p-nitrobenzyl, triphenylmethyl (trityl), 4,4'-dimethoxytrityl, trimethylsilyl, triethylsilyl, t-butyldimethyl silyl, t-butyldiphenyl silyl, triphenylsilyl, triisopropylsilyl, benzoylformate, chloroacetyl, trichloroacetyl, trifiuoroacetyl, pivaloyl, 9- fluorenylmethyl carbonate, mesylate, tosylate, triflate, trityl, monomcthoxytrityl (MMTr), 4,4'-dimethoxytrityl, (DMTr) and 4,4',4"-trimethoxytrityl (TMTr), 2-cyanoethyl (CE or Cne), 2-(trimethylsilyl)ethyl (TSE), 2-(2-nitrophenyl)ethyl, 2-(4-cyanophenyl)ethyl 2-(4-nitrophenyl)ethyl (NPE). 2-(4-nitrophenylsulfonyl)ethyl, 3, 5 -dichlorophenyl, 2.4-dimethylphenyl, 2-nitrophenyl, 4-nitrophenyl. 2,4,6-trimethylphenyl, 2-(2-nitrophenyl)ethyl, butylthiocarbonyl, 4,4',4"-tris(benzoyloxy)trityl, diphenylcarbamoyl, levulinyl, 2-(dibromomethyl)benzoyl (Dbmb), 2-(isopropylthiomethoxymethyl)benzoyl (Ptmt), 9-phenylxanthen-9-yl (pixyl) or 9-(p-methoxyphenyl)xanthine-9-yl (MOX). In some embodiments, each of the hydroxyl protecting groups is, independently selected from acetyl, benzyl, t- butyldimethylsilyl, t-butyldiphenylsilyl and 4,4'-dimethoxytrityl. In some embodiments, the hydroxyl protecting group is selected from tire group consisting of trityl, monomethoxytrityl and 4.4'-dimcthoxytrityl group. In some embodiments.Page 22 of 27013160427vlAttorney Docket No.: 2012675-0415a phosphorous linkage protecting group is a group attached to the phosphorous linkage (e.g., an intemucleotidic linkage) throughout oligonucleotide synthesis. In some embodiments, a protecting group is attached to a sulfur atom of an phosphorothioate group. In some embodiments, a protecting group is attached to an oxygen atom of an intcmuclcotidc phosphorothioate linkage. In some embodiments, a protecting group is attached to an oxygen atom of the intemucleotide phosphate linkage. In some embodiments a protecting group is 2-cyanoethyl (CE or Cne), 2 -trimethylsilylethyl, 2 -nitroethyl. 2-sulfonylethyl, methyl, benzyl, o-nitrobenzyl, 2-(p-nitrophenyl)ethyl (NPE or Npe), 2-phenylethyl, 3-(N-tert-butylcarboxamido)-l-propyl, 4-oxopentyl, 4-methylthio-l-butyl, 2-cyano- 1,1 -dimethylethyl, 4-N -methylaminobutyl, 3-(2-pyridyl)-l-propyl, 2-[N-methyl-N-(2-pyridyl)]aminoethyl, 2-(N-formyl, N-methyl)aminoethyI, or 4-[N-methyl-N-(2,2,2-trifluoroacctyl)amino]butyl.

[0103] Protected thiols are well known in the art and include those described in detail in Greene (1999). Suitable protected thiols further include, but are not limited to, disulfides, thioethers, silyl thioethers, thioesters, thiocarbonates, and thiocarbamates, and the like. Examples of such groups include, but are not limited to, alkyl thioethers, benzyl and substituted benzyl thioethers, triphenylmethyl thioethers, and trichloroethoxycarbonyl thioester, to name but a few.

[0104] Reference: As used herein describes a standard or control relative to which a comparison is performed. For example, in some embodiments, an agent, animal, individual, population, sample, sequence or value of interest is compared with a reference or control agent, animal, individual, population, sample, sequence or value. In some embodiments, a reference or control is tested and / or determined substantially simultaneously with the testing or determination of interest. In some embodiments, a reference or control is a historical reference or control, optionally embodied in a tangible medium. Typically, as would be understood by those skilled in the art, a reference or control is determined or characterized under comparable conditions or circumstances to those under assessment. Those skilled in tire art will appreciate when sufficient similarities are present to justify reliance on and / or comparison to a particular possible reference or control.

[0105] Specificity'. As is known in the art, “specificity” is a measure of the ability of a particular ligand (e.g., an agent) to distinguish its binding partner (e.g., beta-catenin) from other potential binding partners (e.g., another protein, another portion (e.g., domain) of beta-catenin).

[0106] Subject: As used herein, the term “subject” or “test subject” refers to any organism to which a provided compound or composition is administered in accordance with the present disclosure e.g.. for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans; insects; worms; etc.) and plants. In some embodiments, a subject may be suffering from, and / or susceptible to a disease, disorder, and / or condition. In some embodiments, a subject is a human.

[0107] Susceptible to: An individual who is “susceptible to” a disease, disorder, and / or condition is one who has a higher risk of developing the disease, disorder, and / or condition than does a member of the general public. In some embodiments, an individual who is susceptible to a disease, disorder and / or condition may not Page 23 of 27013160427vlAttorney Docket No.: 2012675-0415have been diagnosed with the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition may exhibit symptoms of the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition may not exhibit symptoms of the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition will develop the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition will not develop the disease, disorder, and / or condition.

[0108] Therapeutic agent: As used herein, the phrase “therapeutic agent” refers to an agent that, when administered to a subject, has a therapeutic effect and / or elicits a desired biological and / or pharmacological effect. In some embodiments, a therapeutic agent is any substance that can be used to alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and / or reduce incidence of one or more symptoms or features of a disease, disorder, and / or condition.

[0109] Therapeutic regimen'. A “therapeutic regimen”, as that term is used herein, refers to a dosing regimen whose administration across a relevant population may be correlated with a desired or beneficial therapeutic outcome.

[0110] Treat: As used herein, the tenn “treat,” “treatment,” or “treating” refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of. reduce severity of, and / or reduce incidence of one or more symptoms or features of a disease, disorder, and / or condition. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and / or condition. In some embodiments, treatment may be administered to a subject who exhibits only early signs of the disease, disorder, and / or condition, for example for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and / or condition.[0H1] Unit dose: The expression “unit dose” as used herein refers to an amount administered as a single dose and / or in a physically discrete unit of a pharmaceutical composition. In many embodiments, a unit dose contains a predetermined quantity of an active agent. In some embodiments, a unit dose contains an entire single dose of the agent. In some embodiments, more than one unit dose is administered to achieve a total single dose. In some embodiments, administration of multiple unit doses is required, or expected to be required, in order to achieve an intended effect. A unit dose may be, for example, a volume of liquid (e.g., an acceptable carrier) containing a predetennined quantity of one or more therapeutic agents, a predetermined amount of one or more therapeutic agents in solid form, a sustained release formulation or drug delivery device containing a predetermined amount of one or more therapeutic agents, etc. It will be appreciated that a unit dose may be present in a formulation that includes any of a variety of components in addition to the therapeutic agent(s). For example, acceptable carriers (e.g., pharmaceutically acceptable carriers), diluents, stabilizers, buffers, preservatives, etc., may be included as described infra. It will be appreciated by those skilled in the art, in many embodiments, a total appropriate daily dosage of a particular therapeutic agent may comprise a portion, or a plurality, of unit doses, and may be decided, for example, by the attending physician Page 24 of 27013160427vlAttorney Docket No.: 2012675-0415within the scope of sound medical judgment. In some embodiments, the specific effective dose level for any particular subject or organism may depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of specific active compound employed; specific composition employed; age, body weight, general health, sex and diet of the subject; time of administration, and rate of excretion of the specific active compound employed; duration of the treatment; drugs and / or additional therapies used in combination or coincidental with specific compound(s) employed, and like factors well known in the medical arts.

[0112] Unless otherwise specified, salts, such as pharmaceutically acceptable acid or base addition salts, stereoisomeric forms, and tautomeric forms, of provided compound are included.

[0113] As used herein in the present disclosure, unless otherwise clear from context, (i) the term “a” or ‘‘an'' may be understood to mean “at least one'’; (ii) the term “or” may be understood to mean “and / or”; (iii) the tenns “comprising”, “comprise”, “including” (whether used with “not limited to” or not), and “include” (whether used with “not limited to” or not) may be understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps; (iv) the term “another” may be understood to mean at least an additional / second one or more; (v) the terms “about” and “approximately” may be understood to permit standard variation as would be understood by those of ordinary skill in tire art; and (vi) where ranges are provided, endpoints are included.

[0114] The following abbreviations may be utilized in the present disclosure:Abbreviation Definition / Explanation2L second line3L third line5-FU 5 -fluorouracil"mTc MDP99mtcchnctiurn methylene diphosphonatc bone scanACTH adrenocorticotropic hormoneADA antidrug antibodiesAE adverse eventAFP alpha fetoproteinALK alkaline phosphataseALT alanine aminotransferaseANC absolute neutrophil countAPC adenomatous polyposis coliAST aspartate aminotransferaseAxIMP auxiliary investigational medicinal productPage 25 of 27013160427vlAttorney Docket No.: 2012675-0415Abbreviation Definition / ExplanationBCLC Barcelona Clinic Liver Cancer BCRP breast cancer resistance proteinBID twice dailyBIW two times weeklyBMD bone mineral densityBOR best overall responseBUN blood urea nitrogenC CycleCBC complete blood countCEA carcinoembryonic antigenCI confidence intervalCL clearanceCK creatine kinasemaximum observed concentration CNS central nervous systemCombo combinationCPD confinned progressive diseasecPSA complexed prostate-specific antigen CR complete responseCRC colorectal cancerCRO Contract Research OrganizationCT computed tomographyCTC circulating tumor cellctDNA circulating tumor DNAtrough concentrationCYP cytochrome P450D DayDXA dual-energy X-ray absorptiometry DLT dose-limiting toxicityPage 26 of 270 13160427vlAttorney Docket No.: 2012675-0415Abbreviation Definition / ExplanationdMMR deficient DNA mismatch repairDOR duration of responseDRE disease-related eventECG electrocardiogramECOG Eastern Cooperative Oncology GroupeCRF electronic case report formEOI end of infusionFDA Food and Drug AdministrationFDG-PET fluorodeoxyglucose positron emission tomographyFIH first-in-humanGCP Good Clinical PracticeGEJ gastroesophageal junctionGI gastrointestinalGLP Good Laboratory PracticeHBV / HCV hepatitis B / hepatitis C virusHCC hepatocellular carcinomaHIV human immunodeficiency virusHMG-CoA 3 -hydroxy-3 -methylglutaryl-coenzyme AHNSTD highest non-severely toxic doseIB Investigator’s BrochureICF informed consent formICH International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human UseIEC Independent Ethics CommitteeIMP investigational medicinal productINR international normalized ratioIRB Institutional Review BoardiRECIST immune Response Evaluation Criteria in Solid TumorsIRT Interactive Response TechnologyPage 27 of 27013160427vlAttorney Docket No.: 2012675-0415Abbreviation Definition / ExplanationITT intent-to-treatIV intravenous(ly)LAR legally authorized representativeLDH lactate dehydrogenaseLoF loss of functionmCRPC metastatic castration-resistant prostate cancerMedDRA Medical Dictionary for Regulatory ActivitiesmF0LF0X-6 modified FOLFOX-6Mono monotherapym RECI ST modified Response Evaluation Criteria in Solid TumorsMSI-H microsatellite instability-highMRI magnetic resonance imagingMSS microsatellite stableMTD maximum tolerated doseNCI CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events NE not evaluableNGS next-generation sequencingNIMP non-investigational medicinal productNSCLC non-small cell lung cancerNTI narrow therapeutic indexOATP1B1 organic anion transporting polypeptide 1B1ORR objective response rateOS overall survivalPD progressive diseasePD-1 programmed cell death- 1PDX patient-derived xenograftPET positron emission tomographyPFS progression-free survivalP-gP P-glycoproteinPage 28 of 27013160427vlAttorney Docket No.: 2012675-0415Abbreviation Definition / ExplanationPK pharmacokinetic(s)PO orallyPR partial responserPFS radiographic progression-free survivalpRP2D preliminary recommended Phase 2 dosePS performance statusPSA prostate-specific antigenPSA30 >30% reduction of PSA from baselinePSA50 >50% reduction of PSA from baselinePSA90 >90% reduction of PSA from baselinePSADT prostate-specific antigen doubling timePT prothrombin timePTT partial thromboplastin timeQ2W every 2 weeksQW once weeklyRANKL Receptor activator of nuclear factor kappa beta ligand RECIST 1.1 Response Evaluation Criteria in Solid Tumors Version 1.1 RP2D recommended Phase 2 doseRR response rateSAE serious adverse eventSAP statistical analysis planSC subcutancous(ly)SD stable diseaseSoA Schedule of ActivitiesSoC standard of careSRC Safety Review CommitteeSTD 10 severely toxic dose in 10% of animalsSUSAR suspected unexpected serious adverse reaction TEAE treatment-emergent adverse eventPage 29 of 27013160427vlAttorney Docket No.: 2012675-0415Abbreviation Definition / ExplanationTCF T-cell factorTmaxtime to CmaxULN upper limit of normalUPD unconfirmed progressive diseaseUS United Statesvdvolume of distributionVEGF vascular endothelial growth factorWPAM Wnt pathway activating mutationWnt-Pathway Activating Tumors

[0115] In various cases, secreted Wnt ligands have been reported to engage cell surface receptors (e.g., LRP, FZD, etc.) in multiple cell types during mammalian development, and in a restricted set of adult cell populations, to drive a signal transduction pathway that leads to stabilization of cytosolic beta-catenin protein (see. e.g., Rim, EY, Clevers H, & Nusse R. The Wnt Pathway: From Signaling Mechanisms to Synthetic Modulators. Annual Reviews in Biochemistry, 2022: 91: 15.1-15.28). It has been reported that engagement of the Wnt receptor complex can lead to blockade of a constitutive ‘destruction complex’ that drives proteasome-mediated degradation of beta-catenin in tire absence of Wnt ligand. In some cases, the ‘destruction complex’ has been reported to contain multiple proteins, including AXIN, adenomatous polyposis coli (APC), GSK3 and CK1, that cooperate to drive beta-catenin degradation. Following stabilization of cytosolic beta-catenin, it is reportedly translocated to tire nucleus and activates a transcriptional program by virtue of interaction with members of the TCF transcriptional factor family (TCF1 / 3 / 4 and LEF1). The beta-catenin: TCF complex can bind to cognate deoxyribonucleic acid (DNA) sequences and drives a gene expression program involved in cell proliferation, stem cell maintenance, and epithelial-to-mesenchymal transition (EMT).

[0116] It has been reported that dysregulation of the Wnt / beta-catenin pathway frequently occurs in human cancers (see, e.g., Zhong Z, Yu J, Virshup DM, Madan B. Wnts and the hallmarks of cancer. Cancer Metastasis Rev. 2020;39(3):625-45). Wnt pathway mutations, including adenomatous polyposis coli (APC) loss of function (LoF) mutations and beta-catenin activating mutations, are reported to impact cancer cell proliferation, differentiation, and apoptosis (see, e.g., Starnos JL, Weis WI. Tire beta-catenin destruction complex. Cold Spring Harb Perspect Biol. 2013;5(l):a007898). It has been reported that APC LoF mutations can incapacitate the beta-catenin destruction complex and can lead to subsequent beta-catenin activation (see, e.g., Starnos JL, Weis WI. The beta-catenin destruction complex. Cold Spring Harb Perspect Biol.2013;5(l):a007898). LoF mutations in APC, activating mutations in beta-catenin, along with other driver WntPage 30 of 27013160427vlAttorney Docket No.: 2012675-0415pathway mutations (e.g., driver mutations in other 12 Wnt pathway genes), are frequently detected in common cancer types (see, e.g., Hoadley KA, Yau C, Hinoue T, et al. Cell-of-origin patterns dominate the molecular classification of 10,000 tumors from 33 types of cancer. Cell, 2018;173(2):291-304. E6; Gajos-Michniewicz A, Czyz M. Wnt signaling in melanoma. Int J Mol Sci. 2020;21(14):4852; Stewart DJ. Wnt signaling pathway in non-small cell lung cancer. JNatl Cancer Inst. 2014; 106( l):djt356; Teeuwssen M, Fodde R. Wnt signaling in ovarian cancer sternness, EMT, and therapy resistance. J Clin Med. 2019:8(10): 1658: etc.). Tire prevalence of these Wnt pathway-activating mutations (WPAMs) can be up to 80.7% in CRC, 33.1% in liver cancer, 85% in desmoid tumors, and -13% in prostate cancer (see, e.g., Broderick A, et al. Clinical implications of Wnt pathway genetic alterations in men with advanced prostate cancer. Prostate Cancer Prostatic Dis. 2024 Jul 17. doi: 10.1038 / s41391-024-00869-l. PMID: 39019980; FcdcnnanN. Molecular pathogenesis of desmoid tumor and tire role of y-secretase inhibition. NPJ Precis Oncol. 2022;6(l):62; Stewart DJ. Wnt signaling pathway in non-small cell lung cancer. J Natl Cancer Inst. 2014:106(l):djt356; etc.).

[0117] The functional relevance of key WPAM mutations in the initiation and maintenance of cancer has been reported preclinically. For instance, LoF mutations in the APC gene observed in patient colorectal tumor samples have been reported to drive tumorigenesis in cell and animal models of cancer (see, e.g., Bian J, Dannappel M, Wan C, et al. Transcriptional Regulation of Wnt / p-Catenin Pathway in Colorectal Cancer. Cells, 2020: 9:2125). Genetic perturbation of APC gene in mouse models is reported to lead to intestinal polyps and tumorigenesis. particularly in combination with additional cancer driver mutations, like KRAS, TP53 and SMAD4 (all of which have been reported to be commonly observed in CRC patients). It has been reported that restoration of wild-type APC, or complete blockade of beta-catenin activity (using short hairpin RNA [shRNA], CRISPR) in preclinical cancer models carrying APC mutations, leads to strong inhibition of cancer cell and tumor growth, and knockdown of TCF proteins in tumor cells with activated beta-catenin also leads to inhibition of cancer cell proliferation.

[0118] It has been reported that the majority of human colorectal cancer (>80%). and many cancers representing multiple additional indications (e.g., hepatocellular, gastric, endometrial and non-small cell lung cancers), harbor mutations in genes of the Wnt / beta-catenin pathway. APC and CTNNB1 (encodingP-catenin) are two of the most frequently mutated genes in this pathway. These mutations lead to the stabilization of beta-catenin at tire protein level and the hyperactivation of its transcriptional activity in the nucleus of tumor cells, in complex with TCF family proteins.

[0119] In some embodiments, a WPAM is or comprises an APC mutation. In some embodiments, a WPAM is or comprises an APC loss-of-function (LoF or LOF) mutation. In some embodiments, an APC mutation is frameshift, nonsense or splice site. In some embodiments, an APC mutation is somatic. In some embodiments, an APC mutation is a germline mutation. In some embodiments, an APC mutation is a frameshift mutation. In some embodiments, an APC mutation is a pathogenic frameshift mutation. In some embodiments, an APC mutation is E1554_K1555fs. In some embodiments, an APC mutation is Q739fs / Q1459X. In some embodiments, an APC mutation is L946fs / L1471fs. In some embodiments, an APC Page 31 of 27013160427vlAttorney Docket No.: 2012675-0415mutation is S1549X / P1693fs / V1690fs / G1659fs / A1661fs. In some embodiments, an APC mutation is S1549X, P1693fs, V1690fs, G1659fs, and / or A 1661 fs. In some embodiments, an APC mutation is S1549X. In some embodiments, an APC mutation is P1693fs. In some embodiments, an APC mutation is V1690fs. In some embodiments, an APC mutation is G1659fs. In some embodiments, an APC mutation is P1693fs. In some embodiments, an APC mutation is R876* / Q1429*. In some embodiments, an APC mutation is R876* and / or Q 1429*. In some embodiments, an APC mutation is R876*. In some embodiments, an APC mutation is Q1429*. In some embodiments, an APC mutation is p. Thrl556Asnfs*3. In some embodiments, an APC mutation is D849*. In some embodiments, an APC mutation is p. Y935*. In some embodiments, a WPAM is or comprises a CTNNB1 mutation. In some embodiments, it is or comprises a CTNNB1 gain-of-function (GoF or GOF) mutation. In some embodiments, a CTNNB1 mutation is missense, in-frame insertion, or deletion at codons 32-37, 41, and 45, or alterations leading to Exon 3 skipping. In some embodiments, a CTNNB1 mutation is missense, in-frame insertion, or deletion at codons 32-37, 41, and / or 45. For example, in some embodiments, a CTNNB1 mutation is a T41I mutation, a T41A mutation, S45F mutation, a S45P mutation, a D32V mutation, a H36P mutation, and / or a S45_G48del mutation. For example, in some embodiments, a CTNNB1 mutation is a T41I mutation, a T41A mutation, and / or a S45F mutation. In some embodiments, a CTNNB1 mutation is a T41I mutation. In some embodiments, a CTNNB1 mutation is a T41A mutation. In some embodiments, a CTNNB1 mutation is a S45F mutation. In some embodiments, a CTNNB1 mutation is a S45P mutation. In some embodiments, a CTNNB1 mutation is a D32V mutation. In some embodiments, a CTNNB1 mutation is a H36P mutation. In some embodiments, a CTNNB1 mutation is a S45_G48del mutation. In some embodiments, a WPAM is or comprises a RNF43 mutation. In some embodiments, a WPAM is or comprises a RNF43 LOF mutation. In some embodiments, a WPAM is or comprises RSPO2 and RSPO3 fusion. In some embodiments, a WPAM is or comprises a mutation in another Wnt-pathway genes, such as AMER1. AXIN1. AXIN2, BCL9, CSNK1A1, GSK3B, LRP5 (GoF), LRP6 (GoF), LGR5 (GoF), TCF7L2 (GoF), and WIFI. In some embodiments, a WPAM is an alteration of pathogenic, likely pathogenic or equivalent nature. In some embodiments, a WPAM is pathogenic. In some embodiments, a WPAM is likely pathogenic. In some embodiments, a WPAM is a pathogenic mutation of APC or CTNNB1. Those skilled in the art appreciate that various such WPAMs are reported, or can be identified, characterized and / or determined using available technologies in accordance with the present disclosure.

[0120] Transcriptional programs driven by beta-catenin: TCF complex have been reported to activate multiple biological pathways that promote tumor growth including cell cycle regulators and the C-MY C transcription factor, which itself is a well-described oncogenic driver (see, e.g., Rennoll S, Yochum G. 2015. Regulation of MYC gene expression by aberrant Wnt / B-catenin signaling in colorectal cancer. World J Biol Chem. 6(4):290-300)). Directly blocking p-catenin: TCF interaction offers a useful strategy to treat tumors carrying WPAMs. It has been an area of intense interest for decades, but few if any safe and effective therapeutics in this area have been reported and approved.

[0121] Various in vitro and in vivo assays have confirmed that 1-66 can modulate beta-catenin: TCF Page 32 of 27013160427vlAttorney Docket No.: 2012675-0415interactions and can inhibit tumor growth including in various PDX tumor models. Among other things, the present disclosure provides technologies, e.g., formulations, doses, dosage regimens, etc., for using 1-66 to treat cancers in human subjects.1-66

[0122] In some embodiments, the present disclosure provides technologies for manufacturing, formulating and utilizing 1-66 for treating conditions, disorders or diseases including cancer.

[0123] The linear sequence of 1-66 is Ac-PL31-Asp2-Npg3-B54-Asp3-3COOHFb-Aib7-Ala8-Phe9-Lys10-PyrS2n-3Thi12-BztA13-Glu14-Ala15-NH2; it has olefin staples between PL31and B54and between B54and PyrS2n, and a lactam staple between Lys10and Glu14. 1-66 has such a structure that it has NMR spectra as shown in Figure 1, Figure 2. Figure 3, Figure 4, Figure 5, Figure 6, Figure 7, Figure 8, Figure 9, Figure 10, Figure 11 and / or Figure 12. In some embodiments,13C NMR in MeOD at 25 °C (e.g.. 900MHz Bruker AVANCE III system with a cryoprobe, sample concentration 10 mg / 750 uL) of 1-66 in a preparation or composition thereof comprises or consists of the following peaks (chemical shift (8, ppm)): 17, 17.76, 23.2, 23.2, 23.29, 23.32, 23.87, 24.46, 27.46, 27.47, 28.98, 29.61, 29.99, 30, 30.18, 30.63, 31.36, 31.76, 31.81, 32.6, 33.09, 33.8, 33.84, 35.69, 35.8, 35.96, 36.18, 36.46, 38.1, 38.18, 39.25, 45.37, 45.96, 49.5, 51.2, 53.94, 54.54, 55.33, 55.56, 55.69, 56.48, 56.93, 57.28, 57.7, 59.94, 60.7, 60.94, 62.78, 65.89, 67.18, 70.51. 122.71, 123.42, 123.87, 125.19, 125.2, 125.37, 126.96, 126.99, 128.08, 129.15, 129.2. 129.37, 129.54, 129.83, 129.83, 130.39, 130.39, 131.26, 131.47, 131.96, 132.12, 132.57, 135.08, 137.36, 138.06, 138.13, 139.58, 141.98, 156.51, 169.51, 172.38, 172.48, 173.13, 174.1, 174.39, 174.47, 175.44, 175.55, 175.55, 175.6, 175.7, 175.8, 175.8, 175.8, 176.97, 177, 177.56, 178.08, and 178.58. In some embodiments, H NMR in MeOD at 25 °C (e.g., 900MHz Bruker AVANCE III system with a cryoprobe, sample concentration 10 mg / 750 uL) of 1-66 in a preparation or composition thereof comprises the following peaks (chemical shift (5, ppm)): 3.96. 6.34, 6.84, 6.36. 4.38. 4.31, 3.82, 4.21, 7.21, 7.24. 7.07. 7.24, 7.21, 4.03, 4.25, 7.97. 7.94. 7.42, 7.5. 4.4. 5.29. 5.31, 4.27, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93, 2.38, 2.92, 3.45, 1.18, 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37, 2.38, 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3.92, 2.2, 2.42, 2.22, 3.08, 3.40, 1.55, 1.07, 1.42, 1.59, 1.33, and 2.23. In some embodiments, 'H NMR in MeOD at 25 °C (e.g., 900MHz Bruker AVANCE III system with a cryoprobe, sample concentration 10 mg / 750 uL) of 1-66 in a preparation or composition thereof comprises the following peaks (chemical shift (5, ppm)): 3.96. 6.34.6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93 (2H), 2.38 (2H), 2.92, 3.45, 1.18 (2H), 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74.2.96, 1.92, 2.07, 1.37 (2H), 2.38 (2H), 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84. 1.42, 1.57, 2.69. 3.76, 3.92, 2.2 (2H), 2.42, 2.22, 3.08, 3.40. 1.55 (3H), 1.07 (3H). 1.42 (3H), 1.59 (3H). 1.33 (3H), and 2.23 (3H). wherein each peak represents 1H unless indicated otherwise. In some embodiments, ¹H NMR Page 33 of 27013160427vlAttorney Docket No.: 2012675-0415in MeOD at 25 °C (e.g., 900MHz Broker AVANCE III system with a cryoprobe, sample concentration 10 mg / 750 uL) of 1-66 in a preparation or composition thereof comprises the following peaks (chemical shift (5, ppm)): 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22. 2.29, 2.41, 3.53, 3.25, 3.06, 2.95. 1.93, 2.38, 2.92, 3.45, 1.18, 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44. 2.74. 2.96, 1.92, 2.07, 1.37, 2.38. 1.80, 1.88, 2.71, 2.81, 3.20, 2.05. 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3.92, 2.2, 2.42, 2.22, 3.08, 3.40, 1.55, 1.07, 1.42, 1.59, 1.33, 2.23, 8.32, 7.73, 8.17, 8.19, 8.25, 8.44, 8.89, 8.1, 8.42, 7.45, 7.39, 8.15, 8.86, and 7.69. In some embodiments, ’H NMR in MeOD at 25 °C (e.g., 900MHz Broker AVANCE III system with a cryoprobc. sample concentration 10 mg / 750 uL) of 1-66 in a preparation or composition thereof comprises the following peaks (chemical shift (5, ppm)): 3.96, 6.34, 6.84, 6.36. 4.38, 4.31, 3.82, 4.21, 7.21, 7.24. 7.07, 7.24, 7.21, 4.03, 4.25, 7.97. 7.94, 7.42, 7.5, 4.4. 5.29, 5.31, 4.27, 4.31. 5.56. 5.36, 7.89, 7.38, 7.41, 7.89. 7, 4.3, 2.00, 2.10, 1.60. 1.65, 3.73, 4.15, 3.15, 4.22, 2.29. 2.41, 3.53, 3.25, 3.06, 2.95, 1.93 (2H), 2.38 (2H), 2.92, 3.45, 1.18 (2H), 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37 (2H), 2.38 (2H), 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3.92, 2.2 (2H), 2.42, 2.22, 3.08, 3.40, 1.55 (3H), 1.07 (3H), 1.42 (3H), 1.59 (3H), 1.33 (3H), 2.23 (3H), 8.32, 7.73, 8.17, 8.19, 8.25, 8.44, 8.89, 8.1, 8.42, 7.45, 7.39, 8.15, 8.86, and 7.69, wherein each peak represents 1H unless indicated otherwise. As those skilled in the art readily appreciate, chemical shifts of the same compound may be deferent between or among different experiments and / or samples; despite the slight differences, those skilled in the art can determine whether two NMR results are of the same compound. Identity of 1-66 is confirmed by various technologies including NMR as described herein. Various stereoisomers, including E / Z isomers of each double bond in the staples, may exist. 1-66 is the isomer that has the characterization data, including NMR and HPLC data, that described herein. In some embodiments, 1-66 is referred to by the following structure:Page 34 of 27013160427vlAttorney Docket No.: 2012675-0415stereochemistry (e.g., one or more of (S), (R), (E), and (Z)) may be omitted, for example:Page 35 of 27013160427vlAttorney Docket No.: 2012675-0415

[0124] The molecular formula of 1-66 is C102H134N18O25S2. The molecular weight of 1-66 is 2076.42.

