MDM2 degraders and uses thereof

Abstract

The present invention relates to MDM2 degraders, their liquid formulations, and methods of use thereof for treating cancer.

Description

MDM2 DEGRADERS AND USES THEREOF TECHNICAL FIELD OF THE INVENTION

[0001] This application claims the benefit of priority to U.S. Provisional Appl. No. 63 / 595,215, filed November 1, 2023, U.S. Provisional Appl. No.63 / 554,480, filed February 16, 2024, U.S. Provisional Appl. No. 63 / 565,375, filed March 14, 2024, U.S. Provisional Appl. No. 63 / 649,701, filed May 20, 2024, and U.S. Provisional Appl. No. 63 / 655,392, filed June 3, 2024, the contents of each of which is herein incorporated by reference. TECHNICAL FIELD OF THE INVENTION

[0002] The present invention relates to formulations and dosages forms of MDM2 degrader (3'R,4'S,5'R)- 6''-chloro-4'-(3-chloro-2-fluorophenyl)-N-((1R,4R)-4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo- 2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-1-carbonyl)cyclohexyl)-2''-oxodispiro[cyclohexane- 1,2'-pyrrolidine-3',3''-indoline]-5'-carboxamide (Compound A), and methods of use thereof. BACKGROUND OF THE INVENTION

[0003] The murine double minute 2 (MDM2) oncoprotein is a key E3 ubiquitin ligase that degrades the tumor-suppressor p53. Reversible small molecule inhibitors (SMIs) of the MDM2 / p53 interaction have been developed to stabilize p53 and to induce apoptosis in wildtype p53 tumors. However, MDM2 SMIs induce a p53 / MDM2 feedback loop, resulting in upregulation of MDM2 protein levels and p53 pathway inhibition thus drastically limiting their biological activity and clinical application. MDM2 targeted protein degradation suppresses p53-dependent MDM2 protein feedback upregulation and is therefore expected to lead to a superior response compared to MDM2 SMIs.

[0004] A need exists to develop formulations for MDM2 degraders for use in cancer therapy. SUMMARY OF THE INVENTION

[0005] It has been found that a MDM2 degrader, and its salts, formulations and unit dosage forms, as described herein, have certain advantages in treating solid cancers and hematological malignancies, wherein the MDM2 degrader is (3'R,4'S,5'R)-6''-chloro-4'-(3-chloro-2-fluorophenyl)-N-((1R,4R)-4-(4-(1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-1- carbonyl)cyclohexyl)-2''-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indoline]-5'-carboxamide (Compound A). 32154354.1Page 1 of 78397731-105WO (213618)

[0006] Accoringly, in one aspect, the present disclosure provides a liquid formulation or unit dosage form comprising Compound A, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient and / or carrier.

[0007] In another aspect, the present invention provides a method for treating a solid cancer or hematological malignancy in a patient, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, or a liquid formulation described herein. In some embodiments, the solid cancer or hematological malignancy is selected from Merkel cell carcinoma, fibromyxoid sarcoma, myxofibrosarcoma, rectal cancer, prostate cancer, adenoid cystic carcinoma, renal cell carcinoma, osteosarcoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), large granular lymphocytic leukemia (LGL-L), B-cell prolymphocytic leukemia, acute myeloid leukemia (AML), Burkitt lymphoma / leukemia, myelofibrosis, primary effusion lymphoma, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), diffuse large B-cell lymphoma (DLBCL), advanced B-cell diffuse large B-cell lymphoma (ABC DLBCL), intravascular large B-cell lymphoma, lymphoplasmacytic lymphoma, Waldenström’s macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, uveal melanoma, myelodysplastic syndrome (MDS), or myelodysplastic / myeloproliferative neoplasms (MDS / MPN). In certain embodiments, the solid cancer or hematological malignancy is a relapsed and / or refractory (R / R) solid cancer or hematological malignancy. In some embodiments, the patient receiving Compound A or a pharmaceutically acceptable salt thereof to treat a solid cancer or hematological malignancy has received at least one prior therapies. In some embodiments, the patient is a human. In some embodiments, the patient is an adult human or a pediatic human.

[0008] These and other aspects of this disclosure will be apparent upon reference to the following detailed description. To this end, various references are set forth herein which describe in more detail certain background information and procedures and are each hereby incorporated by reference in their entirety. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] FIG.1 show a flow diagram of the liquid formulation manufacturing process.

[0010] FIG.2 shows study schema of the dose escalation in Arms A and B with MTD / RP2D confirmation.

[0011] FIG. 3A and 3B shows that Compound A (1 mg / kg, Q3W) achieves tumor regression in a CTG- 2227 AML patient-derived xenograft (PDX) model and partial responses in CTG-2240 and CTG-2700 AML PDX models.

[0012] FIG.4A and 4B shows the combinatorial benefit of Compound A with venetoclax and midostaurin in MOLM-13 cell line. 32154354.1Page 2 of 78397731-105WO (213618)

[0013] FIG.5 shows the significant combinatorial benefit of Compound A with standard of care in AML in vivo model.

[0014] FIG. 6 shows that Compound A is active across multiple heme indications in vitro with AML, T cell lymphomas, mantle cell lymphoma, and DLBCL being the most sensitive.

[0015] FIG. 7 shows that Compound A is highly active in p53WTABC-subtype DLBCL. Compound A was highly active in OCI-LY10 p53WTABC-subtype DLBCL xenograft model (A) but not TMD8 p53MUTABC-subtype DLBCL xenograft model (B).

[0016] FIG.8 shows that a single dose of Comopund A drives sustained tumor regression and is superior to MDM2 / p53 small molecule inhibitors (SMIs).

[0017] FIG. 9 shows that Compound A potently degrades MDM2 and upregulates the p53 pathway in tumors.

[0018] FIG. 10 shows a single dose of Compound A leads to robust activation of the p53 pathway and apoptosis in ALL while exposure-matched weekly dosing and SMIs do not.

[0019] FIG. 11 shows a single dose of Compound A leads to more robust activation of the p53 pathway and apoptosis than exposure-matched weekly dosing and SMIs in AML.

[0020] FIG. 12A and 12B shows that exposures are required for tumor regression are associated with induction of apototic markers.

[0021] FIG.13 shows kinetics of plasma GDF15 upregulation in a single subject on DL1.

[0022] FIG.14 shows initial clinical activity demonstrated at DL1.

[0023] FIG.15 shows that Compound A potently induces p53 transciptional gene targets MDM2, GDF15, CDKN1A, GADD44A, TNFRSF10B, FAS, and BBC3.

[0024] FIG. 16 shows that treatment with Compound A leads to potent induction of apoptosis in a panel of AML, ALL, B-cell, and diffuse large B-cell lymphoma (DLBCL) cell lines.

[0025] FIG. 17 shows cell cycle distribution and viability in RS4;11 and MV4;11 cell lines treated with Compound A or DS-3032.

[0026] FIG.18 shows the activity of Compound A alone or in combination with venetoclax in a MOLM13 subcutaneous xenograft model.

[0027] FIG. 19 shows that Compound A treatment showed strong single agent activity in a primary systemic model of AML that was resistant to venetoclax treatment.

[0028] FIG.20 shows clinical responses in Arm A and B.

[0029] FIG.21 shows preliminary plasma PK parameters in cycle 1.

[0030] FIG. 22 shows upregulation of PD biomarkers by MDM2 degradation-mediated p53 pathway activation in blood.

[0031] FIG.23 shows an updated study schema. 32154354.1Page 3 of 78397731-105WO (213618)

[0032] FIG.24 shows that Compound A is active in multiple p53 WT solid tumor cell lines in vitro.

[0033] FIG. 25 shows that 38% of pediatric solid tumors show complete and durable responses to Compound A.

[0034] FIG.26 shows that Compound A is active in multiple adult solid tumor types including tumors that are insensitive to an MDM2 small molecule inhibitor BI907828.

[0035] FIG.27 shows a method of finding a gene expression signature that predicts response to Compound A.

[0036] FIG.28 shows that disseminated AML PDX models show complete responses to Compound A.

[0037] FIG. 29 shows that prospectively selected PDX models demonstrate improved response rates and survival. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description of Certain Embodiments of the Invention:

[0038] Compound A is a highly potent heterobifunctional small molecule therapeutic agents targeting MDM2 to mediate the selective degradation of MDM2 protein. Compound A displays superior activity compared to SMIs of MDM2 in wildtype p53 cell lines and xenograft models. For instance in acute lymphoblastic leukemia (ALL) cell line RS4;11, Compound A can overcome the p53-dependent upregulation of MDM2 protein levels as seen for reversible SMIs. Short 2 hour exposures of Compound A can more potently stabilize p53 than SMIs. In addition, washout experiments in these cells showed that a pulsed dose of Compound A can lead to apoptosis mediated through p53 target genes. The superior MDM2 / p53 pathway inhibition and induction of apoptosis by Compound A translates into a >200-fold stronger cell growth inhibition, compared to SMIs, across a panel of solid and hematological tumor cell lines. In some embodiments, provided herein is a treatment of adult patients with solid cancers or hematological malignances who have received at least one prior therapy. Compound A of the current invention is provided by oral and intravenous administration at the doses and schedules described herein.

[0039] Accordingly, in some embodiments, the present disclosure provides a method for treating a relapsed and / or refractory solid cancer or hematological malignancy. In some embodiments, the present disclosure provides a method for treating a relapsed and / or refractory acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) in a patient, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, or a liquid formulation thereof as described herein.

[0040] In some embodiments, the present disclosure provides a liquid formulation, which comprises Compound A, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient and / or carrier. In some embodiments, the present disclosure provides a unit dosage form, which comprises 32154354.1Page 4 of 78397731-105WO (213618)Compound A, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient and / or carrier.

[0041] In the following disclosure, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the methods and uses described herein may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0042] Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise. 2. Definitions:

[0043] As used in the specification and appended claims, unless specified to the contrary, the following terms and abbreviations have the following meanings.

[0044] As used herein, the term “about” refers to within 20% of a given value. In some embodiments, the term “about” refers to within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of a given value.

[0045] As used herein, the term “BCL-2 inhibitor” includes, but is not limited to compounds having inhibitory activity against B-cell lymphoma 2 protein (BCL-2), including but not limited to ABT-199, ABT- 731, ABT-737, apogossypol, Ascenta’s pan-BCL-2 inhibitors, curcumin (and analogs thereof), dual Bcl- 2 / Bcl-xL inhibitors (Infinity Pharmaceuticals / Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and analogs thereof; see WO 2008 / 118802, US 2010 / 0197686), navitoclax (and analogs thereof, see US 7,390,799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and analogs thereof, see WO 2004 / 106328, US 2005 / 0014802), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ. of 32154354.1Page 5 of 78397731-105WO (213618)Michigan), and venetoclax. In some embodiments the BCL-2 inhibitor is a small molecule therapeutic. In some embodiments the BCL-2 inhibitor is a peptidomimetic.

[0046] As used herein, the term “Compound A” refers to (3'R,4'S,5'R)-6''-chloro-4'-(3-chloro-2- fluorophenyl)-N-((1R,4R)-4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidine-1-carbonyl)cyclohexyl)-2''-oxodispiro[cyclohexane-1,2'-pyrrolidine- 3',3''-indoline]-5'-carboxamide having the formula: . In someis in amorphous form. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof, is in crystalline form.

[0047] As used herein, the term “FLT3 inhibitor” includes, but is not limited to compounds having inhibitory activity against FMS-like Tyrosine Kinase 3 protein (FLT3), including but not limited to sunitinib, lestaurtinib, tandutinib, crenolanib, gilteritinib, midostaurin, quizartinib, and sorafenib, FLX925, and G-749.

[0048] As used herein, the term “inhibitor” is defined as a compound that binds to and / or inhibits MDM2 protein with measurable affinity. In certain embodiments, an inhibitor has an IC50 and / or binding constant of less than about 50 µM, less than about 1 µM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.

[0049] As used herein, the term “MDM2 degrader” refers to an agent that degrades MDM2 protein. Various MDM2 degraders have been described previously, for example, in WO 2021 / 188948, the contents of which are incorporated herein by reference in their entireties. In certain embodiments, an MDM2 degrader has an DC50 of less than about 50 µM, less than about 1 µM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM. In certain embodiments, the MDM2 degrader is Compound A disclosed herein.

[0050] The term “patient,” as used herein, means an animal, preferably a mammal, and most preferably a human.

[0051] As used herein, a term “pediatric patient” is a human patient who is 21 years old or younger at the time of diagnosis or treatment. 32154354.1Page 6 of 78397731-105WO (213618)

[0052] As used herein, the term “MEK inhibitor” includes, but is not limited to compounds having inhibitory activity against mitogen-activated protein kinase kinase enzymes MEK1 and / or MEK2, including but not limited to binimetinib, cobimetinib, selumetinib, trametinib, mirametinib (PD-325901), and TAK- 733.

[0053] As used herein, the term “mg / kg” or “mpk” refers to the milligram of medication (for example, Compound A) per kilogram of the body weight of the subject taking the medication.

[0054] As used herein, the term "pharmaceutically acceptable salt" refers to those 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 in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts 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, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like.

[0055] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0056] The term “pharmaceutically acceptable excipient or carrier” refers to a non-toxic excipient or carrier that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable excipient or carrier that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such 32154354.1Page 7 of 78397731-105WO (213618)as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0057] The term “reference” refers to 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 to 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 corresponds to a value of i) the treated patient prior to a disease, disorder, or condition, ii) a healthy patient, or iii) a population of patients. 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 the art will appreciate when sufficient similarities are present to justify reliance on and / or comparison to a particular possible reference or control.

[0058] The term “therapeutically effective amount” or “therapeutically effective dosage” as used herein refers to an amount of Compound A that is sufficient to treat the stated disease, disorder, or condition or have the desired stated effect on the disease, disorder, or condition or one or more mechanisms underlying the disease, disorder, or condition in a subject. In certain embodiments, when Compound A is administered for the treatment of a solid cancer or hematological malignancy, therapeutically effective amount refers an amount of Compound A which, upon administration to a subject, treats or ameliorates the solid cancer or hematological malignancy in the subject, or exhibits a detectable therapeutic effect in the subject that results in partial to complete tumor regression.

[0059] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0060] The phase “woman of childbearing potential” (WOCBP) are considered fertile: 1. Following menarche; 2. From the time of menarche until becoming postmenopausal unless permanently sterile. A 32154354.1Page 8 of 78397731-105WO (213618)postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, confirmation with more than one FSH measurement is required. Females on HRT and whose menopausal status is in doubt will be required to use one of the non-estrogen hormonal highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status before study enrollment. Permanent sterilization methods (for the purpose of this study) include: documented hysterectomy; documented bilateral salpingectomy’ documented bilateral oophorectomy; for individuals with permanent infertility due to an alternate medical cause other than the above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), Investigator discretion should be applied to determining study entry. 3. Description of Exemplary Embodiments:

[0061] The present disclosure provides a method for treating a relapsed and / or refractory solid cancer or hematological malignancy. In some embodiments, the present disclosure provides a method for treating a myeloid malignancy, acute lymphocytic leukemia, lymphoma, myelofibrosis, or solid tumor in a patient, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, or a liquid formulation thereof as described herein.

[0062] In some embodiments, the present disclosure provides a liquid formulation, which comprises Compound A, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient and / or carrier. In some embodiments, the present disclosure provides a unit dosage form, which comprises Compound A, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient and / or carrier.

[0063] In some embodiments, a patient has a myeloid malignancy, acute lymphocytic leukemia, lymphoma, myelofibrosis, or solid tumor (i.e., a myeloid malignancy, acute lymphocytic leukemia, lymphoma, myelofibrosis, or solid tumor patient). In some embodiments, a myeloid malignancy, acute lymphocytic leukemia, lymphoma, myelofibrosis, or solid tumor patient has a relapsed and / or refractory myeloid malignancy, acute lymphocytic leukemia, lymphoma, myelofibrosis, or solid tumor.

[0064] In some embodiments, a myeloid malignancy, acute lymphocytic leukemia, lymphoma, myelofibrosis, or solid tumor patient is male or female aged ≥ 18 years on the day of signing informed consent. 32154354.1Page 9 of 78397731-105WO (213618)

[0065] In some embodiments, a myeloid malignancy, acute lymphocytic leukemia, lymphoma, myelofibrosis, or solid tumor patient has Eastern Cooperative Oncology Group (ECOG) performance status: 0-2.

[0066] In some embodiments, a myeloid malignancy, acute lymphocytic leukemia, lymphoma, myelofibrosis, or solid tumor patient is female of child-bearing potential (WOCBP) who agrees to use highly effective contraceptive methods for the duration of study treatment and 30 days after the last dose of Compound A as described herein.

[0067] In some embodiments, a myeloid malignancy, acute lymphocytic leukemia, lymphoma, myelofibrosis, or solid tumor patient is female of child-bearing potential having a negative serum pregnancy test including within 72 hrs prior to first dose of Compound A as described herein.

[0068] In some embodiments, a myeloid malignancy, acute lymphocytic leukemia, lymphoma, myelofibrosis, or solid tumor patient is male and agrees to use highly effective contraceptive methods during the study treatment and for 30 days after the last dose of Compound A as described herein if the partner is a WOCBP.

[0069] In some embodiments, a myeloid malignancy, acute lymphocytic leukemia, lymphoma, myelofibrosis, or solid tumor patient has resolved acute effects of any prior therapy except for alopecia to baseline severity or Grade ≤1 NCI CTCAE and Grade ≤2 neuropathy.

[0070] In some embodiments, a myeloid malignancy, acute lymphocytic leukemia, lymphoma, myelofibrosis, or solid tumor patient has adequate organ function defined as one of more of the following: a) Liver Function i) Aspartate aminotransferase (AST), alanine transaminase (ALT) ≤ 3x upper limit of normal (ULN) or < 5x ULN in cases of documented liver metastases or lymphoma involvement of liver or considered to be due to leukemic disease. ii) Total serum bilirubin ≤ 1.5 x ULN or < 5x ULN if secondary to Gilbert’s syndrome or documented liver metastases, or lymphoma involvement of liver or considered to be due to leukemic disease. b) Renal Function i) Serum creatinine clearance ≥60 mL / min, either measured or calculated using standard Cockcroft-Gault formula (Appendix 10). ii) Serum electrolyte (potassium, calcium, and magnesium) levels within the normal reference range (may be supplemented according to institutional standards).

[0071] In some embodiments, a patient has lymphoma or solid tumor (i.e., a lymphoma or solid tumor patient). In some embodiments, a lymphoma or solid tumor patient has a relapsed and / or refractory lymphoma or solid tumor.

[0072] In some embodiments, a lymphoma or solid tumor patient has histologically or pathologically confirmed solid tumor or lymphoma. 32154354.1Page 10 of 78397731-105WO (213618)

[0073] In some embodiments, a lymphoma or solid tumor patient has relapsed and / or refractory disease to at least two prior standard of care treatments or tumors for whom standard therapies are not available.

[0074] In some embodiments, a lymphoma or solid tumor patient has at least one bi-dimensionally measurable disease site. In some embodiments, a lymphoma or solid tumor patient has a lesion that has a greatest transverse diameter of at least 1.5 cm and greatest perpendicular diameter of at least 1.0 cm at Baseline.

[0075] In some embodiments, a lymphoma or solid tumor patient has adequate organ function at Screening defined as one of more of the following: a) Bone Marrow Function: i) Absolute neutrophil count (ANC) ≥ 1000 / μL. ii) Hemoglobin ≥ 8 g / dL (for those patients undergoing red blood cell [RBC] transfusion, hemoglobin must be evaluated after at least 14 days after the last RBC transfusion). iii) Platelet count ≥ 100,000 / μL (assessed ≥ 7 days following last platelet transfusion in patients with thrombocytopenia requiring platelets).

[0076] In some embodiments, a patient has myelofibrosis (e.g., a myelofibrosis patient). In some embodiments, a myelofibrosis patient has a relapsed and / or refractory myelofibrosis.

[0077] In some embodiments, a myelofibrosis patient has a confirmed diagnosis of primary myelofibrosis (PMF) based on 2016 World Health Organization (WHO) criteria or post polycythemia vera / essential thrombocythemia myelofibrosis (PPV / ET MF) based on the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria.

[0078] In some embodiments, a myelofibrosis patient has one or more of the following: a) Dynamic International Prognostic Scoring System (DIPSS) risk category intermediate-2 or higher. b) Platelet count ≥ 75 x 109 / L without assistance of thrombopoietic factors or transfusions for at least 7 days. c) Palpable spleen ≥ 5 cm below costal margin on physical examination. d) Peripheral blast blood count <10%. e) Ineligible to receive JAK inhibitor (JAKi) or was previously treated with a JAKi and discontinued due to intolerance or refractory or resistant disease.

