Radiopharmaceutical compositions and methods

Abstract

Provided herein are pharmaceutical compositions and methods for treating a cancer characterized by upregulated surface expression of DLL3, comprising a radiopharmaceutical compound targeting DLL3 and an additional therapeutic agent.

Description

[0001] PAT060054-PCT-SEC01

[0002] RADIOPHARMACEUTICAL COMPOSITIONS AND METHODS RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Application No. 63 / 789,882, filed on April 16, 2025, the content of which is hereby incorporated by reference in its entirety.

[0004] BACKGROUND

[0005] Chemotherapy and immunotherapy have transformed cancer treatment, but present significant limitations. Chemotherapy is non-selective, often causing off-target toxicity and promoting resistance through tumor heterogeneity. Immunotherapy, including immune checkpoint inhibitors, benefits only a subset of patients, with many tumors exhibiting poor immunogenicity or developing adaptive resistance. Both approaches can lead to substantial adverse effects, underscoring the need for more targeted and tumor-specific strategies.

[0006] Combination drug therapies hold promise for overcoming these limitations by targeting cancer through multiple mechanisms and reducing the likelihood of resistance by disrupting parallel survival pathways.

[0007] SUMMARY

[0008] In one aspect, provided herein is a method for treating cancer, comprising administering to the subject a radiopharmaceutical compound targeting Delta-like ligand 3 (DLL3) and an additional therapeutic agent selected from the group consisting of an immunotherapeutic agent, a chemotherapeutic agent, and combinations thereof.

[0009] In another aspect, provided herein is a method for treating a cancer characterized by upregulated surface expression of DLL3 in a subject in need thereof, comprising administering to the subject a combination therapy which comprises a radiopharmaceutical compound targeting DLL3 and an additional therapeutic agent selected from the group consisting of an immunotherapeutic agent, a chemotherapeutic agent, and combinations thereof.

[0010] In another aspect, provided herein is a method for treating a DLL3 positive cancer in a subject in need thereof, comprising administering to the subject a combination therapy which comprises a radiopharmaceutical compound targeting DLL3 and an additional therapeutic agentPAT060054-PCT-SEC01

[0011] selected from the group consisting of an immunotherapeutic agent, a chemotherapeutic agent, and combinations thereof.

[0012] In another aspect, provided herein are pharmaceutical compositions comprising a radiopharmaceutical compound targeting DLL3 and an additional therapeutic agent selected from the group consisting of an immunotherapeutic agent, a chemotherapeutic agent, and combinations thereof.

[0013] In certain embodiments, the radiopharmaceutical compound comprises a compound of Formula (I):

[0014]

[0015] or a pharmaceutically acceptable salt thereof.

[0016] BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows mean tumor growth by group (Last Observation Carried Forward (LOCF) Adjusted) according to the studies described in Example 1. The study groups G1-G6 are outlined in Table 1-5. Group 1 (Gl) is the control group. Group 2 (G2) were administered Compound 1 at 0.25 pCi / animal and isotype control (Clone LTF-2). Group 3 (G3) were administered Compound 1 at 0.125 pCi / animal and isotype control (Clone LTF-2). Group 4 (G4) were administered vehicle and anti-mPD-Ll (Clone 10F.9G2). Group 5 (G5) were administered Compound 1 at 0.25 pCi and anti-mPD-Ll (Clone 10F.9G2). Group 6 (G6) were administered Compound 1 at 0.125 pCi and anti-mPD-Ll (Clone 10F.9G2). Mean tumor volumes in the mice of G5, treated with 0.25 pCi Compound 1 and anti-PD-Ll grew to about 200 mm3, whereas mean tumorPAT060054-PCT-SEC01

[0017] volumes in the mice of G2 (Compound 1 only), and G4 (anti-PD-Ll only) grew to about 700 mm3and about 1250 mm3, respectively.

[0018] FIG. 2 shows median tumor growth by group (LOCF Adjusted) according to the studies described in Example 1. The study groups G1-G6 are outlined in Table 1-5. Median tumor volumes in the mice of G5 (treated with 0.25 pCi Compound 1 and anti-PD-Ll) and G6 (treated with 0.125 pCi and anti-mPD-Ll) decreased to baseline by about day 32 and did not increase within the study period.

[0019] FIG. 3 shows percent progression free survival by group according to the studies described in Example 1. The study groups G1-G6 are outlined in Table 1-5.