[0125] In some embodiments, 1-66 is referred to by the chemical name of 2,2'- ((l" S,2R,2'S,5'S,8'S.10" E,12'Z,18" S,21" S,27" S,30" S,33" S.42" S,45" S,48" S)-l-acetyl-42"-(((S)-l-amino-l-oxopropan-2-yl)carbamoyl)-45"-(benzo[b]thiophen-3-yhnethyl)-30"-benzyl-21"-(3-carboxybenzyl)-24",24",27"-tnmethyl-5'-neopentyl-3',5",6', 16', 16", 19",22",25",28",31 ",39",44",47",50",52"-pentadecaoxo-48"-(thiophen-3-ylmethyl)-6"-oxa-T,4',4",7',17",20",23",26",29",32",38",43",46",49",51"-pentadecaazadispiro[pyrrolidine-2,15'-cyclohexadecane-8',15"-tricyclo[31.17.2.1 l,4]tripentacontane]-10",12'-dien-2', 18"-diyl)diacetic acid.

[0126] In some embodiments, 1-66 is provided as a white or slightly colored solid. In some embodiments, dissociate constant (pKa) is reported to be about 5.0 (all carboxylic acids). In some embodiments, 1-66 is formulated as a salt to provide higher solubility compared to free acid. Some salts, e.g., sodium salt, of 1-66 have solubility of > 100 mg / mL in water compared to < 26 mg / mL for free acid. 1-66 preparations may be hygroscopic under certain conditions. For example, for a sodium salt preparation, 13% wt gain from 40 to 80% RH is reported, and max wt gain -30% is reported. In some embodiments, 1-66 preparations are amorphous. In some embodiments, an 1-66 preparation is amorphous sodium salt. In some embodiments, a sodium salt is a trisodium salt. Unless noted otherwise, an 1-66 sodium salt is trisodium salt in the present disclosure.

[0127] In biochemical and cellular studies, Applicant has shown that 1-66 can potently and selectivelyPage 36 of 27013160427vlAttorney Docket No.: 2012675-0415disrupt the interaction of [3-catenin with its obligate transcription factor, TCF. In preclinical studies. Applicant has demonstrated the ability of 1-66 to cause tumor growth inhibition (TGI) and regression by disrupting f>-catenin-dependent signaling. In some embodiments, 1-66 can provide the benefits and advantages from blocking TCF-bcta-catcnin engagement, reportedly the most downstream node in the canonical Wnt pathway, thus abrogating the hyperactivation of Wnt pathway induced by most, if not all, known Wnt pathw ay mutations. In some embodiments, the present disclosure provides technologies, e.g.. clinical trial designs, that are useful for studying and confirming clinical effects and benefits of 1-66.Compositions

[0128] Among other things, the present disclosure provides compositions that comprise 1-66. In some embodiments, 1-66 in a composition exists as a salt form. In some embodiments, 1-66 in a composition exists as a pharmaceutically acceptable salt form. In some embodiments, multiple forms of 1-66 may exist in a composition. In some embodiments, 1-66 is provided as a trisodium salt, e.g., as a prepared drug substance.

[0129] In some embodiments, the present disclosure provides technologies for formulating 1-66 to provide compositions of sufficient concentrations and stability, e.g., for clinical uses. In some embodiments, the present disclosure provides an 1-66 drug product. In some embodiments, an 1-66 pharmaceutical composition is an 1-66 drug product. In some embodiments, a composition is a liquid composition.

[0130] In some embodiments, a composition comprises or consists of:1-66;a solubilizing agent;a buffer agent;optionally a pH adjustment agent; anda solvent.

[0131] In some embodiments, a composition comprises or consists of:1-66;an amino acid;a buffer agent;optionally a pH adjustment agent; anda solvent.

[0132] In some embodiments, a composition comprises or consists of:1-66;a PEG or a surfactant;a buffer agent;optionally a pH adjustment agent; anda solvent.

[0133] In some embodiments, a composition comprises or consists of:Page 37 of 27013160427vlAttorney Docket No.: 2012675-04151-66;a PEG;a buffer agent;optionally a pH adjustment agent; anda solvent.

[0134] In some embodiments, a composition comprises or consists of:1-66;a surfactant;a buffer agent;optionally a pH adjustment agent; anda solvent.

[0135] In some embodiments, a composition comprises or consists of:1-66;an amino acid;a PEG or a surfactant;a buffer agent;optionally a pH adjustment agent; anda solvent.

[0136] In some embodiments, a composition comprises or consists of:1-66;an amino acid;a PEG;a buffer agent;optionally a pH adjustment agent; anda solvent.

[0137] In some embodiments, a composition comprises or consists of:1-66;an amino acid;a surfactant;a buffer agent;optionally a pH adjustment agent; anda solvent.

[0138] In some embodiments, a composition comprises or consists of:1-66;a solubilizing agent;a buffer agent;Page 38 of 27013160427vlAttorney Docket No.: 2012675-0415optionally a pH adjustment agent; anda solvent.

[0139] In some embodiments, a composition comprises or consists of:1-66;an amino acid;a buffer agent;optionally a pH adjustment agent; anda solvent.

[0140] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 1-25 mg / mL;an amino acid, wherein the concentration of the amino acid is about 1-20 mg / mL;a PEG or a surfactant, wherein the concentration of the PEG or surfactant is about 0.5%-5% w / v; a buffer agent, wherein the concentration of the buffering agent is about 1-100 mM;optionally a pH adjustment agent; andwater;wherein the pH of the composition is about 7.0-9.0.

[0141] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 1-25 mg / mL;arginine, wherein the concentration of arginine is about 1-20 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 0.5%-5% w / v;a buffer agent, wherein the concentration of the buffering agent is about 1-100 mM;optionally a pH adjustment agent; andwater;wherein the pH of the composition is about 7.0-9.0.

[0142] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 1-25 mg / mL;arginine, wherein the concentration of arginine is about 1-20 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 0.5%-5% w / v;sodium phosphate monobasic, wherein the concentration of sodium phosphate monobasic is about 1- 100 mM;optionally a pH adjustment agent; andwater;wherein the pH of the composition is about 7.0-9.0.

[0143] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 1-25 mg / mL;arginine, wherein the concentration of arginine is about 1-20 mg / mL;Page 39 of 27013160427vlAttorney Docket No.: 2012675-0415PEG-400, wherein the concentration of PEG-400 is about 0.5%-5% w / v;sodium phosphate monobasic, wherein the concentration of sodium phosphate monobasic is about 1- 100 mM;optionally sodium hydroxide;optionally hydrochloric acid; andwater;wherein the pH of the composition is about 7.0-9.0.

[0144] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 1-25 mg / mL;arginine, wherein the concentration of arginine is about 1-20 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 2%-5% w / v;sodium phosphate monobasic, wherein the concentration of sodium phosphate monobasic is about 1- 100 mM;optionally sodium hydroxide;optionally hydrochloric acid; andwater;wherein the pH of the composition is about 7.0-9.0.

[0145] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 1-25 mg / mL;arginine, wherein the concentration of arginine is about 1-20 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 2%-5% w / v;sodium phosphate monobasic, wherein the concentration of sodium phosphate monobasic is about 1- 100 mM;optionally sodium hydroxide;optionally hydrochloric acid; andwater;wherein the pH of the composition is about 7.0-9.0.

[0146] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 1-25 mg / mL;arginine, wherein the concentration of arginine is about 5-20 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 2%-5% w / v;sodium phosphate monobasic, wherein the concentration of sodium phosphate monobasic is about 1- 20 mM;optionally sodium hydroxide;optionally hydrochloric acid; andwater;Page 40 of 27013160427vlAttorney Docket No.: 2012675-0415wherein the pH of the composition is about 7.0-9.0.

[0147] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 5-25 mg / mL;arginine, wherein the concentration of arginine is about 5-20 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 2%-5% w / v;sodium phosphate monobasic, wherein the concentration of sodium phosphate monobasic is about 1- 20 mM;optionally sodium hydroxide;optionally hydrochloric acid; andwater;wherein the pH of the composition is about 7.0-9.0.

[0148] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 10 mg / mL;arginine, wherein the concentration of arginine is about 5-20 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 2%-5% w / v;sodium phosphate monobasic, wherein the concentration of sodium phosphate monobasic is about 1- 20 mM;optionally sodium hydroxide;optionally hydrochloric acid; andwater;wherein the pH of the composition is about 7.0-9.0.

[0149] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 10-25 mg / mL;arginine, wherein the concentration of arginine is about 10 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 2%-5% w / v;sodium phosphate monobasic, wherein the concentration of sodium phosphate monobasic is about 10 mM;optionally sodium hydroxide;optionally hydrochloric acid; andwater;wherein the pH of the composition is about 7.0-9.0.

[0150] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 10-25 mg / mL;arginine, wherein the concentration of arginine is about 10 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 3% w / v;sodium phosphate monobasic, wherein the concentration of sodium phosphate monobasic is about 10Page 41 of 27013160427vlAttorney Docket No.: 2012675-0415mM;optionally sodium hydroxide;optionally hydrochloric acid; andwater;wherein the pH of the composition is about 7.0-9.0.

[0151] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 10 mg / mL;arginine, wherein the concentration of arginine is about 10 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 3% w / v;sodium phosphate monobasic, wherein the concentration of sodium phosphate monobasic is about 10 mM;optionally sodium hydroxide;optionally hydrochloric acid; andwater;wherein the pH of the composition is about 7.0-9.0.

[0152] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 1-25 mg / mL;an amino acid, wherein the concentration of the amino acid is about 1-20 mg / mL:a PEG or a surfactant, wherein the concentration of the PEG or surfactant is about 0.5%-5% w / v; and a buffer;wherein the pH of the composition is about 7.0-9.0.

[0153] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 1-25 mg / mL;arginine, wherein the concentration of arginine is about 1-20 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 0.5%-5% w / v: anda buffer;wherein the pH of the composition is about 7.0-9.0.

[0154] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 1-25 mg / mL;arginine, wherein the concentration of arginine is about 1-20 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 2%-5% w / v; anda buffer;wherein the pH of the composition is about 7.0-9.0.

[0155] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 1-25 mg / mL;arginine, wherein the concentration of arginine is about 5-20 mg / mL;Page 42 of 27013160427vlAttorney Docket No.: 2012675-0415PEG-400, wherein the concentration of PEG-400 is about 2%-5% w / v; and a buffer;wherein the pH of the composition is about 7.0-9.0.

[0156] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 5-25 mg / mL; arginine, wherein the concentration of arginine is about 5-20 mg / mL; PEG-400, wherein the concentration of PEG-400 is about 2%-5% w / v; and a buffer;wherein the pH of the composition is about 7.0-9.0.

[0157] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 10 mg / mL; arginine, wherein the concentration of arginine is about 5-20 mg / mL; PEG-400, wherein the concentration of PEG-400 is about 2%-5% w / v; and a buffer;wherein the pH of the composition is about 7.0-9.0.

[0158] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 10 mg / mL; arginine, wherein the concentration of arginine is about 5-20 mg / mL; PEG-400, wherein the concentration of PEG-400 is about 2%-5% w / v: and a buffer;wherein the pH of the composition is about 7.0-9.0.

[0159] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 5-25 mg / mL; arginine, wherein the concentration of arginine is about 5-20 mg / mL; PEG-400, wherein the concentration of PEG-400 is about 3% w / v; and a buffer;wherein the pH of the composition is about 7.0-9.0.

[0160] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 5-25 mg / mL; arginine, wherein the concentration of arginine is about 10 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 3% w / v; and a buffer;wherein the pH of the composition is about 7.0-9.0.

[0161] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 5-15 mg / mL; arginine, wherein the concentration of arginine is about 10 mg / mL;Page 43 of 27013160427vlAttorney Docket No.: 2012675-0415PEG-400, wherein the concentration of PEG-400 is about 3% w / v; anda buffer;wherein the pH of the composition is about 7.0-9.0.

[0162] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 10 mg / mL;arginine, wherein the concentration of arginine is about 10 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 3% w / v; anda buffer;wherein the pH of the composition is about 7.0-9.0.

[0163] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 1-25 mg / mL;an amino acid, wherein the concentration of the amino acid is about 1-20 mg / mL:a PEG or a surfactant, wherein the concentration of the PEG or surfactant is about 0.5%-5% v / v; a buffer agent, wherein the concentration of the buffering agent is about 1-100 mM;optionally a pH adjustment agent; andwater;wherein the pH of the composition is about 7.0-9.0.

[0164] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 1-25 mg / mL;arginine, wherein the concentration of arginine is about 1-20 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 0.5%-5% v / v;a buffer agent, wherein the concentration of the buffering agent is about 1-100 mM;optionally a pH adjustment agent; andwater;wherein the pH of the composition is about 7.0-9.0.

[0165] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 1-25 mg / mL;arginine, wherein the concentration of arginine is about 1-20 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 0.5%-5% v / v;sodium phosphate monobasic, wherein the concentration of sodium phosphate monobasic is about 1- 100 mM;optionally a pH adjustment agent; andwater;wherein the pH of the composition is about 7.0-9.0.

[0166] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 1-25 mg / mL;Page 44 of 27013160427vlAttorney Docket No.: 2012675-0415arginine, wherein the concentration of arginine is about 1-20 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 0.5%-5% v / v;sodium phosphate monobasic, wherein the concentration of sodium phosphate monobasic is about 1- 100 mM;optionally sodium hydroxide;optionally hydrochloric acid; andwater;wherein the pH of the composition is about 7.0-9.0.

[0167] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 1-25 mg / mL;arginine, wherein the concentration of arginine is about 1-20 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 2%-5% v / v;sodium phosphate monobasic, wherein the concentration of sodium phosphate monobasic is about 1- 100 mM;optionally sodium hydroxide;optionally hydrochloric acid; andwater;wherein the pH of the composition is about 7.0-9.0.

[0168] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 1-25 mg / mL;arginine, wherein the concentration of arginine is about 1-20 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 2%-5% v / v;sodium phosphate monobasic, wherein the concentration of sodium phosphate monobasic is about 1- 100 mM;optionally sodium hydroxide;optionally hydrochloric acid; andwater;wherein the pH of the composition is about 7.0-9.0.

[0169] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 1-25 mg / mL;arginine, wherein the concentration of arginine is about 5-20 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 2%-5% v / v;sodium phosphate monobasic, wherein the concentration of sodium phosphate monobasic is about 1- 20 mM;optionally sodium hydroxide;optionally hydrochloric acid; andPage 45 of 27013160427vlAttorney Docket No.: 2012675-0415water;wherein the pH of the composition is about 7.0-9.0.

[0170] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 5-25 mg / mL;arginine, wherein the concentration of arginine is about 5-20 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 2%-5% v / v;sodium phosphate monobasic, wherein the concentration of sodium phosphate monobasic is about 1- 20 mM;optionally sodium hydroxide;optionally hydrochloric acid; andwater;wherein the pH of the composition is about 7.0-9.0.

[0171] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 10 mg / mL;arginine, wherein the concentration of arginine is about 5-20 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 2%-5% v / v;sodium phosphate monobasic, wherein the concentration of sodium phosphate monobasic is about 1- 20 mM:optionally sodium hydroxide;optionally hydrochloric acid; andwater;wherein the pH of the composition is about 7.0-9.0.

[0172] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 10-25 mg / mL;arginine, wherein the concentration of arginine is about 10 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 2%-5% v / v;sodium phosphate monobasic, wherein the concentration of sodium phosphate monobasic is about 10 mM;optionally sodium hydroxide;optionally hydrochloric acid; andwater;wherein the pH of the composition is about 7.0-9.0.

[0173] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 10-25 mg / mL;arginine, wherein the concentration of arginine is about 10 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 3% v / v;Page 46 of 27013160427vlAttorney Docket No.: 2012675-0415sodium phosphate monobasic, wherein the concentration of sodium phosphate monobasic is about 10 mM:optionally sodium hydroxide;optionally hydrochloric acid; andwater;wherein the pH of the composition is about 7.0-9.0.

[0174] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 10 mg / mL;arginine, wherein the concentration of arginine is about 10 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 3% v / v;sodium phosphate monobasic, wherein the concentration of sodium phosphate monobasic is about 10 mM;optionally sodium hydroxide;optionally hydrochloric acid; andwater;wherein the pH of the composition is about 7.0-9.0.

[0175] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 1-25 mg / mL;an amino acid, wherein the concentration of the amino acid is about 1-20 mg / mL;a PEG or a surfactant, wherein the concentration of the PEG or surfactant is about 0.5%-5% v / v; and a buffer;wherein the pH of the composition is about 7.0-9.0.

[0176] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 1-25 mg / mL;arginine, wherein the concentration of arginine is about 1-20 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 0.5%-5% v / v; anda buffer;wherein the pH of the composition is about 7.0-9.0.

[0177] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 1-25 mg / mL;arginine, wherein the concentration of arginine is about 1-20 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 2%-5% v / v; anda buffer;wherein the pH of the composition is about 7.0-9.0.

[0178] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 1-25 mg / mL;Page 47 of 27013160427vlAttorney Docket No.: 2012675-0415arginine, wherein the concentration of arginine is about 5-20 mg / mL; PEG-400, wherein the concentration of PEG-400 is about 2%-5% v / v; and a buffer;wherein the pH of the composition is about 7.0-9.0.

[0179] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 5-25 mg / mL; arginine, wherein the concentration of arginine is about 5-20 mg / mL; PEG-400, wherein the concentration of PEG-400 is about 2%-5% v / v; and a buffer;wherein the pH of the composition is about 7.0-9.0.

[0180] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 10 mg / mL; arginine, wherein the concentration of arginine is about 5-20 mg / mL; PEG-400, wherein the concentration of PEG-400 is about 2%-5% v / v; and a buffer;wherein the pH of the composition is about 7.0-9.0.

[0181] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 10 mg / mL; arginine, wherein the concentration of arginine is about 5-20 mg / mL; PEG-400, wherein the concentration of PEG-400 is about 2%-5% v / v; and a buffer;wherein the pH of the composition is about 7.0-9.0.

[0182] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 5-25 mg / mL; arginine, wherein the concentration of arginine is about 5-20 mg / mL; PEG-400, wherein the concentration of PEG-400 is about 3% v / v; and a buffer;wherein the pH of the composition is about 7.0-9.0.

[0183] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 5-25 mg / mL; arginine, wherein the concentration of arginine is about 10 mg / mL; PEG-400, wherein the concentration of PEG-400 is about 3% v / v; and a buffer;wherein the pH of the composition is about 7.0-9.0.

[0184] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 5-15 mg / mL;Page 48 of 27013160427vlAttorney Docket No.: 2012675-0415arginine, wherein the concentration of arginine is about 10 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 3% v / v; anda buffer;wherein the pH of the composition is about 7.0-9.0.

[0185] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 10 mg / mL;arginine, wherein the concentration of arginine is about 10 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 3% v / v; anda buffer;wherein the pH of the composition is about 7.0-9.0.

[0186] 1-66 in a composition may exist in various forms. In some embodiments, a form of 1-66 is a pharmacally acceptable salt form. In some embodiments. 1-66 exists as one or more dissolved pharmaceutically acceptable salt forms. In some embodiments, there are two or more forms of 1-66 in a composition. In some embodiments, concentration of 1-66 is about 1-25 mg / mL (unless otherwise noted, assessed as free acid). In some embodiments, concentration of 1-66 is about 10 mg / mL. In some embodiments, concentration of 1-66 is about 20 mg / mL. In some embodiments, concentration of 1-66 is about 25 mg / mL.

[0187] In some embodiments, there is one solubilizing agent in a composition. In some embodiments, there are two or more solubilizing agents in a solution. In some embodiments, a solubilizing agent is an amino acid. In some embodiments, a solubilizing agent is a basic amino acid. In some embodiments, a solubilizing agent is arginine. In some embodiments, a solubilizing agent is PEG. In some embodiments, a solubilizing agent is PEG-400. In some embodiments, a solubilizing agent is a surfactant. In some embodiments, a solubilizing agent is a nonionic surfactant. In some embodiments, a solubilizing agent is Tween 80. In some embodiments, each solubilizing agent is independently selected from an amino acid, a polyethylene glycol, and a surfactant. In some embodiments, each solubilizing agent is independently selected from an amino acid, a polyethylene glycol, and a nonionic surfactant. In some embodiments, a solubilizing agent is a basic amino acid. In some embodiments, there are two solubilizing agent in a composition. In some embodiments, a composition comprises two or more solubilizing agents, for example, in some embodiments, a composition comprises both arginine and PEG-400 as solubilizing agent. In some embodiments, a solubilizing agent is Tween 80. In some embodiments, concentration of a solubilizing agent is about 1-20 mg / mL. In some embodiments, concentration of a basic amino acid is about 1-20 mg / mL. In some embodiments, concentration of arginine is about 1-20 mg / mL. In some embodiments, concentration of arginine is about 10 mg / mL. In some embodiments, concentration of a solubilizing agent, e.g., of a PEG, a surfactant, etc., is about 0.5%-5% (w / v). In some embodiments, concentration of PEG is about 0.5%-5% (w / v). In some embodiments, concentration of PEG is about 2%-5% (w / v). In some embodiments, concentration of PEG is about 3% (w / v). In some embodiments, concentration of PEG-400 is about 0.5%-5% (w / v). In some embodiments.Page 49 of 27013160427vlAttorney Docket No.: 2012675-0415concentration of PEG-400 is about 2%-5% (w / v). In some embodiments, concentration of PEG-400 is about 3% (w / v). In some embodiments, concentration of PEG-400 is about 3.4% (w / v). For example, as shown in Table E-8, concentration of PEG-400 is 0.336 mg / mL. In some embodiments, concentration of a surfactant is about 0.5%-5% (w / v). In some embodiments, concentration of PEG is about 2%-5% (w / v). In some embodiments, concentration of PEG is about 3% (w / v). In some embodiments, concentration of Tween 80 is about 0.01%-5%, 0.05%-2%, 0.1%-2%, 0.5%-2%, or 0.5-1.5% (w / v). In some embodiments, concentration of Tween 80 is about 1% (w / v). In some embodiments, a concentration described herein, e.g., for PEG-400, is v / v instead of w / v; in some embodiments, a composition is otherwise identical except that the concentration is v / v instead of w / v. In some embodiments, concentration of a solubilizing agent, e.g., of a PEG, a surfactant, etc., is about 0.5%-5% (v / v). In some embodiments, concentration of PEG is about 0.5%-5% (v / v). In some embodiments, concentration of PEG is about 2%-5% (v / v). In some embodiments, concentration of PEG is about 3% (v / v). In some embodiments, concentration of PEG-400 is about 0.5%-5% (v / v). In some embodiments, concentration of PEG-400 is about 2%-5% (v / v). In some embodiments, concentration of PEG-400 is about 3% (v / v). In some embodiments, concentration of PEG-400 is about 3.4% (v / v). For example, as shown in Table E-8, concentration of PEG-400 is 0.336 mg / mL. In some embodiments, concentration of a surfactant is about 0.5%-5% (v / v). In some embodiments, concentration of PEG is about 2%-5% (v / v). In some embodiments, concentration of PEG is about 3% (v / v). In some embodiments, concentration of Tween 80 is about 0.01%-5%, 0.05%-2%, 0.1%-2%, 0.5%-2%. or 0.5-1.5% (v / v). In some embodiments, concentration of Tween 80 is about 1% (v / v).

[0188] In some embodiments, w / v may be replaced with w / w and vice versa when density is about 1.

[0189] In some embodiments, a buffering agent is a phosphate salt. In some embodiments, a buffering agent is sodium phosphate monobasic. In some embodiments, a buffering agent is Tris. In some embodiments, concentration of a buffering agent is about 10 mM.

[0190] In some embodiments, a composition is or comprises a buffer. Various pharmaceutically acceptable buffer systems may be utilized in accordance with the present disclosure. For example, in some embodiments, a buffer is a phosphate buffer. In some embodiments, a buffer is a Tris buffer.

[0191] In some embodiments, a composition comprises a pharmaceutically acceptable salt. In some embodiments, a pharmaceutically acceptable salt is not a salt of 1-66, a solubilizing agent, an amino acid or a buffering agent. In some embodiments, a pharmacally acceptable salt is NaCl. In some embodiments, a pharmaceutically acceptable salt is formed when adjusting pH (e.g.. when HC1 is added or when NaOH is added).

[0192] Various pH adjustment agents may be utilized in accordance with the present disclosure. In some embodiments, a pH adjustment agent is NaOH. In some embodiments, a pH adjustment agent is HC1. For example, in some embodiments, a buffer is a sodium phosphate monobasic buffer whose pH is adjusted with NaOH or HC1. Those skilled in the art appreciate that typically, pH adjustments are utilized as needed to adjust pH.Page 50 of 27013160427vlAttorney Docket No.: 2012675-0415

[0193] In some embodiments, a composition is or comprises a buffer. In some embodiments, a buffer is a phosphate buffer.

[0194] In some embodiments, pH of a composition is about 6-9. In some embodiments, pH of a composition is about 6.5-9.0. In some embodiments, pH of a composition is about 7.0-9.0. In some embodiments, pH of a composition is about 7.5-8.0. In some embodiments, pH of a composition is about 7.8-8.0. In some embodiments, pH of a composition is about 7.5. In some embodiments, pH of a composition is about 7.8. In some embodiments, pH of a composition is about 8.0. In some embodiments, pH of a composition is about 7.8-8.0. In some embodiments, a composition is pH adjusted using NaOH and / or HC1. In some embodiments, a composition is pH adjusted with NaOH. In some embodiments, a composition is pH adjusted with HC1.

[0195] In some embodiments, a solvent is water.

[0196] In some embodiments, a pharmaceutical composition comprises or consists of 1-66. arginine, PEG 400, sodium phosphate, optionally NaOH or HC1, and water.

[0197] For example, in some embodiments, an 1-66 drug product is or comprises a 20 mg / mL concentration of 1-66 in a 10 mg / mL arginine / 3% PEG 400 (w / v) / 10 mM sodium phosphate pH= 7.8-8.0 solution. In some embodiments, an 1-66 drug product is or comprises 10 mg / mL 1-66 in a 10 mg / mL arginine / 3% PEG 400 (w / v) / 10 mM sodium phosphate pH 7.8-8.0 solution. In some embodiments, an 1-66 drug product is or comprises a 20 mg / mL concentration of 1-66 in a 10 mg / mL arginine / 3% PEG 400 (v / v) / 10 mM sodium phosphate pH= 7.8-8.0 solution. In some embodiments, an 1-66 drag product is or comprises 10 mg / mL 1-66 in a 10 mg / mL arginine / 3% PEG 400 (v / v) / 10 mM sodium phosphate pH 7.8-8.0 solution. In some embodiments, a composition comprises up to 25 mg / mL 1-66 in 10 mM sodium phosphate pH 8, 10 mg / mL arginine, 6% PEG 400 solution or in a 1% Tween 80 / 99% 10 mM PBS pH 7.4 solution.

[0198] In some embodiments, an 1-66 drag product, 1-66 Injection, is supplied as a 10 mg / mL liquid in Type 1 glass vials with appropriate elastomer stoppers and aluminum seals. In some embodiments, 1-66 Injection contains 10 mg / mL 1-66, 10 mg / mL L-arginine and 33.6 mg / mL PEG 400 as excipients, in 10 mM sodium phosphate adjusted to pH 8.0.

[0199] In some embodiments, a composition, e.g., a drag product described herein, is prepared and dosed with 5% dextrose (e.g., 5% Dextrose Injection, USP). In some embodiments, 5% dextrose is used as a control article and vehicle. In some embodiments, a drag product is diluted with a pharmaceutically acceptable diluent to a set volume for administration. In some embodiments, a pharmaceutically acceptable dilute is a dextrose solution. In some embodiments, a pharmaceutically acceptable dilute is 5% Dextrose Injection, USP. In some embodiments, a set volume is about 250 m. In some embodiments, a drag product is diluted by about 1.1-200, 1.5-150, 1.5-100, 1.5-50, 2-100, 2-50, 1.2, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 100, 150, 200 fold, e.g., depending on amount to be administered.