[0079] In some embodiments, a patient has a myeloid malignancy or acute lymphocytic leukemia (i.e., a myeloid malignancy or acute lymphocytic leukemia patient). In some embodiments, a myeloid malignancy or acute lymphocytic leukemia patient has a relapsed and / or refractory myeloid malignancy or acute lymphocytic leukemia. 32154354.1Page 11 of 78397731-105WO (213618)

[0080] In some embodiments, a myeloid malignancy or acute lymphocytic leukemia patient has primary diagnosis of AML based on World Health Organization (WHO) 2022 or International Consensus Classification (ICC) 2022.

[0081] In some embodiments, a myeloid malignancy or acute lymphocytic leukemia patient has primary diagnosis of relapsed AML defined as: ≥ 5% myeloblasts in the bone marrow after achieving a CR (measurable residual disease [MRD] positive or negative), CRh, or CRi. In some embodiments, the refractory AML is defined as: ≥ 5% myeloblasts after any one of the following regimens: ^ 2 cycles of intensive induction chemotherapy with at least one cycle of a cytarabine containing regimen (e.g., 7+3, mitoxantrone, etoposide, and cytarabine (MEC), High dose cytarabine (HiDAC), etc.); ^ 2 cycles of hypomethylating agents (HMA) / venetoclax or low-dose Cytarabine (LDAC) / glasdegib; and ^ 4 cycles of HMA monotherapy.

[0082] In some embodiments, a myeloid malignancy or acute lymphocytic leukemia patient has primary diagnosis of ALL based on WHO 2022 classification. In some embodimens, a myeloid malignancy or acute lymphocytic leukemia patient has primary diagnosis of ALL relapsed or refractory to standard of care therapy. In some embodiments, a Philadelphia chromosome-positive ALL (Ph+ ALL) patient failed at least one second generation tyrosine kinase inhibitor.

[0083] In some embodiments, a myeloid malignancy or acute lymphocytic leukemia patient has primary diagnosis of high / very high risk Myelodysplastic Syndromes (MDS). In some embodiments, a myeloid malignancy or acute lymphocytic leukemia patient has primary diagnosis of high / very high risk Myelodysplastic Syndromes (MDS) relapsed or refractory to standard of care therapy. In some embodiments, relapsed MDS is defined as: ≥ 5% myeloblasts after achieving an IWG defined response. In some embodiments, refractory MDS is defined as: ≥ 5% myeloblasts after one of the following regimens: ^ 4 cycles of HMA monotherapy ^ 2 cycles of HMA + venetoclax

[0084] In some embodiments, a myeloid malignancy or acute lymphocytic leukemia patient has primary diagnosis of Myelodysplastic / myeloproliferative neoplasms (MDS / MPN) diagnosis based on WHO 2022 or ICC 2022 classification. In some embodiments, a myeloid malignancy or acute lymphocytic leukemia patient has primary diagnosis of high / very high risk Myelodysplastic Syndromes (MDS) relapsed or refractory to standard of care therapy as defined by standardized criteria. In some embodiments, MDS patients with ≥ 5% blasts in the bone marrow and disease that has relapsed or is refractory to standard therapy for which no standard therapies are anticipated to result in a durable remission according to the Investigator. 32154354.1Page 12 of 78397731-105WO (213618)

[0085] In some embodiments, a myeloid malignancy or acute lymphocytic leukemia patient has myeloproliferative neoplasms in blast phase (MPN-BP) or accelerated phase (MPN-AP). In some embodiments, a myeloid malignancy or acute lymphocytic leukemia patient has confirmed diagnosis of PMF based on 2016 WHO criteria or PPV / ET MF based the IWG-MRT criteria with ≥ 20% peripheral blasts or 10-19% bone marrow blasts that is refractory to one cycle of intensive induction chemotherapy or at least two cycles of HMA plus venetoclax or two cycles of low intensity therapy (e.g. azacytidine plus JAKi, cladribine plus low dose Ara-C, etc.).

[0086] In some embodiments, a myeloid malignancy or acute lymphocytic leukemia patient has life expectancy of ≥ 12 weeks.

[0087] In some embodiments, a myeloid malignancy or acute lymphocytic leukemia patient is amenable to serial bone marrow sampling, peripheral blood sampling, and urine sampling during study. If an aspirate is unobtainable (i.e., a “dry tap”), the diagnosis may be made from core biopsy.

[0088] In some embodiments, the patient has a solid tumor (eg., a solid tumor patient). In some embodiments, a solid tumor patient has a relapsed and / or solid tumor.

[0089] In some embodiments, the solid tumor patient has histologically or pathologically confirmed solid tumor.

[0090] In some embodiments, the solid tumor patient has documented TP53WT status based on medical records.

[0091] In some embodiments, the solid tumor patient has relapsed and / or refractory disease to at least two prior standard of care treatments or tumors for whom standard therapies are not available.

[0092] In some embodiments, the solid tumor patient has at least one bi-dimensionally measurable disease site. In some embodiments, the solid tumor patient lesion must have a greatest transverse diameter of at least 1.5 cm and greatest perpendicular diameter of at least 1.0 cm at Baseline.

[0093] In some embodiments, the solid tumor patient has adequate organ function at screening.

[0094] In some embodiments, the solid tumor patient has one or more of the defined bone marrow functions: i) Absolute neutrophil count (ANC) ≥ 1000 / μL. ii) Hemoglobin ≥ 8 g / dL (for those patients undergoing red blood cell [RBC] transfusion, hemoglobin must be evaluated after at least 14 days after the last RBC transfusion). iii) Platelet count ≥ 100,000 / μL (assessed ≥ 7 days following last platelet transfusion in patients with thrombocytopenia requiring platelets).

[0095] In some embodiments, a myeloid malignancy, acute lymphocytic leukemia, lymphoma, myelofibrosis, or solid tumor patient is not a pregnant female; breastfeeding female; male patient with partners currently pregnant; male patient able to father children and female patients of childbearing 32154354.1Page 13 of 78397731-105WO (213618)potential who are unwilling or unable to use two highly effective methods of contraception as outlined in this protocol for the duration of the study and for at least 30 days after last dose of study drug.

[0096] In some embodiments, a myeloid malignancy, acute lymphocytic leukemia, lymphoma, myelofibrosis, or solid tumor patient is not a patient who is unable or unwilling to discontinue prohibited concomitant medications or adhere to restrictions for use of concomitant medications including use of strong P-gp or BCRP inhibitors or inducers within 14 days or 5 half-lives (whichever is longer) prior to first dose.

[0097] In some embodiments, a myeloid malignancy, acute lymphocytic leukemia, lymphoma, myelofibrosis, or solid tumor patient has not had one or more of the following in the previous 3 months: myocardial infarction, Torsades de pointes, severe or life-threatening arrhythmias (including sustained ventricular tachyarrhythmia and ventricular fibrillation), right bundle branch block and left anterior hemiblock (bifascicular block), unstable angina, coronary / peripheral artery bypass graft, symptomatic congestive heart failure (CHF New York Heart Association class III or IV), cerebrovascular accident, transient ischemic attack, or symptomatic pulmonary embolism.

[0098] In some embodiments, a myeloid malignancy, acute lymphocytic leukemia, lymphoma, myelofibrosis, or solid tumor patient does not have congenital long QT syndrome, or a QT interval corrected by Fridericia’s formula (QTcF) ≥470 ms (average of triplicate electrocardiograms).

[0099] In some embodiments, a myeloid malignancy, acute lymphocytic leukemia, lymphoma, myelofibrosis, or solid tumor patient has not had major surgery requiring general anesthesia within 4 weeks prior to first dose of Compound A as described herein.

[0100] In some embodiments, a myeloid malignancy, acute lymphocytic leukemia, lymphoma, myelofibrosis, or solid tumor patient does not have known or demonstrated viral infection of one or more of the following: a) Seropositivity for human immunodeficiency virus (HIV) (only if required by local regulations) b) Hepatitis B and / or hepatitis C infection (as detected by positive testing for hepatitis B surface antigen [HbsAg] or antibody to hepatitis C virus with confirmatory testing).

[0101] In some embodiments, a myeloid malignancy, acute lymphocytic leukemia, lymphoma, myelofibrosis, or solid tumor patient has not received live or live-attenuated vaccine within 4 weeks prior to the first dose of Compound A as described herein.

[0102] In some embodiments, a myeloid malignancy, acute lymphocytic leukemia, lymphoma, myelofibrosis, or solid tumor patient has not completed a course of SARS-CoV-2 vaccine within 14 days prior to first dose of Compound A as described herein.

[0103] In some embodiments, a myeloid malignancy, acute lymphocytic leukemia, lymphoma, myelofibrosis, or solid tumor patient does not have concurrent medical conditions including psychiatric 32154354.1Page 14 of 78397731-105WO (213618)disorders that in the judgment of the Investigator will interfere with the patient’s ability to participate or with achieving the objectives of the study or pose a safety risk.

[0104] In some embodiments, a myeloid malignancy, acute lymphocytic leukemia, lymphoma, myelofibrosis, or solid tumor patient does not have a history of or active concurrent malignancy unless the patient has been disease-free for ≥ 2 years.

[0105] In some embodiments, a myeloid malignancy, acute lymphocytic leukemia, lymphoma, myelofibrosis, or solid tumor patient has not had exposures to anticancer therapy within 2 weeks or 5 half- lives whichever is longer; or 4 weeks from any biologics / immunotherapies or any investigational therapy prior to the first dose of study drug.

[0106] In some embodiments, a myeloid malignancy, acute lymphocytic leukemia, lymphoma, myelofibrosis, or solid tumor patient did not receive an MDM2 inhibitor in the most recent prior line of treatment or prior MDM2 inhibitor that was discontinued due to drug-related adverse events at any time.

[0107] In some embodiments, a myeloid malignancy, acute lymphocytic leukemia, lymphoma, myelofibrosis, or solid tumor patient has not had known presence of p53 mutation in tumor tissue (testing not required for study entry).

[0108] In some embodiments, a myeloid malignancy, acute lymphocytic leukemia, lymphoma, myelofibrosis, or solid tumor patient has not had known hypersensitivity to any of the components of Compound A.

[0100] In some embodiments, a myeloid malignancy, acute lymphocytic leukemia, lymphoma, myelofibrosis, or solid tumor patient has not had known systemic vasculitides (e.g., Wegener’s granulomatosis, polyarteritis nodosa, systemic lupus erythematosus).

[0101] In some embodiments, a myeloid malignancy, acute lymphocytic leukemia, lymphoma, myelofibrosis, or solid tumor patient does not have primary or secondary immunodeficiency conditions (such as severe inflammatory disease).

[0102] In some embodiments, a lymphoma or solid tumor patient does not have known active uncontrolled or symptomatic (CNS) metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and / or progressive growth.

[0103] In some embodiments, a lymphoma or solid tumor patient does not have exposures to anticancer therapy or investigational therapy within 2 weeks or 5 half-lives whichever is longer prior to the first dose of Compound A as described herein.

[0104] In some embodiments, a lymphoma or solid tumor patient does not have infection requiring antibiotics, antivirals, or antifungals within 1 week prior to first dose of Compound A as described herein.

[0105] In some embodiments, a lymphoma or solid tumor patient has not had radiation treatment within 4 weeks prior to first dose of Compound A as described herein. 32154354.1Page 15 of 78397731-105WO (213618)

[0106] In some embodiments, a lymphoma or solid tumor patient has not had autologous or allogenic hematopoietic stem cell transplant (HSCT) within 6 months prior to first dose of Compound A as described herein or patient has progressed within 6 months from the day of stem cell infusion (for lymphoma patients only).

[0107] In some embodiments, a lymphoma or solid tumor patient has not received immunotherapy / biologic treatment or investigational therapy within 4 weeks prior to first dose of Compound A as described herein, including tumor vaccines and checkpoint inhibitors.

[0108] In some embodiments, a myelofibrosis patient does not have an infection requiring antibiotics, antivirals, or antifungals within 1 week prior to first dose of study drug. Prophylactic use of these agents is acceptable even if parenteral.

[0109] In some embodiments, a myelofibrosis patient has not had an autologous or allogenic hematopoietic stem cell transplant (HSCT) within 6 months prior to first dose of Compound A as described herein.

[0110] In some embodiments, a myelofibrosis patient has not received immunotherapy / biologic treatment or investigational therapy within 4 weeks prior to first dose of Compound A as described herein, including tumor vaccines and checkpoint inhibitors.

[0111] In some embodiments, a myelofibrosis patient has not received prior splenectomy or prior splenic radiation within 3 months of starting study therapy.

[0112] In some embodiments, a myelofibrosis patient has not received hematopoietic growth factor (granulocyte growth factor, erythropoiesis stimulating agent, thrombopoietin mimetic) or androgenic steroids less than 2 weeks before the first dose of Compound A as described herein.

[0113] In some embodiments, a myelofibrosis patient has not received systemic corticosteroids at daily doses > 10 mg of oral prednisone or equivalent less than 2 weeks before the first dose of Compound A as described herein.

[0114] In some embodiments, a myelofibrosis patient has not been administered a JAKi less than 2 weeks prior to first dose of Compound A as described herein.

[0115] In some embodiments, a myelofibrosis patient has not received exposures to other (non-JAKi) anticancer therapy or investigational therapy within 2 weeks or 5 half-lives whichever is longer prior to the first dose of Compound A as described herein.

[0116] In some embodiments, a patient has a myeloid malignancy or ALL (i.e., a myeloid malignancy or ALL patient). In some embodiments, a myeloid malignancy or ALL patient has a relapsed and / or refractory myeloid malignancy or ALL.

[0117] In some embodiments, a myeloid malignancy or ALL patient does not have active CNS leukemia.

[0118] In some embodiments, a myeloid malignancy or ALL patient has not had prior chemotherapy / radiation (including craniospinal radiation) within ≤ 2 weeks prior to the first dose of 32154354.1Page 16 of 78397731-105WO (213618)Compound A as described herein. In some embodiments, a myeloid malignancy or ALL patient passed nadir white blood cell (WBC) and platelet counts.

[0119] In some embodiments, a myeloid malignancy or ALL patient has not had prior oral mercaptopurine, hydroxyurea, methotrexate, vincristine, thioguanine, and tyrosine kinase inhibitors are permitted within 2 weeks of the first dose of Compound A as described herein as maintenance or to reduce the peripheral blast count.

[0120] In some embodiments, a myeloid malignancy or ALL patient has not had prior CNS prophylaxis for treatment of CNS relapse is permitted.

[0121] In some embodiments, a myeloid malignancy or ALL patient has not received allogeneic hematopoietic cell transplantation (HCT) <12 weeks prior to first dose of Compound A as described herein or donor lymphocyte infusion (DLI) without conditioning <4 weeks prior to first dose.

[0122] In some embodiments, a myeloid malignancy or ALL patient has not received autologous stem cell transplant (ASCT) < 4 weeks prior to first dose or the patient has not recovered from transplant associated toxicities to ≤ grade 1 prior to the first dose of Compound A as described herein.

[0123] In some embodiments, a myeloid malignancy or ALL patient has not received immunotherapy / biologic treatment ≤2 weeks or within 5 half-lives prior to first dose of Compound A as described herein, including tumor vaccines and checkpoint inhibitors.

[0124] In some embodiments, a myeloid malignancy or ALL patient has not received chimeric antigen receptor therapy or other modified T cell therapy <3 weeks prior to first dose of Compound A as described herein.

[0125] In some embodiments, a myeloid malignancy or ALL patient has not received steroids <7 days prior to first dose with the exception of physiologic dosing (equivalent to ≤ 10 mg of prednisone daily) or cytoreductive therapy.

[0126] In some embodiments, a myeloid malignancy or ALL patient does not have peripheral blasts ≥30,000 / µL (treatment with hydroxyurea and / or steroids is permitted within 2 weeks of first dose of study drug to reduce the WBC count).

[0127] In some embodiments, a myeloid malignancy or ALL patient is not a patient refractory to platelet or packed red blood cell transfusions per institutional guidelines (only for ALL and MDS / MPN patients).

[0128] In some embodiments, a myeloid malignancy or ALL patient is not a patient with signs or symptoms of Grade ≥ 2 acute or chronic graft versus host disease (GVHD) within 2 weeks of enrollment.

[0129] In some embodiments, a myeloid malignancy or ALL patient is not a patient with an active severe infection that required anti-infective therapy or with an unexplained fever > 38.5oC during Screening visits or on their first dose of Compound A as described herein. 32154354.1Page 17 of 78397731-105WO (213618)

[0130] In some embodiments, a myeloid malignancy or ALL patient has not had chronic systemic corticosteroid treatment.

[0131] In some embodiments, a myeloid malignancy or ALL patient does not have a history of significant or progressive chronic liver disease or suspected alcohol abuse.

[0132] In some embodiments, a myeloid malignancy or ALL patient does not have a history of hepatic veno-occlusive disease or sinusoidal obstruction syndrome.

[0133] In some embodiments, a method of the present invention comprises intravenously administering a liquid formulation as described herein. In some embodiments, a method of the present invention comprises administering a unit dosage form as described herein. In some embodiments, a method of the present invention comprises administering daily to a patient a liquid formulation or a unit dosage form as described herein. Liquid Formulations

[0134] According to one embodiment, the invention provides a liquid formulation or unit dosage form comprising Compound A, or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable excipient (e.g., a buffer) and / or carrier (e.g., water). The amount of Compound A in liquid formulations or unit dosage forms of this invention is such that it is effective to measurably degrade and / or inhibit MDM2 protein, or a mutant thereof, in a patient. In certain embodiments, a liquid formulation or unit dosage form of this invention is formulated for administration to a patient in need of such composition. In some embodiments, liquid formulation or unit dosage form of this invention is formulated for parenteral (e.g., intravenous) administration to a patient.

[0135] The liquid formulation or unit dosage form of the present invention may be administered parenterally by injection, infusion or implantation (intravenous, intramuscular, subcutaneous, or the like) as the liquid formulation or in unit dosage forms or via suitable delivery devices or implants containing conventional, non-toxic pharmaceutically acceptable carriers and adjuvants. In certain emebodiments, the the liquid formulation or unit dosage form of the present invention is administered by intravenous transfusion.

[0136] In some embodiments, a provided liquid formulation for parenteral use are provided in unit dosage forms (e.g., in single-dose ampoules), or in vials containing several doses and in which a suitable preservative may be added. Typically, such compositions can be prepared as injectable formulations, for example, solutions or suspensions; solid and liquid forms suitable for using to prepare solutions or suspensions upon the addition of a reconstitution or dilution medium prior to injection; emulsions, such as water-in-oil (w / o) emulsions, oil-in-water (o / w) emulsions, and microemulsions thereof, liposomes, or 32154354.1Page 18 of 78397731-105WO (213618)emulsomes. In some embodiments, the liquid formulation or unit dosage forms thereof are administered intravenously.

[0137] In some embodiments, the liquid formulations or unit dosage form comprising Compound A of present invention or pharmacologically acceptable salts thereof can be prepared in water or another solvent or dispersing medium suitably mixed with one or more pharmaceutically acceptable excipients including, but not limited to buffers, surfactants, solubilizing agents, dispersants, emulsifiers, viscosity modifying agents, and combination thereof.

[0138] In some embodiments, a liquid formulation or unit dosage form of the invention comprises Compound A, or a pharmaceutically acceptable salt thereof, at a concentration of about 0.05-5% w / w of the total weight of the formulation or unit dosage form. In some embodiments, a liquid formulation or unit dosage form of the invention comprises Compound A, or a pharmaceutically acceptable salt thereof, at a concentration of about 0.05-0.5%, about 0.1-1.0%, about 0.6-1.4%, about 0.7-1.3%, about 0.8-1.2%, or about 0.9-1.1% w / w of the total weight of the formulation or unit dosage form. In some embodiments, a liquid formulation or unit dosage form of the invention comprises Compound A, or a pharmaceutically acceptable salt thereof, at a concentration of about 0.60%, about 0.65%, about 0.70%, about 0.75%, about 0.80%, about 0.85%, about 0.90%, about 0.95%, about 1.00%, about 1.05%, about 1.10%, about 1.15%, about 1.20%, about 1.25%, about 1.30%, about 1.35%, about 1.40%, about 1.45%, or about 1.50% w / w of the total weight of the formulation or unit dosage form.