[0020] FIG. 4A-4F shows individual tumor growth curves by group according to the studies described in Example 1. The study groups G1-G6 are outlined in Table 1-5.

[0021] FIG. 5 shows percent mean body weight change by group according to the studies described in Example 1. The study groups G1-G6 are outlined in Table 1-5.

[0022] FIG. 6 shows mean tumor growth by group (LOCF Adjusted) according to the studies described in Example 2. The study groups G1-G5 are outlined in Table 2-3. The study groups G1-G5 are outlined in Table 2-3. Group 1 (Gl) is the control group. Group 2 (G2) were administered Compound 1 at 1 pCi / animal. Group 3 (G3) were administered Compound 1 at 0.25 pCi / animal. Group 4 (G4) were administered cisplatin (CDDP) at 2.5 mg / kg and etoposide at 3.5 mg / kg. Group 5 (G5) were administered cisplatin (CDDP) at 2.5 mg / kg, etoposide at 3.5 mg / kg, and Compound 1 at 0.25 pCi / animal.

[0023] FIG. 7 shows median tumor growth by group (LOCF Adjusted) according to the studies described in Example 2. The study groups G1-G5 are outlined in Table 2-3.

[0024] FIG. 8 shows percent progression free survival by group according to the studies described in Example 2. The study groups G1-G5 are outlined in Table 2-3.

[0025] FIG. 9A-9E shows individual tumor growth curves by group according to the studies described in Example 2. The study groups G1-G5 are outlined in Table 2-3.

[0026] FIG. 10 shows mean tumor growth by group according to the studies described in Example 2. The study groups G1-G5 are outlined in Table 2-3.PAT060054-PCT-SEC01

[0027] DETAILED DESCRIPTION

[0028] Definitions

[0029] A “subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)).

[0030] The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject.

[0031] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0032] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0033] An “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response. An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is the amount of a compound, combination, or composition described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound, combination, or composition described herein in multiple doses. In certain embodiments, an effective amount of a compound (e.g., a radiopharmaceutical compound) or an additional therapeutic agent, is a therapeutically effective amount.

[0034] A “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies,PAT060054-PCT-SEC01

[0035] which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and / or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating cancer (e.g., a neuroendocrine neoplasm or non-neuroendocrine neoplasm as discussed herein).

[0036] As used herein, the term “inhibit” or “inhibition” in the context of enzymes, for example, in the context of PD-1, PD-L1, or CTLA-4, refers to a reduction in the activity of the immune checkpoint protein. In some embodiments, the term refers to a reduction of the level of protein activity, e.g., PD-1, PD-L1, or CTLA-4 activity, to a level that is statistically significantly lower than an initial level, which may, for example, be a baseline level of enzyme activity. In some embodiments, the term refers to a reduction of the level of immune checkpoint protein activity, to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level, which may, for example, be a baseline level of enzyme activity.

[0037] The term “small molecule” refers to molecules, whether naturally-occurring or artificially created (e.g., via chemical synthesis) that have a relatively low molecular weight. Typically, a small molecule is an organic compound (i.e., it contains carbon). The small molecule may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyl, carbonyls, and heterocyclic rings, etc.). In certain embodiments, the molecular weight of a small molecule is not more than about 1,000 g / mol, not more than about 900 g / mol, not more than about 800 g / mol, not more than about 700 g / mol, not more than about 600 g / mol, not more than about 500 g / mol, not more than about 400 g / mol, not more than about 300 g / mol, not more than about 200 g / mol, or not more than about 100 g / mol. In certain embodiments, the molecular weight of a small molecule is at least about 100 g / mol, at least about 200 g / mol, at least about 300 g / mol, at least about 400 g / mol, at least about 500 g / mol, at least about 600 g / mol, at least about 700 g / mol, at least about 800 g / mol, or at least about 900 g / mol, or at least about 1,000 g / mol. Combinations of the above ranges (e.g., at least about 200 g / mol and not more than about 500 g / mol) are also possible. In certain embodiments, the small molecule is aPAT060054-PCT-SEC01

[0038] therapeutically active agent such as a drug (e.g., a molecule approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (C.F.R.)). The small molecule may also be complexed with one or more metal atoms and / or metal ions. In this instance, the small molecule is also referred to as a “small organometallic molecule.” Preferred small molecules are biologically active in that they produce a biological effect in animals, preferably mammals, and more preferably humans. Small molecules include, but are not limited to, radionuclides and imaging agents. In certain embodiments, the small molecule is a drug.