[0200] In some embodiments, a composition comprises or consists of:1-66;Page 51 of 27013160427vlAttorney Docket No.: 2012675-0415a solubilizing agent;a buffer agent;optionally a pH adjustment agent;a sugar; anda solvent.

[0201] In some embodiments, a composition comprises or consists of:1-66;an amino acid;a buffer agent;optionally a pH adjustment agent;a sugar; anda solvent.

[0202] In some embodiments, a composition comprises or consists of:1-66:a PEG or a surfactant;a buffer agent;optionally a pH adjustment agent;a sugar; anda solvent.

[0203] In some embodiments, a composition comprises or consists of:1-66;a PEG;a buffer agent;optionally a pH adjustment agent:a sugar; anda solvent.

[0204] In some embodiments, a composition comprises or consists of:1-66;a surfactant;a buffer agent;optionally a pH adjustment agent;a sugar; anda solvent.

[0205] In some embodiments, a composition comprises or consists of:1-66;an amino acid;Page 52 of 27013160427vlAttorney Docket No.: 2012675-0415a PEG or a surfactant;a buffer agent;optionally a pH adjustment agent;a sugar; anda solvent.

[0206] In some embodiments, a composition comprises or consists of:1-66;an amino acid;a PEG;a buffer agent;optionally a pH adjustment agent;a sugar; anda solvent.

[0207] In some embodiments, a composition comprises or consists of:1-66;an amino acid;a surfactant;a buffer agent;optionally a pH adjustment agent;a sugar; anda solvent.

[0208] In some embodiments, a composition comprises or consists of:1-66;a solubilizing agent:a buffer agent;optionally a pH adjustment agent;a sugar; anda solvent.

[0209] In some embodiments, a composition comprises or consists of:1-66;an amino acid;a buffer agent;optionally a pH adjustment agent;a sugar; anda solvent.

[0210] Useful solubilizing agents, buffer agents, amino acids, PEGs, surfactants, pH adjustment agents,Page 53 of 27013160427vlAttorney Docket No.: 2012675-0415sugars and solvents, e.g., are as described herein. For example, in some embodiments, a sugar is dextrose. In some embodiments, the present disclosure provides compositions described below.

[0211] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 0.1-6 mg / mL;an amino acid, wherein the concentration of the amino acid is about 0.1-6 mg / mL;a PEG or a surfactant, wherein the concentration of the PEG or surfactant is about 0.01%-3% w / v; a buffer agent, wherein the concentration of the buffering agent is about 0.01-100 mM; optionally a pH adjustment agent;dextrose, wherein the concentration of the dextrose is about 0.01-0.05 mg / mL; andwater.

[0212] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 0.1-6 mg / mL:arginine, wherein the concentration of arginine is about 0.1-6 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 0.01%-3% w / v;a buffer agent, wherein the concentration of the buffering agent is about 0.01-100 mM; optionally a pH adjustment agent;dextrose, wherein the concentration of tire dextrose is about 0.01-0.05 mg / mL; andwater.

[0213] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 0.1-6 mg / mL;arginine, wherein the concentration of arginine is about 0.1-6 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 0.01%-3% w / v;sodium phosphate monobasic, wherein the concentration of sodium phosphate monobasic is about 0.01-100 mM;optionally a pH adjustment agent;dextrose, wherein the concentration of the dextrose is about 0.01-0.05 mg / mL; andwater.

[0214] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 0.1-6 mg / mL:arginine, wherein the concentration of arginine is about 0.1-6 mg / mL:PEG-400, w herein the concentration of PEG-400 is about 0.01%-3% w / v;sodium phosphate monobasic, wherein the concentration of sodium phosphate monobasic is about 0.01-100 mM;optionally sodium hydroxide;optionally hydrochloric acid;dextrose, wherein the concentration of tire dextrose is about 0.01-0.05 mg / mL; andPage 54 of 27013160427vlAttorney Docket No.: 2012675-0415water.

[0215] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 0.1-6 mg / mL;arginine, wherein the concentration of arginine is about 0.1-6 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 0.01%-3% w / v:sodium phosphate monobasic, wherein the concentration of sodium phosphate monobasic is about 0.01-100 mM;optionally sodium hydroxide;optionally hydrochloric acid;dextrose, wherein tire concentration of the dextrose is about 0.01-0.05 mg / mL; andwater.

[0216] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 0.1-6 mg / mL;arginine, wherein the concentration of arginine is about 0.1-6 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 0.01%-3% w / v;sodium phosphate monobasic, wherein the concentration of sodium phosphate monobasic is about 0.01-100 mM;optionally sodium hydroxide;optionally hydrochloric acid:dextrose, wherein the concentration of the dextrose is about 0.01-0.05 mg / mL; andwater.

[0217] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 0.1-6 mg / mL;arginine, wherein the concentration of arginine is about 0.1-6 mg / mL:PEG-400, wherein the concentration of PEG-400 is about 0.01%-3% w / v;sodium phosphate monobasic, wherein the concentration of sodium phosphate monobasic is about 0.1-10 mM;optionally sodium hydroxide;optionally hydrochloric acid;dextrose, wherein the concentration of tire dextrose is about 0.01-0.05 mg / mL; andwater.

[0218] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 0.2-5 mg / mL;arginine, wherein the concentration of arginine is about 0.2-5 mg / mL;PEG-400, wherein tire concentration of PEG-400 is about 0.05%-2% w / v:sodium phosphate monobasic, wherein the concentration of sodium phosphate monobasic is about Page 55 of 27013160427vlAttorney Docket No.: 2012675-04150.2-5 mM;optionally sodium hydroxide;optionally hydrochloric acid;dextrose, wherein tire concentration of the dextrose is about 0.02-0.05 g / mL; andwater.

[0219] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 0.1-6 mg / mL;an amino acid, wherein the concentration of the amino acid is about 0.1-6 mg / mL;a PEG or a surfactant, wherein the concentration of the PEG or surfactant is about 0.01%-3% w / v; a buffer; anddextrose, wherein the concentration of the dextrose is about 0.02-0.05 g / mL.

[0220] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 0.1-6 mg / mL;arginine, wherein the concentration of arginine is about 0.1-6 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 0.01%-3% w / v;a buffer; anddextrose, wherein the concentration of tire dextrose is about 0.02-0.05 g / mL.

[0221] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 0.2-5 mg / mL;arginine, wherein the concentration of arginine is about 0.1-6 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 0.05%-2% w / v;a buffer; anddextrose, wherein the concentration of tire dextrose is about 0.02-0.05 g / mL.

[0222] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 0.2-5 mg / mL;arginine, wherein the concentration of arginine is about 0.2-5 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 0.05%-2% w / v;a buffer; anddextrose, wherein the concentration of tire dextrose is about 0.02-0.05 g / mL.

[0223] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 0.1-6 mg / mL;an amino acid, wherein the concentration of the amino acid is about 0.1-6 mg / mL;a PEG or a surfactant, wherein the concentration of the PEG or surfactant is about 0.01%-3% v / v; a buffer agent, wherein tire concentration of the buffering agent is about 0.01-100 mM; optionally a pH adjustment agent;dextrose, wherein the concentration of tire dextrose is about 0.01-0.05 mg / mL; andPage 56 of 27013160427vlAttorney Docket No.: 2012675-0415water.

[0224] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 0.1-6 mg / mL;arginine, wherein the concentration of arginine is about 0.1-6 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 0.01%-3% v / v;a buffer agent, wherein the concentration of the buffering agent is about 0.01-100 mM; optionally a pH adjustment agent;dextrose, wherein the concentration of the dextrose is about 0.01-0.05 mg / mL; andwater.

[0225] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 0.1-6 mg / mL;arginine, wherein the concentration of arginine is about 0.1-6 mg / mL:PEG-400, wherein the concentration of PEG-400 is about 0.01 %-3% v / v;sodium phosphate monobasic, wherein the concentration of sodium phosphate monobasic is about 0.01-100 mM;optionally a pH adjustment agent;dextrose, wherein the concentration of tire dextrose is about 0.01-0.05 mg / mL; andwater.

[0226] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 0.1-6 mg / mL;arginine, wherein the concentration of arginine is about 0.1-6 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 0.01%-3% v / v;sodium phosphate monobasic, wherein the concentration of sodium phosphate monobasic is about 0.01-100 mM;optionally sodium hydroxide;optionally hydrochloric acid;dextrose, wherein the concentration of the dextrose is about 0.01-0.05 mg / mL; andwater.

[0227] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 0.1-6 mg / mL:arginine, wherein the concentration of arginine is about 0.1-6 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 0.01%-3% v / v;sodium phosphate monobasic, wherein the concentration of sodium phosphate monobasic is about 0.01-100 mM;optionally sodium hydroxide;optionally hydrochloric acid;Page 57 of 27013160427vlAttorney Docket No.: 2012675-0415dextrose, wherein the concentration of tire dextrose is about 0.01-0.05 mg / mL; andwater.

[0228] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 0.1-6 mg / mL;arginine, wherein the concentration of arginine is about 0.1-6 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 0.01%-3% v / v;sodium phosphate monobasic, wherein the concentration of sodium phosphate monobasic is about 0.01-100 mM;optionally sodium hydroxide;optionally hydrochloric acid;dextrose, wherein the concentration of the dextrose is about 0.01-0.05 mg / mL; andwater.

[0229] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 0.1-6 mg / mL;arginine, wherein the concentration of arginine is about 0.1-6 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 0.01%-3% v / v;sodium phosphate monobasic, wherein the concentration of sodium phosphate monobasic is about 0.1-10 mM:optionally sodium hydroxide;optionally hydrochloric acid;dextrose, wherein the concentration of the dextrose is about 0.01-0.05 mg / mL; andwater.

[0230] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 0.2-5 mg / mL:arginine, wherein the concentration of arginine is about 0.2-5 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 0.05%-2% v / v;sodium phosphate monobasic, wherein the concentration of sodium phosphate monobasic is about 0.2-5 mM;optionally sodium hydroxide;optionally hydrochloric acid;dextrose, wherein the concentration of the dextrose is about 0.02-0.05 g / mL; andwater.

[0231] In some embodiments, a composition comprises or consists of:1-66, wherein tire concentration of 1-66 is about 0.1-6 mg / mL;an amino acid, wherein the concentration of the amino acid is about 0.1-6 mg / mL;a PEG or a surfactant, wherein the concentration of the PEG or surfactant is about 0.01%-3% v / v:Page 58 of 27013160427vlAttorney Docket No.: 2012675-0415a buffer; anddextrose, wherein the concentration of the dextrose is about 0.02-0.05 g / mL.

[0232] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 0.1-6 mg / mL;arginine, wherein the concentration of arginine is about 0.1-6 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 0.01%-3% v / v;a buffer; anddextrose, wherein the concentration of the dextrose is about 0.02-0.05 g / mL.

[0233] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 0.2-5 mg / mL;arginine, wherein the concentration of arginine is about 0.1-6 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 0.05%-2% v / v;a buffer; anddextrose, wherein the concentration of the dextrose is about 0.02-0.05 g / mL.

[0234] In some embodiments, a composition comprises or consists of:1-66, wherein the concentration of 1-66 is about 0.2-5 mg / mL;arginine, wherein the concentration of arginine is about 0.2-5 mg / mL;PEG-400, wherein the concentration of PEG-400 is about 0.05%-2% v / v;a buffer; anddextrose, wherein the concentration of the dextrose is about 0.02-0.05 g / mL.

[0235] In some embodiments, concentration of 1-66 is about 0.1-6 mg / mL. In some embodiments, it is about 0.2-5 mg / mL. Certain concentrations are presented in Example 3 as examples.

[0236] In some embodiments, concentration of a solubilizing agent is about 0.1-6 mg / mL. In some embodiments, concentration of an amino acid is about 0.1-6 mg m / L. In some embodiments, concentration of arginine is about 0.1-6 mg / mL. In some embodiments, it is about 0.2-5 mg / mL. Certain concentrations are presented in Example 3 as examples.

[0237] In some embodiments, concentration of a PEG is about 0.01 %-3% v / v. In some embodiments, concentration of PEG-400 is about 0.01%-3% v / v. In some embodiments, it is about 0.05%-2% v / v. In some embodiments, concentration of a PEG is about 0.01%-3% w / v. In some embodiments, concentration of PEG-400 is about 0.01%-3% w / v. In some embodiments, it is about 0.05%-2% w / v. Certain concentrations are presented in Example 3 as examples.

[0238] In some embodiments, concentration of a surfactant is about 0.01%-3% v / v. In some embodiments, it is about 0.05%-2% v / v. In some embodiments, concentration of a surfactant is about 0.01%-3% w / v. In some embodiments, it is about 0.05%-2% w / v.

[0239] In some embodiments, concentration of dextrose is about 0.01-0.05 mg / mL. In some embodiments, it is about 0.02-0.05 mg / L. Certain concentrations are presented in Example 3 as examples.Page 59 of 27013160427vlAttorney Docket No.: 2012675-0415

[0240] In some embodiments, concentration of a buffer or a buffer agent or sodium phosphate monobasic is about 0.01-100 mM. Tn some embodiments, it is about 0.01-50 mM. Tn some embodiments, it is about 0.01-20 mM. In some embodiments, it is about 0.01-10 mM. In some embodiments, it is about 0.1-10 mM. In some embodiments, it is about 0.2-10 mM.

[0241] In some embodiments, pH of a composition is about 7.0-9.0 as described herein.

[0242] Among other things, provided compositions provide high solubility of 1-66.

[0243] In some embodiments, the present disclosure provides a method for preparing a composition, comprising dissolving various components (e.g., 1-66, solubilizing agents, amino acids, arginine, surfactants, PEG-400, buffering agents, sodium phosphate monobasic, etc.) and adjusting pH with a pH adjusting agents. In some embodiments, a component may be utilized as a salt form, c.g., a pharmaceutically acceptable salt such as a sodium salt fonn. In some embodiments, a form comprises water, e.g.. a hydrate form. In some embodiments, a fomr is a hydrate of a pharmaceutically acceptable salt. In some embodiments, the present disclosure provides a method for preparing a composition for administration, e.g., IV, comprising diluting an 1-66, e.g., a composition comprising a higher concentration of 1-66, e g., about 1-25 mg / mL, about 5-25 mg / mL, about 5-20 mg / mL, about 5-15 mg / mL, about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 15 mg / mL, about 25 mg / mL, etc., with a pharmaceutically acceptable diluent as described herein (e.g., 5% Dextrose for Injection, USP). In some embodiments, tire composition for administration provides the amount of 1-66 to be administered to a patient as described herein. In some embodiments, a volume of composition for administration is about 250 m.

[0244] Various compositions and methods are presented in the Examples as examples.

[0245] In some embodiments, a composition, e.g., a liquid 1-66 composition is stored at 2-8 °C. In some embodiments, a preparation of 1-66, e.g., a drug substance, is stored at -20 °C

[0246] Multiple stereoisomers exist for 1-66. In some embodiments, level of 1-66 in a composition is enriched relative to one or more or all of its stereoisomers. For example, in some embodiments, a particularly configuration of a double bond (E Z) is enrich. In some embodiments, for each double bond a configuration is independently enriched. In some embodiments, for a chiral element, e.g., a chiral center, one configuration is enriched. In some embodiments, for a chiral center bonded to two staples, one configuration is enriched. In some embodiments, for each chiral element a configuration is independently enriched. In some embodiments, for one or more or all stereochemical element (e.g., double bonds, chiral element, etc.), one configuration is independently enriched. In some embodiments, for each double bond in each staple, one configuration is independently enriched. In some embodiments, for each double bond in each staple, one configuration is independently enriched, and for a chiral center bonded to two staples, one configuration is enriched. In some embodiments, enrichment for each double bond is independently E or Z. In some embodiments, enrichment for each chiral element is independently R or. S', In some embodiments, enrichment for each stereochemical element, e.g., double bond, chiral center, etc., is about or at least about a certain level, e.g., 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%. 97%, 98%, or 99% (percentage of an agent). In some embodiments, about or at Page 60 of 27013160427vlAttorney Docket No.: 2012675-0415least about a certain level, e.g., 85%, 90%, 91%. 92%. 93%. 94%. 95%. 96%. 97%, 98%, or 99% of all molecules in a composition that share the constitution of an agent or a salt thereof are the agent or a salt thereof. In some embodiments, it is about or at least about 85%. In some embodiments, it is about or at least about 90%. In some embodiments, it is about or at least about 95%. In some embodiments, it is about or at least about 96%. In some embodiments, it is about or at least about 97%. In some embodiments, it is about or at least about 98%. In some embodiments, it is about or at least about 99%.

[0247] In some embodiments, purity of 1-66 is about or at least about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. In some embodiments, it is about or at least about 85%. In some embodiments, it is about or at least about 90%. In some embodiments, it is about or at least about 95%. In some embodiments, it is about or at least about 96%. In some embodiments, it is about or at least about 97%. In some embodiments, it is about or at least about 98%. In some embodiments, it is about or at least about 99%.

[0248] In some embodiments, the present disclosure provides a method, comprising comparing 1-66 in a preparation with a reference standard. In some embodiments, a method is utilized for confirming identity of I-66 in a preparation. In some embodiments, a method is utilized for quality control of an 1-66 preparation. In some embodiments, a method is utilized for releasing an 1-66 preparation (e g., purify of 1-66 above a certain level and / or impurities are below certain individual and / or total levels). In some embodiments, a reference standard is an 1-66 preparation wherein 1-66 has the structure of Ac-PL31-Asp2-Npg3-B54-Asp5-3COOHFb-Aib7-Ala8-Phe9-Lys10-PyrS211-3Thi13-BztA13-Glu14-Ala15-NH2, wherein there are olefin staples between PL31and B54and between B54and PyrS211and a lactam staple between Lys10and Glu14, and:when characterized by13C NMR in MeOD at 25 °C, its13C NMR comprises the following peaks (chemical shift (5, ppm)): 17, 17.76, 23.2, 23.2, 23.29, 23.32, 23.87, 24.46, 27.46, 27.47, 28.98, 29.61, 29.99, 30, 30.18, 30.63, 31.36, 31.76, 31.81, 32.6, 33.09, 33.8, 33.84, 35.69, 35.8, 35.96, 36.18, 36.46, 38.1, 38.18, 39.25. 45.37, 45.96, 49.5, 51.2, 53.94. 54.54, 55.33, 55.56, 55.69, 56.48, 56.93, 57.28, 57.7. 59.94, 60.7, 60.94, 62.78, 65.89, 67.18, 70.51, 122.71, 123.42, 123.87, 125.19, 125.2, 125.37, 126.96, 126.99, 128.08, 129.15, 129.2, 129.37, 129.54, 129.83, 129.83, 130.39, 130.39, 131.26, 131.47, 131.96, 132.12, 132.57, 135.08, 137.36, 138.06, 138.13, 139.58, 141.98, 156.51, 169.51, 172.38, 172.48, 173.13, 174.1, 174.39, 174.47, 175.44, 175.55, 175.55, 175.6, 175.7, 175.8, 175.8, 175.8, 176.97, 177, 177.56, 178.08, and 178.58: andwhen characterized by 'H NMR in MeOD at 25 °C. its ’H NMR comprises the following peaks (chemical shift (5, ppm)): 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93, 2.38, 2.92, 3.45, 1.18, 1.36, 1.55, 1.84, 1.53, 3.27. 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37, 2.38, 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42. 1.57, 2.69, 3.76, 3.92, 2.2, 2.42, 2.22, 3.08. 3.40, 1.55, 1.07, 1.42, 1.59, 1.33. and 2.23: or its 'H NMR comprises the following peaks (chemical shift (5, ppm)): 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21.Page 61 of 27013160427vlAttorney Docket No.: 2012675-04157.21, 7.24. 7.07. 7.24. 7.21, 4.03, 4.25, 7.97. 7.94. 7.42. 7.5. 4.4, 5.29. 5.31. 4.27, 4.31, 5.56, 5.36. 7.89. 7.38.7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93 (2H), 2.38 (2H), 2.92, 3.45, 1.18 (2H), 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37 (2H), 2.38 (2H), 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76, 3.92, 2.2 (2H), 2.42, 2.22, 3.08. 3.40, 1.55 (3H), 1.07 (3H), 1.42 (3H), 1.59 (3H), 1.33 (3H), and 2.23 (3H), wherein each peak represents 1H unless indicated otherwise; or its H NMR comprises the following peaks (chemical shift (5, ppm)): 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93, 2.38, 2.92, 3.45, 1.18, 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37, 2.38, 1.80, 1.88, 2.71, 2.81, 3.20, 2.05, 1.97, 2.17, 0.84, 1.42, 1.57, 2.69, 3.76. 3.92, 2.2, 2.42, 2.22, 3.08, 3.40, 1.55, 1.07. 1.42, 1.59, 1.33, 2.23, 8.32, 7.73. 8.17, 8.19, 8.25, 8.44, 8.89. 8.1, 8.42, 7.45. 7.39, 8.15, 8.86, and 7.69; or its ’H NMR comprises the following peaks (chemical shift (8, ppm)): 3.96, 6.34, 6.84, 6.36, 4.38, 4.31, 3.82, 4.21, 7.21, 7.24, 7.07, 7.24, 7.21, 4.03, 4.25, 7.97, 7.94, 7.42, 7.5, 4.4, 5.29, 5.31, 4.27, 4.31, 5.56, 5.36, 7.89, 7.38, 7.41, 7.89, 7, 4.3, 2.00, 2.10, 1.60, 1.65, 3.73, 4.15, 3.15, 4.22, 2.29, 2.41, 3.53, 3.25, 3.06, 2.95, 1.93 (2H), 2.38 (2H), 2.92, 3.45, 1.18 (2H), 1.36, 1.55, 1.84, 1.53, 3.27, 3.31, 3.27, 3.44, 2.74, 2.96, 1.92, 2.07, 1.37 (2H), 2.38 (2H), 1.80, 1.88, 2.71, 2.81, 3.20, 2.05. 1.97, 2.17, 0.84, 1.42, 1.57, 2.69. 3.76, 3.92, 2.2 (2H), 2.42, 2.22, 3.08. 3.40, 1.55 (3H), 1.07 (3H), 1.42 (3H). 1.59 (3H), 1.33 (3H). 2.23 (3H), 8.32, 7.73, 8.17. 8.19. 8.25, 8.44, 8.89, 8.1, 8.42, 7.45, 7.39. 8.15, 8.86, and 7.69, wherein each peak represents 1H unless indicated otherwise.

[0249] Those skilled in the art reading the present disclosure appreciate that various technologies including analytical chemistry technologies may be utilized in accordance with the present disclosure. For example, in some embodiments, HPLC is utilized. Various useful HPLC technologies are utilized here as examples. In some embodiments, HPLC condition is as described in Example 1. In some embodiments, HPLC condition is as described in Table E-7. In some embodiments, HPLC condition is as described in Table E-10. In some embodiments, NMR is utilized. In some embodiments, NMR is or comprises ¹H NMR. In some embodiments, NMR is or comprises13C NMR. In some embodiments, NMR is or comprises13N NMR. In some embodiments, NMR is or comprises NOE. In some embodiments, NMR is or comprises two-dimensional NMR. In some embodiments, NMR is or comprises multi-dimensional NMR. In some embodiments, each dimension independently comprises or is ’H or13C NMR. In some embodiments, each dimension independently comprises or is ’H,13C or15N NMR.Uses and Applications

[0250] Provided technologies, e.g., 1-66, its preparations and compositions can be utilized for various purposes.

[0251] In some embodiments, 1-66 is useful as a beta-catenin antagonist. It is reported that the Wnt / beta-catenin pathway is one of the most frequently activated oncogenic pathways (see, e.g., Zhan T et al. Wnt Page 62 of 27013160427vlAttorney Docket No.: 2012675-0415signaling in cancer. Oncogene. 2017;36: 1461-73), and it is a well-described driver of many cancers, including colorectal cancer (CRC), in which this pathway is reportedly activated in most cases (see, e.g., Zhan T et al. Wnt signaling in cancer. Oncogene. 2017;36: 1461-73; Polakis P. Wnt signaling in cancer. Cold Spring Harb Pcrspcct Biol. 2012;4:9; etc.). In some embodiments, 1-66 is useful as a direct inhibitor of bcta-catcnin, which functions by blocking its interaction with the T-cell factor (TCF) family of transcription factors. Preclinical data with 1-66 demonstrate strong in vitro binding and interruption of TCF binding, and a pharmacokinetic (PK) profile enabling once weekly (QW) dosing and even less frequent dosing. Furthermore, regression was also observed in multiple genetically-characterized patient-derived and cell-line derived tumor xenograft models as monotherapy and in combination with other anticancer therapies. In some embodiments, the present disclosure comprises a clinical study, c.g., a Phase 1 / 2 study, to evaluate 1-66 in participants with advanced or metastatic solid tumors.

[0252] In some embodiments, the present disclosure encompasses the recognition that aberrant [3-catenin and RAS signaling commonly co-occur in MSS CRC, driving reciprocal resistance to single-pathway therapies. In some embodiments, the present disclosure encompasses the recognition that inhibition of oncogenic RAS signaling or suppression of Wnt / 0-catenin activity can lead to reciprocal elevation of the either pathway (as determined by nonclinical observations, e.g. in CDX or PDX models). In some embodiments, the present disclosure encompasses the recognition that reciprocal resistance mechanisms via P-catenin / RAS crosstalk suggest combined or sequential inhibition of both pathways (e.g., by combination of agents targeting P-catenin and agents targeting RAS) may be advantageous strategies in Wnt-and RAS-driven cancers. Without wishing to be bound by theory, certain reports indicate that, at transcriptional level, |3-catenin / TCF -driven gene expression promotes proliferation and survival, and RAS-ERK signaling further amplifies growth and tumor progression.

[0253] In some embodiments, the present disclosure encompasses the recognition that 1-66 can modulate KRAS-target gene (e.g.. DUSP6) expression in a system. In some embodiments, a system is a subject. In some embodiments, a system is a PDX model. In some embodiments, a system is or comprises a cancer cell. In some embodiments, a system is or comprises a tumor. In some embodiments, 1-66 provides KRAS-target gene up-regulation. In some embodiments, 1-66 provides KRAS-target gene up-regulation and Wnt-target gene (e.g., AXIN2) suppression. In some embodiments, tire present disclosure encompasses the recognition that 1-66 is particularly effective for inhibiting tumor growth when administered to a system that exhibits KRAS-target gene up-regulation after administration of 1-66. In some embodiments, the present disclosure encompasses the recognition that 1-66 is particularly effective for inhibiting tumor growth when administered to a system that exhibits Wnt-target gene suppression after administration of 1-66. In some embodiments, the present disclosure encompasses the recognition that 1-66 is particularly effective for inhibiting tumor grow th when administered to a system that exhibits KRAS-target gene up-regulation and Wnt-target gene suppression after administration of 1-66. In some embodiments, the present disclosure encompasses the recognition that 1-66 is particularly effective for inhibiting tumor growth or cancer cell proliferation when Page 63 of 27013160427vlAttorney Docket No.: 2012675-0415combined with an agent that can reduce KRAS-target gene up regulation. In some embodiments, the present disclosure encompasses the recognition that 1-66 is particularly effective for inhibiting tumor growth or cancer cell proliferation when combined with RAS inhibition. In some embodiments, the present disclosure encompasses the recognition that 1-66 is particularly effective for inhibiting tumor growth or cancer cell proliferation w hen combined with a RAS inhibitor. In some embodiments, a RAS inhibitor is a KRAS inhibitor.

[0254] In some embodiments, the present disclosure encompasses the recognition that 1-66 provides tumor growth inhibition in systems having APC-mutations and / or KRAS-mutations. In some embodiments, a system is a subject. In some embodiments, a system is a PDX model. In some embodiments, the present disclosure encompasses the recognition that 1-66 provides tumor growth inhibition in systems having APC-mutations. In some embodiments, an APC mutation is a frameshift mutation. In some embodiments, an APC mutation is a pathogenic frameshift mutation. In some embodiments, an APC mutation is E1554_K1555fs. In some embodiments, an APC mutation is Q739fs / Q1459X. In some embodiments, an APC mutation is L946fs / L1471fs. In some embodiments, an APC mutation is S1549X / P1693fs / V1690fs / G1659fs / A1661fs. In some embodiments, an APC mutation is S1549X, P1693fs, V1690fs, G1659fs, and / or A1661fs. In some embodiments, an APC mutation is S1549X. In some embodiments, an APC mutation is P1693fs. In some embodiments, an APC mutation is V1690fs. In some embodiments, an APC mutation is G1659fs. In some embodiments, an APC mutation is P1693fs. In some embodiments, an APC mutation is R876* / Q1429*. In some embodiments, an APC mutation is R876* and / or Q 1429*. In some embodiments, an APC mutation is R876*. In some embodiments, an APC mutation is Q1429*. In some embodiments, an APC mutation is p. Thrl556Asnfs*3. In some embodiments, an APC mutation is D849*. In some embodiments, an APC mutation is ¥1414*. In some embodiments, a KRAS mutation is G12D. In some embodiments, a KRAS mutation is G12C. In some embodiments, a KRAS mutation is G12V. In some embodiments, a KRAS mutation is G12A.