[0139] In some embodiments, a liquid formulation or unit dosage form of the invention comprises Compound A, or a pharmaceutically acceptable salt thereof, at a concentration of about 1-20 mg / mL. In some embodiments, a liquid formulation or unit dosage form of the invention comprises Compound A, or a pharmaceutically acceptable salt thereof, at a concentration of about 1-5 mg / mL, about 1-10 mg / mL, about 6-14 mg / mL, about 6.5-13.5 mg / mL, about 7-13 mg / mL, about 7.5-12.5 mg / mL, about 8-12 mg / mL, about 8.5-11.5 mg / mL, about 9-11 mg / mL, or about 9.5-10.5 mg / mL. In some embodiments, a liquid formulation or unit dosage form of the invention comprises Compound A, or a pharmaceutically acceptable salt thereof, at a concentration of about 8 mg / mL, about 8.5 mg / mL, about 9 mg / mL, about 9.5 mg / mL, about 10 mg / mL, about 10.5 mg / mL, about 11 mg / mL, about 11.5 mg / mL, or about 12 mg / mL.

[0140] In some embodiments, the liquid formulations or unit dose forms are packaged in solutions with one or more aqueous buffer. In some embodiments, the liquid formulations or unit dosage forms are packaged in solutions with sterile isotonic aqueous buffers. In some embodiments, the liquid formulations or unit dosage forms are buffered at about pH 5-8 for parenteral administration upon dilution. Suitable buffers or buffering agents include, but are not limited to, phosphate buffers, citrate buffers, acetate buffers, histidine buffers, or succinate buffers. In some embodiments, the buffer is one or more phosphate buffer. 32154354.1Page 19 of 78397731-105WO (213618)

[0141] In some embodiments, the liquid formulation or unit dosage form may also include a solubilizing agent. The components of the formulation can be either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder (which can be reconstituted before use with a carrier such as saline) or concentrated solution in a hermetically sealed container such as an ampoule or sachet indicating the amount of active agent. If the composition is to be administered by infusion, it can be dispensed with an infusion bottle or bag containing sterile pharmaceutical grade water or saline. Where the formulation is administered by injection, an ampoule of sterile water or saline can be provided so that the ingredients may be mixed prior to injection.

[0142] In some embodiments, the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, one or more polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), oils, such as vegetable oils (e.g., peanut oil, corn oil, sesame oil, etc.), and combinations thereof. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and / or by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. In some embodiments, the carrier is ethanol, a polyol, or a mixture of ethanol and a polyol. In some embodiments, the ethanol is 200 proof (i.e., food grade) ethanol. In some embodiments, the polyol is a liquid polyethylene glycol, such as polyethylene glycol 400.

[0143] In some embodiments, a liquid formulation or unit dosage form of the invention comprises one or more carriers (e.g., ethanol and a polyol) at a concentration of about 60-90% w / w of the total weight of the formulation or unit dosage form. In some embodiments, a liquid formulation or unit dosage form of the invention comprises one or more carriers (e.g., ethanol and a polyol) at a concentration of about 60-80%, about 70-85%, or about 75-90% w / w of the total weight of the formulation or unit dosage form. In some embodiments, a liquid formulation or unit dosage form of the invention comprises one or more carriers (e.g., ethanol and a polyol) at a concentration of about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, or about 90% w / w of the total weight of the formulation or unit dosage form. In some embodiments, a liquid formulation or unit dosage form of the invention comprises at first carrier (e.g., a polyol) at a concentration of about 60-80% of the total weight of the formulation or unit dosage form. In some embodiments, a liquid formulation or unit dosage form of the invention comprises a second carrier (e.g, ethanol) at a concentration of about 5-20% of the total weight of the formulation or unit dosage form. In some embodiment, a liquid formulation or unit dosage form of the invention comprises a first carrier and a second carrier in a ratio of about 1:10 to about 10:1. In some embodiments, the first carrier is a polyol (e.g., polyethylene glycol 400) and the second carrier is ethanol in a ratio of about 5:1 to about 9:1, for example about 6:1, about 7:1, or about 8:1. 32154354.1Page 20 of 78397731-105WO (213618)

[0144] In some embodiments, a liquid formulation or unit dosage form of the invention comprises a carrier (e.g., ethanol and a polyol) at a concentration of about 400-1500 mg / mL. In some embodiments, a liquid formulation or unit dosage form of the invention comprises Compound A, or a pharmaceutically acceptable salt thereof, at a concentration of about 400-600 mg / mL, about 500-700 mg / mL, about 600-800 mg / mL, about 700-900 mg / mL, about 800-1000 mg / mL, about 900-1100 mg / mL, about 1000-1200 mg / mL, about 1100-1300 mg / mL, about 1200-1400 mg / mL, or about 1300-1500 mg / mL. In some embodiments, a liquid formulation or unit dosage form of the invention comprises a first carrier (e.g., a polyol) at a concentration of about 650-850 mg / mL. In some embodiments, a liquid formulation or unit dosage form of the invention comprises a second carrier (e.g., ethanol) at a concentration of about 50-150 mg / mL.

[0145] Suitable surfactants may be anionic, cationic, amphoteric or nonionic surface-active agents. Suitable anionic surfactants include, but are not limited to, those containing carboxylate, sulfonate and sulfate ions. Examples of anionic surfactants include sodium, potassium, ammonium of long chain alkyl sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2-ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate. Cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene, and coconut amine. Examples of nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbates (e.g. polysorbate 80), polyoxyethylene octylphenylether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, Poloxamer® 401, stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide. Examples of amphoteric surfactants include sodium N-dodecyl-beta-alanine, sodium N-laurylβiminodipropionate, myristoamphoacetate, lauryl betaine, and lauryl sulfobetaine.

[0146] In some embodiments, a liquid formulation or unit dosage form of the invention comprises a surfactant (e.g., polysorbate 80) at a concentration of about 10-30% w / w of the total weight of the formulation or unit dosage form. In some embodiments, a liquid formulation or unit dosage form of the invention comprises a surfactant (e.g., polysorbate 80) at a concentration of about 10-20%, about 15-25%, or about 20-30% w / w of the total weight of the formulation or unit dosage form. In some embodiments, a liquid formulation or unit dosage form of the invention comprises a surfactant (e.g., polysorbate 80) at a concentration of about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30% w / w of the total weight of the formulation or unit dosage form. 32154354.1Page 21 of 78397731-105WO (213618)

[0147] In some embodiments, a liquid formulation or unit dosage form of the invention comprises a surfactant (e.g., polysorbate 80) at a concentration of about 100-500 mg / mL of the total weight of the formulation or unit dosage form. In some embodiments, a liquid formulation or unit dosage form of the invention comprises a surfactant (e.g., polysorbate 80) at a concentration of about 100-300, about 200-400, or about 300-500 mg / mL. In some embodiments, a liquid formulation or unit dosage form of the invention comprises a surfactant (e.g., polysorbate 80) at a concentration of about 110, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, about 200, about 210, about 220, about 230, about 240, about 250, about 260, about 270, about 280, about 290, about 300, about 310, about 320, about 330, about 340, about 350, about 360, about 370, about 380, about 390, or about 400 mg / mL.

[0148] The formulation can contain a preservative to prevent the growth of microorganisms. Suitable preservatives include, but are not limited to, parabens, chlorobutanol, phenol, sorbic acid, and thimerosal. The formulation may also contain an antioxidant to prevent degradation of the active agent(s).

[0149] In some embodiments, a liquid formulation or unit dosage form of the invention comprises an antioxidant (e.g., butylated hydroxytoluene) at a concentration of about 0.001-0.1% w / w of the total weight of the formulation or unit dosage form. In some embodiments, a liquid formulation or unit dosage form of the invention comprises an antioxidant (e.g., butylated hydroxytoluene) at a concentration of about 0.001- 0.01%, about 0.005-0.05%, or about 0.01-0.1% w / w of the total weight of the formulation or unit dosage form. In some embodiments, a liquid formulation or unit dosage form of the invention comprises an antioxidant (e.g., butylated hydroxytoluene) at a concentration of about 0.01-1 mg / mL. In some embodiments, a liquid formulation or unit dosage form of the invention comprises an antioxidant (e.g., butylated hydroxytoluene) at a concentration of about 0.01-0.1 mg / mL, about 0.05-0.5 mg / mL, or about 0.1-1 mg / mL.

[0150] In some embodiments, the present invention provides a unit dosage form, which is a liquid formulation of the present invention, as described above, with a volume of from about 1 mL to about 10 mL. In some embodiments, the present invention provides a unit dosage form, which is a liquid formulation of the present invention, as described above, with a volume of about 1 mL, about 2 mL, about 3 mL, about 4 mL, about 5 mL, about 6 mL, about 7 mL, about 8 mL, about 9 mL, or about 10 mL.

[0151] In some embodiments, a liquid formulation or unit dosage form of the invention comprises Compound A or a pharmaceutically acceptable salt thereof at about 0.5-1.5% w / w (e.g., about 0.9% w / w of Compound A), about 15-25% w / w surfactant (e.g., about 10% w / w polysorbate 80), about 60-80% w / w a first carrier (e.g., about 69% w / w polyethylene glycol 400), about 5-15% w / w a second carrier (e.g., about 10% w / w ethanol), and about 0.005-0.05% w / w antioxidant (e.g., about 0.01% w / w butylated hydroxytoluene) of the total weight of the formulation or unit dosage form. In some embodiments, a liquid formulation or unit dosage form of the invention is as depicted in Table 3, below. 32154354.1Page 22 of 78397731-105WO (213618)

[0152] Water-soluble polymers are often used in formulations for parenteral administration. Suitable water-soluble polymers include, but are not limited to, polyvinylpyrrolidone, dextran, carboxymethylcellulose, and polyethylene glycol.

[0153] In some embodiments, the liquid formulation may include a solubilizing agent. In some embodiments, the solubilizing agent is a cyclodextrin. Cyclodextrines include members of a family of cyclic oligosaccharides, composed of 5 or more α-D-glucopyranoside units linked between positions 1 and 4, as known for amylose, a fragment of starch. In some embodimets, the cyclodextrin is an α-cyclodextrin, β-cyclodextrin, and / or γ-cyclodextrin.

[0154] Sterile injectable solutions can be prepared by incorporating the active compounds in the required amount in the appropriate solvent or dispersion medium with one or more of the excipients listed above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. The powders can be prepared in such a manner that the particles are porous in nature, which can increase dissolution of the particles. Methods for making porous particles are well known in the art.

[0155] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. Administration and Dosage

[0156] As described herein, the liquid formulations or unit dosage form comprising Compound A of present invention are administered intravenously. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered by an IV injection. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered by an IV infusion.

[0157] In some embodiments, the methods and uses described herein, such as the method of or use in treating a solid cancer or hematological malignancy in a patient in need thereof, is achieved by administering (e.g., intravenously) a therapeutically effective amount of Compound A, such as up to 100 mg in a single or multiple dosage units. In some embodiments, the method can include administering (e.g., intravenously), in a single or multiple dosage units ranging from about 1 to about 100 mg / dosage form, such as about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 32154354.1Page 23 of 78397731-105WO (213618)mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, or about 100 mg. For example, a liquid formulation can include 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg / dosage form of Compound A or a pharmaceutically acceptable salt thereof.

[0158] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is intravenously administered at a dose of up to 5 mg to the patient. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is intravenously administered at a dose of up to 10 mg to the patient. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is intravenously administered at a dose of up to 15 mg to the patient. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is intravenously administered at a dose of up to 20 mg to the patient. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is intravenously administered at a dose of up to 25 mg to the patient. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is intravenously administered at a dose of up to 30 mg to the patient. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is intravenously administered at a dose of up to 35 mg to the patient. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is intravenously administered at a dose of up to 40 mg to the patient. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is intravenously administered at a dose of up to 45 mg to the patient. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is intravenously administered at a dose of up to 50 mg to the patient. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is intravenously administered at a dose of from about 10 mg to about 40 mg to the patient. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is intravenously administered at a dose of from about 20 mg to about 50 mg to the patient, such as about 30 mg, 35 mg, or 40 mg. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is intravenously administered at a dose of about 35 mg to the patient.

[0159] In some embodiments, a liquid pharmaceutical composition is provided, wherein, the pharmaceutically composition comprises 5 mg to about 50 mg of Compound A, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipient or carrier. In some embodiments, a liquid pharmaceutical composition is provided, wherein, the pharmaceutically composition comprises 25 mg to about 45 mg of Compound A, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipient or carrier.

[0160] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered intravenously to a patient at a dose of up to about 30 32154354.1Page 24 of 78397731-105WO (213618)mg / m2. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered intravenously to a patient at a dose of up to about 25 mg / m2, or up to about 20 mg / m2, or up to about 15 mg / m2. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered intravenously to a patient at a dose of about 1 mg / m2to about 5 mg / m2, or about 3 mg / m2to about 8 mg / m2, or about 5 mg / m2to about 10 mg / m2, or about 7 mg / m2to about 12 mg / m2, or about 10 mg / m2to about 15 mg / m2, or about 12 mg / m2to about 7 mg / m2, or about 15 mg / m2to about 20 mg / m2, or about 17 mg / m2to about 22 mg / m2, or about 20 mg / m2to about 25 mg / m2, or about 22 mg / m2to about 27 mg / m2. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered intravenously to a patient at a dose of about 30 mg / m2, about 27 mg / m2, about 20 mg / m2, about 17 mg / m2, about 15 mg / m2, about 12 mg / m2, about 10 mg / m2, about 7 mg / m2, about 5 mg / m2, about 3 mg / m2, or about 1 mg / m2.

[0161] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered intravenously to a patient at a dose of up to about 0.8 mg / kg. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered intravenously to a patient at a dose of up to about 0.6 mg / kg, or up to about 0.3 mg / kg, or up to about 0.1 mg / kg. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered intravenously to a patient at a dose of about 0.01 mg / kg to about 0.05 mg / kg, or about 0.03 mg / kg to about 0.08 mg / kg, or about 0.05 mg / kg to about 0.1 mg / kg, or about 0.07 mg / kg to about 0.12 mg / kg, or about 0.1 mg / kg to about 0.15 mg / kg, or about 0.12 mg / kg to about 0.17 mg / kg. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered intravenously to a patient at a dose of about 1 mg / kg, about 0.8 mg / kg, about 0.5 mg / kg, about 0.3 mg / kg, about 0.1 mg / kg, about 0.08 mg / kg, or about 0.06 mg / kg.

[0162] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered intravenously to a patient at a dose of about 0.05 mg / kg. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered intravenously to a patient at a dose of about 0.1 mg / kg. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered intravenously to a patient at a dose of about 0.17 mg / kg. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered intravenously to a patient at a dose of about 0.25 mg / kg. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered intravenously to a patient at a dose of about 0.33 mg / kg. In some embodiments, Compound 32154354.1Page 25 of 78397731-105WO (213618)A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered intravenously to a patient at a dose of about 0.42 mg / kg. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered intravenously to a patient at a dose of about 0.53 mg / kg. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered intravenously to a patient at a dose of about 0.66 mg / kg. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered intravenously to a patient at a dose of about 0.82 mg / kg. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered intravenously to a patient at a dose of about 1.00 mg / kg.

[0163] In some embodiments, a method of the present invention comprises administering a liquid formulation or a unit dosage form as described herein, wherein a Cmax of up to about 2000 ng / mL of Compound A in plasma is achieved. In some embodiments, the administration of Compound A or a pharmaceutically acceptable salt thereof (e.g., in a liquid formulation or a unit dose form as described herein) achieves a Cmax of up to about 1500 ng / mL of Compound A in plasma. In some embodiments, the administration of Compound A or a pharmaceutically acceptable salt thereof (e.g., in a liquid formulation or a unit dose form as described herein) achieves a Cmax of up to about 1000 ng / mL of Compound A in plasma. In some embodiments, the administration of Compound A or a pharmaceutically acceptable salt thereof (e.g., in a liquid formulation or a unit dose form as described herein) achieves a Cmax of up to about 500 ng / mL of Compound A in plasma.

[0164] In some embodiments, a Cmax of Compound A in plasma includes about 50 ng / mL, about 100 ng / mL, about 150 ng / mL, about 200 ng / mL, about 250 ng / mL, about 300 ng / mL, about 350 ng / mL, about 400 ng / mL, about 450 ng / mL, about 500 ng / mL, about 550 ng / mL, about 600 ng / mL, about 650 ng / mL, about 700 ng / mL, about 750 ng / mL, about 800 ng / mL, about 850 ng / mL, about 900 ng / mL, about 950 ng / mL, about 1000 ng / mL, about 1050 ng / mL, about 1100 ng / mL, about 1150 ng / mL, about 1200 ng / mL, about 1250 ng / mL, about 1300 ng / mL, about 1350 ng / mL, about 1400 ng / mL, about 1450 ng / mL, about 1500 ng / mL, about 1550 ng / mL, about 1600 ng / mL, about 1650 ng / mL, about 1700 ng / mL, about 1750 ng / mL, about 1800 ng / mL, about 1850 ng / mL, about 1900 ng / mL, about 1950 ng / mL, and about 2000 ng / mL, or any range of Cmax created by using two of the aforementioned concentrations as endpoints. In some embodiments, a Cmax of Compound A in plasma, as listed in Table 7 or Table 9, is achieved.

[0165] In some embodments, a Cmax of Compound A in plasma includes about 100 ng / mL to about 1000 ng / mL, about 100 ng / mL to about 900 ng / mL, about 100 ng / mL to about 800 ng / mL, about 100 ng / mL to about 700 ng / mL, about 100 ng / mL to about 600 ng / mL, about 200 ng / mL to about 1000 ng / mL, about 200 32154354.1Page 26 of 78397731-105WO (213618)ng / mL to about 900 ng / mL, about 200 ng / mL to about 800 ng / mL, about 200 ng / mL to about 700 ng / mL, or about 200 ng / mL to about 600 ng / mL.

[0166] In some embodments, a Cmax of Compound A in plasma includes about 100 ng / mL to about 500 ng / mL, about 100 ng / mL to about 400 ng / mL, about 100 ng / mL to about 300 ng / mL, about 200 ng / mL to about 500 ng / mL, about 200 ng / mL to about 400 ng / mL, or about 300 ng / mL to about 500 ng / mL.

[0167] In some embodments, a Cmax of Compound A in plasma includes about 500 ng / mL to about 2000 ng / mL, about 700 ng / mL to about 1700 ng / mL, about 1000 ng / mL to about 1700 ng / mL, about 500 ng / mL to about 1500 ng / mL, about 700 ng / mL to about 1500 ng / mL, about 700 ng / mL to about 1300 ng / mL, about 900 ng / mL to about 1500 ng / mL, about 900 ng / mL to about 1300 ng / mL, about 1000 ng / mL to about 1500 ng / mL, or about 1000 ng / mL to about 1300 ng / mL.

[0168] In some embodiments, the present disclosure provides a method of administering Compound A to a patient in need thereof, comprising administering to said patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof (e.g., in a liquid formulation or a unit dose form as described herein), wherein an AUC of up to about 3,000 ng*h / mL of Compound A in plasma is achieved. In some embodiments, the administration of Compound A or a pharmaceutically acceptable salt thereof (e.g., in a liquid formulation or a unit dose form as described herein) achieves an AUC of up to about 2000 ng*h / mL of Compound A in plasma. In some embodiments, the administration of Compound A or a pharmaceutically acceptable salt thereof (e.g., in a liquid formulation or a unit dose form as described herein) achieves an AUC of up to about 1000 ng*h / mL of Compound A in plasma.

[0169] In some embodiments, an AUC of Compound A in plasma includes about 100 ng*h / mL, about 150 ng*h / mL, about 200 ng*h / mL, about 250 ng*h / mL, about 300 ng*h / mL, about 350 ng*h / mL, about 400 ng*h / mL, about 450 ng*h / mL, about 500 ng*h / mL, about 550 ng*h / mL, about 600 ng*h / mL, about 650 ng*h / mL, about 700 ng*h / mL, about 750 ng*h / mL, 800 ng*h / mL, 850 ng*h / mL, 900 ng*h / mL, 950 ng*h / mL, 1000 ng*h / mL, 1050 ng*h / mL, 1100 ng*h / mL, 1150 ng*h / mL, 1200 ng*h / mL, 1250 ng*h / mL, 1300 ng*h / mL, 1350 ng*h / mL, 1400 ng*h / mL, 1450 ng*h / mL, 1500 ng*h / mL, 1550 ng*h / mL, 1600 ng*h / mL, 1650 ng*h / mL, 1700 ng*h / mL, 1750 ng*h / mL, 1800 ng*h / mL, 1850 ng*h / mL, 1900 ng*h / mL, 1950 ng*h / mL, or about 2000 ng*h / mL, or any range of AUC created by using two of the aforementioned concentrations as endpoints. In some embodiments, an AUC of Compound A in plasma, as listed in Table 7 or Table 9, is achieved.