[0039] Preferably, though not necessarily, the drug is one that has already been deemed safe and effective for use in humans or animals by the appropriate governmental agency or regulatory body. For example, drugs approved for human use are listed by the FDA under 21 C.F.R. §§ 330.5, 331 through 361, and 440 through 460, incorporated herein by reference; drugs for veterinary use are listed by the FDA under 21 C.F.R. §§ 500 through 589, incorporated herein by reference. All listed drugs are considered acceptable for use in accordance with the present invention.

[0040] 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, 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 known 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,PAT060054-PCT-SEC01

[0041] methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(CI-4 alkyl)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, lower alkyl sulfonate, and aryl sulfonate.

[0042] Therapeutic Methods

[0043] DLL3 is an inhibitory Notch ligand that is aberrantly expressed on the surface of certain cells, such as small cell lung cancer and large cell neuroendocrine carcinoma, while showing minimal expression in normal adult tissues. This tissue selective expression pattern makes DLL3 an attractive therapeutic target. Accordingly, in a first aspect, provided herein is a method for treating cancer, comprising administering to the subject an effective amount of a radiopharmaceutical compound targeting DLL3 and an effective amount of an additional therapeutic agent selected from the group consisting of an immunotherapeutic agent, a chemotherapeutic agent, and combinations thereof.

[0044] Upregulated DLL3 is observed aberrantly localized to the surface of cancer cells, wherein it has been quantified in the low single-digit thousands of copies per cell in representative small cell lung cancer (SCLC) and neuroendocrine prostate cancer (NEPC) cell lines (Giffin, M. J., et al. Clin. Cancer Res, (2021) 27(5), 1526-37; Zhang, Y, et al. Clin. Cancer Res. (2023) 29(5), 971-85) to on the order of 10,000 copies per cell (Sharma SK, et al. Cancer Res. 2017 Jul 15;77(14):3931 -3941 ). Accordingly, the cancer may be characterized as having upregulated surface expression of DLL3. Thus, in a second aspect, provided herein is a method for treating a cancer characterized by upregulated surface expression of DLL3 in a subject in need thereof, comprising administering to the subject a combination therapy which comprises an effective amount of a radiopharmaceutical compound targeting DLL3 and an effective amount of an additional therapeutic agent selected from the group consisting of an immunotherapeutic agent, aPAT060054-PCT-SEC01

[0045] chemotherapeutic agent, and combinations thereof. In this context, “upregulated” refers to the increased expression level of DLL3 on a cancer cell relative to a non-malignant cell.

[0046] Cancers may be characterized in terms of DLL3 positivity, such cancers being “DLL3 positive.” In some embodiments, the cancer is a solid tumor having DLL3 positivity as measured by immunohistochemistry (IHC) (e.g., >1% DLL3 positive cells). See, e.g., Table A.

[0047] Table A: DLL3 IHC Positivity in Exemplary Human Tumors

[0048] Tumor Type % IHC Positive DLL3 Positive / Total Definition of Positive SCLC 85.2%’ 895 / 1050 >25% tumor cells positive

[0049] 68.5% 719 / 1050 >75% tumor cells positive Melanoma 49.6%265 / 131 >1% tumor cells positive

[0050] 89.2%358 / 65 >1% tumor cells positive

[0051] MCC 52.3% 34 / 65 >50% tumor cells positive

[0052] 91.1 %451 / 56 >1% tumor cells positive

[0053] 53.8% 33 / 56 >50% tumor cells positive

[0054] NEPC 76.6%536 / 47 Any staining of any intensity GEP NEC 76.9 %610 / 13 >1% tumor cells positive

[0055] 47.5%728 / 59 >50% tumor cells positive

[0056] MTC 100%233 / 33 >1% tumor cells positive

[0057] 46.2% 6 / 13 >50% tumor cells positive

[0058] 95.2%820 / 21 >1% tumor cells positive

[0059] 75%924 / 32 >50% tumor cells positive 74.5%’° 70 / 94 >1% tumor cells positive

[0060] LCNEC 66.0% 62 / 94 >25% tumor cells positive

[0061] 54.3% 51 / 94 >50% tumor cells positive

[0062] 37.2% 35 / 94 >75% tumor cells positive 51.9%’’ 14 / 27 >25% tumor cells positive SCNECC 80.9%’238 / 47 >50% tumor cells positive

[0063]

[0064] Abbreviations: GEP NEC = gastroenteropancreatic neuroendocrine carcinoma;

[0065] IHC = immunohistochemistry; LCNEC = large- cell neuroendocrine carcinoma; MCC = Merkel cell carcinoma, MTC = medullary thyroid carcinoma; NEPC = neuroendocrine prostate cancer; SCLC = small-cell lung cancer; SCNECC = small-cell neuroendocrine carcinoma of the cervix.