[0255] In some embodiments, the present disclosure encompasses the recognition that the combination of 1-66 with one or more additional agents provides enhanced tumor growth inhibition in systems. In some embodiments, the system is a subject. In some embodiments, the system is a PDX model. In some embodiments, an additional agent is or comprises 5 -fluorouracil. In some embodiments, an additional agent is or comprises and anti-VEGF agent (e.g., bevacizumab). In some embodiments, an additional agent is or comprises a MAPK pathway inhibitor. In some embodiments, a MAPK pathway inhibitor is a RAS inhibitor. In some embodiments, an additional agent is or comprises a RAS pathway inhibitor. In some embodiments, an additional agent is or comprises a RAS inhibitor. In some embodiments, an additional agent is or comprises a KRAS inhibitor. Various RAS inhibitors have been reported and may be utilized in accordance with the present disclosure, e.g., sotorasib (AMG510), adagrasib (MRTX849), VS-7375, ASP-3082, or EFTX-G12V. In some embodiments, a RAS inhibitor is a pan-RAS inhibitor (e.g., RMC-6236). In some embodiments, a RAS inhibitor is a RAS GI2D inhibitor. In some embodiments, a RAS inhibitor is a RAS Page 64 of 27013160427vlAttorney Docket No.: 2012675-0415G12C inhibitor (e.g., adagrasib, etc.). In some embodiments, a RAS inhibitor is a RAS G12V inhibitor. In some embodiments, the present disclosure encompasses the recognition that the combination of 1-66 with a pan-RAS inhibitor provides enhanced tumor inhibition in tumors with G12C KRAS mutations and G12V KRAS mutations. In some embodiments, a combination of 1-66 and a RAS inhibitor is useful for treating, e.g., MSS CRC.

[0256] In some embodiments, the present disclosure encompasses the recognition that 1-66 may be utilized in combination with known therapies and / or therapeutic agents for treatment of cancer (e.g., known therapies and / or therapeutic agents for CRC and / or mCRC). Certain known therapies and / or therapeutic agents for treatment of mCRC are provided in Figure 41. See also ecancer 2023, 17:1544; doi.org / 10.3332 / ccanccr.2023.1544. In some embodiments, 1-66 is useful for combination therapy with one or more additional agents for the treatment of mCRC. In some embodiments, an additional agent is or comprises pembrolizumab. doublet (i.e., FOLFOX, CAPOX. or FOLFIRI), doublet with bevacizumab. triplet (i.e.. FOLFOXIRI), triplet with bevacizumab, doublet with an anti-EGFR agent (e.g., neratinib), iBRAF with an anti-EGFR agent, irinotecan, irinotecan with an anti-EGFR agent, an inhibitor of G12C mutant KRAS with an anti-EGFR agent, an anti-HER2 agent, and trifluridine / tipiracil with bevacizumab and regorafenib.

[0257] In some embodiments, 1-66 is useful for treating various conditions, diseases or disorders, e.g., cancers. In some embodiments, 1-66 is useful for treating solid tumors. In some embodiments. 1-66 is useful for treating advanced solid tumors. In some embodiments. 1-66 is useful for treating metastatic solid tumors.

[0258] In some embodiments, the present disclosure provides technologies for administering or delivering 1-66. In some embodiments, the present disclosure provides technologies for does-linear delivery of 1-66. In some embodiments, the present disclosure provides a method, comprising administering 1-66 to a subject, wherein when assessed, tire delivery of 1-66 is dose-linear. In some embodiments, doses are from about 30 mg / m2to about 500 mg / m2. In some embodiments, doses are from about 36 mg / m2to about 480 mg / m2. In some embodiments, AUClast and dose levels are utilized for assess if PK is dose-linear. In some embodiments, variability is low to moderate. In some embodiments, R2is about 0.5 or more. In some embodiments, R2is about 0.6 or more. In some embodiments, R2is about 0.7 or more. In some embodiments, R2is about 0.8 or more. In some embodiments, R2is about 0.9 or more. In some embodiments, slope estimate from power model is about 0.9 or more. In some embodiments, slope estimate from power model is about 0.95 or more. In some embodiments, 95% CI of slope estimate from power model is about 0.8 to about 1.2. In some embodiments, 95% CI of slope estimate from power model is about 0.8 to about 1.1.

[0259] In some embodiments, the present disclosure provides a method, comprising administering or delivering to a subject 1-66 or a composition thereof. In some embodiments, a subject is as described herein, for example, in some embodiments, a subject has a tumor as described herein (e.g., a WPAM+ tumor). In some embodiments, one or more effects are observed in a subject. In some embodiments, the present disclosure provides a method, comprising administering or delivering to a population of subjects 1-66 or a composition thereof. In some embodiments, subjects in a population are independently as described herein,Page 65 of 27013160427vlAttorney Docket No.: 2012675-0415for example, in some embodiments, subjects of a population have tumors as described herein (e.g., WPAM+ tumors). Tn some embodiments, one or more effects are observed in a population of subjects.

[0260] In some embodiments, the present disclosure provides a method for preventing or treating a condition, disease or disorder, comprising administering or delivering to a human subject susceptible thereto or suffering therefrom 1-66. In some embodiments, the present disclosure provides a method for treating a condition, disease or disorder, comprising administering or delivering to a human subject susceptible thereto or suffering therefrom 1-66. In some embodiments, the present disclosure provides a method for treating a condition, disease or disorder, comprising administering to a human subject susceptible thereto or suffering therefrom 1-66. In some embodiments, the present disclosure provides a method for administering or delivering a human subject 1-66. In some embodiments, tire present disclosure provides a method for delivering a human subject 1-66. In some embodiments, a subject has a condition, disease or disorder. In some embodiments, a condition, disease or disorder is or comprises cancer. In some embodiments, a condition, disease or disorder is or comprises a tumor. For example, in some embodiments, a condition, disease or disorder is or comprises MSS CRC. In some embodiments, a condition, disease or disorder is or comprises WPAM+ solid tumor (e.g., a desmoid tumor, an ameloblastoma tumor, an adamantinomatous craniopharyngioma, Familial Adenomatous Polyposis, etc.). In some embodiments, a condition, disease or disorder is or comprises non-CRC WPAM+ solid tumor. In some embodiments, a condition, disease or disorder is or comprises a desmoid tumor. In some embodiments, durable responses are observed in heavily-pretreated desmoid tumors. In some embodiments, the present disclosure provides a method for reducing size of a desmoid tumor, comprising administering or delivering to a subject with a desmoid tumor 1-66 as described herein. In some embodiments, tire present disclosure provides a method for reducing desmoid tumor grow th, comprising administering or delivering to a subject with a desmoid tumor 1-66 as described herein. In some embodiments, a condition, disease or disorder is or comprises an odontogenic tumor. In some embodiments, a condition, disease or disorder is or comprises an ameloblastoma tumor. In some embodiments, a condition, disease or disorder is or comprises an adamantinomatous craniopharyngioma tumor. In some embodiments, a condition, disease or disorder is or comprises Familial Adenomatous Polyposis (FAP). In some embodiments, the present disclosure provides a method for improving duodenal polyp burden in a subject w ith FAP, comprising administering or delivering to the subject 1-66 as described herein. In some embodiments, the present disclosure provides a method for reducing polyp number in a subject with FAP, comprising administering or delivering to the subject 1-66 as described herein. In some embodiments, the present disclosure provides a method for reducing polyp size in a subject with FAP, comprising administering or delivering to the subject 1-66 as described herein. In some embodiments, the present disclosure provides a method for reducing polyp number and size in a subject with FAP, comprising administering or delivering to the subject 1-66 as described herein. In some embodiments, the present disclosure provides a method for reducing or preventing polyp growth in a subject with FAP, comprising administering or delivering to the subject 1-66 as described herein. In some embodiments, the present Page 66 of 27013160427vlAttorney Docket No.: 2012675-0415disclosure provides a method for reducing or preventing polyp growth in rectum in a subject with FAP, comprising administering or delivering to the subject 1-66 as described herein. In some embodiments, a subject with FAP comprises a mutation in APC. In some embodiments, a polyp comprises an APC mutation. In some embodiments, a mutation is a LOF mutation. Various APC mutations arc reported and certain mutations are described herein. In some embodiments, if left untreated, FAP leads to colorectal cancer. In some embodiments, off-label treatment with NSAIDs and MAPK inhibitors carry lifetime risk of GI, renal and cardiovascular diseases. In some embodiments, provided technologies directly address a molecular cause of FAP. In some embodiments, provided technologies delay or prevent invasive surgery for FAP. In some embodiments, provided technologies prevent CRC, e.g., developed from or associated with FAP. In some embodiments, a condition, disease or disorder is desmoid tumor in a patient with FAP. In some embodiments, a condition, disease or disorder is or comprises FAP in a patient with a desmoid tumor. In some embodiments, a condition, disease or disorder is or comprises a CTNNB 1 -mutated tumor. In some embodiments, a condition, disease or disorder is or comprises a CTNNB 1 -mutated cancer. In some embodiments, a condition, disease or disorder is or comprises ACP. In some embodiments, the present disclosure provides a method for reducing ACP tumor size in a subject, comprising administering or delivering to a subject with an ACP tumor 1-66 as described herein. In some embodiments, a condition, disease or disorder is or comprises ameloblastoma. In some embodiments, tire present disclosure provides a method for reducing ameloblastoma tumor size in a subject, comprising administering or delivering to a subject with an ameloblastoma tumor 1-66 as described herein. In some embodiments, a method comprises a dose level as described herein. In some embodiments, a method comprises two or more dose levels described herein. In some embodiments, 1-66 is administered or delivered about weekly. In some embodiments, 1-66 is administered or delivered about even two weeks. In some embodiments, a method comprises administration or delivery of 1-66 about weekly, and administration or delivery of 1-66 about every two weeks. In some embodiments, a method comprises a cycle as described herein (e.g., a cycle in a clinical trial design in an Example). In some embodiments, a method comprises a period of time longer than a dosing interval (e.g., longer than about one week for about weekly dosing, longer than about two weeks for dosing about every two weeks, etc.). In some embodiments, one or more doses are skipped (e.g., upon clinician instructions). In some embodiments, a method comprises a treatment holiday. As demonstrated in tire Examples, various dose levels and dosing regimens can provide efficacy in various conditions, diseases or disorders (e.g., desmoid tumor, ACP, ameloblastoma. FAP. etc ). In some embodiments, after a period of time (e.g., a treatment holiday), dose level remains the same. In some embodiments, dose level changes after a period of time (e.g., a treatment holiday). In some embodiments, dose level increases after a period of time (e.g., a treatment holiday). In some embodiments, dose level decreases after a period of time (e.g., a treatment holiday). In some embodiments, dosing regimen changes after a period of time (e.g., a treatment holiday). In some embodiments, dosing regimen remains after a period of time (e.g., a treatment holiday). In some embodiments, the present disclosure provides a method for treating cancer, comprising administering or delivering to a human subject suffering therefrom 1-66. In some Page 67 of 27013160427vlAttorney Docket No.: 2012675-0415embodiments, the present disclosure provides a method for treating tumor, comprising administering or delivering to a human subject suffering therefrom 1-66. In some embodiments, the present disclosure provides a method for treating cancer, comprising administering or to a human subject suffering therefrom a pharmaceutical composition as described herein. In some embodiments, a cancer is colorectal cancer. In some embodiments, a subject has a solid tumor. In some embodiments, a subject has advanced and / or metastatic solid tumor. In some embodiments, a subject has locally advanced tumors. In some embodiments, a subject has locally advanced solid tumors. In some embodiments, a subject has metastatic cancer. In some embodiments, a subject has metastatic solid tumors. In some embodiments, a subject has locally advanced and metastatic solid tumors. In some embodiments, a subject has adenomatous polyposis coli. In some embodiments, a subject has familial adenomatous polyposis. In some embodiments, a subject has adamantinomatous craniopharyngioma. In some embodiments, a cancer is gastric cancer (stomach cancer). In some embodiments, a cancer is lung cancer. In some embodiments, a lung cancer is nonsquamous. In some embodiments, a lung cancer is squamous. In some embodiments, a cancer is non-small cell lung cancer. In some embodiments, a cancer is non-small cell carcinoma. In some embodiments, a cancer is non-small cell lung cancer metastatic. In some embodiments, a cancer is non-small cell lung cancer stage IIIB. In some embodiments, a cancer is non-small cell carcinoma of lung, TNM stage 4. In some embodiments, a cancer is gastroesophageal -junction cancer. In some embodiments, a subject has solid tumors with a Wnt-pathway activating mutation (WPAM). In some embodiments, a subject has microsatellite stable (MSS) colorectal cancer. In some embodiments, a cancer is non-small cell lung cancer with a Wnt-pathway activating mutation (WPAM) in APC or CTNNB 1. In some embodiments, a cancer is non-small cell lung cancer with WPAM in APC. In some embodiments, a cancer is non-small cell lung cancer with WPAM in CTNNB 1. In some embodiments, a cancer is gastric cancer / gastroesophageal junction carcinoma (GEJ) with a Wnt-pathway activating mutation (WPAM) in APC or beta-catenin. In some embodiments, a cancer is gastric cancer with WPAM in APC. In some embodiments, a cancer is gastric cancer with WPAM in CTNNB 1. In some embodiments, a cancer is gastroesophageal junction carcinoma with WPAM in APC. In some embodiments, a cancer is gastroesophageal junction carcinoma with WPAM in CTNNB 1. In some embodiments, a cancer is refractory gastric cancer / gastroesophageal junction carcinoma (GEJ) with a Wnt-pathway activating mutation (WPAM) in APC or beta-catenin. In some embodiments, a cancer is refractory’ gastric cancer with WPAM in APC. In some embodiments, a cancer is refractory gastric cancer with WPAM in CTNNB 1. In some embodiments, a cancer is refractory gastroesophageal junction carcinoma with WPAM in APC. In some embodiments, a cancer is refractory gastroesophageal junction carcinoma with WPAM in CTNNB 1. In some embodiments, a subject has solid tumors with a Wnt-pathway activating mutation. In some embodiments, a subject has solid tumors with WPAM in APC. In some embodiments, a subject has solid tumors with WPAM in CTNNB 1. In some embodiments, a solid tumor is not microsatellite instability-high (non-MSI-H). In some embodiments, a solid tumor is not deficient DNA mismatch repair (non-dMMR). In some embodiments, a subject has advanced or metastatic solid tumor that is non-MSI-H or non-dMMR CRC. In somePage 68 of 27013160427vlAttorney Docket No.: 2012675-0415embodiments, a cancer is microsatellite stable (MSS) CRC. In some embodiments, a cancerthat is MSS is characterized by being non-MSI-H and non-dMMR. Tn some embodiments, prolonged stable disease is observed in CRC (e.g., in heavily pre-treated patients). In some embodiments, 1-66 monotherapy activity is observed in late-line CRC including disease stabilization and ctDNA clearance. In some embodiments, 1-66 is utilized in combination for treating CRC. In some embodiments, a cancer is hepatocellular carcinoma (HCC). In some embodiments, a subject has HCC with a WPAM. In some embodiments, a subject has HCC with a WPAM confirmed by local testing. In some embodiments, RECIST response is observed in HCC (e.g., heavily pre-treated HCC). In some embodiments, a subject has a genomically simple tumor. In some embodiments, a subject has a desmoid tumor. In some embodiments, a subject has a desmoid tumor with WPAM. In some embodiments, a subject has a desmoid tumor with WPAM confirmed by local testing. In some embodiments, a subject has Familial Adenomatous Polyposis (FAP). In some embodiments, a subject has Familial Adenomatous Polyposis (FAP) with WPAM. In some embodiments, a subject has Familial Adenomatous Polyposis (FAP) with WPAM confirmed by local testing. In some embodiments, a cancer is adamantinomatous craniopharyngioma (ACP). In some embodiments, a subject has adamantinomatous craniopharyngioma (ACP) with a WPAM. In some embodiments, a subject has adamantinomatous craniopharyngioma (ACP) with a WPAM confirmed by local testing. In some embodiments, a cancer is ameloblastoma. In some embodiments, a subject has ameloblastoma with a WPAM. In some embodiments, a subject has ameloblastoma with a WPAM confirmed by local testing. In some embodiments, a cancer is endometrial cancer. In some embodiments, a subject has endometrial cancer with a WPAM. In some embodiments, a subject has endometrial cancer with a WPAM confirmed by local testing. In some embodiments, a cancer is esophageal cancer. In some embodiments, a subject has esophageal cancer with a WPAM. In some embodiments, a subject has esophageal cancer with a WPAM confirmed by local testing. In some embodiments, a cancer is jejunal cancer. In some embodiments, a subject has jejunal cancer with a WPAM. In some embodiments, a subject has jejunal cancer with a WPAM confirmed by local testing. In some embodiments, a cancer is pancreatic acinar cell carcinoma. In some embodiments, a subject has pancreatic acinar cell carcinoma with a WPAM. In some embodiments, a subject has pancreatic acinar cell carcinoma with a WPAM confirmed by local testing. In some embodiments, a cancer is sal i vary gland cancer. In some embodiments, a subject has salivary gland cancer with a WPAM. In some embodiments, a subject has salivary gland cancer with a WPAM confirmed by local testing. In some embodiments, a cancer is Solid Pseudopapillary Neoplasm (SPN). In some embodiments, a subject has Solid Pseudopapillary Neoplasm (SPN) with a WPAM. In some embodiments, a subject has Solid Pseudopapillary Neoplasm (SPN) with a WPAM confirmed by local testing. In some embodiments, a cancer is uterine cancer. In some embodiments, a subject has uterine cancer with a WPAM. In some embodiments, a subject has uterine cancer with a WPAM confirmed by local testing. In some embodiments, a cancer is vaginal cancer. In some embodiments, a subject has vaginal cancer with a WPAM. In some embodiments, a subject has vaginal cancer with a WPAM confirmed by local testing. In some embodiments, a cancer is synovial sarcoma. In some embodiments, a Page 69 of 27013160427vlAttorney Docket No.: 2012675-0415subject has synovial sarcoma with a WPAM. In some embodiments, a subject has synovial sarcoma with a WPAM confirmed by local testing. In some embodiments, a cancer is prostate cancer. In some embodiments, a cancer is metastatic castration-resistant prostate cancer (mCRPC). In some embodiments, a cancer is mCRPC with WPAM. In some embodiments, a cancer is mCRPC with WPAM confirmed by local testing. In some embodiments, a cancer is endometrial carcinoma. In some embodiments, a cancer is familial adenomatous polyposis. In some embodiments, a cancer is microsatellite instability-high colorectal cancer with WPAM. In some embodiments, a cancer is adamantinomatous craniopharyngioma. In some embodiments, a cancer is advanced or metastatic NSCLC with a WPAM mutation, e.g., in APC or beta-catenin. In some embodiments, a cancer is refractory advanced or metastatic NSCLC with a WPAM mutation, e.g., in APC or bcta-catcnin. In some embodiments, NSCLC is nonsquamous. In some embodiments, NSCLC is squamous. In some embodiments, a cancer is advanced or metastatic gastric with a WPAM mutation, e.g., in APC or beta-catenin. In some embodiments, a cancer is refractory advanced or metastatic gastric cancer with a WPAM mutation, e.g., in APC or beta-catenin. In some embodiments, a cancer is advanced or metastatic GEJ with a WPAM mutation, e.g., in APC or beta-catenin. In some embodiments, a cancer is refractory advanced or metastatic GEJ with a WPAM mutation, e.g., in APC or beta-catenin. Among other things, efficacy has been observed for various conditions, diseases or disorders including rare and CI cancers. For example, 1-66 monotherapy activity (e.g., partial response) has been observed in at least 6 different genomically simple Wnt / beta-catenin-driven solid tumors: e.g., desmoid tumors, HCC, ameloblastoma, ACP, salivary gland, and SPN etc.. It is observed that 1-66 is well tolerated at various efficacious dose levels (e.g., 100-200 mg in various Wnt / beta-catenin-driven tumors) and can provide well-managed safety at various high dose levels (e.g., about 500-1000 mg in CRC).

[0261] In some embodiments, 1-66 technologies can be utilized for chronic treatment in indolent conditions, diseases or disorders (e.g., desmoid tumors). In some embodiments, subcutaneous dosing can be utilized. In some embodiments, 1-66 can be administered at home. In some embodiments, 1-66 can be administered using rapid auto injectors. In some embodiments, lower dose intensity and schedule aligned with chronic dosing may be utilized. In some embodiments, a lower dose level and / or dosing frequency (e.g., about every week) are utilized following a higher dose level and / or dosing frequency (e.g., about every two weeks). In some embodiments, 1-66, alone or in combination w ith one or more other therapies, is utilized for high-burden conditions, diseases or disorders, balancing efficacy and tolerability. In some embodiments, IV dosing, e.g.. in clinic, is utilized. In some embodiments, higher dose intensity and schedule aligned with more acute combination treatment are utilized.

[0262] In some embodiments, a cancer is refractory. In some embodiments, a subject has a refractory tumor. In some embodiments, a subject has a refractory solid tumor. In some embodiments, a subject has a desmoid tumor. In some embodiments, a subject has a refractory WPAM+ solid tumor. In some embodiments, a subject has a refractory WPAM+ desmoid tumor. In some embodiments, a subject has refractory advanced or metastatic solid tumor with a WPAM mutation. In some embodiments, a cancer (e.g.,Page 70 of 27013160427vlAttorney Docket No.: 2012675-0415MSS CRC, WPAM + MSS CRC / solid tumors, etc.) is resistant to another cancer therapy. In some embodiments, a subject has a cancer resistant to another therapy. In some embodiments, a subject has a solid tumor resistant to another therapy. In some embodiments, a subject has a desmoid tumor resistant to another therapy. In some embodiments, a subject has a WPAM+ desmoid tumor resistant to another therapy. In some embodiments, a therapy is or comprises an immunotherapy. In some embodiments, a therapy is or comprise a checkpoint inhibitor. In some embodiments, a therapy is or comprises surgery. In some embodiments, a therapy is or comprises radiation. In some embodiments, a therapy is systemic. In some embodiments, a therapy is or comprises nirogacestat. In some embodiments, a therapy is or comprises sorafenib. In some embodiments, a therapy is or comprises a cytotoxic chemotherapy. In some embodiments, a subject has received sulindac. In some embodiments, a cancer is resistant to an immunotherapy. In some embodiments, a cancer is resistant to a checkpoint inhibitor. In some embodiments, a cancer is resistant to a PD-1 inhibitor. In some embodiments, a cancer is resistant to a PD-L1 inhibitor. In some embodiments, a cancer is resistant to an anti-PD-1 antibody. In some embodiments, a cancer is resistant to an anti-PD-Ll antibody. In some embodiments, a tumor is resistant to an immunotherapy. In some embodiments, a tumor is resistant to a checkpoint inhibitor. In some embodiments, a tumor is resistant to a PD-1 inhibitor. In some embodiments, a tumor is resistant to a PD-L1 inhibitor. In some embodiments, a tumor is resistant to an anti-PD-1 antibody. In some embodiments, a tumor is resistant to an anti-PD-Ll antibody. In some embodiments, a tumor is a solid tumor. In some embodiments, a tumor is a desmoid tumor. In some embodiments, a tumor is a WPAM+ desmoid tumor. In some embodiments, a cancer is MSS CRC resistant to anti-PD-1 or anti-PD-Ll. In some embodiments, a cancer is WPAM+ MSS CRC / solid tumors resistant to anti-PD-l / PD-Ll. In some embodiments, a subject has WPAM+ solid tumors resistant to anti-PD-1 or anti-PD-Ll. In some embodiments, a subject has a cancer or solid tumor resistant to a y-secretase inhibitor. In some embodiments, a cancer or solid tumor is WPAM+. In some embodiments, a subject has a WPAM+ solid tumor resistant to a y-secretase inhibitor. In some embodiments, a subject has a desmoid tumor that is resistant to a y-secretase inhibitor. In some embodiments, a subject has a WPAM+ desmoid tumor that is resistant to a y-secretase inhibitor. In some embodiments, a y-secretase inhibitor is nirogacestat. In some embodiments, a cancer is resistant to nirogacestat. In some embodiments, a subject has a tumor resistant to nirogacestat. In some embodiments, a subject has a solid tumor resistant to nirogacestat. In some embodiments, a subject has a WPAM+ solid tumor resistant to nirogacestat. In some embodiments, a subject has a desmoid tumor resistant to nirogacestat. In some embodiments, a subject has a WPAM+ desmoid tumor resistant to nirogacestat. In some embodiments, a y-secretase inhibitor is varegacestat. In some embodiments, a cancer is resistant to varegacestat. In some embodiments, a subject has a tumor resistant to varegacestat. In some embodiments, a subject has a solid tumor resistant to varegacestat. In some embodiments, a subject has a WPAM+ solid tumor resistant to varegacestat. In some embodiments, a subject has a desmoid tumor resistant to varegacestat. In some embodiments, a subject has a WPAM+ desmoid tumor resistant to varegacestat. In some embodiments, a subject has received at least one prior systemic anti -cancer therapy and either progressed on, not responded Page 71 of 27013160427vlAttorney Docket No.: 2012675-0415to, or be unfit for available therapies. In some embodiments, provided technologies can offer a more direct and disease-relevant approach than another therapy, e.g., a y-secretase inhibitor. Tn some embodiments, provided technologies can offer a more direct and disease-relevant approach than a therapy that inhibits Notch signaling. In some embodiments, provided technologies can offer a more direct and disease-relevant approach than nirogacestat. In some embodiments, provided technologies can offer a more direct and disease-relevant approach than varegacestat. In some embodiments, a tumor, e.g., a desmoid tumor, is intro-abdominal. In some embodiments, a tumor, e.g., a desmoid tumor, is extra-abdominal. As described herein, in some embodiments, a WPAM is or comprises a CTNNB1 gain of function mutation (e g., T41A, S45F, etc.). In some embodiments, a desmoid tumor comprises a CTNNB1 mutation, e.g., S45P, D32V, H36P, S45_G48del, etc. In some embodiments, a desmoid tumor comprises an APC loss of function mutation. Various CTNNBf and APC mutations are reported, or can be identified and assessed according to reported technologies.

[0263] In some embodiments, tumor tissues and peripheral tissues samples (e.g., blood, plasma) are collected. The collected samples may be subject to several molecular and cellular assessments, e.g., tumorspecific protein and DNA / RNA markers relevant to the Wnt / |3-catenin pathway and ctDNA biomarkers. In some embodiments, an assessment comprises analysis of a sample using standard and exploratory techniques to monitor molecular characteristics of a subject’s tumor including genomic, transcriptomic, and proteomic features. In some embodiments, an assessment may indicate a correlation with efficacy of 1-66, or reveal prognostic or cancer-related biomarkers relevant to the clinical utility of 1-66. In some embodiments, an assessment is or comprises the determination of the genomic status and expression levels of genes of interest, such as APC, beta-catenin, Myc, Axin 2, and other Wnt pathway related genes. In some embodiments, a method comprises assess expression level of APC. In some embodiments, a method comprises assessing expression level of beta-catenin. In some embodiments, a method comprises assessing expression level of Myc. In some embodiments, a method comprises assessing expression level of c-Myc. In some embodiments, a method comprises assess expression level of Axin 2.

[0264] Among other things, the present disclosure encompasses the recognition that various measures may? be used to evaluate the efficacy of 1-66 for the treatment of a condition, disease or disorder. In some embodiments, efficacy of 1-66, e.g., for the treatment of a cancer is evaluated by, e.g., RECIST 1.1 response, radiographic measures (e.g., tumor volume, tumor cavitation, etc.), ctDNA levels, etc.. In some embodiments, a provided method is considered effective if it is observed to provide disease stabilization (e.g., results in stable disease, etc.). In some embodiments, a provided method is considered effective if it is observed to provide a reduction in disease progression. In some embodiments, a provided method is considered effective if it is observed to provide a response (e.g., partial response, complete response, etc.). In some embodiments, a provided method results in disease stabilization according to RECIST 1.1. In some embodiments, a provided method is observed to reduce disease progression as according to RECIST 1.1. In some embodiments, a provided method is observed to result in response according to RECIST 1.1. In some embodiments, a provided method is observed to result in partial response according to RECIST 1.1. In some embodiments, a Page 72 of 27013160427vlAttorney Docket No.: 2012675-0415provided method is observed to result in complete response according to RECIST 1.1. In some embodiments, a provided method is observed to result in disease stabilization as measured by radiographic measures. In some embodiments, a provided method is observed to reduce disease progression as measured by radiographic measures. In some embodiments, a provided method is observed to result in disease response as measured by radiographic measures. In some embodiments, a provided method is observed to result in partial response as measured by radiographic measures. In some embodiments, a provided method is observed to result in complete response as measured by radiographic measures. In some embodiments, a provided method results in disease stabilization as measured by tumor volume. In some embodiments, a provided method is observed to reduce disease progression as measured by tumor volume. In some embodiments, a provided method is observed result in reduction of tumor volume (c.g., tumor shrinkage, etc.). In some embodiments, a provided method results an increase in tumor cavitation. In some embodiments, a provided method results in disease stabilization as measured by ctDNA. In some embodiments, a provided method is observed to reduce disease progression as measured by ctDNA. In some embodiments, a provided method is observed result in reduction of ctDNA. In some embodiments, a provided method is observed result in a molecular response. In some embodiments, provided methods are effective for relieving symptoms of a cancer. In some embodiments, provided methods are effective for reducing pain. In some embodiments, when a cancer is Familial Adenomatous Polyposis (FAP), provided methods are effective for reducing duodenal polyp burden.