[0170] In some embodments, an AUC of Compound A in plasma includes about 200 ng*h / mL to about 1500 ng*h / mL, about 200 ng*h / mL to about 1200 ng*h / mL, about 200 ng*h / mL to about 1000 ng*h / mL, about 200 ng*h / mL to about 900 ng*h / mL, about 200 ng*h / mL to about 800 ng*h / mL, about 300 ng*h / mL to about 1500 ng*h / mL, about 300 ng*h / mL to about 1200 ng*h / mL, about 300 ng*h / mL to about 1000 ng*h / mL, about 300 ng*h / mL to about 900 ng*h / mL, or about 300 ng*h / mL to about 800 ng*h / mL. 32154354.1Page 27 of 78397731-105WO (213618)

[0171] In some embodments, an AUC of Compound A in plasma includes about 100 ng*h / mL to about 500 ng*h / mL, about 200 ng*h / mL to about 600 ng*h / mL, about 300 ng*h / mL to about 700 ng*h / mL, about 400 ng*h / mL to about 800 ng*h / mL, about 500 ng*h / mL to about 900 ng*h / mL, or about 600 ng*h / mL to about 1000 ng*h / mL.

[0172] In some embodiments, a method of the present invention comprises administering a liquid formulation or a unit dosage form as described herein, wherein a Vd of up to about 6 L / kg of Compound A in plasma is achieved. In some embodiments, the administration of Compound A or a pharmaceutically acceptable salt thereof (e.g., in a liquid formulation or a unit dose form as described herein) achieves a Vd of up to about 4 L / kg of Compound A in plasma. In some embodiments, the administration of Compound A or a pharmaceutically acceptable salt thereof (e.g., in a liquid formulation or a unit dose form as described herein) achieves a Vd of up to about 3 L / kg of Compound A in plasma.

[0173] In some embodiments, a Vd of Compound A in plasma includes about 1 L / kg, about 1.5 L / kg, about 2 L / kg, about 2.5 L / kg, about 3 L / kg, about 3.5 L / kg, about 4 L / kg, about 4.5 L / kg, or any range of Vd created by using two of the aforementioned concentrations as endpoints. In some embodiments, a Vd of Compound A in plasma, as listed in Table 9, is achieved.

[0174] In some embodiments, a method of the present invention comprises administering a liquid formulation or a unit dosage form as described herein, wherein a CL of up to about 0.5 L / h / kg of Compound A in plasma is achieved. In some embodiments, the administration of Compound A or a pharmaceutically acceptable salt thereof (e.g., in a liquid formulation or a unit dose form as described herein) achieves a CL of up to about 0.4 L / h / kg of Compound A in plasma. In some embodiments, the administration of Compound A or a pharmaceutically acceptable salt thereof (e.g., in a liquid formulation or a unit dose form as described herein) achieves a CL of up to about 0.3 L / h / kg of Compound A in plasma.

[0175] In some embodiments, a CL of Compound A in plasma includes about 0.10 L / h / kg, about 0.11 L / h / kg, about 0.12 L / h / kg, about 0.13 L / h / kg, about 0.14 L / h / kg, about 0.15 L / h / kg, about 0.16 L / h / kg, about 0.17 L / h / kg, about 0.18 L / h / kg, about 0.19 L / h / kg, about 0.20 L / h / kg, about 0.21 L / h / kg, about 0.22 L / h / kg, about 0.23 L / h / kg, about 0.24 L / h / kg, about 0.25 L / h / kg, about 0.26 L / h / kg, about 0.27 L / h / kg, about 0.28 L / h / kg, about 0.29 L / h / kg, about 0.30 L / h / kg, about 0.31 L / h / kg, about 0.32 L / h / kg, about 0.33 L / h / kg, or any range of CL created by using two of the aforementioned concentrations as endpoints. In some embodiments, a CL of Compound A in plasma, as listed in Table 9, is achieved.

[0176] In some embodiments, a method of the present invention comprises administering a liquid formulation or a unit dosage form as described herein, wherein a t1 / 2 of up to about 30 h of Compound A in plasma is achieved. In some embodiments, the administration of Compound A or a pharmaceutically acceptable salt thereof (e.g., in a liquid formulation or a unit dose form as described herein) achieves a t1 / 2 of up to about 25 h of Compound A in plasma. In some embodiments, the administration of Compound A 32154354.1Page 28 of 78397731-105WO (213618)or a pharmaceutically acceptable salt thereof (e.g., in a liquid formulation or a unit dose form as described herein) achieves a t1 / 2 of up to about 20 h of Compound A in plasma.

[0177] In some embodiments, a t1 / 2 of Compound A in plasma includes about 5 h, about 6 h, about 7 h, about 8 h, about 9 h, about 10 h, about 11 h, about 12 h, about 13 h, about 14 h, about 15 h, about 16 h, about 17 h, about 18 h, about 19 h, about 20 h, about 21 h, about 22 h, or any range of t1 / 2 created by using two of the aforementioned concentrations as endpoints. In some embodiments, a t1 / 2 of Compound A in plasma, as listed in Table 9, is achieved.

[0178] In some embodiments, the present disclosure provides a method of administering Compound A to a patient in need thereof, comprising administering to said patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof (e.g., in a liquid formulation or a unit dose form as described herein), wherein up to about a 500 fold increase of one or more markers of p53 activity (e.g., GDF15) in plasma is achieved over pre-dose reference (e.g., baseline) levels. In some embodiments, the administration of Compound A or a pharmaceutically acceptable salt thereof (e.g., in a liquid formulation or a unit dose form as described herein) achieves up to about a 300 fold increase of one or more markers of p53 activity (e.g., GDF15) in plasma. In some embodiments, the administration of Compound A or a pharmaceutically acceptable salt thereof (e.g., in a liquid formulation or a unit dose form as described herein) achieves up to about a 200 fold increase of one or more markers of p53 activity (e.g., GDF15) in plasma. In some embodiments, the administration of Compound A or a pharmaceutically acceptable salt thereof (e.g., in a liquid formulation or a unit dose form as described herein) achieves up to about a 100 fold increase of one or more markers of p53 activity (e.g., GDF15) in plasma. In some embodiments, the administration of Compound A or a pharmaceutically acceptable salt thereof (e.g., in a liquid formulation or a unit dose form as described herein) achieves up to about a 50 fold increase of one or more markers of p53 activity (e.g., GDF15) in plasma. In some embodiments, the administration of Compound A or a pharmaceutically acceptable salt thereof (e.g., in a liquid formulation or a unit dose form as described herein) achieves up to about a 25 fold increase of one or more markers of p53 activity (e.g., GDF15) in plasma. In some embodiments, the administration of Compound A or a pharmaceutically acceptable salt thereof (e.g., in a liquid formulation or a unit dose form as described herein) achieves up to about a 10 fold increase of one or more markers of p53 activity (e.g., GDF15) in plasma.

[0179] In some embodiments, an increase of one or more markers of p53 activity (e.g., GDF15) in plasma includes about 3 fold, about 5 fold, about 10 fold, about 15 fold, about 20 fold, about 25 fold, about 30 fold, about 35 fold, about 40 fold, about 45 fold, about 50 fold, about 55 fold, about 60 fold, about 65 fold, about 70 fold, about 75 fold, about 80 fold, about 85 fold, about 90 fold, about 95 fold, about 100 fold, about 105 fold, about 110 fold, about 115 fold, about 120 fold, about 125 fold, about 130 fold, about 135 fold, about 140 fold, about 145 fold, about 150 fold, about 155 fold, about 160 fold, about 165 fold, about 170 fold, 32154354.1Page 29 of 78397731-105WO (213618)about 175 fold, about 180 fold, about 185 fold, about 190 fold, about 195 fold, about 200 fold, about 205 fold, about 210 fold, about 215 fold, about 220 fold, about 225 fold, about 230 fold, about 235 fold, about 240 fold, about 245 fold, about 250 fold, about 255 fold, about 260 fold, about 265 fold, about 270 fold, about 275 fold, about 280 fold, about 285 fold, about 290 fold, about 295 fold, about 300 fold, about 305 fold, about 310 fold, about 315 fold, about 320 fold, about 325 fold, about 330 fold, about 335 fold, about 340 fold, about 345 fold, about 350 fold, about 355 fold, about 360 fold, about 365 fold, about 370 fold, about 375 fold, about 380 fold, about 385 fold, about 390 fold, about 395 fold, about 400 fold, about 410 fold, about 420 fold, about 430 fold, about 440 fold, about 450 fold, about 460 fold, about 470 fold, about 480 fold, about 490 fold, or about 500 fold, or any range of fold increase created by using two of the aforementioned concentrations as endpoints. In some embodiments, a fold increase of GDF15 in plasma, as listed in Table 7, is achieved. In some embodiments, a fold increase of MDM2, GDF15, CDKN1A, GADD45A, TNFRSF10B, FAS, or BBC3 in plasma, as shown in FIG. 15, is achieved. In some embodiments, a fold increase of GDF15, CDKN1A, or PHLDA3 in plasma, as shown in FIG. 22, is achieved.

[0180] In some embodments, an increase of one or more markers of p53 activity (e.g., GDF15) in plasma includes about 10 fold to about 200 fold, about 10 fold to about 180 fold, about 10 fold to about 160 fold, about 10 fold to about 140 fold, about 10 fold to about 120 fold, about 10 fold to about 100 fold, about 10 fold to about 80 fold, about 10 fold to about 60 fold, about 20 fold to about 200 fold, about 20 fold to about 180 fold, about 20 fold to about 160 fold, about 20 fold to about 140 fold, about 20 fold to about 120 fold, about 20 fold to about 100 fold, about 20 fold to about 80 fold, about 20 fold to about 60 fold.

[0181] In some embodments, an increase of one or more markers of p53 activity (e.g., GDF15) in plasma includes about 3 fold to about 15 fold, about 5 fold to about 15 fold, about 10 fold to about 20 fold, about 15 fold to about 25 fold, about 20 fold to about 30 fold, about 25 fold to about 35 fold, about 35 fold to about 45 fold, about 40 fold to about 50 fold, about 45 fold to about 55 fold, about 50 fold to about 60 fold, about 55 fold to about 65 fold, about 60 fold to about 70 fold, about 65 fold to about 75 fold, about 70 fold to about 80 fold, about 75 fold to about 85 fold, about 80 fold to about 90 fold, about 85 fold to about 95 fold, or about 90 fold to about 100 fold.

[0182] In some embodments, an increase of one or more markers of p53 activity (e.g., GDF15) in plasma includes about 3 fold to about 20 fold, about 5 fold to about 25 fold, about 10 fold to about 30 fold, about 15 fold to about 35 fold, about 20 fold to about 40 fold, about 25 fold to about 45 fold, about 30 fold to about 50 fold, about 35 fold to about 55 fold, about 40 to about 60 fold, about 45 fold to about 65 fold, about 50 fold to about 70 fold, about 55 fold to about 75 fold, about 60 fold to about 80 fold, about 65 fold to about 85 fold, about 70 fold to about 90 fold, about 75 fold to about 95 fold, or about 80 fold to about 100 fold. 32154354.1Page 30 of 78397731-105WO (213618)Dosing Schedule

[0183] As provided herein, Compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered to a patient at a dosing schedule appropriate to give the desired tumor regression effect with minimum side effects. In some embodiments, Compound A or pharmaceutical composition thereof is administered to a patient once every 1, 2, 3, 4, 5, 6, 7, 14, or 21 days. In some embodiments, Compound A or pharmaceutical composition thereof is administered to a patient daily (QD). In some embodiments, Compound A or pharmaceutical composition thereof is administered to a patient biweekly (BW). In some embodiments, Compound A or pharmaceutical composition thereof is administered to a patient weekly (QW). In some embodiments, Compound A or pharmaceutical composition thereof is administered to a patient every two weeks (Q2W). In some embodiments, Compound A or pharmaceutical composition thereof is administered to a patient every three weeks (Q3W).

[0184] In some embodiments, an IV infusion of a pharmaceutical composition of the invention lasts about 5-30 minutes. In some embodiments, an IV infusion of a pharmaceutical composition of the invention lasts about 30-90 minutes. In some embodiments, an IV infusion of a pharmaceutical composition of the invention lasts about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 minutes. In some embodiments, an IV infusion of a pharmaceutical composition of the invention lasts about 2, 2.5, 3, 3.5, or 4 hours.

[0185] In some embodiments, a pharmaceutical composition of the invention is administered intravenously weekly at a dose of from about 0.1 mg / m2to about 30 mg / m2. In some embodiments, a pharmaceutical composition of the invention is administered intravenously weekly at a dose of from about 1 mg / m2to about 10 mg / m2. Methods and Uses for Treating Disease

[0186] Compound A and compositions described herein are useful for the degradation and / or inhibition of MDM2 protein activity.

[0187] Thus, in certain embodiments, the present invention provides a method for treating a MDM2- mediated disorder comprising the step of administering to a patient in need thereof Compound A of the present invention, or pharmaceutically acceptable composition thereof.

[0188] As used herein, the terms “MDM2-mediated” disorders, diseases, and / or conditions as used herein means any disease or other deleterious condition in which MDM2 protein or a mutant thereof, are known to play a role. Accordingly, another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which MDM2 protein or a mutant thereof, are known to play a role. 32154354.1Page 31 of 78397731-105WO (213618)

[0189] In some embodiments, the present invention provides a method for treating one or more disorders, diseases, and / or conditions wherein the disorder, disease, or condition is a cancer, a neurodegenerative disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hereditary disorder, a hormone-related disease, a metabolic disorder, conditions associated with organ transplantation, immunodeficiency disorders, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder, or a CNS disorder.

[0190] In some embodiments, the cancer is selected from adrenal cancer, acinic cell carcinoma, acoustic neuroma, acral lentiginous melanoma, acrospiroma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell leukemia / lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic fibroma, anaplastic large cell lymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, astrocytoma, rhabdoid (e.g., atypical teratoid rhabdoid tumor), B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, B-cell lymphoma, basal cell carcinoma, bile duct cancer, biliary tract cancer, bladder cancer, blastoma, bone cancer, myelofibrosis, Brenner tumor, Brown tumor, Burkitt's lymphoma, breast cancer, brain cancer, carcinoma, carcinoma in situ, carcinosarcoma, cartilage tumor, cementoma, myeloid sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, clear-cell sarcoma of the kidney, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, Degos disease, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, dysembryoplastic neuroepithelial tumor, dysgerminoma, embryonal carcinoma, endocrine gland neoplasm, endodermal sinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, fetus in fetu, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, ganglioneuroma, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of the bone, glial tumor, glioblastoma multiforme, glioma, gliomatosis cerebri, glucagonoma, gonadoblastoma, granulosa cell tumor, gynandroblastoma, gallbladder cancer, gastric cancer, hairy cell leukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma, hematological malignancy, hepatoblastoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna, lethal midline carcinoma, leukemia, leydig cell tumor, liposarcoma, lung cancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma, acute lymphocytic leukemia, acute myelogeous leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, MALT lymphoma, malignant fibrous histiocytoma, malignant 32154354.1Page 32 of 78397731-105WO (213618)peripheral nerve sheath tumor, malignant triton tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, medullary carcinoma of the breast, medullary thyroid cancer, medulloblastoma, melanoma, meningioma, Merkel cell cancer, mesothelioma, metastatic urothelial carcinoma, mixed Mullerian tumor, mucinous tumor, multiple myeloma, muscle tissue neoplasm, mycosis fungoides, myxoid liposarcoma, myxoma, myxosarcoma, nasopharyngeal carcinoma, neurinoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, ocular cancer, oligoastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, optic nerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor, papillary thyroid cancer, paraganglioma, pinealoblastoma, pineocytoma, pituicytoma, pituitary adenoma, pituitary tumor, plasmacytoma polyembryoma, precursor T- lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, primary peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, pseudomyxoma periotonei, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's transformation, rectal cancer, sarcoma, Ewing sarcoma, Schwannomatosis, seminoma, Sertoli cell tumor, sex cord-gonadal stromal tumor, signet ring cell carcinoma, skin cancer, Merkel cell carcinoma, fibromyxoid sarcoma, myxofibrosarcoma, small blue round cell tumors, small cell carcinoma, soft tissue sarcoma, somatostatinoma, soot wart, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, Sezary's disease, small intestine cancer, squamous carcinoma, stomach cancer, T-cell lymphoma, testicular cancer, thecoma thyroid cancer, transitional cell carcinoma, throat cancer, urachal cancer, urogenital cancer, urothelial carcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, visual pathway ghoma, vulvar cancer, vaginal cancer, Waldenstrom's macroglobulinemia, Warthin's tumor, and Wilms' tumor.

[0191] MDM2 hyperactivity, due to amplification / overexpression or mutational inactivation of the ARF locus, inhibits the function of wild-type p53 and can lead to the development of a wide variety of cancers. In some embodiments, the MDM2 hyperactivity which can be treated according to the methods of this invention is a human cancer. In some embodiments, the human cancer which can be treated according to the methods of this invention is selected from a solid cancer or hematological malignancy. In some embodimentsm, the wild-type p53 cancer is mesothelioma, melanoma, DLBCL, prostate cancer, cholangiocarcinoma, cervical cancer, AML, renal cell cancer, uveal melanoma, thyroid cancer, liposarcoma, HCC, or breast cancer.

[0192] In some embodiments, the solid cancer includes solid tumors that have an abnormal mass of tissue that may not contain cysts or liquid areas. Solid tumors may be benign or malignant. In some embodiments, examples of solid tumors include sarcomas, carcinomas, and lymphomas. In some embodiments, the solid cancer is carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus, 32154354.1Page 33 of 78397731-105WO (213618)larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas, gastrointestinal cancer, such as colon carcinoma or colorectal adenoma, a tumor of the neck and head, an epidermal hyperproliferation, prostate hyperplasia, a neoplasia, a neoplasia of epithelial character, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small-cell lung carcinoma, such as Hodgkin’s and Non-Hodgkin’s, a mammary carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, an IL-1 driven disorder, an MyD88 driven disorder, or Smoldering of indolent multiple myeloma. In some embodiments, the hematological malignancy is a cancer that affects the blood, bone marrow, and lymph nodes. In some embodiments the hematological malignancy includes leukemias, lymphomas, and myelomas, such as acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), large granular lymphocytic leukemia (LGL-L), B-cell prolymphocytic leukemia, acute myeloid leukemia (AML), Burkitt lymphoma / leukemia, myelofibrosis, primary effusion lymphoma, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), diffuse large B-cell lymphoma (DLBCL), advanced B-cell diffuse large B-cell lymphoma (ABC DLBCL), intravascular large B-cell lymphoma, lymphoplasmacytic lymphoma, Waldenström’s macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, uveal melanoma, myelodysplastic syndrome (MDS), or myelodysplastic / myeloproliferative neoplasms (MDS / MPN).

[0193] In some embodiments the solid cancer or hematological malignancy is relapsed and / or refractory (R / R) high grade myeloid malignancies, acute lymphocytic leukemia (ALL), R / R lymphoma, or R / R solid tumors.

[0194] In some embodiments, the AML is caused by protein (e.g., of KMT2A or MLL) mutation or fusion. In some embodiments, the AML is a mutant or fusion protein AML, such as IDH1, DNMT3A, NPM1, ASXL1, FLT3-ITD, KMT2A-MLLT3, MLL-MLLT3, or MLL-AF9.

[0195] In some embodiment, the present disclosure provides a method of treating a benign proliferative disorder, such as, but are not limited to, benign soft tissue tumors, bone tumors, brain and spinal tumors, eyelid and orbital tumors, granuloma, lipoma, meningioma, multiple endocrine neoplasia, nasal polyps, pituitary tumors, prolactinoma, pseudotumor cerebri, seborrheic keratosis, stomach polyps, thyroid nodules, cystic neoplasms of the pancreas, hemangiomas, vocal cord nodules, polyps, and cysts, Castleman disease, chronic pilonidal disease, dermatofibroma, pilar cyst, pyogenic granuloma, and juvenile polyposis syndrome.

[0196] In some embodiments, the cancer is a leukemia, for example a leukemia selected from acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia and mixed lineage leukemia (MLL). In another embodiment the cancer is NUT-midline carcinoma. In another embodiment the cancer is multiple myeloma. In another embodiment the cancer is a lung cancer such as small cell lung cancer (SCLC). In another embodiment the cancer is a neuroblastoma. 32154354.1Page 34 of 78397731-105WO (213618)In another embodiment the cancer is Burkitt's lymphoma. In another embodiment the cancer is cervical cancer. In another embodiment the cancer is esophageal cancer. In another embodiment the cancer is ovarian cancer. In another embodiment the cancer is colorectal cancer. In another embodiment, the cancer is prostate cancer. In another embodiment, the cancer is breast cancer.