[0066] (1) Rojo et al. Lung Cancer. 2020 Sep;147:237-43. (2) Mansfield et al. NPJ Precis Oncol. 2021 Aug 5;5(1), 74. (3) Rand et al. J Am Acad Dermatol. 2021 Sep;85(3):749-50. (4) Xie et al. Oncologist, 2020 Sep;25(9):810-817. (5) Puca et al. Sci Transl Med. 2019 Mar 20; ll(484):eaav0891. (6) Liverani et al. Endocr Pathol. 2021 Jun;32(2):309-17. (7) Ingenwerth et al. Endocr Connect. 2021 Mar;10(3):283- 9. (8) Garcia- Alvarez et al. ENETS 2023. (9) Ali, G. et al. Front Oncol. 2021

[0067] Sep9;ll:729765. (10) Hermans et al. Lung Cancer. 2019 Dec;138:102-8. (11) Brcic et al. Diagn Pathol.

[0068] 2019 May 20;14(l):47. (12) Cimic et al. Appl Immunohistochem Mol Morphol. 2021 Apr 1;29(4):299-304.PAT060054-PCT-SEC01

[0069] As such, in a third aspect, provided herein is a method for treating a DLL3 positive cancer in a subject in need thereof, comprising administering to the subject a combination therapy which comprises an effective amount of radiopharmaceutical compound targeting DLL3 and an effective amount of an additional therapeutic agent selected from the group consisting of an immunotherapeutic agent, a chemotherapeutic agent, and combinations thereof. In some embodiments, the DLL3 positive cancer is characterized by IHC has having >1% DLL3 positive cells. In some embodiments, the DLL3 positive cancer is characterized by IHC has having >5% DLL3 positive cells. In some embodiments, the DLL3 positive cancer is characterized by IHC has having >10% DLL3 positive cells. In some embodiments, the DLL3 positive cancer is characterized by IHC has having >25% DLL3 positive cells. In some embodiments, the DLL3 positive cancer is characterized by IHC has having >50% DLL3 positive cells. In some embodiments, the DLL3 positive cancer is characterized by IHC has having >75% DLL3 positive cells. In some embodiments, the DLL3 positive cancer is characterized by IHC has having staining of any intensity.In some embodiments, IHC is performed according to the method of Example 3.

[0070] Further embodiments of the first, second, and third aspects are provided.

[0071] In some embodiments, the cancer is selected from Table A. In some embodiments, the cancer is selected from the listings of exemplary indications in Table 1 and Table 2.

[0072] The cancer may be a neuroendocrine neoplasm, or the cancer may be a non-neuroendocrine neoplasm. In some embodiments, the neuroendocrine neoplasm is selected from small cell lung cancer (SCLC), medullary thyroid carcinoma (MTC), large cell neuroendocrine cancer (LCNEC), gastroenteropancreatic neuroendocrine carcinoma (GEP NEC), neuroendocrine prostate cancer (NEPC), small cell prostate cancer (SCPC), Merkel cell carcinoma (MCC), neuroendocrine cervical carcinoma, and Grade 3 neuroendocrine tumors (NETs). In some embodiments, the neuroendocrine neoplasm is extrapulmonary neuroendocrine carcinoma (NEC) of the cervix. In some embodiment, the small cell lung cancer can be extensive-stage (ES)-SCLC or Limited-stage (LS)-SCLC. In some embodiments, the neuroendocrine prostate cancer (NEPC), can be treatment emergent NEPC.

[0073] In some embodiments, the cancer is lung cancer. In a particular embodiment, the lung cancer is SCLC. The SCLC may be ES-SCLC. Alternatively, the SCLC may be LS-SCLC.PAT060054-PCT-SEC01

[0074] In some embodiments, the cancer is prostate cancer. In a particular embodiment, the prostate cancer is NEPC. In another particular embodiment, the prostate cancer is SCPC.