[0265] In some embodiments, a subject has Wnt pathway activation. In some embodiments, a subject has Wnt pathway activating mutation. In some embodiments, a tumor has Wnt pathway activating mutation. In some embodiments, a cancer cell has Wnt pathway activating mutation. In some embodiments, a sample is utilized for assessment. In some embodiments, a sample is utilized for assessment, and a cancer is determined to have Wnt pathway activating mutation. In some embodiments, a sample is utilized for assessment, and a tumor is determined to have Wnt pathway activating mutation. In some embodiments, a sample is or comprises a tumor sample. In some embodiments, a sample is or comprises a cancer cell. Various technologies can be utilized as described herein. For example, in some embodiments, sequencing (e.g., genome, transcripts, etc.) is utilized to identify or confirm presence of a mutation, e.g., a Wnt pathway activating mutation. In some embodiments, increased expression of Wnt / fycatenin pathway genes (e.g., AXIN1, AXIN2, APCDD1, NKD1, WIFI, DLX3, TCF4, etc.) is utilized to assess Wnt pathway activation. In some embodiments, increased expression of one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, or twelve or more Wnt / p-catenin pathway related genes (e.g., AXIN1, AXIN2, APCDD1, NKD1, WIFI, DLX3 and / or TCF4) are assessed. In some embodiments, expression levels of multiple Wnt / 0-catenin pathway genes are assessed, and they are utilized to determine whether a subject has Wnt pathway activation or Wnt pathway activating mutation. In some embodiments, a subject is detennined to have increased expression of Wnt / p-catenin pathway genes, and is determined to have Wnt pathway activation or Wnt pathway activating mutation. In some embodiments, P-catenin nuclear level is assessed. In some embodiments, evidence of Wnt pathway Page 73 of 27013160427vlAttorney Docket No.: 2012675-0415activation or Wnt pathway activating mutation is or comprises P-catenin nuclear positivity. In some embodiments, evidence of Wnt pathway activation or Wnt pathway activating mutation is or comprises increased -catenin nuclear level. In some embodiments, P-catenin nuclear level is assessed by Immunohistochemistry (IHC). In some embodiments, P-catenin nuclear positivity, c.g., per IHC, is utilized as evidence for Wnt pathway activation or Wnt pathway activating mutation. In some embodiments, P-catenin nuclear positivity, e.g., per IHC. is observed in a subject or a sample thereof and a subject is detennined to have Wnt pathway activation or Wnt pathway activating mutation. In some embodiments, a cancer cell or tumor comprises Wnt pathway activation. In some embodiments, a cancer cell or tumor comprises Wnt pathway activating mutation. In some embodiments, evidence of Wnt pathway activation (e.g., for ACP) is or comprises documented activating mutations in CTNNB1 or p-catcnin nuclear positivity (c.g., per IHC). In some embodiments, a tumor is microsatellite stable.

[0266] In some embodiments, Wnt pathway activating mutation is a mutation in APC. In some embodiments, Wnt pathway activating mutation is a mutation in beta-catenin. In some embodiments, a Wnt pathway activating mutation is selected from APC loss of function mutations (LOF, including frameshift, nonsense, or splice site), CTNNB1 gain of function mutations (GOF, including missense, in-frame insertion, or deletion at codons 32-37, 41, and 45, alternations leading to exon 3 skipping, etc.), RNF43 LOF mutations, and RSPO2 and RSPO3 fusions. In some embodiments, a Wnt pathway activating mutation is selected from mutations in APC. CTNNB1, RNF43, RSPO2 and RSPO3. In some embodiments, a Wnt pathway activating mutation is selected from mutations in other Wnt-pathway genes, such as AMER1, AXIN1, AXIN2. BCL9, CSNK1AL GSK3B, LRP5 (e.g., GoF), LRP6 (e.g. GoF), LGR5 (e.g. GoF), TCF7L2 (e.g. GoF), and WIFI.

[0267] In some embodiments, 1-66 is administered or delivered intravenously. In some embodiments, I-66 is provided as a sterile solution for intravenous (IV) administration. In some embodiments, 1-66 injection, 10 mg / mL, is supplied as a sterile, aseptically processed solution labeled for storage at 2-8 °C in single-use vials for intravenous (IV) administration. In some embodiments, an 1-66 injection is diluted using a pharmaceutically acceptable diluent, e.g., 5% Dextrose Injection, USP, to a set volume, e.g., 250 mL for administration, e.g., intravenous administration. Various 1-66 compositions for delivering or administering I-66 are as described herein. As described herein, 1-66 can be delivered or administered as various forms including pharmaceutically acceptable salt such as sodium salt forms. In some embodiments, 1-66 is delivered as a trisodium salt. In some embodiments, 1-66 is administered as a trisodium salt. In some embodiments, 1-66 in a composition is in a trisodium salt form. In some embodiments, 1-66 in a composition is dissolved trisodium salt.

[0268] In some embodiments, a dosing schedule is about weekly. In some embodiments, a dosing schedule is weekly in 28-day cycles. In some embodiments, a dosing schedule is about once weekly in 28-day cycles. In some embodiments, 1-66 is administered or delivered about once weekly in continuous cycles of about 21 or about 28 days. In some embodiments, 1-66 is administered or delivered intravenously about once weekly in continuous cycles of about 21 or about 28 days. In some embodiments, each dose in a cycle Page 74 of 27013160427vlAttorney Docket No.: 2012675-0415contains or delivers about the same amount of 1-66. In some embodiments, doses of several (e.g., 2 3, 4, 5 or more) or all cycles contain or deliver about the same amount of 1-66. In some embodiments, all doses for a subject are about the same. In some embodiments, a dose is different (higher or lower) than another dose. In some embodiments, dose of a cycle is different (higher or lower) than dose of another cycle. In some embodiments, a cycle is about 21 days. In some embodiments, each cycle is independently about 21 days. In some embodiments, a cycle is about 28 days. In some embodiments, each cycle is independently about 28 days. In some embodiments, a dose is about 18 mg / m2(unless noted otherwise, of 1-66 free acid). In some embodiments, a dose is about 36 mg / m2. In some embodiments, a dose is about 72 mg / m2. In some embodiments, a dose is about 144 mg / m2. In some embodiments, a dose is about 240 mg / m2. In some embodiments, a dose is about 360 mg / m2. In some embodiments, a dose is about 420 mg / m2. In some embodiments, a dose is about 480 mg / m2. In some embodiments, a dose is about 600 mg / m2. In some embodiments, a dose of a cycle is about 18 mg / m2. In some embodiments, a dose of a cycle is about 36 mg / m2. In some embodiments, a dose of a cycle is about 72 mg / m2. In some embodiments, a dose of a cycle is about 144 mg / m2. In some embodiments, a dose of a cycle is about 240 mg / m2. In some embodiments, a dose of a cycle is about 360 mg / m2. In some embodiments, a dose of a cycle is about 420 mg / m2. In some embodiments, a dose of a cycle is about 480 mg / m2. In some embodiments, a dose of a cycle is about 600 mg / m2. Certain useful technologies for calculating body surface area and amounts of 1-66 are described in the Examples. As appreciated by those skilled in the art, in a pharmaceutical composition such as a drug product, 1-66 may exist in one or more forms including one or more pharmaceutically acceptable salt fonns. For example, in some embodiments, 1-66 may exist as one or more dissolved salt forms (e.g., sodium salt). In some embodiments, a patient may start with a lower dose. In some embodiments, a patient may start with a higher dose. In some embodiments, there are one or more loading doses. In some embodiments, there are no loading doses.

[0269] In some embodiments, a dosing regimen comprises or consists of an induction period and a maintenance period. In some embodiments, 1-66 is administered about once weekly at a first dose level during the induction period of one or more cycles and once weekly at a second dose level during the maintenance period of one or more cycles. In some embodiments, 1-66 is administered once weekly at a first dose level during the induction period of one or more cycles and once every two weeks at a second dose level during the maintenance period of one or more cycles. In some embodiments, 1-66 is administered once weekly at a first dose level during the induction period and once weekly at a second dose level during the maintenance period. In some embodiments, an induction period is about two cycles (e.g., two 28-day cycles). In some embodiments, an induction period is about 1-2 months. In some embodiments, the induction period is about four cycles (e.g., four 28-day cycles). In some embodiments, each cycle is independently about 28 days. In some embodiments, each cycle administers about 4 doses. In some embodiments, 1-66 is administered about weekly during an induction period. In some embodiments, 1-66 is administered about weekly during a maintenance period. In some embodiments, 1-66 is administered about every two weeks during a maintenance Page 75 of 27013160427vlAttorney Docket No.: 2012675-0415period. In some embodiments, the first dose level and the second dose level are the same. In some embodiments, the first dose level is higher than the second dose level. In some embodiments, the first dose level is lower than the second dose level. In some embodiments, the first dose level is about 36 mg / m2. In some embodiments, the first dose level is about 72 mg / m2. In some embodiments, tire first dose level is about 144 mg / m2. In some embodiments, the first dose level is about 240 mg / m2. In some embodiments, the first dose level is about 360 mg / m2. In some embodiments, the first dose level is about 420 mg / m2. In some embodiments, the first dose level is about 480 mg / m2. In some embodiments, the first dose level is about 600 mg / m2. In some embodiments, the second dose level is about 36 mg / m2. In some embodiments, the second dose level is about 72 mg / m2. In some embodiments, the second dose level is about 144 mg / m2. In some embodiments, the second dose level is about 240 mg / m2. In some embodiments, the second dose level is about 360 mg / m2. In some embodiments, the second dose level is about 420 mg / m2. In some embodiments, the second dose level is about 480 mg / m2. In some embodiments, the second dose level is about 600 mg / m2. In some embodiments, the first dose level is about 240 mg / m2and the second dose level is about 240 mg / m2. In some embodiments, the first dose level is about 240 mg / m2and is administered about once weekly during the induction period of one or more cycles and the second dose level is about 240 mg / m2and is administered about once every two weeks during the maintenance period of one or more cycles. In some embodiments, tire first dose level is about 240 mg / m2and is administered about once weekly during the induction period of two cycles (e.g., two 28-day cycles) and the second dose level is about 240 mg / m2and is administered about once every two weeks during the maintenance period of one or more cycles. In some embodiments, the first dose level is about 240 mg / m2and is administered about once weekly during the induction period of one or more cycles and tire second dose level is about 72 mg / m2and is administered about once weekly during tire maintenance period of one or more cycles. In some embodiments, the first dose level is about 240 mg / m2and is administered about once weekly during the induction period of four cycles (e.g., four 28-day cycles) and the second dose level is about 72 mg / m2and is administered about once weekly during the maintenance period of one or more cycles. In some embodiments, the first dose level is about 72 mg / m2and is administered about once weekly during the induction period of one or more cycles and the second dose level is about 72 mg / m2and is administered about once weekly during the maintenance period of one or more cycles. In some embodiments, the first dose level is about 72 mg / m2and is administered about once weekly during the induction period of four cycles (e.g., four 28-day cycles) and the second dose level is about 72 mg / m2and is administered once weekly during the maintenance period of one or more cycles. In some embodiments, an induction period comprises or consists of about 8 doses of 1-66 at a first dose level administered about weekly. In some embodiments, an induction period comprises or consists of about 16 doses of 1-66 at a first dose level administered about weekly. In some embodiments, a first dose level is about 72 mg / m2. In some embodiments, a first dose level is about 300-450 mg. In some embodiments, a first dose level is about 240 mg / m2. In some embodiments, a maintenance period comprises or consists of administering 1-66 at a second dose level about weekly. In some embodiments, a maintenance period comprises or consists Page 76 of 27013160427vlAttorney Docket No.: 2012675-0415of administering 1-66 at a second dose level about every two weeks. In some embodiments, a second dose level is the same or lower than the first dose level. Tn some embodiments, a second dose level is about 72 mg / m2. In some embodiments, a second dose level is about 150 mg. In some embodiments, a second dose level is about 240 mg / m2. In some embodiments, a dosing regimen comprises or consists of administering about 8 doses of 1-66 at a dose level of about 240 mg / m2about weekly, followed by administering 1-66 at a dose level of about 240 mg / m2about every two weeks. In some embodiments, a dosing regimen comprises or consists of administering about 16 doses of 1-66 at a dose level of about 240 mg / m2about weekly, followed by administering 1-66 at a dose level of about 72 mg / m2about weekly. In some embodiments, a dosing regimen comprises or consists of administering about 16 doses of 1-66 at a dose level of about 72 mg / m2about weekly, followed by administering 1-66 at a dose level of about 72 mg / m2about every’ two weeks.

[0270] In some embodiments, provided technologies, e.g., 1-66 doses and dosing regimens, manages, reduces and / or avoids one or more risks and toxicities, e.g., increased bone turnover, intestinal mucosal atrophy, elevations in muscle enzymes (e.g., creatine kinase [CK], aspartate aminotransferase [AST], alanine aminotransferase [ALT], etc.), transient platelet consumption, renal dysfunction, elevated liver enzymes, elevations in some markers of systemic inflammation, and electrolyte and adrenal abnormalities. In some embodiments, provided technologies comprises assessing one or more of bone turnover (e.g., beta-isomerized C-terminal telopeptides level, bone density, dual-energy X-ray absorptiometry (DXA) scanning, etc.), intestinal mucosal atrophy (e.g.. symptoms associated with GI mucosal atrophy (e.g., diarrhea, nausea, vomiting, weight loss, etc.)), muscle enzymes (e.g., creatine kinase [CK], aspartate aminotransferase [AST], etc.), platelet (e.g., platelet count, coagulation parameters (e.g., prothrombin time [PT], partial thromboplastin time [PTT], etc.), etc.), renal functions (e.g., plasma creatinine, BUN, urinalysis, etc.), liver enzymes (e.g., standard liver enzymes and / or bilirubin), and systemic inflammation (e.g., one or more markers (e.g., C-reactive protein (CRP), globulin, fibrinogen, albumin, etc.)), electrolytes (e.g.. sodium salt), and aldosterone. For example, in some embodiments, provided methods comprise assessing ALT levels. In some embodiments, provided methods comprise assessing alopecia. In some embodiments, alopecia is reversable. In some embodiments, provided methods comprise assessing AST level. In some embodiments, change in AST level is reversible. In some embodiments, provided methods comprise assessing epistaxis. In some embodiments, provided methods comprise assessing blood bilirubin level. In some embodiments, provided methods comprise assessing hyperbilirubinemia. In some embodiments, hyperbilirubinemia is observed and is asymptomatic and reversable. In some embodiments, provided methods comprise assessing ALT level. As observed in clinical trials, many changes, e.g., alopecia, AST increases, hyperbilirubinemia, etc. are reversible. In some embodiments, an event is managed by adjusting dosing levels and / or frequency, and / or dosing hold for a period of time. In some embodiments, provided methods comprise assessing level of serum CEA (e.g., for CRC). In some embodiments, provided methods comprise assessing level of serum PSA (e g., for prostate cancer). In some embodiments, provided methods comprise assessing level of testosterone (e.g., for prostate cancer). In some embodiments, provided methods comprise assessing tumors. In somePage 77 of 27013160427vlAttorney Docket No.: 2012675-0415embodiments, provided methods comprise DXA scan. In some embodiments, provided methods comprise PET-CT scan. In some embodiments, provided methods comprise MRI scan. In some embodiments, provided methods comprise assessing T2 cellularity. In some embodiments, provided methods comprise tumor biopsy. In some embodiments, provided methods comprise assessing PK (c.g., in blood). In some embodiments, provided methods comprise assessing ADA (e.g., in blood, toward 1-66 or another therapeutic agent). In some embodiments, provided methods comprise assessing NGS. In some embodiments, provided methods comprise assessing PD (e.g., in blood). In some embodiments, provided methods comprise assessing ctDNA (e.g., in blood). In some embodiments, provided methods comprise assessing level of viable PBMC (e.g., in blood). In some embodiments, provided methods comprise assessing patient reported outcomes (PROs, e.g., pain, ctc.)Thosc skilled in the art will appreciate that other parameters (c.g., vital signs, ECG, etc.) may be assessed in accordance with tire present disclosure. In some embodiments, baseline levels are assessed. In some embodiments, baseline samples are collected.

[0271] Among other things, the present disclosure provides technologies, e.g., 1-66 dosing levels and regimens, with usefid safety profdes. In some embodiments, no treatment related adverse events (TRAEs) of grade 4 or higher are observed in a subject or a population of subject. In some embodiments, no treatment related adverse events (TRAEs) of grade 3 or higher are observed in a subject or a population of subject. In some embodiments, TRAEs of grade 3 or higher are no more than about 20% in a population of subjects. In some embodiments, no treatment related adverse events (TRAEs) of grade 3 or higher, other than increased AST and increased blood bilirubin, are observed in a subject or a population of subject. In some embodiments, in a population of subjects, no TRAE of ALT increase of grade 3 or higher is observed. In some embodiments, no TRAE of epistaxis of grade 3 or higher is observed. In some embodiments, no TRAE of hypoaldosteronism of grade 3 or higher is observed. In some embodiments, TRAE of AST increase of grade 3 or higher is lower than about 10% in a population of subjects. In some embodiments, TRAE of blood bilirubin increase of grade 3 or higher is lower than about 10% in a population of subjects. See, e.g., the Examples. In some embodiments, percentage of one or more TRAEs in a population of subjects is about 20% or lower, about 19% or lower, about 18% or lower, about 17% or lower, about 16% or lower, about 15% or lower, about 14% or lower, about 13% or lower, about 12% or lower, about 11% or lower, about 10% or lower, about 9% or lower, about 8% or lower, about 7% or lower, about 6% or lower, about 5% or lower, about 4% or lower, about 3% or lower, about 2% or lower, or about 1% or lower. In some embodiments, most commonly reported TRAEs were low-grade and reversible. In some embodiments, no grade of 3 or higher TRAEs at dose level of 240 mg / nr or lower are observed. In some embodiments, no grade 4 or 5, serious, or TRAEs resulting in treatment discontinuation are observed. In some embodiments, no high-grade gastrointestinal or skin toxicity are observed. In some embodiments, no dysgeusia is observed. In some embodiments, no grade 3, 4, or 5 diarrhea is observed. In some embodiments, no diarrhea is observed. In some embodiments, no grade 3, 4. or 5 rash is observed. In some embodiments, no rash is observed. In some embodiments, no high-grade reproductive toxicity is observed. In some embodiments, no reproductive Page 78 of 27013160427vlAttorney Docket No.: 2012675-0415toxicity is observed. In some embodiments, no high-grade ovarian toxicity is observed. In some embodiments, no ovarian toxicity is observed. In some embodiments, no high grade muscle pain / cramps is observed. In some embodiments, toxicity can be managed by modification of dosing (e.g., dose level, dose frequency, etc.). In some embodiments, toxicity can be managed by modification of dosing (e.g., dose level, dose frequency, etc.) that preserves efficacy. In some embodiments, toxicity can be managed by modification of dosing (e.g.. dose level, dose frequency, etc.) while maintaining an observed treatment response.

[0272] In some embodiments, 1-66 is administered or delivered about weekly. In some embodiments, I-66 is administered or delivered about every two weeks. In some embodiments, 1-66 is administered or delivered about every three weeks. In some embodiments, 1-66 is administered or delivered weekly for about at least two weeks before 1-66 is administered or delivered less frequently. In some embodiments, 1-66 is administered or delivered weekly for about at least four weeks before 1-66 is administered or delivered less frequently. In some embodiments, a less frequent dosing schedule is about every two weeks. In some embodiments, a less frequent dosing schedule is about 1 week off after about 3 weekly doses (3W on / lW off).

[0273] In some embodiments, after one or more doses effects of 1-66, alone or in combination with other agents, are assessed. In some embodiments, biopsies may be taken from a subject to assess one or more biomarkers, e.g., transcripts or polypeptides levels (e.g., of cMyc, Axin2, etc.), or immune-related markers or signatures. In some embodiments, the size of tumors is assessed. In some embodiments, assessment is compared to baseline.

[0274] In some embodiments, the present disclosure provides a method for treating cancer, comprising intravenously administering 1-66 to a subject suffering therefrom in cycles of about 28 days. In some embodiments, a cancer is MSS CRC. In some embodiments, a cancer is MSS CRC with WPAM. In some embodiments, a subject has solid tumor. In some embodiments, a subject has solid tumor with WPAM. In some embodiments, a subject has locally advanced or metastatic solid tumor with documented WPAM. In some embodiments, a subject has non-MSI-H or non-dMMR (e.g., by local testing) colorectal adenocarcinoma. In some embodiments, a subject has locally advanced or metastatic non-MSI-H or non-dMMR (e.g., by local testing) colorectal adenocarcinoma. In some embodiments, a cancer is HCC with WPAM. In some embodiments, a cancer is HCC with WPAM in AFC or CTNNBJ. In some embodiments, a subject has desmoid tumor with WPAM. In some embodiments, a cancer is mCRPC with WPAM. In some embodiments, a cancer is mCRPC with WPAM in AFC or CTNNBl. In some embodiments. 1-66 is administered about weekly in a cycle. In some embodiments, 1-66 is administered on days 1, 8, 15, and 22. In some embodiments, 1-66 is administered about weekly in each cycle. In some embodiments, 1-66 is administered about every two weeks in a cycle. In some embodiments, 1-66 is administered on days 1 and 15. In some embodiments, 1-66 is administered about weekly in one or more cycles (loading cycles) followed by one or more cycles in which 1-66 is administered about every two weeks. In some embodiments, the number of loading cycles is 1. In some embodiments, in a cycle 1-66 is administered on days 1, 8, and 15 followed by a rest week. In some embodiments, doses of 1-66 in a cycle are about the same (e.g., as described herein, Page 79 of 27013160427vlAttorney Docket No.: 2012675-0415about 18, 36, 72, 144. 240, 360. 420, 480. 600, etc. mg / m2).

[0275] In some embodiments, the present disclosure provides methods for modulating a property, activity and / or function of beta-catenin, comprising contacting beta-catenin with 1-66. In some embodiments, the present disclosure provides methods for modulating a property, activity and / or function of bcta-catcnin in a system comprising beta-catenin, comprising administering or delivering 1-66 to the system. In some embodiments, the present disclosure provides methods for modulating a property, activity and / or function of beta-catenin in a system expressing beta-catenin, comprising administering or delivering 1-66 to the system. In some embodiments, an activity of beta-catenin is inhibited or reduced. In some embodiments, a function of beta-catenin is inhibited or reduced. In some embodiments, a property, activity and / or function is associated with bcta-catcnin / TCF interaction. In some embodiments, the present disclosure provides methods for modulating beta-catenin / TCF interaction. In some embodiments, the present disclosure provides methods for modulating beta-catenin / TCF interaction, comprising contacting beta-catenin with 1-66. In some embodiments, the present disclosure provides methods for modulating beta-catenin / TCF interaction in a system comprising beta-catenin and TCF, comprising administering or delivering 1-66 to the system. In some embodiments, the present disclosure provides methods for modulating beta-catenin / TCF interaction in a system expressing beta-catenin and TCF, comprising administering or delivering 1-66 to tire system. In some embodiments, interactions between beta-catenin and TCF is reduced. In some embodiments, interactions between beta-catenin and TCF is inhibited. In some embodiments, the present disclosure provides methods for inhibiting cell proliferation, comprising administering or delivering 1-66 to a population of cells. In some embodiments, the present disclosure provides methods for inhibiting cell proliferation in a system, comprising administering or delivering 1-66 to the system. In some embodiments, the present disclosure provides methods for inhibiting cell grow th, comprising administering or delivering 1-66 to a population of cells. In some embodiments, the present disclosure provides methods for inhibiting cell grow th in a system, comprising administering or delivering 1-66 to the system. In some embodiments, such cell proliferation is beta-catenin dependent. In some embodiments, such cell growth is beta-catenin dependent. In some embodiments, such proliferation or growth is dependent on beta-catenin interactions with TCF. In some embodiments, the present disclosure provides methods for reducing or preventing activation of a Wnt pathway. In some embodiments, the present disclosure provides methods for reducing or preventing activation of a Wnt pathway in a system, comprising administering or delivering 1-66 to the system. In some embodiments, the present disclosure provides methods for reducing levels of transcripts of one or more Wnt pathway markers (e.g., AXIN2, NKD1, RNF43, ZNRF3, NOTUM, etc.) in a system, comprising administering or delivering 1-66 to the system. In some embodiments, in a provided method, levels of transcripts of one or more Wnt pathway markers (e.g., AXIN2, NKD1, RNF43, ZNRF3, NOTUM, etc.) are reduced (e.g., in a subject or a population of subjects receiving 1-66 compared to baseline). In some embodiments, the present disclosure provides methods for reducing levels of transcripts of one or more sternness markers (e.g., SOX9, MEX3A, EPHB2, ASCL2, LGR5, etc.) in a system, comprising administering or delivering 1-66 to the system. In some Page 80 of 27013160427vlAttorney Docket No.: 2012675-0415embodiments, in a provided method, levels of transcripts of one or more sternness markers (e.g, SOX9, MEX3A, EPHB2, ASCL2, LGR5, etc.) are reduced (e.g., in a subject or a population of subjects receiving I-66 compared to baseline). In some embodiments, the present disclosure provides methods for increasing levels of transcripts of one or more differentiation markers (e.g., MUC2, KRT20, ALPI, ANPEP, CA2, etc.) in a system, comprising administering or delivering 1-66 to the system. In some embodiments, in a provided method, levels of transcripts of one or more differentiation markers (e.g., MUC2, KRT20. ALPI, ANPEP. CA2, etc.) are increased (e.g., in a subject or a population of subjects receiving 1-66 compared to baseline). In some embodiments, the present disclosure provides methods for decreasing levels of transcripts of one or more DNA damage response markers (e.g., BRCA1, RAD51, RAD51AP1, BRCA2, FANCI, FANCD2, FANCB, FANCA, FANCM, XRCC2, and FANCG, etc.) in a system, comprising administering or delivering 1-66 to the system. In some embodiments, in a provided method, levels of transcripts of one or more DNA damage response markers (e g., BRCA1, RAD51, RAD51AP1, BRCA2, FANCI, FANCD2, FANCB.FANCA, FANCM, XRCC2, and FANCG, etc.) are decreased (e.g., in a subject or a population of subjects receiving 1-66 compared to baseline). In some embodiments, the present disclosure provides methods for increasing levels of transcripts of one or more angiogenesis and / or endothelium-related pathway markers (e.g., HGF, MMP2, CSCL12, FGF2, PDGFC, VEGFC, FSTL1, SELE, SEMA3G, MMP2, ANGPT2, ENG, VWF, TEK, KDR, and CD34, etc.) in a system, comprising administering or delivering 1-66 to tire system. In some embodiments, in a provided method, levels of transcripts of one or more angiogenesis and / or endothelium-related pathway markers (e.g., HGF, MMP2, CSCL12, FGF2, PDGFC, VEGFC, FSTL1, SELE, SEMA3G, MMP2, ANGPT2, ENG, VWF, TEK, KDR, and CD34, etc.) are increased (e.g, in a subject or a population of subjects receiving 1-66 compared to baseline). In some embodiments, the present disclosure provides methods for increasing levels of transcripts of one or more inflammatory markers (e.g, CD8A, NKG7, HLA-DQA1, HLA-DRB1, CMKLR1, IFNG, CCL5, CXCL9, CD27, IDOL STAT1, TIGIT, LAG3, PD-L1, PD-L2, etc.) in a system, comprising administering or delivering 1-66 to the system. In some embodiments, in a provided method, levels of transcripts of one or more inflammatory markers (e.g, CD8A, NKG7, HLA-DQA1, HLA-DRB1, CMKLR1, IFNG, CCL5, CXCL9, CD27, IDO1, STAT1, TIGIT, LAG3, PD-L1, PD-L2, etc.) are increased (e.g, in a subject or a population of subjects receiving 1-66 compared to baseline). In some embodiments, transcript levels of one or more Wnt pathway markers (e.g, AXIN2, NKD1, RNF43, ZNRF3, NOTUM, VEGFA, etc.) are reduced, transcript levels of one or more sternness markers (e.g, SOX9. MEX3A. EPHB2, ASCL2. LGR5, etc.) are reduced, transcript levels of one or more differentiation markers (e.g, MUC2, KRT20, ALPI, ANPEP, CA2, etc.) are increased, and / or transcript levels of one or more inflammatory markers (e.g, CD8A, NKG7, HLA-DQA1, HLA-DRB1, CMKLR1, IFNG, CCL5, CXCL9, CD27, IDO1, STAT1, TIGIT, LAG3, PD-L1, PD-L2, etc.) are increased. In some embodiments, the present disclosure provides methods for increasing levels of transcripts of one or more hypoxia markers (e.g.. EPAS1, HIF2A, HIF1A, HIF3A, etc.) in a system, comprising administering or delivering 1-66 to the system. In some embodiments, in a provided method, levels of transcripts of one or Page 81 of 27013160427vlAttorney Docket No.: 2012675-0415more hypoxia markers (e.g., EPAS1, HIF2A, HIF 1A, HIF3A, etc.) are increased (e.g., in a subject or a population of subjects receiving 1-66 compared to baseline). Tn some embodiments, modulation is assessed using geometric means of multiple transcripts, e.g., in some embodiments, downregulation of Wnt transcriptional signatures is assessed using geometric means of levels of transcripts of AXIN2, NKD1, RNF43, ZNRF3 and NOTUM. Various technologies can be utilized to assess transcript levels. In some embodiments, RNASeq is utilized to assess levels of transcripts, e.g., RNA. In some embodiments, a system is in vitro. In some embodiments, a system is ex vivo. In some embodiments, a system is in vivo. In some embodiments, a system is or comprise a cell. In some embodiments, a system is or comprise a cancer cell, e.g., of a cancer present disclosure. In some embodiments, a system is or comprises a tumor. In some embodiments, a system is or comprises a tissue. In some embodiments, a system is or comprises an organ. In some embodiments, a system is or comprises an organism. In some embodiments, a system is an animal. In some embodiments, a system is human. In some embodiments, a system is or comprises cells, tissues or organs associated with a condition, disorder or disease. In some embodiments, a system is or comprises cancer cells, e.g., of a cancer as described herein. In some embodiments, a system is or comprises a tumor, e.g., of a cancer as described herein. In some embodiments, a system comprises a WPAM as described herein.