[0197] In some embodiments, the present invention provides a method of treating a myeloid malignancy in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0198] In some embodiments, the present invention provides a method of treating a lymphoma in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0199] In some embodiments, the present invention provides a method of treating a leukemia in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0200] In some embodiments, the present invention provides a method of treating triple negative breast cancer in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0201] In some embodiments, the present invention provides a method of treating acute lymphoblastic leukemia (ALL) in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0202] In some embodiments, the present invention provides a method of treating chronic lymphocytic leukemia (CLL), comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0203] In some embodiments, the present invention provides a method of treating large granular lymphocytic leukemia (LGL-L) in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0204] In some embodiments, the present invention provides a method of treating B-cell prolymphocytic leukemia, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0205] In some embodiments, the present invention provides a method of treating Merkel cell carcinoma in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0206] In some embodiments, the present invention provides a method of treating fibromyxoid sarcoma in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof. 32154354.1Page 35 of 78397731-105WO (213618)

[0207] In some embodiments, the present invention provides a method of treating myxofibrosarcoma in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0208] In some embodiments, the present invention provides a method of treating uveal melanoma in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0209] In some embodiments, the present invention provides a method of treating rectal cancer in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0210] In some embodiments, the present invention provides a method of treating prostate cancer in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0211] In some embodiments, the present invention provides a method of treating adenoid cystic carcinoma in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0212] In some embodiments, the present invention provides a method of treating renal cell carcinoma in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0213] In some embodiments, the present invention provides a method of treating osteosarcoma in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0214] In some embodiments, the present invention provides a method of treating acute myeloid leukemia (AML) in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0215] In some embodiments, the present invention provides a method of treating post-MPN AML in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0216] In some embodiments, the present invention provides a method of treating myelofibrosis in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0217] In some embodiments, the present invention provides a method of treating leukemia (e.g., AML) in a patient in need thereof, comprising administering Compound A of the present invention or a pharmaceutically acceptable salt thereof and a BCL-2 inhibitor (e.g., venetoclax). In some aspects of the method of treating leukemia (e.g., AML) with a combination of Compound A and a BCL-2 inhibitor (e.g., 32154354.1Page 36 of 78397731-105WO (213618)venetoclax), the combination is additive. In some aspects of the method of treating leukemia (e.g., AML) with a combination of Compound A and a BCL-2 inhibitor (e.g., venetoclax), the combination acts synergistically.

[0218] In some embodiments, the present invention provides a method of treating leukemia (e.g., AML) in a patient in need thereof, comprising administering Compound A of the present invention or a pharmaceutically acceptable salt thereof and a BCL-2 inhibitor (e.g., venetoclax), wherein the lymphoma is resistant to treatment (e.g., refractory) with the BCL-2 inihibitor (e.g., venetoclax) alone.

[0219] In some embodiments, Compound A of the present invention or a pharmaceutically acceptable salt thereof is administered to a patient at the doses and schedules provided herein and the BCL-2 inhibitor (e.g., venetoclax) is administered to the patient once every 1, 2, 3, 4, 5, 6, 7, 14, or 21 days.

[0220] In some embodiments, the BCL-2 inihibitor (e.g., venetoclax) is administered to the patient daily (QD). In some aspects, the BCL-2 inhibitor (e.g., venetoclax) is administered to the patient orally. In other aspects, the BCL-2 inhibitor (e.g., venetoclax) is administered to the patient at a dose of about 5 mg / kg to about 20 mg / kg (e.g., about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg).

[0221] In some embodiments, the BCL-2 inihibitor (e.g., venetoclax) is administered to the patient daily (QD). In some aspects, the BCL-2 inhibitor (e.g., venetoclax) is administered to the patient orally. In other aspects, the BCL-2 inhibitor (e.g., venetoclax) is administered to the patient at a dose of about 50 mg / kg to about 100 mg / kg (e.g., about 50 mg / kg, about 75 mg / kg, or about 100 mg / kg).

[0222] In some embodiments, the present invention provides a method of treating melanoma (e.g., uveal melanoma) comprising administering to a patient in need thereof Compound A or a pharmaceutically acceptable salt thereof and a BCL-2 inhibitor (e.g., venetoclax). In some aspects of the method of treating melanoma (e.g., uveal melanoma) with a combination of Compound A and a BCL-2 inhibitor (e.g., venetoclax), the combination is additive. In some aspects of the method of treating melanoma (e.g., uveal melanoma) with a combination of Compound A and a BCL-2 inhibitor (e.g., venetoclax), the combination acts synergistically.

[0223] In some embodiments, the present invention provides a method of treating melanoma (e.g., uveal melanoma) comprising administering to a patient in need thereof Compound A or a pharmaceutically acceptable salt thereof and a BCL-2 inhibitor (e.g., venetoclax), wherein the melanoma is resistant to treatment with the BCL-2 inihibitor (e.g., venetoclax) alone.

[0224] In some embodiments, the present invention provides a method of treating leukemia (e.g., AML) comprising administering to a patient in need thereof Compound A or a pharmaceutically acceptable salt thereof and a FLT3 inhibitor (e.g., midostaurin). In some aspects of the method of treating leukemia (e.g., AML) with a combination of Compound A and FLT3 inhibitor (e.g., midostaurin), the combination is 32154354.1Page 37 of 78397731-105WO (213618)additive. In some aspects of the method of treating leukemia (e.g., AML) with a combination of Compound A and a FLT3 inhibitor (e.g., midostaurin), the combination acts synergistically.

[0225] In some embodiments, the present invention provides a method of treating leukemia (e.g., AML) comprising administering to a patient in need thereof Compound A or a pharmaceutically acceptable salt thereof and a FLT3 inhibitor (e.g., midostaurin), wherein the lymphoma is resistant to treatment with the FLT3 inhibitor (e.g., midostaurin) alone.

[0226] In some embodiments, the present invention provides a method of treating a solid cancer comprising administering to a patient in need thereof Compound A or a pharmaceutically acceptable salt thereof and azacitidine.

[0227] In some embodiments, the present invention provides a method of treating a solid cancer comprising administering to a patient in need thereof Compound A or a pharmaceutically acceptable salt thereof and cytarabine.

[0228] In some embodiments, the present invention provides a method of treating a solid cancer comprising administering to a patient in need thereof a provided MDM2 degrader or a pharmaceutically acceptable salt thereof and a MEK inhibitor (e.g., selumetinib).

[0229] In some embodiments, Compound A of the present invention or a pharmaceutically acceptable salt thereof is administered to a patient at the doses and schedules provided herein and the MEK inhibitor (e.g., selumetinib) is administered to the patient once every 1, 2, 3, 4, 5, 6, 7, 14, or 21 days.

[0230] In some embodiments, the MEK inhibitor (e.g., selumetinib) is administered to the patient daily (QD). In some aspects, the MEK inhibitor (e.g., selumetinib) is administered to the patient orally. In other aspects, the MEK inhibitor (e.g., selumetinib) is administered to the patient at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 mg / kg, about 0.5 mg / kg, or about 1 mg / kg).

[0231] In some embodiments, the present invention provides a method of treating Burkitt lymphoma / leukemia in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0232] In some embodiments, the present invention provides a method of treating primary effusion lymphoma in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0233] In some embodiments, the present invention provides a method of treating peripheral T-cell lymphoma (PTCL) in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0234] In some embodiments, the present invention provides a method of treating cutaneous T-cell lymphoma (CTCL) in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof. 32154354.1Page 38 of 78397731-105WO (213618)

[0235] In some embodiments, the present invention provides a method of treating diffuse large B-cell lymphoma (DLBCL) in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0236] In some embodiments, the present invention provides a method of treating advanced B-cell diffuse large B-cell lymphoma (ABC DLBCL) in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0237] In some embodiments, the present invention provides a method of treating intravascular large B- cell lymphoma in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0238] In some embodiments, the present invention provides a method of treating lymphoplasmacytic lymphoma in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0239] In some embodiments, the present invention provides a method of treating Waldenström’s macroglobulinemia (WM) in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0240] In some embodiments, the present invention provides a method of treating splenic marginal zone lymphoma in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0241] In some embodiments, the present invention provides a method of treating multiple myeloma in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0242] In some embodiments, the present invention provides a method of treating plasmacytoma in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0243] In some embodiments, the present invention provides a method of treating myelodysplastic syndrome (MDS) in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0244] In some embodiments, the present invention provides a method of treating myelodysplastic / myeloproliferative neoplasms (MDS / MPN) in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0245] In some embodiments, the present invention provides a method of treating malignant peripheral nerve sheath tumors (MPNST) in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof. 32154354.1Page 39 of 78397731-105WO (213618)

[0246] In some embodiments, the present invention provides a method of treating pancreatic cancer in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0247] In some embodiments, the present invention provides a method of treating primary CNS lymphomas in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0248] In some embodiments, the present invention provides a method of treating Hodgkin’s lymphoma in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0249] In some embodiments, the present invention provides a method of treating primary cutaneous T- cell lymphoma in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0250] In some embodiments, the present invention provides a method of treating solid and liquid tumors in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0251] In some embodiments, the present invention provides a method of treating MYD88 mutant Waldenström macroglobulinemia in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0252] In some embodiments, the present invention provides a method of treating NSCLC in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0253] In some embodiments, the present invention provides a method of treating uveal melanoma in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0254] In some embodiments, the present invention provides a method of treating Ewing sarcoma in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0255] In some embodiments, the present invention provides a method of treating a myeloid malignancy, acute lymphocytic leukemia, lymphoma, myelofibrosis, or solid tumor in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.

[0256] In some embodiments, the present invention provides a method for the treatment of adult patients with a solid cancer or hematological malignancy who have received no prior therapy (i.e., treatment with Compound A is a first line treatment). 32154354.1Page 40 of 78397731-105WO (213618)

[0257] In some embodiments, the patient is a pediatric patient.

[0258] In some embodiments, the present invention provides a method for the treatment of adult patients with a solid cancer or hematological malignancy who have received one prior therapy.

[0259] In some embodiments, the present invention provides a method for the treatment of adult patients with a solid cancer or hematological malignancy who have received two prior therapies.

[0260] In some embodiments, the present invention provides a method for the treatment of adult patients with a solid cancer or hematological malignancy who have received three prior therapies.

[0261] In some embodiments, the present invention provides a method for the treatment of adult patients with a solid cancer or hematological malignancy who have received four prior therapies.

[0262] In some embodiments, the present invention provides a method for the treatment of adult patients with a solid cancer or hematological malignancy who have received five prior therapies.

[0263] In some embodiments, the present invention provides a method for the treatment of adult patients with a solid cancer or hematological malignancy who have received at least one prior therapy.

[0264] In some embodiments, the present invention provides a method for the treatment of adult patients with a solid cancer or hematological malignancy who have received at least two prior therapies.

[0265] In some embodiments, the present invention provides a method for the treatment of adult patients with a solid cancer or hematological malignancy who have received at least three prior therapies.

[0266] In some embodiments, the one or more prior therapies is a standard of care (SoC) treatment. In some embodiments, the SoC treatment is chemotherapy, targeted therapy, hormone therapy, radiopharmaceuticals, ablation and embolization, surgery, radiation therapy, immunotherapy (e.g., immune checkpoint inhibitors), photocoagulation, thermotherapy, or mixtures thereof. In some embodiments, a prior therapy for Merkel cell carcinoma is chemotherapy, immunotherapy (e.g., pembrolizumab, atezolizumab, nivolumab, or ipilimumab), or mixtures thereof. In some embodiments, a prior therapy for fibromyxoid sarcoma is cytoreductive surgery. In some embodiments, a prior therapy for uveal melanoma is surgery, radiation therapy, photocoagulation, thermotherapy, immunotherapy, or mixtures thereof. In some embodiments, a prior therapy for rectal cancer is surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, or mixtures thereof. In some embodiments, a prior therapy for prostate cancer is surgery, radiation therapy, hormone therapy, chemotherapy, targeted therapy, radiopharmaceuticals, or mixtures thereof. In some embodiments, a prior therapy for adenoid cystic carcinoma is surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, or mixtures thereof. In some embodiments, a prior therapy for renal cell carcinoma is surgery, targeted therapy, immunotherapy, cytoreductive nephrectomy, ablation and embolozation, radiation therapy, or mixtures thereof. In some embodiments, a prior therapy for osteosarcoma is surgery, chemotherapy, or mixtures thereof. 32154354.1Page 41 of 78397731-105WO (213618)

[0267] In some embodiments, the present invention provides a method of increasing one or more protein markers (e.g., GDF15, p53, p21, and PUMA) or apoptotic markers (e.g., PHLDA3) in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof. In some embodiments, the method of increasing one or more protein markers (e.g., GDF15, p53, p21, and PUMA) or apoptotic markers (e.g., PHLDA3) comprises treating a solid cancer or hematological malignancy in a patient.

[0268] In some embodiments, the present invention provides a method of increasing one or more markers of p53 activity in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a method of decreasing one or more markers of p53 activity in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof. In some embodiments, the one or more markers of p53 activity is a downstream target of p53 transcriptional activity. In some embodiments, the one or more markers of p53 activity is selected from MDM2, GDF15, CDKN1A, GADD44A, TNFRSF10B, FAS, FASIPO8, BBC3, BAX, PHLDA2, PHLDA3, BCL2L1, BCL2, CASP8, TP53, TP53I3, PUM1, PARK7, GAPDH, MCL1, CRBN, ACTB, and ACTA2.

[0269] In some embodiments, the one or more markers of p53 activity is a p53 mRNA target encoded by MDM2, GDF15, CDKN1A, GADD44A, TNFRSF10B, FAS, BBC3, BAX, PHLDA2, or TP53I3, as determined by RT-qPCR. In some embodiments, the one or more markers of p53 activity is a non-p53 mRNA target encoded by IPO8 or PUM1, as determined by RT-qPCR. In some embodiments, the one or more markers of p53 activity is a p53 protein target encoded by MDM2, GDF15, BCL2L1, BCL2, BAX, BBC3, CASP8, TP53, GADD44A, CDKN1A, PHLDA3, TP53I3, or FAS, as determined by mass spectrometry. In some embodiments, the one or more markers of p53 activity is a non-p53 protein target encoded by PARK7, GAPDH, MCL1, CRBN, ACTB, or ACTA2, as determined by mass spectrometry.

[0270] In some embodiments, the method of increasing one or more markers of p53 activity comprises treating a solid cancer or hematological malignancy in a patient. In some embodiments, the method of decreasing increasing one or more markers of p53 activity comprises treating a solid cancer or hematological malignancy in a patient.

[0271] In some embodiments, the present invention provides a method of selecting a patient having a solid cancer or hematological malignancy for treatment, comprising: i) determining a predictive signature from a baseline expression profile from a biological sample of the solid cancer or hematological malignancy from the patient; ii) identifying the patient as a potential responder for treatment based on applying said predictive signature to a reference, e.g., a pan-cancer dataset such as The Cancer Genome Atlas (TCGA). 32154354.1Page 42 of 78397731-105WO (213618)

[0272] In some embodiments, the present invention provides a method of treating a solid cancer or hematological malignancy in a patient, comprising: i) determining a predictive signature from a baseline expression profile from a biological sample of the solid cancer or hematological malignancy from the patient; ii) identifying the patient as a potential responder for treatment based on applying said predictive signature to a reference, e.g., a pan-cancer dataset such as The Cancer Genome Atlas (TCGA); and iii) administering treatment with Compound A to the patient.

[0273] In some embodiments, the predictive signature is determined by machine learning software. In some embodiments, the treatment of the patient identified as a potential responder results in an increased response rate to Compound A in the patient as compared to treatment of a patient with Compound A without prior identification as a potential responder. In some embodiments, the increased response rate to Compound A in a population of patients is about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% greater as compared to treatment of a population of patients with Compound A without prior identification as a potential responder. In some embodiments, the increased response rate of Compound A in the population of patients is about 10% to about 37% greater. In some embodiments, the increased response rate of Compound A in the population of patients results in prolonged median survival. In some embodiments, the increased response rate of Compound A in the population of patients and prolonged median survival is as shown in FIG.29. EXEMPLIFICATION

[0274] Compound A can be prepared by methods known to one of ordinary skill in the art, for example, as disclosed in WO 2021 / 188948, the contents of which are incorporated herein by reference in their entireties. Abbreviations AE adverse event BOIN Bayesian Optimal Interval ALL acute lymphocytic leukemia CAR-T chimeric antigen receptor T- ALT alanine transaminase cells AML acute myeloid leukemia C1D1 Cycle 1 Day 1 ANC absolute neutrophil count C2D1 Cycle 2 Day 1 ASCO American Society of Clinical CCR complete cytogenetic remission Oncology CFR Code of Federal Regulations ASCT autologous stem cell transplants CL apparent total body clearance AST aspartate transaminase Cmax maximum plasma drug AUC area under the concentration- concentration time curve CNS central nervous system BCRP breast cancer resistance protein COVID-19 Coronavirus disease 2019 BM bone marrow CR complete response BME bone marrow examination eCRF electronic case report form 32154354.1Page 43 of 78397731-105WO (213618)CRh CR with partial hematologic MF myelofibrosis recovery MPN Myeloproliferative neoplasms CRO contract research organization MPN-AP / BP Myeloproliferative Neoplasm – CT computerized tomography accelerated phase / blast phase ctDNA circulating tumor DNA MLFS morphologic leukemia-free state CYP cytochrome P450 MPN-SAF TSS Myeloproliferative Neoplasm- DDI drug-drug interaction Symptom Assessment Form DL dose level Total Symptom Score DLBCL diffuse large B-cell lymphoma MRI magnetic resonance imaging DLT dose-limiting toxicity MTD maximum tolerated dose DNA deoxyribonucleic acid NCI CTCAE National Cancer Institute DoCR / DoRh duration of CR / duration of CRh Common Terminology Criteria DoOR duration of response for Adverse Events ECG electrocardiogram NGS next-generation sequencing ECOG Eastern Cooperative Oncology ORR overall response rate Group OS overall survival EDC electronic data capture p53WT wild type p53 ELN European LeukaemiaNet PAD pharmacologically active dose EMA European Medicine Agency PBMC peripheral blood mononuclear EOT end of treatment cell FDA Food and Drug Administration PD pharmacodynamic(s) FIH first-in-human PET positron emission tomography FISH fluorescent in situ hybridization P-gp P-glycoprotein FLT FMS-like tyrosine kinase PHI protected health iInformation GCP Good Clinical Practice PK pharmacokinetic(s) GLP Good Laboratory Practice PR partial response hERG human ether-a-go-go-related Q3W once every 3 weeks gene QTcF QT interval corrected by Hgb hHemoglobin Fridericia's formula HI h ematologic improvement R / R relapsed or refractory HIV human immunodeficiency virus RBC red blood cell HMA hypomethylating agents RECIST response evaluation criteria in HNSTD highest non-severely toxic dose solid tumors HRT hormonal replacement therapy RP2D recommended Phase 2 dose IB Investigator’s Brochure SAE serious adverse event ICC International Consensus SAP Statistical Analysis Plan Classification SARS-CoV-2 severe acute respiratory ICF informed consent form syndrome coronavirus 2 ICH International Council for SD stable disease Harmonisation SMI small molecule inhibitors IDH isocitrate dehydrogenase SoA Schedule of Assessment IEC Independent Ethics Committee SRC Safety Review Committee IRB Institutional Review Board TEAE treatment-emergent adverse IRR infusion-related reactions event IV intravenous TI transfusion independence IWG International Working Group TLS tumor lysis syndrome JAKi Janus kinase inhibitor ULN upper limit of normal MAD maximum administered dose VAF Variant allele frequency MDM2 murine double minute 2 WBC white blood cell MDS Myelodysplastic syndromes WHO World Health Organization 32154354.1Page 44 of 78397731-105WO (213618)WOCBP woman of childbearing potential Example 1. Pharmaceutical Development Drug Substance

[0275] Compound A was manufactured in free base form. Excipients

[0276] Polyethylene glycol 400, polysorbate 80, ethanol and butylated hydroxytoluene were used in the manufacture of the drug product. A liquid mixture of the above excipients was used to dissolve the drug substance. Both polyethylene glycol 400 and ethanol were used as the co-solvents, and polysorbate 80 was used as the surfactant to dissolve Compound A drug substance. Butylated hydroxytoluene was used as antioxidant to prevent polyethylene glycol 400 and polysorbate 80 from oxidation. All excipients met their respective pharmacopeial standards. The excipient selection and levels were based upon manufacturability, driven by solubility enhancement, stability, and functionality. Drug Product Formulation Developement

[0277] Compound A for injection was manufactured as a concentrated frozen solution containing 10 mg / mL of free base intended to be diluted with an intravenous (IV) infusion vehicle (normal saline, 0.9% sodium chloride, injection). Compound A drug substance has poor aqueous solubility of less than 0.01 mg / mL at pH range between 3 to 8. The measured pKa and Log D of Compound A free base were 5.0 and >3.7, respectively. To achieve drug concentration of 10 mg / mL, formulation development focused on identifying acceptable pharmaceutical solvents, surfactants, and pH modifiers to achieve the required solubility of Compound A.