[0075] In one embodiment, the cancer is small cell lung cancer (SCLC). In another embodiment, the cancer is neuroendocrine prostate cancer (NEPC). In another embodiment, the cancer is large cell neuroendocrine carcinoma (LCNEC). In another embodiment, the cancer is gastroenteropancreatic neuroendocrine tumor (GEP-NET). In another embodiment, the cancer is melanoma.

[0076] Immunotherapeutic Agents

[0077] In certain embodiments, the additional therapeutic agent is an immunotherapeutic agent. Immunotherapeutic agents may be used to harness or modify the immune system to fight cancer. These agents include a broad range of strategies such as immune checkpoint inhibitors, cancer vaccines, cytokines, monoclonal antibodies, and cell based therapies like CAR-T cells. Unlike traditional chemotherapy, which directly kills rapidly dividing cells, immunotherapeutics empower or redirect the body's own immune defenses to recognize and eliminate cancerous cells. They can enhance immune activation, block immune suppression, or even deliver targeted cytotoxic effects.

[0078] In certain embodiments, the immunotherapeutic agent is an immune checkpoint inhibitor. Immune checkpoint inhibitors are a class of drugs that enhance the immune system's ability to recognize and destroy cancer cells. They work by blocking proteins such as PD-1, PD-L1, and CTLA-4 that normally act as brakes on the immune response, and that are often exploited by tumors to avoid detection and destruction by the immune system. By inhibiting the checkpoint proteins, checkpoint inhibitors allow T cells to become more active and attack cancer more effectively.

[0079] In certain embodiments, the immune checkpoint inhibitor is an inhibitor of PD-1, PD-L1, or CTLA-4. In certain embodiments, the immune checkpoint inhibitor is a small molecule, antibody or biologically active fragment thereof, fusion protein, or therapeutic oligonucleotide.

[0080] In one embodiment, the immune checkpoint inhibitor is a PD-1 inhibitor. Such checkpoint inhibitors block the PD-1 receptor on T cells, preventing it from binding to PD-L1 on tumor cells, thus restoring T cell activity against cancer. Non-limiting examples of suchPAT060054-PCT-SEC01

[0081] checkpoint inhibitors include nivolumab, pembrolizumab, cemiplimab, toripalimab, and tislelizumab.

[0082] In another embodiment, the immune checkpoint inhibitor is a PD-L1 inhibitor. Such checkpoint inhibitors block PD-L1, the ligand that binds PD-1, preventing it from inactivating T cells, thereby helping the immune system recognize and attack cancer cells. Such checkpoint inhibitors include atezolizumab, durvalumab, avelumab, and envafolimab.

[0083] In another embodiment, the immune checkpoint inhibitor is a CTLA-4 inhibitor. Such checkpoint inhibitors work by blocking CTLA-4, a receptor on T cells that downregulates immune activation. By inhibiting CTL A-4, these agents help sustain T cell activity, promoting a stronger and more sustained immune response against tumors. Non-limiting examples of CTLA-4 inhibitors include ipilimumab, tremelimumab, and quavonlimab.

[0084] In some embodiments, the immunotherapeutic agent is selected from the agents listed in Table 1.

[0085] Table 1. Exemplary Immunotherapeutic Agents

[0086] Agent Modality Route Exemplary Dosage Regimen Exemplary Indication

[0087] Atezolizumab Anti-PD-Ll mAb IV 840 mg Q2W; 1200 mg Multiple oncology Q3W; 1680 mg Q4W indications (label dosing) Durvalumab Anti-PD-Ll mAb IV 10 mg / kg Q2W or 1500 mg NSCLC, ES-SCLC, UC Q4W

[0088] Avelumab Anti-PD-Ll mAb IV 10 mg / kg Q2W or fixed 800 Merkel cell carcinoma, mg Q2W urothelial carcinoma Envafolimab Anti-PD-Ll-Fc sc 150 mg weekly or 300 mg Advanced

[0089] fusion Q2W MSI-H / dMMR solid tumors Sugemalimab Anti-PD-Ll mAb IV 1200 mg Q3W NSCLC, ENKTL, gastric cancer (GEMSTONE trials) Adebrelimab Anti-PD-Ll mAb IV 20 mg / kg Q3W or flat 1200 Extensive-stage SCLC mg Q3W (CAPSTONE-1) Cosibelimab Anti-PD-Ll mAb IV 800 mg Q2W Metastatic cutaneous squamous cell