[0276] In some embodiments, the present disclosure provides 1-66 compositions for modulating beta-catenin functions. In some embodiments, the present disclosure provides 1-66 compositions for modulating beta-catenin: TCF interactions. In some embodiments, the present disclosure provides 1-66 compositions for modulating functions associated with beta-catenin: TCF interactions.

[0277] In some embodiments, provided technologies can decrease, suppress or block one or more of such interactions. In some embodiments, the present disclosure provides methods for modulating an interaction between beta-catenin and its binding partner (e.g., a TCF / LEF family member) comprising contacting beta-catenin with 1-66.

[0278] In some embodiments, binding of 1-66 to beta-catenin competes or inhibits binding of another agent. In some embodiments, binding of 1-66 to beta-catenin competes or inhibits binding of another agent. In some embodiments, binding of 1-66 to beta-catenin competes or inhibits binding of TCF or a fragment thereof.

[0279] In some embodiments, provided technologies can reduce or block beta-catenin ’s interactions with all TCF family members, E-cadherin and APC, but did not significantly affect its interactions with ICAT, AXIN and BCL9. In some embodiments, provided technologies can interrupt beta-catenin / TCF interaction at both physical interaction level (e.g., as confirmed by NanoBRET, co-IP, etc.) and transcriptional level (e.g., as confirmed by reporter cell line, endogenous gene expression, etc.). In some embodiments, provided technologies show no effect on beta-catenin stability.

[0280] Among other things, the present disclosure provides technologies for modulating levels and / or activities of transcripts and / or products thereof. In some embodiments, levels and / or activities of transcripts and levels and / or activities of products thereof, e.g., polypeptides, may be modulated independently, or may Page 82 of 27013160427vlAttorney Docket No.: 2012675-0415be increased, decreased or maintained at the same or comparable levels independently.

[0281] In some embodiments, a reduction is about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%. In some embodiments, an increase is about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%. In some embodiments, the present disclosure provide increases and / or decreases at least several days, e.g., 1. 2, 3, 4, 5. 6, 7, 8, 9. or 10 days or more after administration is completed.

[0282] In some embodiments, a system, cell, tissue, organ or subject comprises or expresses a WPAM as described herein. In some embodiments, a system, cell, tissue, organ or subject comprises or expresses a mutant beta-catenin. In some embodiments, a system, cell, tissue, organ or subject comprises beta-catenin hyperactivity. In some embodiments, a system, cell, tissue, organ or subject comprises uprcgulatcd beta-catenin transcript level. In some embodiments, a system, cell, tissue, organ or subject comprises upregulated beta-catenin polypeptide level. In some embodiments, a system, cell, tissue, organ or subject comprises or expresses a mutant c-Myc. In some embodiments, a system, cell, tissue, organ or subject comprises c-Myc hyperactivity. In some embodiments, a system, cell, tissue, organ or subject comprises upregulated c-Myc transcript level. In some embodiments, a system, cell, tissue, organ or subject comprises upregulated c-Myc polypeptide level. In some embodiments, a system, cell, tissue, organ or subject comprises or expresses a mutant N-Myc. In some embodiments, a system, cell, tissue, organ or subject comprises N-Myc hyperactivity. In some embodiments, a system, cell, tissue, organ or subject comprises upregulated N-Myc transcript level. In some embodiments, a system, cell, tissue, organ or subject comprises upregulated N-Myc polypeptide level.

[0283] In some embodiments, the present disclosure provides combination therapies comprising 1-66. In some embodiments, 1-66 is utilized in combination with another therapy (in some embodiments, with one other therapy; in some embodiments, with two or more other therapies). In some embodiments, 1-66 is utilized in combination with another cancer therapy. In some embodiments, 1-66 is utilized in combination with another therapeutic agent (in some embodiments, one other therapeutic agent: in some embodiments, two or more other therapeutic agents). In some embodiments, another therapy or therapeutic agent is administered prior to an administration or delivery of 1-66. In some embodiments, another therapy or therapeutic agent is administered at about the same time as an administration or delivery of 1-66. In some embodiments, 1-66 and another therapy or therapeutic agent is in the same pharmaceutical composition. In some embodiments, another therapy or therapeutic agent is administered subsequently to an administration or delivery of 1-66. In some embodiments, a subject is exposed to both 1-66 and another therapy or therapeutic agent. In some embodiments, both 1-66 and another therapy or therapeutic agent can be detected in a subject. In some embodiments, 1-66 is administered before another therapy or therapeutic agent is cleared out by a subject or vice versa. In some embodiments, 1-66 is administered within the half-life, or 2, 3, 4, 5 or 6 times of the half-life, of another therapy or therapeutic agent or vice versa. In some embodiments, a subject is exposed to an effect of 1-66 and an effect of another therapy or therapeutic agent. In some embodiments, an agent may Page 83 of 27013160427vlAttorney Docket No.: 2012675-0415provide an effect after an agent is cleared out or metabolized by a subject. In some embodiments, a procedure, e.g., surgery, radiation, etc., may provide an effect after the procedure is completed.

[0284] In some embodiments, another therapy is a cancer therapy. In some embodiments, another therapy is or comprises surgery. In some embodiments, another therapy is or comprises one or more therapeutic agents. In some embodiments, another therapy is or comprises radiation therapy. In some embodiments, another therapy is or comprises immunotherapy. In some embodiments, another therapy is or comprises honnone therapy. In some embodiments, another therapy is or comprises chemotherapy. In some embodiments, another therapeutic agent is or comprises a drag. In some embodiments, another therapeutic agent is or comprises a cancer drag. In some embodiments, another therapeutic agent is or comprises a chemotherapeutic agent. In some embodiments, another therapeutic agent is or comprises a honnone therapy agent. In some embodiments, another therapeutic agent is or comprises a kinase inhibitor. In some embodiments, another therapy or therapeutic agent is or comprises an EGFR inhibitor, e.g., erlotinib, gefitinib, lapatinib, panitumumab, vandetanib, cetuximab, etc. In some embodiments, another therapy or therapeutic agent is or comprises an VEGF and / or VEGFR inhibitor, e.g., pazopanib, bevacizumab, sorafenib, sunitinib, axitinib, ponatinib, regorafenib, vandetanib, cabozantinib, ramucirumab, lenvatinib, ziv-aflibercept, fruquintinib, etc. In some embodiments, a VEGF inhibitor is bevacizumab. In some embodiments, another therapy or therapeutic agent is or comprises a kinase inhibitor. In some embodiments, another therapy or therapeutic agent is or comprises a chemotherapeutic agent. In some embodiments, another therapy or therapeutic agent is or comprises an anti-cancer drag, e.g., cyclophosphamide, methotrexate, 5 -fluorouracil (5-FU), doxorubicin, mustine, vincristine, procarbazine, prednisolone, dacarbazine, bleomycin, etoposide, cisplatin, epirubicin, capecitabine, folinic acid, actinomycin, all-trans retinoic acid, azacitidine, azathioprine, bortezomib, carboplatin, chlorambucil, cytarabine, daunorabicin, docetaxel, doxifluridine, fluorouracil, gemcitabine, hydroxyurea, idarubicin, imatinib, irinotecan, mechlorethamine, mercaptopurine, mitoxantrone, paclitaxel, pemetrexed, teniposide, tioguanine, topotecan, valrabicin, vinblastine, vindesine. vinorelbine, oxaliplatin, etc.

[0285] In some embodiments, another therapy or therapeutic agent is or comprises a checkpoint inhibitor, an EGFR inhibitor, a VEGF inhibitor, a VEGFR inhibitor, a kinase inhibitor, or an anti-cancer drug. In some embodiments, another therapy or therapeutic agent is or comprises anti-angiogenics. In some embodiments, another therapy or therapeutic agent is or comprises an anti-VEGF therapy. In some embodiments, another therapy or therapeutic agent is or comprises a VEGF inhibitor. In some embodiments, another therapy or therapeutic agent is or comprises a VEGF-A inhibitor. In some embodiments, an inhibitor is an antibody or an antigen-binding fragment thereof. For example, In some embodiments, another therapy or therapeutic agent is or comprises bevacizumab. In some embodiments, another therapy or therapeutic agent decreases tumor angiogenesis and / or inhibits of tumor growth. In some embodiments, another therapy or therapeutic agent is or comprises a VEGF inhibitor (e.g., a VEGF-A inhibitor) and chemotherapy (e.g., fluorouracil-based chemotherapy). In some embodiments, another therapy or therapeutic agent is or comprises Page 84 of 27013160427vlAttorney Docket No.: 2012675-0415a VEGF inhibitor (e.g., a VEGF-A inhibitor) and fluorouracil. In some embodiments, another therapy or therapeutic agent is or comprises a VEGF inhibitor (e.g., a VEGF-A inhibitor) and leucovorin, fluorouracil, and oxaliplatin. In some embodiments, another therapy or therapeutic agent is or comprises a VEGF inhibitor (e.g., a VEGF-A inhibitor) and trifluridinc / tipiracil (e.g., Lonsurf®, TAS-102, etc.). Among other things, bevacizumab has been reported to be used in combination with fluorouracil-based chemotherapy for first- or second-line treatment of metastatic CRC and in combination with trifluridine / tipiracil (Lonsurf®) for third-and later-line treatment (see, e.g., prescribing information).

[0286] In some embodiments, another therapy is or comprises FOLFOX. FOLFOX is a combination chemotherapy regimen that is useful for treating, e.g., cancer (e.g., CRC). It includes leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin. FOLFOX regimens can differ in tire doses and the ways in which the 3 drugs are administered. In some embodiments, modified FOLFOX-6 (mFOLFOX-6) is used in a study. In some embodiments, another therapeutic agent is or comprises folinic acid a salt thereof. In some embodiments, another therapeutic agent is or comprises folinic acid calcium. In some embodiments, another therapeutic agent is or comprises fluorouracil. In some embodiments, another therapeutic agent is or comprises oxaliplatin. In some embodiments, a combination is or comprises 1-66, leucovorin calcium (folinic acid), fluorouracil, oxaliplatin and bevacizumab. In some embodiments, a combination is or comprises 1-66, FOLFOX bevacizumab. In some embodiments, a combination is or comprises 1-66, mFOLFOX bevacizumab.

[0287] In some embodiments, another therapy or therapeutic agent is or comprises trifluridine. In some embodiments, another therapy or therapeutic agent is or comprises tipiraciL In some embodiments, another therapy or therapeutic agent is or comprises a combination of trifluridine tipiracil, which is a combination of two drugs that has been reported to be used alone and in combination with bevacizumab to treat adults with metastatic CRC (third line and later) (see, e.g., prescribing information for trifluridine / tipiracil), stomach, and gastroesophageal junction cancer. In some embodiments, another therapy or therapeutic agent is or comprises a nucleoside analog (e.g., a thymidine -based nucleoside analog such as trifluridine) and / or a thymidine phosphorylase inhibitor (e.g., tipiracil). In some embodiments, a combination is or comprises 1-66, trifluridine, tipiracil and bevacizumab. In some embodiments, a combination is or comprises 1-66, LONSURF® and bevacizumab.

[0288] In some embodiments, another therapy or therapeutic agent is or comprises a gamma secretase inhibitor. In some embodiments, another therapy or therapeutic agent is nirogacestat. In some embodiments, another therapy or therapeutic agent is varegacestat.

[0289] In some embodiments, a combination therapy is administered in continuous cycles as described herein, e.g., cycles of about 28 days.

[0290] In some embodiments, a combination therapy is 1-66, folinic acid or a salt thereof, fluorouracil, oxaliplatin and bevacizumab.

[0291] In some embodiments, the present disclosure provides a method for treating cancer, comprising administering a combination of 1-66, folinic acid or a salt thereof, fluorouracil, oxaliplatin and bevacizumab.Page 85 of 27013160427vlAttorney Docket No.: 2012675-0415In some embodiments, folinic acid or a salt thereof, fluorouracil and oxaliplatin is administered as FOLFOX. In some embodiments, folinic acid or a salt thereof, fluorouracil and oxaliplatin is administered as mFOLFOX. In some embodiments, the combination is administered intravenously. In some embodiments, I-66 is administered on a day of administration before folinic acid or a salt thereof, fluorouracil, oxaliplatin, and bevacizumab. In some embodiments, the combination is administered in cycles, e.g., of 28 days. For example, in some embodiments, 1-66 is administered on days 1.8, 15 and 22, mFOLFOX is administered on days 1 and 15, and bevacizumab is administered on days 1 and 15. In some embodiments, doses of 1-66 in a cycle are about the same (e.g., as described herein, about 18, 36, 72, 144, 240, 360, 420, 480, 600, etc. mg / m2). In some embodiments, doses of bevacizumab are about 5 mg / kg. In some embodiments, doses of folinic acid are about 400 mg / m2. In some embodiments, doses of oxaliplatin arc about 85 mg / m2. In some embodiments, fluorouracil (5-FU) are administered 2800 mg / m2on a day (e.g.. 400 mg / m2+ 1400 mg / m2). In some embodiments, a cancer is locally advanced or metastatic non-MSI-H or non-dMMR (e.g., by local testing) colorectal adenocarcinoma. In some embodiments, a cancer is MSS CRC. In some embodiments, a cancer is MSS CRC with WPAM.

[0292] In some embodiments, the present disclosure provides a method for treating cancer, comprising administering a combination of 1-66 and a PD-1 inhibitor. In some embodiments, the present disclosure provides a method for treating cancer, comprising administering a combination of 1-66 and nivolumab. In some embodiments, the combination is administered intravenously. In some embodiments, 1-66 is administered on a day of administration before nivolumab. In some embodiments, the combination is administered in cycles, e.g., of 28 days. For example, in some embodiments, 1-66 is administered on days 1, 8, 15 and 22, and nivolumab is administered on days 1 and 15. In some embodiments, doses of 1-66 in a cycle are about the same (e.g., as described herein, about 18, 36, 72, 144, 240, 360, 420, 480, 600, etc. mg / m2). In some embodiments, doses of nivolumab are about 240 mg. In some embodiments, a subject has locally advanced or metastatic solid tumors who have non-MSI-H or non-dMMR (e.g., by local testing) colorectal adenocarcinoma with liver metastases. In some embodiments, a subject has locally advanced or metastatic solid tumors who have non-MSI-H or non-dMMR (e.g., by local testing) colorectal adenocarcinoma without liver metastases. In some embodiments, a subject has locally advanced or metastatic solid tumors who have WPAM and has demonstrated resistance on anti-PD-l / PD-Ll therapy.

[0293] In some embodiments, the present disclosure provides a method for treating cancer, comprising administering a combination of 1-66, trifluridine, tipiracil. and bevacizumab. In some embodiments. 1-66 is administered intravenously. In some embodiments, bevacizumab is administered intravenously. In some embodiments, 1-66 is administered on a day of administration before trifluridine / tipiracil, and bevacizumab. In some embodiments, trifluridine / tipiracil is administered as LONSURF® or a generic thereof. In some embodiments, the combination is administered in cycles, e.g., of 28 days. For example, in some embodiments, 1-66 is administered on days 1, 8, 15 and 22, bevacizumab is administered on days 1 and 15, and trifluridine and tipiracil and administered orally twice daily on days 1 to 5 and days 8 to 12. In some embodiments, doses Page 86 of 27013160427vlAttorney Docket No.: 2012675-0415of 1-66 in a cycle are about the same (e.g., as described herein, about 18, 36, 72, 144, 240, 360, 420, 480, 600, etc. mg / m2). Tn some embodiments, doses of bevacizumab are about 5 mg / kg. In some embodiments, doses of trifluridine / tipiracil are about 35 mg / m2. In some embodiments, trifluridine / tipiracil are administered as tablets (e.g., 15 mg trifluridine / 6.14 mg tipiracil or 20 mg trifluridine / 8.19 mg tipiracil). In some embodiments, a subject has locally advanced or metastatic non-MSI-H or non-dMMR (e.g., by local testing) colorectal adenocarcinoma.

[0294] In some embodiments, a WPAM is documented. In some embodiments, a WPAM is determined by local testing. In some embodiments, a WPAM is detected or confirmed by sequencing, e.g., NGS. In some embodiments, a WPAM is in APC or CTNNB1. In some embodiments, a WPAM is an APC LoF mutation or a CTNNB1 GoF mutation. In some embodiments, a subject has a histologically or cytologically proven diagnosis.

[0295] In some embodiments, another therapy or therapeutic agent is or comprises a checkpoint inhibitor (e.g., antibodies against PD-1, PD-L1, CTLA-4, etc. or antigen-binding fragments thereof). In some embodiments, a combination is 1-66 and a checkpoint inhibitor. In some embodiments, a combination is 1-66 and a PD-1 inhibitor. In some embodiments, a combination is 1-66 and an anti-PD-1 agent. In some embodiments, a combination is 1-66 and an anti-PD-1 antibody (e.g., those approved by US FDA). For example, in some embodiments, a combination is 1-66 and nivolumab. In some embodiments, a combination is 1-66 and a PD-L1 inhibitor. In some embodiments, a combination is 1-66 and an anti-PD-Ll agent. In some embodiments, a combination is 1-66 and an anti-PD-Ll antibody (e.g., those approved by US FDA). In some embodiments, another therapy or therapeutic agent is or comprises a checkpoint inhibitor. In some embodiments, another therapy or therapeutic agent is or comprises an immune oncology agent. In some embodiments, another therapy or therapeutic agent is or comprises an antibody against a checkpoint molecule, or antigen-binding fragment thereof. In some embodiments, another therapy or therapeutic agent is or comprises an antibody against a checkpoint molecule. In some embodiments, another therapy or therapeutic agent is or comprises an antibody of PD-1, PDL-1, CTLA4, A2AR, B7-H3, B7-H4, BTLA, IDO, KIR, LAG3, TIM-s, C10orf54, etc., or an antigen-binding fragment thereof. In some embodiments, another therapy or therapeutic agent is or comprises a PD- 1 inhibitor. In some embodiments, another therapy or therapeutic agent is or comprises a PD-1 antibody or an antigen-binding fragment thereof. In some embodiments, another therapy or therapeutic agent is or comprises a PD-1 antibody. In some embodiments, another therapy or therapeutic agent is pembrolizumab. nivolumab. cemiplimab, durvalumab, dostarlimab. retifanlimab, toripalimab, or tislelizumab, or an antigen-binding fragment thereof. In some embodiments, another therapy or therapeutic agent is pembrolizumab, nivolumab, cemiplimab, durvalumab, dostarlimab, retifanlimab, toripalimab, or tislelizumab. In some embodiments, another therapy or therapeutic agent is pembrolizumab. In some embodiments, another therapy or therapeutic agent is nivolumab. In some embodiments, another therapy or therapeutic agent is cemiplimab. In some embodiments, another therapy or therapeutic agent is durvalumab. In some embodiments, another therapy or therapeutic agent is dostarlimab. In somePage 87 of 27013160427vlAttorney Docket No.: 2012675-0415embodiments, another therapy or therapeutic agent is retifanlimab. In some embodiments, another therapy or therapeutic agent is toripalimab. Tn some embodiments, another therapy or therapeutic agent is tislelizumab. In some embodiments, another therapy or therapeutic agent is or comprises a PD-L1 inhibitor. In some embodiments, another therapy or therapeutic agent is or comprises a PD-L1 antibody or an antigen-binding fragment thereof. In some embodiments, another therapy or therapeutic agent is or comprises a PD-L1 antibody. In some embodiments, another therapy or therapeutic agent is or comprises atezolizumab or antigen-binding fragment thereof. In some embodiments, another therapy or therapeutic agent is or comprises atezolizumab. In some embodiments, another therapy or therapeutic agent is or comprises durvalumab or antigen-binding fragment thereof. In some embodiments, another therapy or therapeutic agent is or comprises durvalumab.

[0296] For example, in some embodiments, another therapy or therapeutic agent is or comprises nivolumab (Opdivo®). which is a human immunoglobulin (Ig) G4 monoclonal antibody that binds to the programmed cell death- 1 (PD-1) receptor and blocks its interaction with ligands, including programmed cell death-ligand 1 (PD-L1) and programmed cell death-ligand 2 (PD-L2). PD-1 is expressed on T-cells and can attenuate their immune response upon binding its ligands and antigen presenting cells, including tumor cells in the tumor microenvironment. Blocking the interaction between PD-1 and its ligands can release the PD-1 pathway-mediated inhibition of the immune response, leading to an antitumor immune response. Nivolumab is used alone and in combination with other anticancer agents for the treatment of many advanced and metastatic solid tumors including microsatellite instability-high (MSI-H) or deficient DNA mismatch repair (dMMR) metastatic CRC, melanoma, non-small cell lung cancer (NSCLC), gastric, gastroesophageal junction, and esophageal cancers (see, e.g., prescribing information for nivolumab).

[0297] In some embodiments, another therapy or therapeutic agent reduces or avoids a side effect. In some embodiments, another therapy or therapeutic agent reduces or avoids bone turnover. In some embodiments, another therapy or therapeutic agent is or comprises antiresorptive therapy (e.g., bisphosphonates or denosumab). In some embodiments, a subject receives an antiresorptive therapy when increased bone turnover is observed after 1-66 dosing. In some embodiments, provided technologies provide the advantage that bone toxicity can be fully managed.

[0298] In some embodiments, another therapy is or comprises treatment for hyponatremia. In some embodiments, another therapy is or comprises treatment for hyponatremia. In some embodiments, another therapy or therapeutic agent is or comprises a salt tab. In some embodiments, another therapy or therapeutic agent is or comprises a mineralocorticoid, e.g., fludrocortisone. In some embodiments, another therapy or therapeutic agent is or comprises fludrocortisone. In some embodiments, fludrocortisone is administered upon observed decrease in sodium level.

[0299] In some embodiments, another therapy is ore comprises treatment for cytopenia. In some embodiments, another therapy or therapeutic agent is or comprises romiplostim.

[0300] Among other things, combinations of 1-66 with FOLFOX + bevacizumab, anti-PD-1 agents, or Page 88 of 27013160427vlAttorney Docket No.: 2012675-0415trifluridine / tipiracil + bevacizumab. respectively, have been tolerated in mouse pharmacology studies.Additionally, preclinical studies with 1-66 in combination with FOLFOX suggested additive or synergistic efficacy benefits. Also, preclinical testing suggests that treatment of CRC tumors with 1-66 can result in a favorable tumor microenvironment in which addition of an anti-PD-1 treatment could be beneficial.Preclinical studies adding trifluridine / tipiracil treatments with 1-66 suggest additive or synergistic efficacy benefits. In some embodiments, a condition, disease or disorder is advanced-stage and metastatic CRC progressed after therapy with oxaliplatin and irinotecan. In some embodiments, 1-66 is combined with a chemotherapy. For example, 1-66 + 5-FU exhibited robust anti-tumor activity when assessed in PDX models (for example, it was observed in CRC PDX models, 1-66 + SoC 5-FU can provide robust anti-tumor activity compared to vehicle, 1-66, and 5-FU, including many days (c.g., about 30 or more days) after the dosing phase). In some embodiments. 1-66 is combined with anti-angiogenics. In some embodiments, 1-66 is combined with an anti-VEGF therapy (e.g., bevacizumab). In some embodiments. 1-66 + bevacizumab exhibited robust anti-tumor activity in PDX models (for example, it was observed in CRC PDX models, 1-66 + anti-VEGF therapy can provide robust anti-tumor activity compared to vehicle, 1-66, and anti-VEGF, including many days (e.g., about 50 or more days) after the dosing phase). In some embodiments, 1-66 is combined with a checkpoint immunotherapy. In some embodiments, 1-66 is combined with anti-PDl. For example, in assessments in MC38 syngeneic model, the combination of 1-66 and anti-PD-1 exhibited robust anti -tumor activity and mice showed immunity upon rechallenge. In some embodiments, 1-66 + anti-PDl exhibited robust anti-tumor activity in CRC xenografts (for example, it was observed in CRC xenografts, 1-66 + anti-PDl therapy can provide robust anti -tumor activity compared to vehicle, 1-66, and anti-PDl.

[0301] In some embodiments, a cancer is resistant to another therapy or therapeutic agent. In some embodiments, a combination of 1-66 with another therapy or therapeutic agent provides more benefits compared to another therapy or therapeutic agent. In some embodiments, another therapy or therapeutic agent is administered or delivered according to their prescribing information. For example, in some embodiments. FOLFOX, bevacizumab, PD-1 inhibitor (e.g., nivolumab), Trifluridine / Tipiracil, etc., is administered according to their prescribing information, e.g., their US prescribing information which is available at fda.gov and is incorporated herein by reference.

[0302] In some embodiments, a cancer is advanced CRC. In some embodiments, a cancer is CRC resistant to chemotherapy. In some embodiments, a cancer is CRC resistant to FOLFOX. In some embodiments, a cancer is CRC resistant to mFOLFOX. In some embodiments, a cancer is CRC resistant to FOLFOX followed by FOLFIRI or vice versa. In some embodiments, cancer stem cells are chemoresistant. In some embodiments, cancer stem cells are reported to be associated with or be responsible for solid tumor recurrence. In some embodiments, CRC stem cells are reported to be dependent upon Wnt / beta-catenin signaling for initial activation and self-renewal. In some embodiments, in addition to maintaining selfrenewal. beta-catenin has been reported to increase 5-FU resistance in preclinical models of CRC. e.g., via upregulation of CRC stem cell ATP-binding cassette (ABC) transporters, such as ABCB1 that functions as a Page 89 of 27013160427vlAttorney Docket No.: 2012675-04155-FU efflux pump. In some embodiments, provided technologies reduces chemoresistance of cancer stem cell (e.g., CRC cancer stem cell). In some embodiments, provided technologies reduces initial activation and / or self-renewal of cancer stem cell (e.g., CRC cancer stem cell). In some embodiments, provided technologies can kill and / or reduce proliferation of cancer stem cell (e.g., CRC cancer stem cell). It has been reported that bevacizumab can bind human VEGF, preventing its interaction to its receptors (vascular endothelial growth factor receptor [VEGFR] 1 and VEGFR2) on the surface of normal endothelial cells, neovascular tumor endothelial cells, and tumor cells. Upon VEGF binding to its receptors, it is reported that intracellular signaling can initiate endothelial cell proliferation and new blood vessel formation. According to some reports, VEGF / VEGFR2 signaling leads to inhibition of GSK3B mediated inhibition of beta-catenin, promoting beta-catenin translocation to the nucleus where it has been shown to directly transcribe and upregulate VEGF in both normal endothelial cells as well as from tumor cells. VEGF production and VEGFR2 surface expression have been reported to be higher from tumor cells than normal healthy tissue. While VEGFR1 expression is reported to be lower in tumor cells than normal cells, upon binding to VEGF, VEGF / VEGFR1 is reported to be internalized via endocycling and has been reported to directly translocate to the nucleus and bind to beta-catenin / TCF complexes to promote cell survival. Among other things, the present disclosure encompasses the recognition of elevated beta-catenin activity promoting pathways to chemoresistance in CRC and activation of VEGF / VEGFR neovascular development, and benefit of combining 1-66 with current SoC chemotherapy (e.g., mF0LF0X-6) and bevacizumab. Among other things, preclinical studies in mice xenograft studies using 2 distinct CRC PDX models with LoF APC mutations demonstrated that 1-66 in combination with bevacizumab could provide deeper and more durable efficacy in such models. In these models, mice (n=5 / cohort) were administered 5 mg / kg 1-66 by IV dosing QW and 5 mg / kg bevacizumab intraperitoneally twice weekly. Control mice were supplied vehicle alone or with the appropriate IgG control. Animals were monitored for efficacy and body weights over repeat administration out to 50 days of treatment. No reportable body weight loss was observed in either study from any treatment or vehicle arm across studies. In each study, added TGI was observed from the combination when compared with either single agent alone. These 2 models were used to assess the combination of 1-66 with 5-FU. In both models, mice (n=5 / cohort) were administered 5 mg / kg 1-66 by IV dosing QW and 50 mg / kg 5-FU intraperitoneally QW. Control mice were supplied vehicle alone. Animals were monitored for efficacy and body weights over repeat administration out to 50 days of treatment. No reportable body weight loss was observed in either study from any treatment or vehicle arm across studies. In each study, added TGI was observed from the combination when compared with either single agent alone.