[0278] Initial solubility screening of Compound A focused on using different enabling excipients suitable for IV administration. The screening included surfactants, cosolvents, and pH modifiers (i.e., glacial acetic acid, and hydrochloric acid). The study indicated that the solubility of Compound A was significantly enhanced in formulations containing propylene glycol, polyethylene glycol 400, Solutol HS15 and polysorbate 80 at low pH. As a result, the selected formulation to support the GLP toxicology study was comprised of 30% propylene glycol, 3% Solutol HS15, and 0.01 M in acetate buffer at pH 5±0.2.

[0279] The clinical formulation development was centered on using organic concentrates without water to avoid hydrolysis of Compound A. Additional solubility and stability evaluations of Compound A were conducted with different types of co-solvents and surfactants with and without butylated hydroxytoluene as antioxidant. Thes studies revealed that combination of polyethylene glycol 400, ethanol, polysorbate 80 and butylated hydroxytoluene provide sufficient solubility and stabilility for Compound A at 10 mg / mL. Data from the development batch demonstrated that Compound A drug product remains stable through 1 32154354.1Page 45 of 78397731-105WO (213618)month at the long-term storage condition of -20 °C and the accelerated condition of 5 ± 3 °C with no significant changes in stability-indicating attributes as shown in Table 1 and Table 2. Table 1. Stability of Drug Product at -20 ± 3 °C Time, months Attribute Acceptance Criteria Initial 1 eTime, months Attribute Acceptance Criteria eDescription and Composition

[0280] The drug product, Compound A Injection (Concentrate Solution for Infusion), consists of a clear, colorless to slightly yellow solution of Compound A in clear glass vials with stopper and flip-off seal. The drug product was formulated as 10 mg / mL Compound A drug substance dissolved in an organic mixture containing polyethylene glycol 400, polysorbate 80, ethanol, and butylated hydroxytoluene. 32154354.1Page 46 of 78397731-105WO (213618)

[0281] The label fill volume was 5.0 mL. Each vial contains adequate sterile Compound A solution to deliver nominally 5.0 mL of the solution. The drug product solution is intended to be diluted to the required concentration with normal saline for intravenous infusion. The composition of the drug product is given in Table 3. Table 3. Composition of Compound A for Injection Component Function % w / w Amount per 5.0 mL Compound A drug substance Active ingredient 0.93 0.05 g (active)

[0282] The drug product was manufactured by preparing a solution of polyethylene glycol (PEG) 400, polysorbate 80, ethanol (200 proof), and butyl-hydroxytoluene. Compound A drug substance was dissolved in the organic solution at about 23oC to achieve a concentration of 10 mg / mL.

[0283] The prepared solution was first prefiltered through a 0.45 µm filter. After testing for appearance, pH and bioburden, the prefiltered solution was passed through two sterilizing filters (0.22 µm) in series to obtain a sterile solution. The sterile solution was filled into glass vials, stoppered, and crimped aseptically. Each vial was filled by weight to contain 5.0 mL of the sterile solution. The finished product was 100% visually inspected, and a post-sterile filtration filter integrity test was conducted. The vials were stored at - 20oC. The flow diagram of the manufacturing process is shown in FIG.1.

[0284] Frozen concentrated solutions of formulated Compound A were developed to be diluted in an IV vehicle before dosing intravenously through an administration kit. The compatibility of the formulated Compound A at 10 mg / mL was confirmed with 0.9% sodium chloride (normal saline) based on an assessment of appearance, pH, assay, and impurity profile. The drug product was sterile filtered and filled into a 10 mL, Type 1 clear pre-sterilized borosilicated glass vials fitted with stopper with Flurotec barrier film secured by a flip-off seal. Injection Freeze-Thaw (FT) Study

[0285] To assess the stability of the thawed drug product, laboratory experiments were carried out under conditions representative of clinical dose preparation.

[0286] A freeze-thaw stability study was conducted for the frozen Compound A Injection, 10 mg / mL. Each FT cycle involved freezing the drug product vial at -20oC for 24 hours followed by the complete 32154354.1Page 47 of 78397731-105WO (213618)thawing at room temperature. Three FT cycles were performed, with ten samples taken after each cycle (FT-1x, FT-2x, and FT-3x). All the vials were tested for appearance, assay, and impurities.

[0287] As presented in Table 4, the results show acceptable physicochemical stability at least up to 3 FT cycles. All stability-indicating parameters of FT-1x, FT-2x and FT-3x are comparable to the initial sample (FT-T0) and remained well within the product specifications at each FT cycle. Table 4: Freeze-Thaw Cycle Study Data for Compound A Injection, 10 mg / mL FT-T0 FT-1x FT-2x FT-3x Appearance ofCompound A Injection IV Dosing Solutions

[0288] Studies were conducted to assess the stability and compatibility of Compound A Injection IV dosing solutions with the IV administration supplies (bag, tubing and close system transfer device) that are intended for use in the clinical trials. Laboratory experiments were carried out under conditions representative of the clinical dose preparation. The IV bag, administration sets (tubing), and closed system transfer device (CSTD) that were utilized in this study are provided in Table 5. Table 5: IV Administration Components Used in Stability and Compatibility Studies of Compound A Injection Dosing Solutions IV Administration Minimal Requirements of Example Component Used in 3)32154354.1Page 48 of 78397731-105WO (213618)Add on air elimination No DEHP and not made with B. Braun 1.2 µm air-eliminating filter filter natural (Product# 473994) ieswere conduc ed a rac e ng ag so u on concen ra ons o . an . mg / m ( an 30 mg equivalents in a 1000 cc bag). Once the drug product solution was added to the IV bag, the resulting diluted IV dosing solution was thoroughly mixed by hand and allowed to remain under ambient laboratory lighting and temperature conditions for the duration of the study. Samples were then pulled at 0, 4, and 24 hours from the IV bag port via syringe. These samples were subsequently tested for stability-indicating parameters, including appearance, pH, assay, and impurities. The in-use stability data showed that the IV dosing solutions at both ends of the concentration range (0.3 mg / mL and 0.03 mg / mL) are compatible with the IV bag and IV tubing and stable up to 24 hours (IV bag) and 8 hours (IV tubing) at ambient laboratory conditions. All stability-indicating parameters remained within the product specifications at each time point and showed no significant change. Conclusions

[0289] The data from these studies indicates that Compound A Injection solution, 10 mg / mL, shows acceptable physicochemical stability after 3 cycles of freezing and thawing. The drug product also shows acceptable stability under ambient storage conditions in the IV bag and IV infusion tubing for 24 hours and 8 hours, respectively. Moreover, the results from these studies suggest acceptable compatibility of Compound A injection with the intended diluent (0.9% sodium chloride) and containment / administration system (IV bag / tubing) to be used in the clinical setting. Example 2. A Phase 1, Multicenter, Open-Label, Dose-Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of Intravenously Administered Compound A in Adult Patients With High Grade Myeloid Malignancies and Acute Lymphocytic Leukemia, Myelofibrosis, Lymphoma and Advanced Solid Tumors

[0290] Study Rationale: Targeted protein degraders represent a new therapeutic class of compounds that utilize the ubiquitin proteasome system to target the specific degradation of proteins. Compound A is a is a potent and selective, heterobifunctional small molecule therapeutic mediating the degradation of mouse double minute 2 (MDM2), an E3 ubiquitin ligase and critical negative regulator of the tumor suppressor p53. Given MDM2 overexpression and amplification is implicated in a variety of hematological and solid tumors, Compound A represents a rationale therapeutic opportunity for the treatment of acute myeloid 32154354.1Page 49 of 78397731-105WO (213618)leukemia (AML), lymphomas, myelofibrosis, and solid tumors that express functional wild-type p53 (p53WT). Objectives and Endpoints

[0291] The following objectives will be in assessed in patiets in Phase 1a. Objectives Endpoints s) te ts nd as t’s ne32154354.1Page 50 of 78397731-105WO (213618)Objectives Endpoints id se ic se ), all an R ic al ry I) G) ): R, N R) no of a e re % he nt ’s N ed nd ng R32154354.1Page 51 of 78397731-105WO (213618)Objectives Endpoints al he or or ar s ld ue ue lls A) le C

[0292] The following objectives will be in assessed in patiets in Phase 1b. Objectives Endpoints to al I, N)32154354.1Page 52 of 78397731-105WO (213618)Objectives Endpoints t toe toits ne or st- ld ue ueOverall Design

[0293] This first-in-human (FIH) study of Compound A is an open-label, Phase 1a / b study in adult patients with advanced high grade myeloid malignancies, ALL, lymphomas, and solid tumors. The objective of Phase 1a is to identify the MTD or maximum administered dose (MAD, if MTD is not reached) of Compound A. Once the MTD / MAD is identified for each arm independently, expansion cohorts may be enrolled as follows: ^ A Phase 1a exploratory expansion cohort in patients with p53WT solid tumors may be enrolled with the objective to evaluate the safety and clinical activity of Compound A in a homogenous population of patients with a solid tumor to help better identify potentially sensitive solid tumor types for further clinical development of Compound A. 32154354.1Page 53 of 78397731-105WO (213618)^ Up to two Phase 1b expansion cohorts (Cohorts 1 and 2) in patients with AML may be enrolled with the objective to confirm the safety, PK, PD and clinical activity of Compound A.

[0294] Patients who provide informed consent and meet all eligibility criteria for the study will be enrolled and will be treated with Compound A on Day 1 of continuous 21-day cycles until disease progression, unacceptable toxicity, withdrawal of consent, any study-specific discontinuation criteria are met, or if the Investigator determines that it is in the best interest of the patient to discontinue study treatment.

[0295] For patients with AML who achieve CR (or CRh), continued treatment will be based on Investigator judgement. Patients who discontinue from Compound A will undergo an end of treatment (EOT) visit within 7 days of the decision to discontinue treatment and prior to initiation of a new anticancer therapy, whichever occurs first. A safety follow-up (FU) visit will also be scheduled within 30 days from the last dose of Compound A, or prior to initiation of a new anticancer therapy, whichever occurs first.

[0296] The study schema is provided in FIG.2 and FIG.23.

[0297] The Phase 1a part of the study will be initiated in patients with lymphomas, MF, and solid tumors (Arm A), and then subsequently in patients with advanced high grade myeloid malignancies and ALL (Arm B). The dose escalation portion of the study will characterize the safety and tolerability of ascending doses of Compound A in each arm separately. The primary objective is to define the MTD or MAD (if MTD is not reached) for each arm. Up to 100 evaluable patients will be enrolled and will depend on the number of dose levels explored. Prospective documentation of the tumor p53 status (mutant or wild type) will not be required for study entry and will be assessed retrospectively. ^ Arm A (n=approximately 50): Patients with lymphomas, MF, and advanced solid tumors ^ Arm B (n=approximately 50): Patients with high grade myeloid malignancies and ALL

[0298] Dosing will start first in Arm A in adult patients with lymphomas and advanced solid tumors. Once a potential pharmacologically active dose (PAD) has been identified in Arm A, it will be used to determine the starting dose in patients with high grade myeloid malignancies and ALL who will be enrolled in Arm B. This approach will avoid exposing patients with rapidly progressing acute leukemias in Arm B to potentially subtherapeutic doses where assessment of toxicity may be confounded by adverse events (AEs) due to the underlying leukemia. Specific to Compound A, preclinical toxicology findings suggest myelosuppression to be a potential expected on-target toxicity, and observation of moderate grade myelosuppression in patients in Arm A may be used as a surrogate marker of pharmacological activity to guide initiation of dose escalation in Arm B. In addition, PK / PD data from Arm A may be used to guide the selection of the starting dose in Arm B.

[0299] The starting dose level in Arm B and initiation of dose-escalation will be determined by the Safety Review Committee (SRC) following review of the safety and available PK and PD data and the starting dose will not exceed the highest dose evaluated in Arm A. 32154354.1Page 54 of 78397731-105WO (213618)

[0300] Arms A and B will continue dose-escalation separately based on the Bayesian Optimal Interval (BOIN) Design until the MTD is determined in each arm. Planned dose levels include 0.05 mg / kg, 0.1 mg / kg, 0.17 mg / kg, 0.25 mg / kg, 0.33 mg / kg, 0.42 mg / kg, 0.53 mg / kg, 0.66 mg / kg, 0.82 mg / kg, and 1.00 mg / kg. Sponsor may determine to evaluate additional interim dose levels based on emerging safety and PK data from the preceding cohorts in each study arm. Escalation to the MTD may not be necessary if a minimum safe and biologically effective dose is identified based on observed safety, PK, PD, and efficacy. In this scenario, the highest administered dose will be the MAD. Safety data will be evaluated continuously by the Sponsor and reviewed prior to confirmation of the MTD with the SRC and the Investigators participating in dose escalation.