[0090]

[0091] carcinomaPAT060054-PCT-SEC01

[0092] Pembrolizumab Anti-PD-1 mAB IV 200 mg Q3W mCRPC

[0093] Nivolumab Anti-PD-1 mAB IV 240 mg Q2W or equivalent Neuroendocrine tumors / flat dosing NEC, NSCLC, bladder cancer, head & neck cancers Ipilimumab Anti-CTLA-4 mAB IV 3 mg / kg Q3W up to 4 doses Unresectable or metastatic melanoma Quavonlimab Anti-CTLA-4 mAB IV 25-200 mg, Q3W-Q6W Advanced solid tumors (e.g., NSCLC) Tremelimumab Anti-CTLA-4 mAB IV 4 mg / kg x 1 dose, then 20 Hepatocellular (with mg / kg Q4W Carcinoma; NSCLC Durvalumab)

[0094] CA-170 Inhibitor of PD-L 1 , Oral 50 mg QD to 1200 mg BID Advanced solid tumors PD-L2, and VISTA

[0095]

[0096] Chemotherapeutic Agents

[0097] In certain embodiments, the additional therapeutic agent is a chemotherapeutic agent.

[0098] Chemotherapeutic agents are drugs used to treat cancer by targeting and killing rapidly dividing cells, a hallmark of tumors. These agents work through various mechanisms, such as damaging DNA, inhibiting cell division, or interfering with essential metabolic processes. Common classes include alkylating agents, anti-metabolites, topoisomerase inhibitors, and mitotic inhibitors. The class of alkylating agents includes platinum-based compounds such as carboplatin, cisplatin, and oxaliplatin. Topoisomerase inhibitors include, for example, irinotecan, topotecan, etoposide, and doxorubicin.

[0099] In certain embodiments, the chemotherapeutic agent is one or more agents selected from the group consisting of topoisomerase inhibitors, and platinum-based compounds. In one embodiment, the chemotherapeutic agent is a topoisomerase inhibitor and a platinum-based compound. In a particular embodiment, the chemotherapeutic agent is cisplatin and etoposide. The topoisomerase inhibitor (e.g., etoposide) and platinum-based compound (cisplatin) may be administered in the same treatment cycle, but on different days and / or by different routes. For example, the platinum-based compound may be administered intravenously on day 1, and the topoisomerase inhibitor is administered either intravenously or orally, once daily, on days 1-5.PAT060054-PCT-SEC01

[0100] In some embodiments, the immunotherapeutic agent is selected from the agents listed in Table 2.

[0101] Table 2. Exemplary Chemotherapeutic Agents and Combinations

[0102] Agent Route Exemplary Dosage Regimen Exemplary Indication Cisplatin IV 20 mg / m2days 1-5, Q21D; Testicular cancer;

[0103] 70 mg / m2day 1, Q21D; Bladder cancer;

[0104] 100 mg / m2day 1, Q21D x 3; Head & neck (concurrent CRT); 40 mg / m2weekly Cervical cancer (concurrent CRT) Carboplatin IV AUC 5-7 day 1, Q21-28D; Ovarian cancer;

[0105] AUC 5-7 day 1, Q21D NSCLC

[0106] Oxaliplatin IV 85 mg / m2day 1, Q14D Colorectal cancer

[0107] Lobaplatin IV 30 mg / m2day 1, Q21-28D Breast cancer

[0108] Dicycloplatin IV 450 mg / m2IV day 1, Q21d NSCLC

[0109] Cisplatin + IV Cis 75 mg / m2dl SCLC (concurrent CRT) Etoposide Etop 100 mg / m2dl— 3

[0110] Q21-28D

[0111] Cisplatin + IV Cis 80 mg / m2dl NSCLC, Cervical cancer Vinorelbine Vin 25 mg / m2dl ,8

[0112] Q21D

[0113] Cisplatin + IV Cis 70 mg / m2dl (or d2) Bladder cancer, NSCLC, Pancreatic Gemcitabine Gem 1000-1250 mg / m2dl, 8 cancer