[0303] Wnt pathway, and beta-catenin in particular, have been reported to play roles in preventing immune infiltration into many solid tumor types, thereby resulting in a relative resistance to ICI therapy. In some embodiments, a role in preventing the recruitment of activated dendritic cells to the tumor has been reported. In some embodiments, a condition, disease or disorder is a cancer resistant to ICI therapy. In some embodiments, a condition, disease or disorder is or comprises solid tumor resistant to ICI therapy. In some Page 90 of 27013160427vlAttorney Docket No.: 2012675-0415embodiments, a condition, disease or disorder is CRC resistant to ICI therapy. In some embodiments, a condition, disease or disorder is CRC resistant to a checkpoint inhibitor, e.g., a PD-1 inhibitor. In some embodiments, a condition, disease or disorder is CRC resistant to anti -PD-1. In some embodiments, elevated beta-catenin activity reduces immune-mediated antitumor activity. In a syngeneic CRC model with APC heterozygous knockout (APC KO / +), strong combination benefit was observed between 1-66 and anti -PD-1 therapy, including comparing to in the matched isogenic control tumors that retained wild-type APC in a homozygous state (APC+ / +).

[0304] The Wnt / beta-catenin pathway is implicated in tumorigenesis and cancer stem cell maintenance in various reports. It has been reported that beta-catenin signaling is implicated in supporting resistance to various therapies, including cytotoxic therapies such as trifluridine / tipiracil, through maintenance of the cancer stem cell population. In some embodiments, a condition, disease or disorder is a cancer (e.g.. MSS CRC) resistant to a cytotoxic therapy, e.g., trifluridine / tipiracil. Cancer stem cells are reported to be intrinsically resistant to chemotherapies. Moreover, the Wnt / beta-catenin pathway is reported to be associated with the regulation of VEGF, so inhibiting 0-catcnin through 1-66 treatment can potentially enhance the antiangiogenic effect of bevacizumab and potentially prevent or delay resistance to cytotoxic therapies such as trifluridine / tipiracil. In some embodiments, provided technologies can simultaneously target DNA replication (trifluridine / tipiracil), angiogenesis (bevacizumab), and Wnt signaling (0-catenin inhibitor), providing more complete pathway inhibition. In some embodiments, provided technologies reduce cancer stem cell (e.g., CRC stem cell) maintenance.

[0305] In some embodiments, an anti-PDl antibody is nivolumab. In some embodiments, a dose of nivolumab is about 240 mg. In some embodiments, 1-66 is administered weekly and nivolumab is administered every two weeks. For example, in some embodiments, for a 28-day cycle, nivolumab is administered Q2W on days 1 and 15. In some embodiments, for the same cycle 1-66 is administered weekly on days 1. 8, 15 and 22. In some embodiments, an antibody is an anti-PD-Ll antibody. In some embodiments, an antibody is an anti-CTLA4.

[0306] In some embodiments, another agent is folinic acid. In some embodiments, a dose of folinic acid is about 400 mg / m2. In some embodiments, another agent is oxaliplatin. In some embodiments, a dose of oxaliplatin is about 85 mg / m2. In some embodiments, another agent is 5 -fluorouracil. In some embodiments, a dose of 5 -fluorouracil is about 2800 mg / m2. In some embodiments, another therapy is or comprises folinic acid, oxaliplatin, and 5 -fluorouracil. In some embodiments, another therapy is modified FOLFOX-6. In some embodiments, another therapy further comprises a VEGF inhibitor. In some embodiments, a VEGF inhibitor is bevacizumab. In some embodiments, a dose of bevacizumab is at least about 5 mg / kg. In some embodiments, 1-66 is administered or delivered weekly and bevacizumab and modified FOLFOX-6 are administered every two weeks. For example, in some embodiments, for a 28-day cycle, mFOLFOX-6 and bevacizumab are administered Q2W on days 1 and 15. In some embodiments, for the same cycle 1-66 is administered weekly on days 1, 8, 15 and 22.Page 91 of 27013160427vlAttorney Docket No.: 2012675-0415

[0307] In some embodiments, another agent is trifluridine. In some embodiments, another agent is tipiracil. In some embodiments, another therapy is or comprises administering trifluridine and tipiracil. In some embodiments, trifluridine / tipiracil is LONSURF® (those skilled in the art appreciate that for medications described herein, generic versions, if available, may also be utilized). In some embodiments, another therapy is LONSURF®. In some embodiments, LONSURF® is administered orally twice daily. In some embodiments, another therapy further comprises administering bevacizumab. In some embodiments, a dose of bevacizumab is at least 5 mg / kg. In some embodiments, 1-66 is administered weekly, bevacizumab is administered every two weeks, and LONSURF® is administered orally twice daily. In some embodiments, I-66 is administered weekly, bevacizumab is administered every two weeks, and LONSURF® is administered orally tw ice daily on days 1 to 5 and days 8 to 12 for a 28-day cycle. For example, in some embodiments, for a 28-day cycle, bevacizumab is administered Q2W on days 1 and 15 and trifluridine / tipiracil is administered orally tw ice daily on days 1 to 5 and days 8 to 12. In some embodiments, for the same cycle 1-66 is administered weekly on days 1, 8, 15 and 22.

[0308] In some embodiments, another agent reduces one or more side effects of 1-66. In some embodiments, another agent is or comprises an anti-resorptive agent. In some embodiments, an anti-resorptive agent is zoledronic acid or denosumab. In some embodiments, tire dose of an anti-resorptive agent is increased upon measurement of elevated beta-isomerized C-terminal telopeptide (beta-CTX) levels. In some embodiments, elevated beta-CTX levels are >250 pg / mL. In some embodiments, the dose of an anti-resorptive agent is increased upon observation of worsening osteopenia. In some embodiments, osteopenia comprises a T score below -2 and a >20% reduction of T score relative to baseline. In some embodiments, the dose of an anti-resorptive agent is increased upon observation of a non-traumatic fracture in the subject.

[0309] In some embodiments, a subject has received a therapy, e.g., cancer therapy. In some embodiments, a subject has received multiple therapies, e.g., cancer therapies. In some embodiments, a subject has progressed on one or more therapies, e.g., cancer therapies. In some embodiments, a subject is non-responsive or is less responsive to one or more therapies, e.g., cancer therapies. In some embodiments, a subject is resistant to one or more therapies, e.g., cancer therapies. Certain prior therapies, and certain such subjects, are described in Example 3. For example, in some embodiments, a subject has a histologically or cytologically proven diagnosis of locally advanced or metastatic solid tumor with documented WPAM (e.g., by local testing). In some embodiments, a subject has a histologically or cytologically proven diagnosis of locally advanced or metastatic non-MSI-H or non-dMMR (e.g., by local testing) colorectal adenocarcinoma. In some embodiments, a subject has received at least one prior systemic therapy. In some embodiments, a subject has progressed on or is nonresponsive to one or more therapies. In some embodiments, a subject is a CRC patient who has received prior 5-FU, oxaliplatin, irinotecan, and / or appropriate biologic therapy in the metastatic setting. In some embodiments, a subject has a histologically or cytologically proven diagnosis of locally advanced or metastatic non-MSI-H or non-dMMR (e.g., by local testing) colorectal adenocarcinoma and has received one or more lines of fluoropyrimidine-containing chemotherapy. In some embodiments, such Page 92 of 27013160427vlAttorney Docket No.: 2012675-0415a subject has progressed on or is nonresponsive to one or more therapies. In some embodiments, a subject has at least one tumor lesion / lymph node that meets RECIST 1.1 for measurable disease. In some embodiments, a subject has histologically or cytologically confirmed HCC with a documented WPAM (e.g., by local testing), c.g., in APC or CTNNBl. In some embodiments, a subject has HCC that is radiographically confirmed and has a documented CTNNBl mutation (e.g., by ctDNA). In some embodiments, a subject is Barcelona Clinic Liver Cancer (BCLC) stage C. In some embodiments, a subject is BCLC stage B but is not amenable to locoregional therapy or relapsed after locoregional therapy. In some embodiments, a subject has progressed on or intolerant to at least 1 line of systemic immune-based therapy or VEGF / tyrosinc kinase inhibitor (TKI)-based therapy for unresectable HCC. In some embodiments, a subject has a histologically confirmed desmoid tumor (aggressive fibromatosis) with a documented WPAM (c.g., by local testing) in APC or CTNNBl. In some embodiments, a subject has disease progressed by >10% as measured by RECIST 1.1 within 12 months prior to the first dose. In some embodiments, a subject has disease progressed by >20% as measured by RECIST 1.1 within 12 months prior to screening. In some embodiments, a subject has desmoid tumor progressed by >20% as measured by RECIST 1.1 within 12 months prior to screening. In some embodiments, a subject is a treatment-naive subject. In some embodiments, a subject has recurrent / refractory disease following at least 1 line of therapy (e.g., surgery, radiation, or systemic therapy). In some embodiments, a subject has a histologically or cytologically proven diagnosis of locally advanced or metastatic non-MSI-H or non-dMMR (e.g., by local testing) colorectal adenocarcinoma. In some embodiments, subjects with tumors (e.g., CRC tumors) known to be negative for A C LoF mutations or CTNNBl GoF mutations (e.g., per NGS tests) are not administered or delivered 1-66. In some embodiments, a subject has a histologically or cytologically proven diagnosis of locally advanced or metastatic solid tumors who have non-MSI-H or non-dMMR (e.g., by local testing) colorectal adenocarcinoma with liver metastases, has APC LoF and / or CTNNBl GoF mutations (e.g., per NGS tests), and optionally has received prior 5-FU, oxaliplatin, and / or irinotecan in the metastatic setting. In some embodiments, a subject has a histologically or cytologically proven diagnosis of locally advanced or metastatic solid tumors who have Non-MSI-H or non-dMMR (e.g., by local testing) colorectal adenocarcinoma without liver metastases, has APC LoF and / or CTNNBl GoF mutations (e.g., per NGS tests), and optionally has received, and optionally has received prior 5-FU, oxaliplatin, and irinotecan in the metastatic setting. In some embodiments, a subject has a histologically or cytologically proven diagnosis of locally advanced or metastatic solid tumors who have a documented WPAM by local testing (e.g., MSI-H CRC) for which anti-PD-l / PD-Ll with or without anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) therapy is SoC and has demonstrated primary or secondary resistance on anti-PD-l / PD-Ll therapy and optionally has received or are ineligible for SoC therapy. In some embodiments, a subject has a histologically or cytologically proven diagnosis of locally advanced or metastatic non-MSI-H or non-dMMR (e.g., by local testing) colorectal adenocarcinoma, the subject’s tumors are not known to be negative for APC LoF mutations or CTNNBl GoF mutations (per NGS tests) are not eligible, and has received prior 5-FU, oxaliplatin, irinotecan, and / or appropriate biologic therapy in the metastatic setting, and optionally has no more than a Page 93 of 27013160427vlAttorney Docket No.: 2012675-0415maximum of 2 lines of therapy in the metastatic setting. In some embodiments, for combination of 1-66, trifluridine / tipiracil and bevacizumab, a subject has not received trifluridine / tipiracil prior to initiation of the combination. In some embodiments, a subject has a histologically or cytologically proven diagnosis of locally advanced or metastatic non-MSI-H or non-dMMR (c.g., by local testing) colorectal adenocarcinoma, the subject’s tumors are not known to be negative for APC LoF mutations or CTNNB1 GoF mutations (e.g., per NGS tests). In some embodiments, a subject, e.g., a CRC patient, has received prior 5-FU, oxaliplatin, irinotecan, and / or appropriate biologic therapy, e.g., in the metastatic setting. In some embodiments, a subject, e g., a CRC patient, has no more than a maximum of 2 lines of therapy in the metastatic setting. In some embodiments, a subject is ineligible for surgery or chemoradiation with curative intent. In some embodiments, a subject has a histologically or cytologically proven diagnosis of advanced or metastatic solid tumors with a documented WPAM (e.g., by local testing) or equivalent evidence and has received at least 1 prior systemic therapy and either 1) has progressed on or is nonresponsive to one or more therapies known to provide meaningful clinical benefit or 2) are unfit for available therapies.

[0310] In some embodiments, a subject has mCRPC with a documented WPAM (e.g., by local testing) in APC and / or CTNNB1. In some embodiments, a subject has documented progressive mCRPC per Prostate Cancer Working Group 3 (PCWG3). In some embodiments, a subject after the last prior therapy an increase in PSA. In some embodiments, a subject after the last prior therapy has soft tissue disease progression (e.g., new or progressive soft tissue disease documented by CT or MRI). In some embodiments, a subject has bone disease progression. In some embodiments, a subject has histologically or cytologically confirmed adenocarcinoma of the prostate. In some embodiments, a subject has progressed on androgen deprivation therapy (ADT) and / or at least 1 of the following secondary hormonal therapies: abiraterone, enzalutamide, apalutamide, or darolutamide. In some embodiments, a subject has received prior taxane chemotherapy. In some embodiments, a subject has castrate level of serum testosterone <50 ng / dL. In some embodiments, a subject continues ADT with a luteinizing hormone releasing hormone (LHRH) agonist / antagonist (e.g., if he has not undergone bilateral orchiectomy). In some embodiments, a subject has received abiraterone acetate, rucaparib, olaparib, enzalutamide flutamide, nilutamide, bicalutamide, or another secondary hormonal therapy, chemotherapy, or immunotherapy. In some embodiments, a subject has baseline PSA >2 ng / mL.

[0311] In some embodiments, a subject has received a cancer therapy, e.g., surgery, radiation therapy, chemotherapy, immunotherapy, etc. In some embodiments, a subject has received surgery. In some embodiments, a subject has received radiation therapy. In some embodiments, a subject has received chemotherapy. In some embodiments, a subject has received immunotherapy. In some embodiments, a subject has progressed on a received therapy. In some embodiments, a cancer is resistant to a received therapy. In some embodiments, reduced response or non-response has been observed for a therapy. In some embodiments, a subject has metastasis. In some embodiments, a subject has bone metastasis. In some embodiments, a subject has liver metastasis. In some embodiments, a subject does not have metastasis. In some embodiments, a subject does not have bone metastasis. In some embodiments, a subject does not have Page 94 of 27013160427vlAttorney Docket No.: 2012675-0415liver metastasis. In some embodiments, a subject does not have symptomatic brain metastasis or leptomeningeal carcinomatosis.

[0312] In some embodiments, after one or more doses of 1-66 are administered or delivered as described herein, downregulation of one or more Wnt transcriptional signatures (c.g., AXIN2, NKD1, RNF43, ZNRF3, NOTUM, etc.), downregulation of one or more sternness markers (e.g., SOX9, MEX3A, EPHB2, ASCL2, LGR5, etc.), upregulation of one or more differentiation markers (e.g., MUC2, KRT20, ALPI, ANPEP, CA2, etc.), and / or upregulation of one or more inflammatory markers (e.g., CD8A, NKG7, HLA-DQA1, HLA-DRB1, CMKLR1, IFNG, CCL5, CXCL9, CD27, IDO1, STAT1, TIGIT, LAG3, PD-L1, PD-L2, etc.) are observed. In some embodiments, downregulation and upregulation are assessed using, e.g., RNASeq.

[0313] In some embodiments, the present disclosure provides technologies for assessing 1-66, sec, c.g., Figure 16 and Example 3. In some embodiments, key inclusion criteria include 8 years or older, ECOG score of 0-1. adequate organ and marrow function. In some embodiments, for a cohort, key inclusion criteria further include:1) MSS or pMMR CRC with WPAM+ solid tumors with <1 prior systemic therapy and progressed on, not responded to, or unfit for available therapies; or2) MSS CRC; received >1 fluoropyrimidine-containing therapy and progressed on, not responded to, or unfit for available therapies; prior 5-FU, oxaliplatin, irinotecan, and appropriate biological therapy in metastatic setting, and <4 prior metastatic lines; >1 lesion or lymph node measurable by RECIST vl.l; and / or >1 lesion suitable for lymph node biopsy.In some embodiments, key exclusion criteria include known history of bone metastasisl; vertebral compression fracture or non-traumatic bone fracture in past 12 months and not receiving antire sorptive therapy; osteoporosis; inflammatory bowel disease; symptomatic pleural effusion requiring intermittent thoracentesis; inadequate cardiac function; malignant bowel obstruction in past 3 months; and known meningeal carcinomatosis, leptomeningeal carcinomatosis, spinal core compression, or symptomatic or unstable brain metastases.

[0314] In some embodiments, a clinical study contains the following:Arms and interventions:Anns Assigned Interventions Experimental: Part la Drug: 1-66Solid Tumors with any Wnt-Pathway 1-66 is administered IV at assigned doses in continuous Activating Mutation (WPAM) or cycles of 28 daysMicrosatellite Stable (MSS) ColorectalCancer (CRC), irrespective of WPAMstatusExperimental: Part lb Drug: 1-66Page 95 of 27013160427vlAttorney Docket No.: 2012675-0415MSS CRC (known WPAM negative 1-66 is administered IV at assigned doses in continuous participants are not eligible) cycles of 28 daysExperimental: Part 1c Drug: 1-66Hepatocellular Carcinoma (documented 1-66 is administered IV at assigned doses in continuous WPAM in APC or CTNNB 1 required) cycles of 28 daysExperimental: Part Id Drug: 1-66Desmoid Tumors (documented WPAM in 1-66 is administered IV at assigned doses in continuous APC or CTNNB 1 required) cycles of 28 daysExperimental: Part le-1 Drug: 1-66Solid Tumors with documented WPAM or 1-66 is administered IV at assigned doses in continuous MSS CRC. irrespective of WPAM status cycles of 28 daysExperimental: Part le-2 Drug: I-66Solid Tumors with documented WPAM or 1-66 is administered IV at assigned doses in continuous MSS CRC, irrespective of WPAM status cycles of 28 daysExperimental: Part lf-1 Drug: 1-66MSS CRC (known WPAM negative 1-66 is administered IV at assigned doses in continuous participants are not eligible) cycles of 28 daysDrug: mFOLFOX-6mFOLFOX-6 is administered per the prescribing information in combination with 1-66Other Names: Leucovorin, 5 -fluorouracil, Oxaliplatin Drug: BevacizumabBevacizumab is administered per the prescribing information in combination with 1-66Other Names: AvastinExperimental: Part lf-2 Drug: 1-66Solid Tumors with documented WPAM or 1-66 is administered IV at assigned doses in continuous MSS CRC (known WPAM negative cycles of 28 daysparticipants are not eligible) Drug: NivolumabNivolumab is administered per tire prescribing information in combination with 1-66Other Names: OpdivoExperimental: Part lf-3 Drug: 1-66MSS CRC (known WPAM negative 1-66 is administered IV at assigned doses in continuous participants are not eligible) cycles of 28 daysPage 96 of 27013160427vlAttorney Docket No.: 2012675-0415Drug: Trifluridine / tipiracilTrifluridine / tipiracil is administered per the prescribing information in combination with 1-66Other Names: LonsurfDrug: BevacizumabBevacizumab is administered per the prescribing infonnation in combination with 1-66Other Names: AvastinExperimental: Part 2a Drug: 1-66MSS CRC, irrespective of WPAM status 1-66 is administered IV at assigned doses in continuous cycles of 28 daysExperimental: Part 2b Drug: 1-66Solid Tumors with documented WPAM 1-66 is administered IV at assigned doses in continuous cycles of 28 daysExperimental: Part 2c Drug: 1-66Hepatocellular Carcinoma (documented 1-66 is administered IV at assigned doses in continuous WPAM in APC or CTNNB 1 required) cycles of 28 daysExperimental: Part 2d Drug: 1-66Desmoid Tumors (documented WPAM in 1-66 is administered IV at assigned doses in continuous APC or CTNNB 1 required) cycles of 28 daysExperimental: Part 2e Drug: 1-66Metastatic Castration-Resistant Prostate 1-66 is administered IV at assigned doses in continuous Cancer (documented WPAM in APC or cycles of 28 daysCTNNB 1 required)Experimental: Part 2f-1 Drug: 1-66MSS CRC (known WPAM negative 1-66 is administered IV at assigned doses in continuous participants are not eligible) cycles of 28 daysDrug: mFOLFOX-6mFOLFOX-6 is administered per the prescribing information in combination with 1-66Other Names:• Leucovorin, 5 -fluorouracil,Oxaliplatin Drug: BevacizumabBevacizumab is administered per the prescribing infonnation in combination with 1-66Page 97 of 27013160427vlAttorney Docket No.: 2012675-0415Other Names:AvastinExperimental: Part 2f-2 Drug: 1-66Solid Tumors with documented WPAM or 1-66 is administered IV at assigned doses in continuous MSS CRC (known WPAM negative cycles of 28 daysparticipants are not eligible) Drug: NivolumabNivolumab is administered per the prescribing information in combination with 1-66Other Names:OpdivoExperimental: Part 2f-3 Drug: 1-66MSS CRC (known WPAM negative 1-66 is administered IV at assigned doses in continuous participants are not eligible) cycles of 28 daysDrug: Trifluridine / tipiracilTrifluridine / tipiracil is administered per the prescribing information in combination with 1-66Other Names: LonsurfDrug: BevacizumabBevacizumab is administered per the prescribing information in combination with 1-66Other Names: AvastinOutcome MeasuresPrimary Outcome Measure:1. During dose escalation and dose expansion measure incidence and severity of treatment emergent adverse events by CTCAE v5.0Number and severity of treatment emergent adverse events as assessed by CTCAE v5.0[Time Frame: Through study completion, an average of 10 months]2. During dose escalation characterize dose-limiting toxicities (DLTs)Incidence of DLTs[Time Frame: 1 treatment cycle (28 days)]3. During dose expansion describe the Overall Response Rate using RECIST vl.lThe rate of objective responses (Partial & Complete) using RECIST vl.l[Time Frame: Every 63 days until study completion, approximately 10 months on average]4. During dose expansion describe the Disease Control Rate using RECIST vl.l (Part 2a only)The rate of objective responses (Stable, Partial, & Complete) using RECIST vl.lPage 98 of 27013160427vlAttorney Docket No.: 2012675-0415[Time Frame: 4 months]5. During dose expansion describe the PSA30 response rate for participants with prostate cancer The response to treatment as a 30% or greater reduction in PSA levels from baseline[Time Frame: Baseline, weekly during the first 2 cycles (56 days), bi-weekly during the Cycle 3 (28 days), and then monthly (up to approximately 7 months)]Secondary Outcome Measure:6. Maximum observed plasma concentration (Cmax) of 1-66 and associated metabolites[Time Frame: During first 2 cycles (56 days)]7. Time to achieve Cmax (Tmax) of 1-66 and associated metabolites in plasma[Time Frame: During first 2 cycles (56 days)]8. Area under the plasma concentration-time curve (AUC) of 1-66 and associated metabolites[Time Frame: During first 2 cycles (56 days)]9. Plasma trough concentration (Ctrough) of 1-66 and associated metabolites[Time Frame: During first 2 cycles (56 days)]10. Clearance (CL) of 1-66 from the plasma[Time Frame: During first 2 cycles (56 days)]11. Volume of distribution of 1-66[Time Frame: During first 2 cycles (56 days)]12. During dose escalation select the preliminary recommended Phase 2 dose and dosing schedule of study drug[Time Frame: Through Part 1 study completion]13. Rate of DLTs across dose levels[Time Frame: During Cycle 1 (28 days)]14. During dose escalation Part lb to evaluate the pharmacodynamic activity in tumorsChange in tumor Myc expression (on-study compared to baseline)[Time Frame: During first 2 cycles (56 days)]15. During dose escalation and expansion to describe Best Overall Response Rate using RECIST vl.l Best response to treatment using RECIST vl.l[Time Frame: Every 63 days until study completion, approximately 10 months on average]16. During dose escalation and expansion to describe Duration of Response using RECIST vl.l Time from initial objective response (partial response or complete response) to disease progression [Time Frame: Every 63 days until study completion, approximately 10 months on average]17. During dose escalation and expansion describe Progression Free SurvivalProgression Free Survival (PFS) using RECIST vl.l[Time Frame: From date of randomization until the date of first disease progression, an average of 10 months]Page 99 of 27013160427vlAttorney Docket No.: 2012675-041518. During dose escalation and expansion describe the Disease Control Rate using RECIST vl.lThe rate of objective responses (Stable, Partial, & Complete) using RECIST vl.l[Time Frame: Every 63 days until study completion, approximately 10 months on average]19. During dose escalation and expansion describe the Time To Progression using RECIST vl.lTime To Progression (TTP) using RECIST vl.l[Time Frame: From date of randomization until the date of first disease progression, an average of 10 months]20. During dose escalation and expansion describe radiographic Progression Free Survival for participants with prostate cancerRadiographic Progression Free Survival (rPFS) using PCWG3 assessment criteria[Time Frame: From date of randomization until the date of first disease progression, an average of 10 months]EligibilityMinimum Age: 18 YearsMaximum Age:Sex: AllGender Based: NoAccepts Healthy Volunteers: NoCriteria: Inclusion Criteria:• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.• Adequate organ and marrow function.Additional Inclusion Criteria for Dose Escalation Cohorts (Part la and Part le):• Diagnosis of treatment-refractory advanced / metastatic solid tumor that is non-MSI-H or non-dMMR colorectal cancer (CRC) or any other solid tumor with documented Wnt- pathway activating mutations (WPAMs).Additional Inclusion Criteria for Dose Escalation Cohorts (Part lb):• Diagnosis of treatment-refractory advanced / metastatic non-MSI-H or non-dMMR CRC.• At least one lesion that is suitable for a core needle biopsy.Additional Inclusion Criteria for Dose Escalation and Dose Expansion Cohorts (Part 1c and Part 2c):• Diagnosis of HCC with a documented WPAM (by local testing) in APC or CTNNB 1. HCC that is radiographically confirmed without tissue biopsy may be enrolled with a documented CTNNB 1 mutation (e.g., by ctDNA).Additional Inclusion Criteria for Dose Escalation and Dose Expansion Cohorts (Part Id and Part 2d):• Desmoid tumor (aggressive fibromatosis) with a documented WPAM (by local testing) in APC or CTNNB 1.Additional Inclusion Criteria for Dose Escalation and Dose Expansion Cohorts (Part If- 1 and Part 2f- 1) 1-66Page 100 of 27013160427vlAttorney Docket No.: 2012675-0415+ FOLFOX + Bevacizumab:• Diagnosis of locally advanced or metastatic non-MSI-H or non-dMMR CRC• Participants with tumors known to be negative for APC LoF mutations or CTNNB 1 GoF mutations (per NGS tests) are not eligible.• One dose of mF0LF0X6 in the unresectable or metastatic setting prior to enrollment may be allowed. Additional Inclusion Criteria for Dose Escalation and Dose Expansion Cohorts (Part lf-2 and Part 2f-2): 1-66 + Nivolumab• Non-MSI-H or non-dMMR (by local testing) CRC with or without liver metastases.• MSI-H CRC or solid tumors that are WPAM and resistant to a-PD-l / PD-Ll• Participants with tumors known to be negative for APC LoF mutations or CTNNB 1 GoF mutations (per NGS tests) are not eligibleAdditional Inclusion Criteria for Dose Escalation and Dose Expansion Cohorts (Part lf-3 and Part 2f-3): 1-66 + Trifluridine / Tipiracil + Bevacizumab• Diagnosis of locally advanced or metastatic non-MSI-H or non-dMMR (by local testing) CRC• Participants with tumors known to be negative for APC LoF mutations or CTNNB 1 GoF mutations (per NGS tests) are not eligible.Additional Inclusion Criteria for Dose Expansion Cohort (Part 2a):• Diagnosis of locally advanced or metastatic non-MSI-H or non-dMMR (by local testing) CRC Additional Inclusion Criteria for Dose Expansion Cohort (Part 2b):• Diagnosis of advanced or metastatic solid tumors with a documented WPAM (by local testing) or equivalent evidenceExclusion Criteria:• Known history of bone metastasis. Bone metastasis are allowed for patients with mCRPC.• Evidence of vertebral compression fracture or non-traumatic bone fracture within the past 12 months and who are not receiving antiresorptive therapy.• Osteoporosis, which is defined as a T-score of <-2.5 at the lumbar spine (LI - L4), left (or right) femoral neck or left (or right) total hip as determined by DXA scan.• Inflammatory bowel disease (i.e., ulcerative colitis or Crohn’s disease) that is recently active or requires therapy currently, or that is uncontrolled.• Unstable / inadequate cardiac function.• Has known meningeal carcinomatosis, leptomeningeal carcinomatosis, spinal cord compression, or symptomatic or unstable brain metastases.• Pregnant, lactating, or planning to become pregnant.

[0315] Among other things, 1-66 can target beta-catenin and modulate its function. The present disclosure, among other things, describes clinical observations from human subjects, including side effects and technologies for managing them. In some embodiments, the present disclosure provides combination Page 101 of 27013160427vlAttorney Docket No.: 2012675-0415therapies comprising 1-66. Observations described herein, e.g., side effects, and technologies for managing them, and combination therapies, can be applicable to other agents that may function through similar mechanisms, e.g., target beta-catenin (e.g., at the TCF sites). Various such agents are described, generically or specifically, in US 20240116985, US 20240360179, WO 2024130217 and WO 2024130218, and are incorporated herein by reference.