[0301] Once an MTD / MAD dose is identified in Arm A, subjects with R / R p53WT solid tumors may be enrolled into a Phase 1a exploratory expansion cohort. Once an MTD / MAD dose is identified in Arm B, subjects with R / R p53WT AML may be enrolled into Phase 1b Cohorts 1 and 2. Patient Eligibility for All Patients Inclusion Criteria 1. Male or female aged ≥ 18 years on the day of signing informed consent. 2. Provide signed written informed consent and voluntary consent prior to any mandatory studyspecific procedures, sampling, and analyses. 3. Eastern Cooperative Oncology Group (ECOG) performance status: 0-2. 4. Women of child-bearing potential (WOCBP) must agree to use highly effective contraceptive methods for the duration of study treatment and 30 days after the last dose of study drug. 5. Women of child-bearing potential must have a negative serum pregnancy test at Screening and within 72 hrs prior to first dose of study drug. 6. Men must agree to use highly effective contraceptive methods during the study treatment and for 30 days after the last dose of study drug if the partner is a WOCBP. 7. Resolved acute effects of any prior therapy except for alopecia to baseline severity or Grade ≤1 NCI CTCAE and Grade ≤2 neuropathy. 8. Adequate organ function at Screening defined as: a) Liver Function i) Aspartate aminotransferase (AST), alanine transaminase (ALT) ≤ 3x upper limit of normal (ULN) or < 5x ULN in cases of documented liver metastases or lymphoma involvement of liver or considered to be due to leukemic disease. ii) Total serum bilirubin ≤ 1.5 x ULN or < 5x ULN if secondary to Gilbert’s syndrome or documented liver metastases, or lymphoma involvement of liver or considered to be due to leukemic disease. b) Renal Function i) Serum creatinine clearance ≥60 mL / min, either measured or calculated using standard Cockcroft-Gault formula (Appendix 10). 32154354.1Page 55 of 78397731-105WO (213618)ii) Serum electrolyte (potassium, calcium, and magnesium) levels within the normal reference range (may be supplemented according to institutional standards). Phase 1a Dose Escalation Arm A: Solid Tumors and Lymphoma ONLY 2. Histologically or pathologically confirmed solid tumor or lymphoma. 3. Relapsed and / or refractory disease to at least two prior standard of care treatments or tumors for whom standard therapies are not available. Note: For patients with lymphoma, the following apply: ^ must be ineligible for autologous stem cell transplants (ASCT) or chimeric antigen receptor T-cells (CAR-T) therapy or ^ patient has refused ASCT or CAR-T therapy. 4. At least one bi-dimensionally measurable disease site. The lesion must have a greatest transverse diameter of at least 1.5 cm and greatest perpendicular diameter of at least 1.0 cm at Baseline. Note: Patients without measurable disease per Lugano Classification OR RECIST 1.1 may be eligible, following discussion with the Investigator and the Sponsor, if the patient presents with non- measurable but assessable disease of any size unequivocally attributable to advanced solid tumor or lymphoma. 5. Adequate organ function at Screening defined as: a) Bone Marrow Function: i) Absolute neutrophil count (ANC) ≥ 1000 / μL. ii) Hemoglobin ≥ 8 g / dL (for those patients undergoing red blood cell [RBC] transfusion, hemoglobin must be evaluated after at least 14 days after the last RBC transfusion). iii) Platelet count ≥ 100,000 / μL (assessed ≥ 7 days following last platelet transfusion in patients with thrombocytopenia requiring platelets). Phase 1a Dose Escalation Arm A: Myelofibrosis ONLY 1. Confirmed diagnosis of Primary Myelofibrosis (PMF) based on 2016 World Health Organization (WHO) criteria or post Polycythemia Vera / Essential Thrombocythemia Myelofibrosis (PPV / ET MF) based on the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria. 2. Must have all of the following: f) Dynamic International Prognostic Scoring System (DIPSS) risk category intermediate-2 or higher. g) Platelet count ≥ 75 x 109 / L without assistance of thrombopoietic factors or transfusions for at least 7 days. h) Palpable spleen ≥ 5 cm below costal margin on physical examination. i) Peripheral blast blood count <10%. j) Ineligible to receive JAK inhibitor (JAKi) or was previously treated with a JAKi and discontinued due to intolerance or refractory or resistant disease. 32154354.1Page 56 of 78397731-105WO (213618)Phase 1a Dose Escalation Arm A: Advanced high grade myeloid malignancies, and Acute Lymphocytic Leukemia (ONLY) 1. Primary diagnosis a) AML: diagnosis based on World Health Organization (WHO) 2022 or International Consensus Classification (ICC) 2022, patients with relapsed or refractory disease to standard of care therapy or for which no standard therapies are anticipated to result in a durable remission as defined by ELN criteria (2022). Relapsed AML is defined as: ≥ 5% myeloblasts in the bone marrow after achieving a CR (measurable residual disease [MRD] positive or negative), CRh, or CRi. Patients with mutations in FMS-like tyrosine kinase (FLT3), isocitrate dehydrogenase (IDH)1 or IDH2 must have failed or been intolerant of an approved FLT3, IDH1 or IDH2 inhibitor before enrolling on study. (Patients with concurrent FLT3 and IDH mutations must have failed both inhibitors before enrolling on study). Refractory AML is defined as: ≥ 5% myeloblasts after one of the following regimens: ^ 2 cycles of intensive induction chemotherapy with at least one cycle of a cytarabine containing regimen (e.g., 7+3, mitoxantrone, etoposide, and cytarabine (MEC), High dose cytarabine (HiDAC), etc.) ^ 2 cycles of hypomethylating agents (HMA) / venetoclax or low-dose Cytarabine (LDAC) / glasdegib ^ 4 cycles of HMA monotherapy b) ALL: diagnosis based on WHO 2022 classification, patients with relapsed or refractory disease to standard of care therapy. Philadelphia chromosome-positive ALL (Ph+ ALL) patients must have failed at least one second generation tyrosine kinase inhibitor. c) High / very high risk Myelodysplastic Syndromes (MDS): Relapsed or refractory disease to standard of care therapy as defined by the revised IWG criteria (2023), or subject patient that is intolerant to established therapy known to provide clinical benefit for their condition (i.e., patients must not be candidates for regimens known to provide clinical benefit), according to the treating physician and with approval of the Medical Monitor. Relapsed MDS is defined as: ≥ 5% myeloblasts after achieving an IWG defined response. Refractory MDS is defined as: ≥ 5% myeloblasts after one of the following regimens: ^ 4 cycles of HMA monotherapy ^ 2 cycles of HMA + venetoclax d) Myelodysplastic / myeloproliferative neoplasms (MDS / MPN): diagnosis based on WHO 2022 or ICC 2022 classification, patients with disease that has relapsed or is refractory to standard of care therapy as defined by standardized criteria. Patients with ≥ 5% blasts in the bone marrow and disease that has relapsed or is refractory to standard therapy for which no standard therapies are anticipated to result in a durable remission according to the Investigator e) Myeloproliferative neoplasms in blast phase (MPN-BP) or accelerated phase (MPN-AP): Confirmed diagnosis of PMF based on 2016 WHO criteria or PPV / ET MF based the IWG-MRT criteria with ≥ 20% peripheral blasts or 10-19% bone marrow blasts that is refractory to one cycle of intensive induction chemotherapy or at least two cycles of HMA plus venetoclax or two cycles of low intensity therapy (e.g. azacytidine plus JAKi, cladribine plus low dose Ara-C, etc.). 32154354.1Page 57 of 78397731-105WO (213618)2. Life expectancy of ≥ 12 weeks. 3. Patients must be amenable to serial bone marrow sampling, peripheral blood sampling, and urine sampling during study. If an aspirate is unobtainable (i.e., a “dry tap”), the diagnosis may be made from core biopsy. Phase 1a Exploratory Expansion: Solid Tumors ONLY 1. Histologically or pathologically confirmed solid tumor. 2. Documented TP53WT status based on medical records. 3. Relapsed and / or refractory disease to at least two prior standard of care treatments or tumors for whom standard therapies are not available. 4. At least one bi-dimensionally measurable disease site. The lesion must have a greatest transverse diameter of at least 1.5 cm and greatest perpendicular diameter of at least 1.0 cm at Baseline. 5. Adequate organ function at Screening defined as: a) Bone Marrow Function: iv) Absolute neutrophil count (ANC) ≥ 1000 / μL. v) Hemoglobin ≥ 8 g / dL (for those patients undergoing red blood cell [RBC] transfusion, hemoglobin must be evaluated after at least 14 days after the last RBC transfusion). vi) Platelet count ≥ 100,000 / μL (assessed ≥ 7 days following last platelet transfusion in patients with thrombocytopenia requiring platelets). Phase 1b Dose Expansion Cohort 1 and Cohort 2 ONLY 1. Primary Diagnosis: AML: diagnosis based on World Health Organization (WHO) 2022 or ICC 2022, patients with R / R disease to standard of care therapy or for which no standard therapies are anticipated to result in a durable remission as defined by ELN criteria (2022). a) Relapsed AML is defined as: ≥ 5% myeloblasts in the bone marrow (or reappearance of blasts in the blood in at least two peripheral blood samples at least one week apart; or development of extramedullary disease) after achieving a CR (measurable residual disease [MRD] positive or negative), CRh, or CRi. Patients with mutations in FLT3, IDH1 or IDH2 must have failed or been intolerant of an approved FLT3, IDH1 or IDH2 inhibitor before enrolling on study (patients with concurrent FLT3 and IDH mutations must have failed both inhibitors before enrolling on study). b) Refractory AML is defined as: ≥ 5% myeloblasts after one of the following regimens: i) 2 cycles of intensive induction chemotherapy with at least one cycle of a cytarabine containing regimen (e.g., 7+3, mitoxantrone, etoposide, and cytarabine (MEC), High dose cytarabine (HiDAC), etc.) ii) 2 cycles of hypomethylating agents (HMA) / venetoclax or low-dose Cytarabine (LDAC) / glasdegib iii) 4 cycles of HMA monotherapy c) Documented TP53WT status based on medical records. 2. Life expectancy of ≥ 12 weeks. 32154354.1Page 58 of 78397731-105WO (213618)3. Patients must be amenable to serial bone marrow sampling, peripheral blood sampling, and urine sampling during study. If an aspirate is unobtainable (i.e., a “dry tap”), the diagnosis may be made from core biopsy. Exclusion Criteria All Patients: 1. Pregnant females; breastfeeding females; male patients with partners currently pregnant; male patients able to father children and female patients of childbearing potential who are unwilling or unable to use two highly effective methods of contraception as outlined in this protocol for the duration of the study and for at least 30 days after last dose of study drug. 2. Patient is unable or unwilling to discontinue prohibited concomitant medications or adhere to restrictions for use of concomitant medications including use of strong P-gp or BCRP inhibitors or inducers within 14 days or 5 half-lives (whichever is longer) prior to first dose. 3. Patient is unable or unwilling to comply with all requirements of the study. 4. Person who has been committed to an institution by official or judicial order. 5. Sponsor or Investigator site staff who are directly involved in the conduct of the study, site staff otherwise supervised by the investigator, and their respective family members. 6. Any of the following in the previous 3 months: myocardial infarction, Torsades de pointes, severe or life-threatening arrhythmias (including sustained ventricular tachyarrhythmia and ventricular fibrillation), right bundle branch block and left anterior hemiblock (bifascicular block), unstable angina, coronary / peripheral artery bypass graft, symptomatic congestive heart failure (CHF New York Heart Association class III or IV), cerebrovascular accident, transient ischemic attack, or symptomatic pulmonary embolism. 7. Congenital long QT syndrome, or a QT interval corrected by Fridericia’s formula (QTcF) ≥470 ms (average of triplicate electrocardiograms) at Screening and pre-dose C1D1. Note: If a patient has a prolonged QT interval and the prolongation is deemed to be due to a pacemaker or based in the presence of a bundle branch block, the patient may be eligible to participate in the study following discussion with the Medical Monitor. 8. Major surgery requiring general anesthesia within 4 weeks prior to first dose of study drug. If patient required general anesthesia within the prior 4 weeks, consultation with the Medical Monitor is required prior to enrollment. 9. Known or demonstrated viral infection as listed below: a) Seropositivity for human immunodeficiency virus (HIV) (only if required by local regulations) b) Hepatitis B and / or hepatitis C infection (as detected by positive testing for hepatitis B surface antigen [HbsAg] or antibody to hepatitis C virus with confirmatory testing). 10. Received live or live-attenuated vaccine within 4 weeks prior to the first dose of study drug. 11. Patient has completed a course of SARS-CoV-2 vaccine within 14 days prior to first dose of study drug. 12. Concurrent medical conditions including psychiatric disorders that in the judgment of the Investigator will interfere with the patient’s ability to participate or with achieving the objectives of the study or pose a safety risk. 13. History of or active concurrent malignancy unless the patient has been disease-free for ≥ 2 years. Exceptions to the ≥ 2-yrs time limit include treated basal cell or localized squamous cell skin 32154354.1Page 59 of 78397731-105WO (213618)carcinoma, localized prostate cancer, or other localized carcinomas such as carcinoma in situ of cervix, breast, or bladder. 14. MDM2 inhibitor in the most recent prior line of treatment or prior MDM2 inhibitor that was discontinued due to drug-related adverse events at any time. 15. Known presence of p53 mutation in tumor tissue (testing not required for study entry). 16. Known hypersensitivity to any of the components of Compound A. 17. Known systemic vasculitides (e.g., Wegener’s granulomatosis, polyarteritis nodosa, systemic lupus erythematosus). 18. Primary or secondary immunodeficiency conditions (such as severe inflammatory disease). Phase 1a Dose Escalation Arm A (Solid Tumors and Lymphoma (ONLY) and Exploratory Expansion 1. Known active uncontrolled or symptomatic (CNS) metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and / or progressive growth. Note: Patients with solid tumors are eligible if their CNS metastases or cord compression have been definitively treated (e.g., radiotherapy, stereotactic surgery) and are clinically stable, off anticonvulsants and steroids for at least 4 weeks before enrollment and have no evidence of progression at time of study enrollment. Note: Patients with lymphomas are eligible if their CNS metastases or cord compression have been treated effectively (i.e. achieved CR) and there is no clinical or radiographic evidence of active lymphoma. 2. Exposures to anticancer therapy or investigational therapy within 2 weeks or 5 half-lives whichever is longer prior to the first dose of study drug. Note: Low dose steroids (oral prednisone or equivalent ≤ 10 mg / day) or localized non-CNS radiotherapy for patients with lymphoma, hormonal therapy with luteinizing hormone-releasing hormone (LHRH) agonists for prostate cancer, hormonal therapies administered as a prophylactic or as maintenance therapy in the absence of active disease, and treatment with bisphosphonates and receptor activator of the nuclear factor kappa B ligand (RANKL) inhibitors are not criteria for exclusion. 3. Infection requiring antibiotics, antivirals, or antifungals within 1 week prior to first dose of study drug. Prophylactic use of these agents is acceptable even if parenteral. 4. Radiation treatment within 4 weeks prior to first dose of study drug. 5. Autologous or allogenic hematopoietic stem cell transplant (HSCT) within 6 months prior to first dose of study drug or patient has progressed within 6 months from the day of stem cell infusion (for lymphoma patients only). Note patients need to have discontinued immunosuppressive medication. 6. Received immunotherapy / biologic treatment or investigational therapy within 4 weeks prior to first dose of Compound A, including tumor vaccines and checkpoint inhibitors. Phase 1a Dose Escalation Arm A: Myelofibrosis ONLY 1. Infection requiring antibiotics, antivirals, or antifungals within 1 week prior to first dose of study drug. Prophylactic use of these agents is acceptable even if parenteral. 2. Autologous or allogenic hematopoietic stem cell transplant (HSCT) within 6 months prior to first dose of study drug. Note, patients need to have discontinued immunosuppressive medication including calcineurin for at least 28 days (4 weeks), except for physiological doses of steroids. 32154354.1Page 60 of 78397731-105WO (213618)3. Received immunotherapy / biologic treatment or investigational therapy within 4 weeks prior to first dose of Compound A, including tumor vaccines and checkpoint inhibitors. 4. Prior splenectomy or prior splenic radiation within 3 months of starting study therapy. 5. Hematopoietic growth factor (granulocyte growth factor, erythropoiesis stimulating agent, thrombopoietin mimetic) or androgenic steroids less than 2 weeks before the first dose of study drug. 6. Systemic corticosteroids at daily doses > 10 mg of oral prednisone or equivalent less than 2 weeks before the first dose of study drug. NOTE: Topical, nasal and inhaled corticosteroids are allowed. 7. JAKi less than 2 weeks prior to first dose a) Exposures to other (non-JAKi) anticancer therapy or investigational therapy within 2 weeks or 5 half-lives whichever is longer prior to the first dose of study drug. Note: hormonal therapy with luteinizing hormone-releasing hormone (LHRH) agonists for prostate cancer, hormonal therapies administered as a prophylactic or as maintenance therapy in the absence of active disease, and treatment with bisphosphonates and receptor activator of the nuclear factor kappa B ligand (RANKL) inhibitors are not criteria for exclusion Phase 1a Dose Escalation Arm B and Phase 1b Expansion Cohort 1 and Cohort 2 1. Active CNS leukemia. Patients with symptoms suggestive of CNS disease will require a lumbar puncture to rule out CNS disease. 2. Prior chemotherapy / radiation (including craniospinal radiation) within ≤ 2 weeks prior to the first dose of study drug. Patients must have passed nadir white blood cell (WBC) and platelet counts. a) Oral mercaptopurine, hydroxyurea, methotrexate, vincristine, thioguanine, and tyrosine kinase inhibitors are permitted within 2 weeks of the first dose of study drug as maintenance or to reduce the peripheral blast count. b) CNS prophylaxis for treatment of CNS relapse is permitted. Note: please refer to exclusion criterion #7) for guidance regarding prior steroid therapy 3. Received allogeneic hematopoietic cell transplantation (HCT) <12 weeks prior to first dose or donor lymphocyte infusion (DLI) without conditioning <4 weeks prior to first dose. Note, patients need to have discontinued immunosuppressive medication. 4. Received autologous stem cell transplant (ASCT) < 4 weeks prior to first dose or the patient has not recovered from transplant associated toxicities to ≤ grade 1 prior to the first dose of study drug. 5. Received immunotherapy / biologic treatment ≤2 weeks or within 5 half-lives prior to first dose, including tumor vaccines and checkpoint inhibitors. 6. Received chimeric antigen receptor therapy or other modified T cell therapy <3 weeks prior to first dose. 7. Received steroids <7 days prior to first dose with the exception of physiologic dosing (equivalent to ≤ 10 mg of prednisone daily) or cytoreductive therapy. Cytoreductive therapy must have approval of the Medical Monitor. 8. Peripheral blasts ≥30,000 / µL (treatment with hydroxyurea and / or steroids is permitted within 2 weeks of first dose of study drug to reduce the WBC count). 32154354.1Page 61 of 78397731-105WO (213618)9. Patient is known to be refractory to platelet or packed RBC transfusions per institutional guidelines (only for ALL and MDS / MPN patients). 10. Patients with signs or symptoms of Grade ≥ 2 acute or chronic graft versus host disease (GVHD) within 2 weeks of enrollment. All patients with prior hematopoietic transplants must be off all systemic immunosuppressive therapy and calcineurin inhibitors for at least 2 weeks prior to enrollment. Patients may be on physiological doses of steroids (equivalent to ≤10 mg of prednisone daily). 11. Patients with an active severe infection that required anti-infective therapy or with an unexplained fever > 38.5oC during Screening visits or on their first day of study drug administration (at the discretion of the Investigator, patients with tumor fever may be enrolled). 12. Chronic systemic corticosteroid treatment. Note: Topical applications, inhaled sprays, eye drops, local injections of corticosteroids and systemic steroids required for acute medical interventions and low dose steroids (oral prednisone or equivalent ≤ 10 mg / day) are allowed. 13. History of significant or progressive chronic liver disease or suspected alcohol abuse. 14. History of hepatic veno-occlusive disease or sinusoidal obstruction syndrome. Preliminary Arm A Results

[0302] Interim Phase 1 data from Arm A show evidence of target engagement and p53 pathway activation and initial signs of antitumor activity without DLTs including typical hematological toxicity.

[0303] Proof of mechanism (POM) was confirm with robust PD in blood for the first two dose cohorts and antitumor activity was found at dose level 1. No DLTs or homological toxicities were observed. A summary of the Arm A enrollent is provided in Table 6. Table 6. Arm A Enrollment Status rollment DosDose Level 2 Dose Level 3 Overall Arm A En e Level 1)32154354.1Page 62 of 78397731-105WO (213618)Merkel Cell Carcinoma 1 (33.3) 1 (11.1) Fibromyxoid Sarcoma 1 (33.3) 1 (11.1)

[0304] GDF15 is a downstream biomarker of p53 upregulation following MDM2 degradation. Table 7 shows cycle 1 plasma exposure and fold-change in GDF15 levels (mean ± SEM). Table 7. Cycle 1 Plasma Exposure and GDF15 Levels Dose Level AUC (ng*h / mL) Cmax (ng / ml)Max Fold Increase inPlasma GDF15*

[0305] FIG. 13 shows kinetics of plasma GDF15 upregulation in a single subject on DL1 which is an indicator of MDM2 target engagement by Compound A at dose levels 1 and 2.

[0306] FIG. 14 shows initial clinical activity demonstrated at DL1. The CT scans of FIG 14 represent a 64-year-old male patient, previously diagnosed with Merkel cell carcinoma. The Merkel cell carcinoma patient received 6 prior regimens including treatment with pembrolizumab, atezolizumab, nivolumab, and ipilimumab. After 4 cycles of treatment with Compound A at DL1, a partial response was confirmed including resolution of skin metastasis and treatment is continuing. Further Results

[0307] Demographics Arm A ll32154354.1Page 63 of 78397731-105WO (213618)(n=3) (n=4) (n=3) (n=5) (n=1) 1)

[0308] Demographics ARM B Dose Level B1bDose Level B2 Dose Level B3 Oll N 832154354.1Page 64 of 78397731-105WO (213618)2 1 (33.3) 1 (25.0) - 2 (25.0) Prior Anti-Cancer Therapy Regimens ivedose n rm ; ye opro era ve neopasm.

[0309] Overall Safety Number of Patients with AE by Grade Occurring in >15% Patients Overall (n, (%)) – All Causality d) 3 2) 2) 2) 2) 3)g and no AEs were reported. Summary

[0310] Adverse Events: There were no observable differences in safety between Arm A and Arm B patients. Most common AEs related to Compound A observed in >15% patients, n (%): nausea 8 (33.3), fatigue 6 (25.0), decreased appetite 4 (16.7). 32154354.1Page 65 of 78397731-105WO (213618)

[0311] Cytopenias in Arm A, Any Grade / Grade ≥3, n (%): Neutropenia: 3 (18.8) / 1 (6.3); Thrombocytopenia: 3 (18.8) / 0. No Grade 4 or 5 events.

[0312] Dose Limiting Toxicities: Arm A - DL3: Gr. 2 fatigue and Gr. 2 arthralgia leading to Compound A discontinuation in 1 patient. Arm B – none.

[0313] Related Serious Adverse Events: Arm A - Gr. 3: hypotension (n=1; DL1) in a pt with decreased oral intake; ventricular tachycardia (VT) leading to treatment discontinuation (n=1; DL3). Arm B – none. Exposure, Duration on Treatment and Disposition

[0314] Twenty-four patients received a mean of 3.1 doses across the first five dose levels in Arm A and the first three dose levels in Arm B.

[0315] Eight patients remain active across both arms (0.1 mg / kg, n=2; 0.17 mg / kg, n=2; 0.25 mg / kg, n=3; 0.33 mg / kg, n=1) and 16 patients discontinued Compound A. Primary reasons for discontinuation were disease progression (n=8), adverse event (n=2), patient decision to discontinue (n=2), clinical progression (n=1), investigator discretion (n=1), protocol non-compliance (n=1) and patient death due to disease progression (n=1). Clinical Responses

[0316] FIG.20 shows clinical responses in Arm A and B. Table 8. Best Overall Response by Arm Arm A (n=131, n (%)) Arm B (n=7, n (%))CC;3Fibromyxoid sarcoma (n=1), adenoid cystic carcinoma (n=2); renal (n=1);4Includes one patient with uveal melanoma assessed as clinical progression;5Post-MPN AML;6Off treatment from death due to underlying disease (n=1) or clinical deterioration (n=2) prior to first response assessment; Arm A responses assessed per RECIST 1.1; Arm B by ENL 2022. Pharmacokinetics Table 9. Preliminary Plasma PK Parameters in Cycle 1 (Arm A and Arm B Combined) PK Parameter 0.05 mg / kg (n = 3) 0.1 mg / kg (n = 6) 0.17 mg / kg (n = 7) 0.25 mg / kg (n = 6)32154354.1Page 66 of 78397731-105WO (213618)Vd (L / kg) 2.65 (114%) 1.69 (45.0%) 4.30 (74.0%) 3.30 (45.7%) CL (L / h / kg) 0.335 (83.9%) 0.188 (33.1%) 0.147 (42.3%) 0.211 (20.9%) tedp . p . g g PK analysis.

[0317] FIG.21 shows the Table 9 data graphically. Concentration-Time profiles starting from the end of infusion at 1 hour are presented. Pharmacodynamics

[0318] FIG. 22 shows upregulation of PD biomarkers by MDM2 degradation-mediated p53 pathway activation in blood. Biomarkers of p53 activation expected to increase with MDM2 degradation showed peak upregulation at 24 hr post start of treatment, with levels recovering towards baseline by D8. Conclusions

[0319] Initial clinical proof of concept in tumor types shown to be sensitive to Compound A in preclinical models was demonstrated, including responses in one of two evaluable patients with MCC (PR) and two of two patients with Post-MPN AML (CR and PR). Compound A treatment resulted in upregulation of p53 pathway activation biomarkers even at the lowest dose levels in solid tumor and AML patients, providing proof of mechanism for MDM2 target engagement. Compound A was well tolerated with no significant myelosuppression or thrombocytopenia typical of MDM2 small molecule inhibitors observed to date. Phase 1a dose escalation is ongoing in patients with solid tumor / lymphoma / MF (Arm A) and high-grade myeloid malignancies and ALL (Arm B). Example 4. Additional in vitro and in vivo Experiments In vitro Assays

[0320] All cell lines were cultured according to recommended procedures unless otherwise noted. For growth inhibition assays, cells were treated with compounds for indicated time points. Viability was assessed using Promega® CellTiter-Glo® assay, and apoptosis was assessed using Promega® Caspase- Glo® 3 / 7 assay. Cell cycle arrest and / or apoptosis in response to single agent or combination treatment was assessed using flow cytometry analysis on cells treated for 24h. In vivo Experiments

[0321] AML patient cells from leukapheresis were intravenously (IV) injected and established in immunocompromised host strain mice. Surrogate animals were used to determine the level of engraftment targeting a threshold of ~20% huCD45+ cells in BM. Mice were randomized on study and treatment was initiated. Vehicle and Compound A, 1 mg / kg were administered IV, every three weeks for six weeks (total 32154354.1Page 67 of 78397731-105WO (213618)of two doses of Compound A). At study end, whole blood, bone marrow and spleen were assessed by flow cytometry.

[0322] RS4;11 and MV4;11 tumors were established subcutaneously in the hind flank of NOD / SCID mice. Mice were randomized and treated with Compound A as either a single pulse dose or weekly for 3 weeks at doses matched for total AUC. MDM2 SMI DS-3032 (Milademetan) was dosed at its clinically equivalent dose and regimen of 3 days on / 11 days off. Pharmacodynamic effects were assessed at mRNA level by RT-qPCR and protein level by quantitative targeted mass spectrometry and immunohistochemistry.

[0323] FIG. 3A and 3B shows that Compound A (1 mg / kg, Q3W) achieves tumor regression in a CTG- 2227 AML patient-derived xenograft (PDX) model and partial responses in CTG-2240 and CTG-2700 AML PDX models. Compound A significantly reduces hCD45+ cells in bone marrow and AML blasts.

[0324] FIG.4A and 4B shows the combinatorial benefit of Compound A with venetoclax and midostaurin in MOLM-13 cell line. The data shows that Compound A combination with venetoclax and midostaurin enhances induction of apoptosis and cell killing in MOLM-12 AML cell line.

[0325] FIG.5 shows the significant combinatorial benefit of Compound A with standard of care in AML in vivo model. Single dose of Compound A in combination with daily dosing of venetoclax achieves sustained tumor regression in MOLM-13 xenograft model whereas cytarabine or combination of cytarabine and venetoclax demonstrates no significant anti-tumor activity.