[0114] Q21D

[0115] Carboplatin + IV Carbo AUC5 dl SCLC

[0116] Etoposide Etop 100 mg / m2dl— 3

[0117] Q21D

[0118] Carboplatin + IV Carbo AUC5-6 dl NSCLC, Ovarian cancer, Paclitaxel Pac 175 mg / m2dl Endometrial cancer

[0119] Q21D

[0120] Carboplatin + IV Carbo AUC5 dl Non-squamous NSCLC Pemetrexed Pem 500 mg / m2dl

[0121] Q21D

[0122]

[0123] PAT060054-PCT-SEC01

[0124] Cisplatin + IV Cis 75 mg / m2dl Non-squamous NSCLC, Pemetrexed Pern 500 mg / m2dl mesothelioma

[0125] Q21D

[0126] Carboplatin + IV Carbo AUC6; Non-squamous NSCLC Paclitaxel + ac 200 mg / m2

[0127] Bevacizumab Bev 15 mg / kg all dl

[0128] Q21D

[0129] Carboplatin + IV Atezo 1200 mg dl ES-SCLC

[0130] Etoposide + Carbo AUC5 dl

[0131] Atezolizumab Etop 100 mg / m2dl— 3

[0132] Q21D

[0133] Carboplatin + IV Durva 1500 mg dl ES-SCLC

[0134] Etoposide + Carbo AUC5-6 dl;

[0135] Durvalumab Etop 80-100 mg / m2dl— 3

[0136] Q21D

[0137]

[0138] Radiopharmaceutical compounds

[0139] The method for treating cancer provided herein comprises administering to a subject a combination therapy which comprises a radiopharmaceutical compound targeting DLL3. In certain embodiments, the radiopharmaceutical compound is a small molecule, a peptide, or an antibody or fragment thereof. In certain embodiments, the radiopharmaceutical compound comprises a cyclic peptide, wherein the cyclic peptide has an affinity for DLL3. In certain embodiments, the radiopharmaceutical compound comprises a chelator. In certain embodiments, the chelator is conjugated to the cyclic peptide at the N-terminus, at the C-terminus, or at an internal position of the cyclic peptide. In certain embodiments, the chelator is selected from the group consisting of ethylenediamine tetraacetic acid (EDTA), diethylenetriamine pentaacetic acid (DTPA), 1,4, 7, 10-tetra-azacylcododecane-N,N',N",N"' -tetraacetic acid (DOTA), 6-((16-((6-Carboxypyridin-2-yl)methyl)-l ,4, 10, 13-tetraoxa-7, 16-diazacyclooctadecan-7-yl)methyl)-4-isothiocyanatopicolinic acid (Macropa), Macrodipa, 2,2’,2”,2”’-(l,10-dioxa-4,7,13,16-tetraazacyclooctadecane-4,7, 13,16-tetrayl)tetraacetic acid) (Crown), 1 ,4,7, 10- Tetraazacyclododecane-l,4,7,10-tetraacetic acid, a-(2-carboxyethyl) (DOTAGA), 1,4,7-Triazacyclononane-N,N',N"-triacetic acid (NOTA), 1 ,4,7, 10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (TETA), l,4,7,10,13-pentaazacyclopentadecane-N,N’,N”,N”’,N””-pentaaceticPAT060054-PCT-SEC01

[0140] acid (PEPA), Deferoxamine (DFO), 5,11,16,22-Tetraazahexacosanediamide (DFO*), N,N'-1,4-Butanediylbis[N-[3-[[(l,6-dihydro-l-hydroxy-6-oxo-2-pyridinyl)carbonyl]amino]propyl]-l,6-dihydro-l-hydroxy-6-oxo-2-pyridinecarboxamide] (HOPO), and 1,4,7,10,13,16-hexaazacyclohexadecane-N,N’,N”,N”’,N””,N””’ -hexaacetic acid (HEHA). In a particular embodiment, the chelator is DOTA.

[0141] In certain embodiments, the radiopharmaceutical compound comprises a radioisotope selected from the group consisting of:227Th,225Ac,223Ra,213Bi,212Bi,212Pb,211At,203Pb,199Au,188Re,186Re,177Lu,161Tb,153Sm,149Tb,1311,90Y,89Sr,67Cu,64Cu,32P, and47Sc. In a particular embodiment the radiopharmaceutical compound comprises225Ac. In another particular embodiment the radiopharmaceutical compound comprises177Lu.

[0142] In certain embodiments, the radiopharmaceutical compound comprises a compound of Formula (I):

[0143]

[0144] ),

[0145] or a pharmaceutically acceptable salt thereof.