[0316] In some embodiments, a composition, e.g., a composition comprising or delivering 1-66, is administered intravenously. In some embodiments, a composition is for IV administration. In some embodiments, a composition is administered subcutaneously. In some embodiments, a composition is for subcutaneous administration. In some embodiments, subcutaneous administration is utilized for desmoid or other Wnt / beta-catenin-driven tumor. In some embodiments, an autoinjector, e.g., a 2 mL autoinjector, is utilized for subcutaneous administration.

[0317] Among other things, the present disclosure provides the Embodiments below:1. A composition, comprising:1-66;a PEG;a buffer agent;optionally a pH adjustment agent; anda solvent.2. A composition, comprising:1-66;a surfactant;a buffer agent;optionally a pH adjustment agent; anda solvent.3. A composition, comprising:1-66;a solubilizing agent;a buffer agent;optionally a pH adjustment agent; anda solvent.4. The composition of Embodiment 3, wherein a solubilizing agent is an amino acid.5. A composition, comprising:1-66;an amino acid;a buffer agent;Page 102 of 27013160427vlAttorney Docket No.: 2012675-0415optionally a pH adjustment agent; anda solvent.6. The composition of any one of Embodiments 3-5, further comprising a PEG.7. The composition of any one of Embodiments 3-6, furt...

Claims

Attorney Docket No.: 2012675-0415CLAIMS1. A method for treating desmoid tumor, comprising administering or delivering I-66 to a subject suffering therefrom.

2. A method for treating familial adenomatous polyposis (FAP), comprising administering or delivering 1-66 to a subject suffering therefrom.

3. A method for treating adamantinomatous craniopharyngioma, comprising administering or delivering 1-66 to a subject suffering therefrom.

4. The method of any one of claims 1-3, comprising a dose level of about 240 mg / nf and / or about 72 mg / m2.

5. Tire method of any one of claims 1-3, comprising a dose level of about 144 mg / m2and / or about 360 mg / m2.

6. The method of any one of claims 1-5, wherein two or more doses of 1-66 are administered about weekly or about every two weeks.

7. A method for treating ameloblastoma, comprising administering or delivering 1-66 to a subject suffering therefrom.

8. Tire method of claim 7, comprising a dose level of about 480 mg / m2.

9. The method of any one of claims 7-8, wherein two or more doses of 1-66 are administered about weekly.

10. A method for treating cancer, comprising administering or delivering 1-66 to a subject suffering therefrom.

11. A method, comprising administering 1-66 to a subject, wherein when assessed, the delivery of 1-66 is dose-linear.

12. The method of claim 11, wherein the subject has cancer and / or a tumor.

13. The method of any one of claims 10-12. wherein the cancer is a solid tumor, optionally wherein the cancer is a locally advanced or metastatic solid tumor.

14. The method of any one of claims 10-13, wherein the cancer is hepatocellular carcinoma (HCC).

15. Tire method of any one of claims 10-13, wherein the cancer is prostate cancer.

16. Tire method of any one of claims 10-13, wherein the cancer is metastatic castration-resistant prostate cancer (mCRPC).

17. The method of any one of claims 10-13. wherein the cancer is colorectal cancer.

18. The method of any one of claims 10-13, wherein the cancer is gastric cancer, lung cancer, non-small cell lung cancer, metastatic non-small cell lung cancer, non-small cell lung cancer stage IIIB, non-small cell carcinoma, non-small cell carcinoma of lung, TNM Stage 4, or gastroesophageal-junction cancer.

19. The method of any one of claims 10-18, wherein:the tumor is non-MSI-H;the tumor is non-dMMR;Page 258 of 27013160427vlAttorney Docket No.: 2012675-0415the cancer is a locally advanced cancer:the cancer is a metastatic cancer: and / orthe cancer is microsatellite stable.

20. Tire method of any one of claims 10-13, wherein the cancer is MSS colorectal cancer.

21. The method of any one of claims 10-13, wherein the cancer is advanced or metastatic MSS colorectal cancer.

22. The method of claim 20, wherein the microsatellite stable cancer is characterized as non-MSI-H and non-dMMR as defined by local testing.

23. Tire method of claim 17, wherein the colorectal cancer is MSI-H colorectal cancer.

24. Tire method of any one of claims 10-13, wherein the cancer is advanced or metastatic non-small cell lung cancer, advanced or metastatic gastric cancer, or advanced or metastatic gastroesophageal junction cancer.

25. The method of any one of claims 10-13, wherein the cancer is adamantinomatous craniopharyngioma, desmoid tumors, ameloblastoma, endometrial cancer, esophageal cancer, HCC, jejunal cancer, NSCLC, pancreatic acinar cell carcinoma (ACC), sal i van gland cancer, solid pscudopapillary neoplasm (SPN), uterine cancer, vaginal cancer, or synovial sarcoma.

26. The method of any one of claims 10-25. wherein the cancer comprises a Wnt pathway activating mutation (WPAM).

27. The method of any one of claims 1-25, wherein a cell or tumor of the cancer:comprises a Wnt pathway activating mutation;comprises increased expression of one or more Wnt / p-catenin pathway genes;is determined to comprise increased expression of Wnt / p-catenin pathway genes;comprises increased expression of AXIN1, AXIN2, APCDD1, NKD1, WIFI, DLX3 and / or TCF4; or comprises increased nuclear P-catenin expression, optionally wherein increased nuclear P-catenin expression is determined by immunohistochemistry (IHC).

28. The method of any one of claims 10-13, wherein the cancer is WPAM+ solid tumor.

29. Tire method of any one of claims 1-28, wherein the tumor or cancer comprises an APC mutation.

30. A method for treating desmoid tumor, comprising administering or delivering 1-66 to a subject suffering therefrom, wherein the tumor comprises an APC mutation.

31. The method of any one of claims 29-30. wherein the APC mutation is a LoF mutation, optionally wherein the APC mutation is D849*.

32. The method of any one of claims 1-31, wherein the tumor or cancer comprises a beta-catenin mutation.

33. The method of claim 32, wherein the beta-catenin mutation is a beta-catenin gain-of-function mutation.

34. The method of any one of claims 32-33, wherein the beta-catenin mutation is missense, in-frame Page 259 of 27013160427vlAttorney Docket No.: 2012675-0415insertion, or deletion at codons 32-37, 41, and / or 45, optionally wherein the beta-catenin mutation is a T41I mutation, a T41 A mutation, a S45F mutation, a S45P mutation, a D32V mutation, a H36P mutation, and / or a S45_G48del mutation, optionally wherein the beta-catenin mutation is a T41I mutation, a T41A mutation, and / or a S45F mutation.

35. The method of any one of claims 10-13, wherein:the cancer is advanced or metastatic non-small cell lung cancer with documented WPAM in APC; the cancer is advanced or metastatic non-small cell lung cancer with documented WPAM in beta-catenin;the cancer is advanced or metastatic gastric cancer with documented WPAM in APC;the cancer is advanced or metastatic gastric cancer with documented WPAM in bcta-catcnin; the cancer is advanced or metastatic gastroesophageal junction cancer with documented WPAM in APC; orthe cancer is advanced or metastatic gastroesophageal junction cancer with documented WPAM in beta-catenin.

36. Tire method of any one of claims 10-35, comprising a mutation selected from APC loss of function mutations, CTNNB1 gain of function mutations, RNF43 LOF mutations, and RSPO2 and RSPO3 fusions.

37. The method of any one of claims 10-36. comprising a mutation selected from mutations in AMER1, AXIN1, AXIN2, BCL9. CSNK1A1. GSK3B, LRP5, LRP6, LGR5, TCF7L2, and WIFI.

38. The method of any one of claims 10-37, wherein the WPAM is determined by local testing.

39. The method of any one of claims 10-38, wherein cMyc expression in a tumor sample is reduced.

40. Tire method of any one of claims 10-39, wherein the tumor or cancer is refractory.

41. A method for modulating beta-catenin interaction with a partner in a system, comprising administering or delivering to the system 1-66.

42. The method of claim 41, wherein the partner is TCF4.

43. A method for modulating a TCF-beta-catenin interaction in a system, comprising:contacting beta-catenin with 1-66 or comprising administering or delivering to the system 1-66; or administering or delivering to the system 1-66.

44. A method for decreasing beta-catenin polypeptide level in a system, comprising administering or delivering to the system 1-66.

45. A method for decreasing c-Myc polypeptide and / or transcript level in a system, comprising administering or delivering to the system 1-66.

46. The method of any one of claims 44-45, wherein c-Myc polypeptide level is reduced and / or c-Myc mRNA level is reduced, optionally wherein the reduction is observed 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more days post a dose.

47. A method for decreasing Axin2 polypeptide and / or transcript level in a system, comprising administering or delivering to the system 1-66.Page 260 of 27013160427vlAttorney Docket No.: 2012675-041548. The method of any one of claims 44-47, wherein Axin2 polypeptide level is reduced and / or Axin2 mRNA level is reduced.

49. A method for decreasing NKD1 transcript level in a system, comprising administering or delivering to the system 1-66.

50. The method of any one of claims 44-49, wherein NKD1 polypeptide level is reduced and / or NKD1 mRNA level is reduced.

51. A method for decreasing ASCL2 transcript level in a system, comprising administering or delivering to the system 1-66.

52. Tire method of any one of claims 44-51, wherein ASCL2 polypeptide level is reduced and / or ASCL2 mRNA level is reduced.

53. A method for decreasing transcript levels of one or more WNT pathway markers (e.g., AXIN2, NKD1, RNF43, ZNRF3, NOTUM, VEGFA, etc.) in a system, comprising administering or delivering to the system 1-66;a method for decreasing transcript levels of one or more sternness markers (e.g., SOX9, MEX3A, EPHB2, ASCL2, LGR5, etc.) in a system, comprising administering or delivering to the system 1-66;a method for increasing transcript levels of one or more differentiation markers (e.g., MUC2, KRT20, ALPI, ANPEP, CA2, etc.) in a system, comprising administering or delivering to the system 1-66;a method for increasing transcript levels of one or more inflammatory markers (e.g., CD8A, NKG7, HLA-DQA1, HLA-DRB1, CMKLR1, IFNG, CCL5, CXCL9, CD27, IDO1, STAT1, TIGIT, LAG3, PD-L1, PD-L2, etc.) in a system, comprising administering or delivering to the system 1-66; ora method for increasing transcript levels of one or more hypoxia markers (e.g., EPAS 1, HIF2A, HIF 1A, HIF3A, etc.) in a system, comprising administering or delivering to tire system 1-66.

54. A method for modulating WNT / beta-catenin pathway in a system, comprising administering or delivering to the system 1-66, wherein expression of a nucleic acid is modulated.

55. A method, comprising administering or delivering to the system 1-66, wherein level of a transcript of a nucleic acid and / or a product thereof is modulated.

56. A method, comprising administering or delivering to the system 1-66, wherein expression of a nucleic acid is modulated.

57. The method of any one of claims 54-56. wherein a nucleic acid is or comprises a gene.

58. The method of any one of claims 54-57. wherein:the nucleic acid is AXIN2;the nucleic acid is NKD1;the nucleic acid is a member of BCAT GDS748 UP gene set;the nucleic acid is a member of BCAT.100 UP. V1 UP gene set;the nucleic acid is a member of HALLMARK WNT BETA CATENIN SIGNALING gene set; the nucleic acid is a member of HALLMARK MYC TARGETS V2 gene set;Page 261 of 27013160427vlAttorney Docket No.: 2012675-0415the nucleic acid is a member of HALLMARK E2F TARGETS gene set: and / orthe nucleic acid is a member of HALLMARK G2M CHECKPOINT gene set.

59. The method of any one of claims 41-58, wherein:a system is an in vitro system;a system is an in vivo system; ora system is or comprises a sample.

60. The method of any one of claims 41-59 wherein:a system is or comprises a cell, tissue or organ;a system is or comprises cancer cells;a system is or comprises a tumor; and ora system is a subject.

61. The method of any one of the preceding claims, comprising administering 1-66:about weekly, optionally for at least about three doses or for at least about four doses;about every two weeks, optionally for at least three doses; orabout every three weeks.

62. Tire method of claim 61, comprising administering 1-66 about w eekly before administering 1-66 at a lower frequency, optionally comprising:administering 1-66 weekly for about 4 or more doses before administering 1-66 about every two weeks; oradministering 1-66 weekly for about 4 or more doses before administering 1-66 about weekly for about 3 doses followed by a week without administration.

63. Tire method of any one of the preceding claims, comprising administering 1-66 in a composition having a volume of about 250 m.

64. The method of any one of the preceding claims, comprising administering or delivering 1-66 intravenously.

65. The method of any one of the preceding claims, w herein a dose of about 18 mg / m21-66, 36 mg / m21- 66. 72 mg / m21-66, 144 mg / m21-66, 240 mg / m21-66, 360 mg / m21-66, 420 mg / m21-66, 480 mg / m21-66, or 600 mg / m21-66 is administered.

66. The method of any one of the preceding claims, comprising administering or delivering 1-66 at assigned doses in continuous cycles, optionally wherein the assigned dose of each cycle is about the same and / or w herein the assigned dose of a cycle is different from another cycle, optionally w herein:a cycle is about 21 days or 28 days; and / oreach cycle is independently about 21 days or about 28 days.

67. The method of claim 66, wherein:a cycle is about 28 days, and 1-66 is administered or delivered about weekly on days 1, 8, 15, and 22; a cycle is about 28 days, and 1-66 is administered or delivered about even' two weeks on days 1 and Page 262 of 27013160427vlAttorney Docket No.: 2012675-041515; and / ora cycle is about 28 days, and 1-66 is administered or delivered about weekly on days 1, 8, and 15, and the number of 1-66 doses in the cycle is 3.

68. Tire method of any one of claims 66-67, wherein:an assigned dose of a cycle is about 18 mg / m21-66;an assigned dose of a cycle is about 36 mg / m21-66;an assigned dose of a cycle is about 72 mg / m21-66;an assigned dose of a cycle is about 144 mg / m21-66;an assigned dose of a cycle is about 240 mg / m21-66;an assigned dose of a cycle is about 360 mg / m21-66;an assigned dose of a cycle is about 420 mg / m21-66;an assigned dose of a cycle is about 480 mg / m21-66; and / oran assigned dose of a cycle is about 600 mg / m21-66.

69. The method of any one of claims 66-68, wherein two or more doses are administered about weekly or three or more doses are administered about weekly, optionally wherein doses are administered about weekly except for the last week of a cycle.

70. The method of any one of the preceding claims, comprising administering or delivering to a subject another therapy or another therapeutic agent, optionally comprising administering or delivering to a subject two or more other therapeutic agents, optionally wherein:an another therapy or therapeutic agent is administered prior to 1-66;an another therapy or therapeutic agent is administered concurrently with 1-66; oran another therapy or therapeutic agent is administered after 1-66.

71. The method of claim 70, wherein an another therapy or therapeutic agent is administered on the same day as 1-66.

72. The method of any one of claims 70-71, wherein an another therapy or therapeutic agent is or comprises chemotherapy, optionally wherein an another therapy or therapeutic agent is or comprises a chemotherapy agent, optionally wherein:an another therapy or therapeutic agent is or comprises fluorouracil;an another therapy or therapeutic agent is or comprises folinic acid or a salt thereof;an another therapy or therapeutic agent is or comprises leucovorin calcium;an another therapy or therapeutic agent is or comprises oxaliplatin;an another therapy or therapeutic agent is or comprises mF0LF0X-6;an another therapy or therapeutic agent is or comprises trifluridine;an another therapy or therapeutic agent is or comprises tipiracil;an another therapy or therapeutic agent is or comprises trifluridine and tipiracil;an another therapy or therapeutic agent is or comprises LONSURF® or a generic thereof;Page 263 of 27013160427vlAttorney Docket No.: 2012675-0415an another therapy or therapeutic agent is or comprises anti-angiogenics;an another therapy or therapeutic agent is or comprises anti-VEGF therapy;an another therapy or therapeutic agent is or comprises anti-VEGF antibody or an antigen-binding fragment thereof;an another therapy or therapeutic agent is or comprises anti-VEGF antibody;an another therapy or therapeutic agent is or comprises bevacizumab or an antigen-binding fragment thereof; and / oran another therapy or therapeutic agent is or comprises bevacizumab.

73. Tire method of any one of claims 70-71, wherein:an another therapy is or comprises folinic acid, oxaliplatin, fluorouracil, and bevacizumab;an another therapy is or comprises mFOLFOX-6 and bevacizumab;an another therapy is or comprises folinic acid, LONSURF® or a generic thereof, and bevacizumab; an another therapy is or comprises trifluridine, tipiracil and bevacizumab;an another therapy is trifluridine, tipiracil and bevacizumab;an another therapy or therapeutic agent is or comprises a hormone therapy;an another therapy or therapeutic agent is or comprises an immunotherapy;an another therapy or therapeutic agent is or comprises a checkpoint inhibitor;an another therapy or therapeutic agent is or comprises a PD-L1 inhibitor: oran another therapy or therapeutic agent is or comprises a PD-1 inhibitor, a PD-1 antibody or antigenbinding fragment thereof, nivolumab or antigen-binding fragment thereof, ornivolumab.

74. Tire method of any one of claims 70-71, wherein 1-66 is administered as part of a combination therapy, wherein the combination therapy is or comprises:1-66, folinic acid or a salt thereof, fluorouracil, oxaliplatin and bevacizumab;1-66, mFOLFOX, and bevacizumab;1-66 and a PD-1 inhibitor;1-66 and nivolumab;1-66, trifluridine, tipiracil, and bevacizumab; or1-66, LONSURF® or a generic thereof, and bevacizumab.

75. The method of claim 74 wherein the cancer is MSS CRC, optionally wherein the subject has tumors with a WPAM.

76. The method of any one of the preceding claims, wherein the subject has a tumor or cancer with a pathogenic mutation of APC or CTNNB1.

77. Tire method of any one of the preceding claims, wherein the subject has a tumor or cancer with an APC LoF mutation and / or a tumor with an CTNNB1 GoF mutation, optionally wherein:the CTNNB1 GoF mutation is missense, in-frame insertion, or deletion at codons 32-37. 41, and / or 45;Page 264 of 27013160427vlAttorney Docket No.: 2012675-0415the CTNNB1 GoF mutation is a T41I mutation, a T41A mutation, a S45F mutation, a S45P mutation, a D32V mutation, a H36P mutation, and / or a S45_G48del mutation; and / orthe CTNNB1 GoF mutation is a T41I mutation, a T41A mutation, and / or a S45F mutation.

78. Tire method of any one of the preceding claims, wherein the subject has a tumor or cancer with a RNF43 LoF mutation.

79. The method of any one of the preceding claims, wherein the subject has a tumor or cancer with a RSPO2 and RSPO3 fusion.

80. The method of any one of the preceding claims, wherein the subject has a tumor or cancer with a mutation of AMER1, AXIN1, AXIN2, BCL9, CSNK1A1, GSK3B, LRP5, LRP6, LGR5, TCF7L2, or WIFI.

81. Tire method of any one of the preceding claims, wherein:downregulation of one or more Wnt transcriptional signatures (e.g., AXIN2, NKD1, RNF43, ZNRF3, NOTUM, VEGFA etc.) is observed:downregulation of one or more sternness markers (e.g., AXIN2, NKD1, RNF43, ZNRF3, NOTUM, etc.) is observed:upregulation of one or more differentiation markers (e.g., MUC2, KRT20, ALPI, ANPEP, CA2, etc.) is observed;upregulation of one or more inflammatory markers (e.g., CD8A, NKG7, HLA-DQA1, HLA-DRB1. CMKLR1, IFNG, CCL5, CXCL9. CD27, IDO1, STAT1, TIGIT, LAG3, PD-L1, PD-L2, etc.) is observed; and / orupregulation of one or more hypoxia markers (e.g., EPAS1, HIF2A, HIF1A, HIF3A, etc.) is observed.

82. Tire method of any one of the preceding claims, wherein an another therapy or therapeutic agent is or comprises bevacizumab. and bevacizumab is administered about every two weeks; optionally wherein:1-66 is administered in about 28-day cycles and bevacizumab is administered about every two weeks on days 1 and 15; and / orthe amount of bevacizumab administered in each dose is at least about 5 mg / kg.

83. Tire method of any one of the preceding claims, wherein an another therapy or therapeutic agent is or comprises folinic acid, and:folinic acid is administered every two weeks; and / orthe amount of folinic acid administered in each dose is about 400 mg / m2.

84. The method of any one of the preceding claims, wherein an another therapy or therapeutic agent is or comprises oxaliplatin, and:oxaliplatin is administered about every' two weeks; and / orthe amount of oxaliplatin administered in each dose is about 85 mg / m2.

85. The method of any one of the preceding claims, wherein an another therapy or therapeutic agent is or comprises fluorouracil, and:Page 265 of 27013160427vlAttorney Docket No.: 2012675-0415fluorouracil is administered about every two weeks: and / orthe amount of fluorouracil administered on the administration day is about 2800 mg / m2.

86. The method of any one of the preceding claims, wherein:1-66 is administered about weekly and bcvacizumab, folinic acid, oxaliplatin, and fluorouracil arc administered about every two weeks; or1-66 is administered in about 28-day cycles, and bevacizumab, folinic acid, oxaliplatin, and fluorouracil are administered about every two weeks on days 1 and 15.

87. The method of any one of the preceding claims, wherein an another therapy or therapeutic agent is or comprises nivolumab, and:nivolumab is administered about every two weeks;1-66 is administered in about 28-day cycles, and nivolumab is administered about every two weeks and on days 1 and 15;the amount of nivolumab administered in each dose is about 240 mg; and / ornivolumab is administered about every two weeks.

88. Tire method of any one of the preceding claims, wherein an another therapy or therapeutic agent is or comprises trifluridine / tipiracil, and:trifluridine / tipiracil is administered about twice per day: and / or1-66 is administered in about 28-day cycles, and trifluridine / tipiracil is administered orally twice daily- on days 1 to 5 and days 8 to 12.

89. The method of any one of the preceding claims, wherein 1-66 is administered in about 28-day cycles, trifluridine / tipiracil is administered orally tw ice daily on days 1 to 5 and days 8 to 12, and bevacizumab is administered about every two weeks on days 1 and 15.

90. The method of any one of the preceding claims, wherein an another therapy or therapeutic agent is or comprises LONSURF®, and:LONSURF® is administered about twice per day; and / or1-66 is administered in about 28-day cycles, and LONSURF® is administered orally twice daily on days 1 to 5 and days 8 to 12.

91. Tire method of any one of the preceding claims, wherein 1-66 is administered in about 28-day cycles, LONSURF® is administered orally tw ice daily on days 1 to 5 and days 8 to 12, and bevacizumab is administered about every two weeks on days 1 and 15.

92. The method of any one of the preceding claims, w herein an another therapeutic agent reduces one or more side effects of 1-66.

93. Tire method of any one of the preceding claims, wherein:an another therapy or therapeutic agent is or comprises an anti -resorptive agent;an another therapy or therapeutic agent is or comprises zoledronic acid or denosumab;an another therapy or therapeutic agent is or comprises a supportive growth factor;Page 266 of 27013160427vlAttorney Docket No.: 2012675-0415an another therapy or therapeutic agent is or comprises romiplostim;an another therapy or therapeutic agent is or comprises a hyponatremia therapy or therapeutic agent: an another therapy or therapeutic agent is or comprises a hypoaldosteronism therapy or therapeutic agent;an another therapy or therapeutic agent is or comprises a mineralocorticoid; and / oran another therapy or therapeutic agent is or comprises fludrocortisone.

94. The method of any one of the preceding claims, wherein an another therapy is or comprises a gamma secretase inhibitor, optionally wherein the gamma secretase inhibitor is or comprises nirogacestat or varegacestat.

95. Tire method of any one of the preceding claims, wherein an another therapy is or comprises a RAS inhibitor, optionally wherein an another therapy is or comprises:a pan-RAS inhibitor;a KRAS inhibitor, optionally a G12D-mutant KRAS inhibitor, a G12C-mutant KRAS inhibitor, or a G12V-mutant KRAS inhibitor;a RAS(ON) inhibitor; orRMC-6236.

96. The method of any one of claims 70-95. wherein an another therapy is or comprises surgery, radiation therapy, honnone therapy, stem cell or bone marrow transplant, T-cell therapy, CAR T-cell therapy, administering to the subject a population of immune cells.

97. The method of any one of the preceding claims, wherein the subject has desmoid tumor and has received a therapy.

98. Tire method of any one of the preceding claims, wherein the subject has desmoid tumor resistant to a therapy.

99. The method of any one of claims 97-98. wherein the therapy is or comprises surgery, radiation, systemic therapy, nirogacestat, sorafenib, a chemotherapy, or sulindac.

100. The method of any one of the preceding claims, wherein 1-66 is administered or delivered to the subject according to a regimen that has been demonstrated to provide tumor reduction in patients having desmoid tumors, oraccording to a regimen that has been demonstrated to provide objective response in patients having desmoid tumors, optionally in desmoid tumor patients who are resistant to nirogacestat.

101. The method of any one of the preceding claims, wherein 1-66 is administered or delivered to the subject according to a regimen that has been demonstrated to provide objective response in patients having adamantinomatous craniopharyngioma.

102. The method of any one of the preceding claims, wherein 1-66 is administered or delivered to the subject according to a regimen that has been demonstrated to provide objective response in patients having ameloblastoma.Page 267 of 27013160427vlAttorney Docket No.: 2012675-0415103. The method of any one of the preceding claims, wherein 1-66 is administered or delivered to the subject:according to a regimen that has been demonstrated not to result in a TRAE of grade 4 or higher; or according to a regimen that has been demonstrated not to result in a TRAE of grade 3 or higher.

104. The method of any one of the preceding claims, wherein 1-66 is administered or delivered to the subject according to a regimen that has been demonstrated not to result in a TRAE other than hyperbilirubinemia or AST increase of grade 3 or higher.

105. The method of any one of the preceding claims, wherein 1-66 is administered or delivered to the subject:according to a regimen that has been demonstrated not to result in a bone toxicity TRAE of grade 4 or higher; oraccording to a regimen that has been demonstrated not to result in a bone toxicity TRAE of grade 3 or higher.

106. The method of any one of the preceding claims, wherein 1-66 is administered or delivered to the subject:according to a regimen that has been demonstrated not to result in a GI toxicity TRAE of grade 4 or higher; oraccording to a regimen that has been demonstrated not to result in a GI toxicity TRAE of grade 3 or higher.

107. The method of any one of the preceding claims, wherein 1-66 is administered or delivered to the subject:according to a regimen that has been demonstrated not to result in dysgeusia of grade 4 or higher; according to a regimen that has been demonstrated not to result in dysgeusia of grade 3 or higher; according to a regimen that has been demonstrated not to result in dysgeusia of grade 2 or higher: or according to a regimen that has been demonstrated not to result in dysgeusia of grade 1 or higher.

108. The method of any one of the preceding claims, wherein 1-66 is administered or delivered to the subject:according to a regimen that has been demonstrated not to result in reproductive toxicity of grade 4 or higher;according to a regimen that has been demonstrated not to result in reproductive toxicity of grade 3 or higher;according to a regimen that has been demonstrated not to result in reproductive toxicity of grade 2 or higher; oraccording to a regimen that has been demonstrated not to result in reproductive toxicity of grade 1 or higher.

109. The method of any one of the preceding claims, wherein 1-66 is administered or delivered to the Page 268 of 27013160427vlAttorney Docket No.: 2012675-0415subject:according to a regimen that has been demonstrated not to result in ovarian toxicity of grade 4 or higher;according to a regimen that has been demonstrated not to result in ovarian toxicity of grade 3 or higher;according to a regimen that has been demonstrated not to result in ovarian toxicity of grade 2 or higher; oraccording to a regimen that has been demonstrated not to result in ovarian toxicity of grade 1 or higher.

110. Tire method of any one of the preceding claims, wherein 1-66 is administered or delivered as the composition of any one of Embodiments 1-254 or a composition prepared according to the method of any one of Embodiments 255-284.

111. 1-66, or a composition comprising 1-66, for manufacturing a medicament for, or for use in, a method of any one of the preceding claims.

112. 1-66, or a composition comprising 1-66, for use in a method of any one of the preceding claims.

113. Tire composition of claim 111 or claim 112, wherein the composition is the composition of any one of Embodiments 1-254 or a composition prepared according to the method of any one of Embodiments 255-284.

114. Use of 1-66 or a composition comprising 1-66 for the treatment of a tumor or cancer according to any one of the preceding claims.

115. The use of claim 114, wherein the composition is the composition of any one of Embodiments 1-254 or a composition prepared according to the method of any one of Embodiments 255-284116. Use of 1-66 or a composition comprising 1-66 for the manufacture of a medicament for the treatment of a tumor or cancer according to any one of the preceding claims.

117. The use of claim 116, wherein the composition is the composition of any one of Embodiments 1-254 or a composition prepared according to the method of any one of Embodiments 255-284.

118. A composition, method, or use of any one of Embodiments 1-630.Page 269 of 27013160427vl

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