[0326] FIG. 6 shows that Compound A is active across multiple heme indications in vitro with AML, T cell lymphomas, mantle cell lymphoma, and DLBCL being the most sensitive.

[0327] FIG. 7 shows that Compound A is highly active in p53WTABC-subtype DLBCL. Compound A was highly active in OCI-LY10 p53WTABC-subtype DLBCL xenograft model (A) but not TMD8 p53MUT

[0328] ABC-subtype DLBCL xenograft model (B).

[0329] In summary of FIGs 3-7, Compound A dosed intermittently is highly active resulting in responses and complete regression in AML PDX xenograft models. Compound A shows combinatorial benefit with SoC agents in AML in-vitro and in-vivo model, suggesting that Compound A combination can be used for larger patient population. Preclinical data suggest potential for Compound A to be active in additional hematological malignancies, such as DLBCL.

[0330] In the RS4;11 ALL model of FIG. 8, the median survival after a single dose of Compound A at 3 mg / kg was 50 dyas vs. 12 days for the clinically equivalent dosing regimen of DS-3032. In the MV4;11 AML model of FIG.8, a single dose of Compound A at 3 mg / kg led to complete responses in 5 of 6 animals, and 4 of 6 remain tumor-free on study 80 days post dosing. No complete responses were observed following treatment with DS-3032. n=6 animals / group.

[0331] FIG.9 shows that targeted proteomic analysis of RS4;11 tumors demonstrates robust degradation of MDM2 one hour post dosing. This is associated with activation of the p53 pathway as evidenced by a 32154354.1Page 68 of 78397731-105WO (213618)corresponding upregulation of proteomics biomarkers p53, p21 (cell cycle arrest marker) and PHLDA3 (apoptotic marker).

[0332] FIG.10 shows that IHC analysis of RS4;11 tumors demonstrates more robust activation of the p53 pathway and induction of cleaved caspase-3 (CC-3) following a single dose of Compound A than following exposure-matched weekly dosing. Induction of CC-3 was not observed following treatment with the SMI DS-3032 (n=3 / group).

[0333] FIG. 11 shows that IHC analysis of MV4;11 tumors demonstrates robust activation of the p53 pathway and induction of cleaved caspase-3 (CC-3) following a single dose of Compound A but not following exposure-matched weekly dosing. Induction of CC-3 following treatment with the DS-3032 was modest and similar to the lower weekly dosing regimen of Compound A (n=3 / group).

[0334] FIG.12 shows that qPCR analysis of RS4;11 tumors demonstrates robust induction of the apoptotic gene BBC3 following single doses of Compound A that lead to tumor regression (n=3 / group). In contrast, exposure-matched weekly dosing of Compound A results in only a moderate increase in apoptotic markers and correlates with tumor stasis (n=3 / group). Similar results were observed with the apoptotic genes FAS and DR5 (data not shown). 12 to 22 hours of Compound A plasma concentrations above 0.01 uM are required for tumor regression. Plasma Compound A concentrations above 0.02 uM are required for induction of the apoptotic gene, BBC3.

[0335] In summary of FIGs 8-12, a single high dose of Compound A leads to robust activation of the p53 pathway, apoptosis, and sustained tumor regression, while exposure-matched weekly dosing leads to cell cycle arrest and tumor stasis, as observed with MDM2 small molecule inhibitors. In the MV4;11 AML model, a single dose of Compound A at 3 mg / kg led to complete responses in 5 of 6 animals, and 4 of 6 remain tumor-free on study 80 days post dosing. The pulse dosing regimen of Compound A has the potential to result in improved efficacy and safety profiles compared to the more frequent dosing of MDM2 / p53 small molecule inhibitors in the clinic.

[0336] FIG. 15 shows that an 8-hour treatment with Compound A showed potent induction of p53 transcriptional gene targets including MDM2, GDF15, CDKN1A, GADD44A, TNFRSF10B, FAS, and BBC3. All these targets showed an approximate 4-fold or higher increase in relative mRNA levels at Compound A concentrations as low as 10 nM. This trend continued in a concentration dependent manner reaching an 8-fold or greater increase in relative mRNA levels for all targets at the highest Compound A treatment concentration evaluated (1 mM). A modest 2-fold induction of p53 downstream targets was observed upon treatment with DS-3032 only at the highest concentration of 1 mM. Furthermore, treatment with Compound A led to potent induction of apoptosis in a panel of AML, ALL, B-cell, and diffuse large B-cell lymphoma (DLBCL) cell lines. Significant growth inhibition (99% or 98% max inhibition) was observed in all but two of the cell lines tested (92% and 86% max inhibition), with HNT-34 and RS4;11 32154354.1Page 69 of 78397731-105WO (213618)cells lines both showing the highest maximal inhibition (99%) and the lowest IC50values of < 0.1 nM (FIG. 16).

[0337] To investigate how Compound A treatment affects cell cycle progression, cell cycle distribution and viability in RS4;11 and MV4;11 cell lines treated with Compound A or DS-3032 was quantified (FIG. 17). In both cell lines, treatment with 1000 nM Compound A resulted in a significantly lower percentage of cells in S phase (0.97% and 0.45% in RS4;11 and MV4;11, respectively) than with 1000 nM DS-3032 treatment (30.6% and 12.0% in RS4;11 and MV4;11, respectively). Additionally, significantly more cells were in late apoptotic stage following treatment with 1000 nM Compound A (75.8% in RS4;11 cells and 62.1% MV4;11 cells) than with 1000 nM DS-3032 treatment (6.9% in RS4;11 cells and 9.3% MV4;11 cells). Viability data also confirms the significantly higher percentage of live 1000 nM DS-3032 treated cells (90.4% in RS4;11 cells and 87.4% MV4;11 cells), compared to 1000 nM Compound A treated cells (17.1% in RS4;11 cells and 23.8% MV4;11 cells) (FIG.17).

[0338] FIG. 18 shows that when a single dose of Compound A was combined with venetoclax, durable complete responses were achieved. Although the clinical dosing regimen for venetoclax is continued daily administration, as little as 1 week of venetoclax administration in combination with a single dose of Compound A, was sufficient to induce complete responses in 6 of 6 animals. Remarkably, administration of venetoclax for just 3 days also induced complete responses in 6 of 6 animals when combined with Compound A, but these responses were less durable (median survival of 68 days vs > 150 days for 1 week of venetoclax). In addition, half the clinically equivalent dose of venetoclax (50 mg / kg) administered daily for 3 weeks in combination with a single dose of Compound A was sufficient to induce durable complete responses in all animals. In addition to the combination benefit, Compound A treatment also showed strong single agent activity in a primary systemic model of AML that was resistant to venetoclax treatment (FIG. 19). Example 5. Additional in vitro and in vivo Experiments Methods

[0339] Activity of Compound A in vitro was explored in a panel of 350 p53 wild-type cell lines spanning 48 indications. The combination of both cell growth inhibition and apoptosis was evaluated using CTG (Promega) and Caspase-Glo 3 / 7 assays in 187 lines. Twenty-four pediatric patient-derived xenograft (PDX) models representing 6 tumor types (Ewing sarcoma, rhabdomyosarcoma, rhabdoid tumor, Wilms tumor, hepatoblastoma, and neuroblastoma) and 101 adult PDX models representing 5 solid tumor types (breast, lung, colorectal, gastric, melanoma) were evaluated using a single mouse trial design. Baseline expression profiles of the adult PDX models were used in a machine learning framework to build a predictive signature of response to Compound A. The signature was validated in 19 prospectively selected PDX models. 32154354.1Page 70 of 78397731-105WO (213618)Results

[0340] In vitro screening indicates a wide range of heme (FIG.6) and solid tumor (FIG.24) cell lines show sub-nanomolar growth inhibition (CTG assay, 96 h) and induction of apoptosis (caspase 3 / 7 activity, 48 h) in response to Compound A. AML, ALL and solid tumor indications that include small round blue cell tumor (SRBCT) types were among the most sensitive. These data demonstrate the potential for Compound A development across a wide variety of heme and solid tumor indications.

[0341] FIG. 25 shows that 38% of pediatric solid tumors show complete and durable responses to Compound A. Waterfall plots show best average response to Compound A relative to baseline tumor volume at start of treatment in a single mouse trial of 24 pediatric PDX models representing 6 tumor types. Tumors were established subcutaneously in the hind flank of SCID mice. Complete responses were achieved in 9 of 24 models. Best average response is defined as the average of the best percent change in tumor volume over the course of 5 weeks. Tumor growth curves are provided for 9 models that showed complete response to Compound A (n=1 / group). Mice were dosed intravenously on day 0, 21, and 42.

[0342] FIG. 26 shows that Compound A is active in multiple adult solid tumor types including tumors that are insensitive to an MDM2 small molecule inhibitor. Waterfall plots show best average response to Compound A relative to baseline tumor volume at start of treatment in a single mouse trial of 101 adult PDX models representing 5 different tumor types. Best average response is defined as the average of the best percent change in tumor volume over the course of 5 timepoints. Tumor growth curves comparing the activity of Compound A to the MDM2 SMI, BI907828, which was administered at the clinically relevant dose (n=3 / group).

[0343] FIG.27 shows a method of finding a gene expression signature that predicts response to Compound A. (A) To identify a broader pan-cancer responder signature, baseline expression profiles of the adult PDX models were used in a machine learning framework to build a predictive signature. (B) The signature was applied to The Cancer Genome Atlas (TCGA) pan-cancer dataset and identified AML and a subset of solid tumors as sensitive, consistent with our preclinical and early clinical findings. (C) Plot of a neuroendocrine (NE) signature (PMID: 29535911) vs. Compound A predictive signature highlighting that the predictive signature identifies both neuroendocrine and non-endocrine tumors that respond to Compound A.

[0344] FIG. 28 shows that disseminated AML PDX models show complete responses to Compound A. Bar graphs of the percent human CD45+ cells in whole blood (WB) and bone marrow (BM) after treatment with Compound A. Sub-lethally irradiated NOG-EXL mice were inoculated with 2x108primary AML cells. Treatment was initiated when tumor engraftment levels in the bone marrow of surrogate animals were 68% (CTG-2233), 39% (CTG-2239), 21% (CTG-2240), 50% (CTG-2702). Mice were dosed on day 0, 21 and 42 and tumor burden was quantified by flow cytometry 24 h after the last dose. Statistical analysis was conducted using a Student’s t-test. Complete responses were achieved in 3 of the 4 models evaluated. 32154354.1Page 71 of 78397731-105WO (213618)

[0345] FIG. 29 shows that prospectively selected PDX models demonstrate improved response rates and survival. (A) Waterfall plot of best average response to Compound A relative to baseline tumor volume at start of treatment in 19 adult PDX models selected using a predictive gene signature.37% of prospectively selected models responded to Compound A vs.11% of unselected models. (B) Bar graph of response calls. Response is defined as the combination of 1) Best response after 14 days of SD or better, 2) Best average response over the course of 5 timepoints of SD or better, and 3) Less than -0.45 change in AUC relative to control. In unselected cohort, 4 PR and 7 SD (11 of 101) were observed. In prospectively selected cohort, 1 CR, 2 PR, 4 SD (7 of 19) were observed. CR: complete response, PR: partial response, SD: stable disease. (C) Kaplan-Meier curves comparing time to endpoint (tumor volume = 1500 mm3) in control vs. Compound A treated animals. Median survival was longer in the prospective models than in the original cohort (48d vs 38d). Odds ratio is 4.7 with 95% CI (1.29, 16.6). p-value= 0.0089. Conclusions

[0346] Single mouse trials show that Compound A has the potential to induce durable complete responses in both pediatric and adult solid tumor types. A machine learning framework was used to build a predictive signature of response to Compound A that is distinct from published signatures. The resulting signature identified AML and solid tumors with neuroendocrine characteristics as sensitive, consistent with preclinical and early clinical findings. Non-neuroendocrine tumors were also identified that respond to Compound A. Application of the responder signature for tumor model selection increased the Compound A response rate in adult solid tumors from ~10 to 37% and prospectively selected models demonstrated prolonged median survival. The signature can be further refined using emerging clinical data to enrich for patients in future trials. * * * * *

[0347] While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example. 32154354.1Page 72 of 78397731-105WO (213618)

Claims

CLAIMS 1. A liquid formulation comprising Compound A, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient and / or carrier, wherein Compound A is (3'R,4'S,5'R)-6''-chloro- 4'-(3-chloro-2-fluorophenyl)-N-((1R,4R)-4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro- 1H-benzo[d]imidazol-5-yl)piperidine-1-carbonyl)cyclohexyl)-2''-oxodispiro[cyclohexane-1,2'- pyrrolidine-3',3''-indoline]-5'-carboxamide.

2. The liquid formulation of claim 1, comprising Compound A at a concentration of about 0.05%-5% w / w of the total weight of the formulation.

3. The liquid formulation of claim 1, comprising Compound A at a concentration of about 1-20 mg / mL.

4. The liquid formulation of any one of claims 1-3, comprising a surfactant at a concentration of about 10-30% w / w of the total weight of the formulation.

5. The liquid formulation of any one of claims 1-3, comprising a surfactant at a concentration of about 100-500 mg / mL.

6. The liquid formulation of any one of claims 1-5, comprising one or more carriers at a concentration of about 60-90% w / w of the total weight of the formulation or unit dosage form.

7. The liquid formulation of any one of claims 1-5, comprising a first carrier and a second carrier, wherein the first carrier is a polyol at a concentration of about 60-80% w / w of the total weight of the formulation or unit dosage form and the second carrier is ethanol at a concentration of about 5-20% w / w of the total weight of the formulation or unit dosage form.

8. The liquid formulation of any one of claims 1-7, comprising a first carrier and a second carrier, wherein the first carrier is a polyol and the second carrier is ethanol in a ratio of about 5:1 to about 9:

1.

9. The liquid formulation of any one of claims 1-8, which is a unit dosage form.

10. A method for treating a solid cancer or hematological malignancy in a patient, comprising 32154354.1Page 73 of 78397731-105WO (213618)administering to the patient a therapeutically effective amount the liquid formuation of any one of claims 1-9.

11. The method of claim 10, wherein the method comprises administering Compound A to the patient once every three weeks (Q3W).

12. The method of claim 10 or claim 11, wherein the method comprises administering Compound A to the patient by intravenous transfusion.

13. The method of any one of claims 10-12, wherein the solid cancer or hematological malignancy is selected from Merkel cell carcinoma, fibromyxoid sarcoma, myxofibrosarcoma, rectal cancer, prostate cancer, adenoid cystic carcinoma, renal cell carcinoma, osteosarcoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), large granular lymphocytic leukemia (LGL-L), B-cell prolymphocytic leukemia, acute myeloid leukemia (AML), Burkitt lymphoma / leukemia, myelofibrosis, primary effusion lymphoma, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), diffuse large B-cell lymphoma (DLBCL), advanced B-cell diffuse large B-cell lymphoma (ABC DLBCL), intravascular large B-cell lymphoma, lymphoplasmacytic lymphoma, Waldenström’s macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, uveal melanoma, myelodysplastic syndrome (MDS), or myelodysplastic / myeloproliferative neoplasms (MDS / MPN).

14. The method of any one of claims 10-13, wherein the hematological malignancy is acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML).

15. The method of any one of claims 10-14, wherein the solid cancer or hematological malignancy is relapsed and / or refractory.

16. The method of any one of claims 10-15, wherein the patient has received at least one prior therapies.

17. The method of any one of claims 10-16, wherein the patient has received at least two prior therapies.

18. The method of any one of claims 10-17, wherein the patient is a human.

19. The method of any one of claims 10-18, wherein the patient does not have one or more of the exclusion criteria as set forth in Example 2. 32154354.1Page 74 of 78397731-105WO (213618)20. The method of any one of claims 10-19, wherein the patient has one or more of the inclusion criteria as set forth in Example 2.

21. The method of any one of claims 10-20, wherein the patient is a pediatric patient.

22. A method for treating a solid cancer or hematological malignancy in a patient, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof; wherein Compound A is (3'R,4'S,5'R)-6''-chloro-4'-(3-chloro-2-fluorophenyl)-N-((1R,4R)-4-(4-(1- (2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-1- carbonyl)cyclohexyl)-2''-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indoline]-5'-carboxamide; and wherein a Cmax of up to about 2000 ng / mL of Compound A in plasma is achieved.

23. The method of claim 22, wherein a Cmax of Compound A in plasma includes about 100 ng / mL to about 1000 ng / mL, about 100 ng / mL to about 900 ng / mL, about 100 ng / mL to about 800 ng / mL, about 100 ng / mL to about 700 ng / mL, about 100 ng / mL to about 600 ng / mL, about 200 ng / mL to about 1000 ng / mL, about 200 ng / mL to about 900 ng / mL, about 200 ng / mL to about 800 ng / mL, about 200 ng / mL to about 700 ng / mL, or about 200 ng / mL to about 600 ng / mL.

24. A method for treating a solid cancer or hematological malignancy in a patient, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof; wherein Compound A is (3'R,4'S,5'R)-6''-chloro-4'-(3-chloro-2-fluorophenyl)-N-((1R,4R)-4-(4-(1- (2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-1- carbonyl)cyclohexyl)-2''-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indoline]-5'-carboxamide; and wherein an AUC of up to about 3,000 ng*h / mL of Compound A in plasma is achieved.

25. The method of claim 24, wherein an AUC of Compound A in plasma includes about 200 ng*h / mL to about 1500 ng*h / mL, about 200 ng*h / mL to about 1200 ng*h / mL, about 200 ng*h / mL to about 1000 ng*h / mL, about 200 ng*h / mL to about 900 ng*h / mL, about 200 ng*h / mL to about 800 ng*h / mL, about 300 ng*h / mL to about 1500 ng*h / mL, about 300 ng*h / mL to about 1200 ng*h / mL, about 300 ng*h / mL to about 1000 ng*h / mL, about 300 ng*h / mL to about 900 ng*h / mL, or about 300 ng*h / mL to about 800 ng*h / mL. 32154354.1Page 75 of 78397731-105WO (213618)26. A method for treating a solid cancer or hematological malignancy in a patient, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof; wherein Compound A is (3'R,4'S,5'R)-6''-chloro-4'-(3-chloro-2-fluorophenyl)-N-((1R,4R)-4-(4-(1- (2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-1- carbonyl)cyclohexyl)-2''-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indoline]-5'-carboxamide; and wherein up to about a 500 fold increase of one or more markers of p53 activity in plasma is achieved over pre-dose reference (e.g., baseline) levels.

27. The method of claim 26, wherein an increase of one or more markers of p53 activity in plasma includes about 3 fold to about 20 fold, about 5 fold to about 25 fold, about 10 fold to about 30 fold, about 15 fold to about 35 fold, about 20 fold to about 40 fold, about 25 fold to about 45 fold, about 30 fold to about 50 fold, about 35 fold to about 55 fold, about 40 to about 60 fold, about 45 fold to about 65 fold, about 50 fold to about 70 fold, about 55 fold to about 75 fold, about 60 fold to about 80 fold, about 65 fold to about 85 fold, about 70 fold to about 90 fold, about 75 fold to about 95 fold, or about 80 fold to about 100 fold over pre-dose reference (e.g., baseline) levels.

28. The method of claim 26 or claim 27, wherein the one or more markers of p53 activity is selected from MDM2, GDF15, CDKN1A, GADD44A, TNFRSF10B, FAS, FASIPO8, BBC3, BAX, PHLDA2, PHLDA3, BCL2L1, BCL2, CASP8, TP53, TP53I3, PUM1, PARK7, GAPDH, MCL1, CRBN, ACTB, and ACTA2.

29. A method of treating a solid cancer or hematological malignancy in a patient, comprising: i) determining a predictive signature from a baseline expression profile from a biological sample of the solid cancer or hematological malignancy from the patient; ii) identifying the patient as a potential responder for treatment based on applying said predictive signature to a reference (e.g., pan-cancer dataset); and iii) administering treatment with Compound A to the patient; wherein Compound A is (3'R,4'S,5'R)-6''-chloro-4'-(3-chloro-2-fluorophenyl)-N-((1R,4R)-4-(4-(1- (2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-1- carbonyl)cyclohexyl)-2''-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indoline]-5'-carboxamide.

30. The method of claim 29, wherein an increased response rate to Compound A in the patient is 32154354.1Page 76 of 78397731-105WO (213618)observed, as compared to treatment of a patient or population of patients with Compound A without prior identification as a potential responder.

31. The method of claim 29 or 30, wherein the increased response rate to Compound A in a population of patients is about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% greater as compared to treatment of a patient or population of patients with Compound A without prior identification as a potential responder. 32154354.1Page 77 of 78397731-105WO (213618)

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