[0146] In certain embodiments, the radiopharmaceutical compound is Compound 1 :PAT060054-PCT-SEC01

[0147]

[0148] or a pharmaceutically acceptable salt thereof.

[0149] In certain embodiments, the radiopharmaceutical compound is Compound 2:

[0150]

[0151] or a pharmaceutically acceptable salt thereof.

[0152] Compounds 1 and 2 are described in international patent publication number WO 2024 / 259147A1, which is incorporated by reference in its entirety.

[0153] Combinations

[0154] In one embodiment of the method disclosed herein, the radiopharmaceutical compound is Compound 1, or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent is an inhibitor of PD-L1. In certain embodiments, the inhibitor of PD-L1 is an anti-PD-Ll antibody.PAT060054-PCT-SEC01

[0155] In another embodiment, the radiopharmaceutical compound is Compound 1, or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent is an inhibitor of PD-1.

[0156] In another embodiment, the radiopharmaceutical compound is Compound 1, or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent is an inhibitor of CTLA-4.

[0157] In another embodiment of the method disclosed herein, the radiopharmaceutical compound is Compound 1 , or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent is a platinum-based compound (e.g., cisplatin) and / or a topoisomerase inhibitor (e.g., etoposide).

[0158] In one embodiment, the radiopharmaceutical compound is Compound 1 and the additional therapeutic agent comprises a platinum-based compound. In one embodiment, the radiopharmaceutical compound is Compound 1 and the additional therapeutic agent comprises cisplatin. In one embodiment, the radiopharmaceutical compound is Compound 1 and the additional therapeutic agent comprises carboplatin. In one embodiment, the radiopharmaceutical compound is Compound 1 and the additional therapeutic agent comprises oxaliplatin. In one embodiment, the radiopharmaceutical compound is Compound 1 and the additional therapeutic agent comprises lobaplatin. In one embodiment, the radiopharmaceutical compound is Compound 1 and the additional therapeutic agent comprises dicycloplatin.

[0159] In another embodiment, the radiopharmaceutical compound is Compound 1 and the additional therapeutic agent comprises a toposimerase inhibitor. In another embodiment, the radiopharmaceutical compound is Compound 1 and the additional therapeutic agent comprises etoposide. In another embodiment, the radiopharmaceutical compound is Compound 1 and the additional therapeutic agent comprises topotecan. In another embodiment, the radiopharmaceutical compound is Compound 1 and the additional therapeutic agent comprises doxorubicin.

[0160] In another embodiment, the radiopharmaceutical compound is Compound 1 and the additional therapeutic agent comprises a PD-1 inhibitor. In another embodiment, the radiopharmaceutical compound is Compound 1 and the additional therapeutic agent comprises nivolumab. In another embodiment, the radiopharmaceutical compound is Compound 1 and the additional therapeutic agent comprises pembrolizumab. In another embodiment, thePAT060054-PCT-SEC01

[0161] radiopharmaceutical compound is Compound 1 and the additional therapeutic agent comprises cemiplimab. In another embodiment, the radiopharmaceutical compound is Compound 1 and the additional therapeutic agent comprises toripalimab. In another embodiment, the radiopharmaceutical compound is Compound 1 and the additional therapeutic agent comprises and tislelizumab.

[0162] In another embodiment, the radiopharmaceutical compound is Compound 1 and the additional therapeutic agent comprises a PD-L1 inhibitor. In another embodiment, the radiopharmaceutical compound is Compound 1 and the additional therapeutic agent comprises atezolizumab. In another embodiment, the radiopharmaceutical compound is Compound 1 and the additional therapeutic agent comprises durvalumab. In another embodiment, the radiopharmaceutical compound is Compound 1 and the additional therapeutic agent comprises avelumab. In another embodiment, the radiopharmaceutical compound is Compound 1 and the additional therapeutic agent comprises envafolimab.

[0163] In another embodiment, the radiopharmaceutical compound is Compound 1 and the additional therapeutic agent comprises a CTLA-4 inhibitor. In another embodiment, the radiopharmaceutical compound is Compound 1 and the additional therapeutic agent comprises ipilimumab. In another embodiment, the radiopharmaceutical compound is Compound 1 and the additional therapeutic agent comprises tremelimumab. In another embodiment, the radiopharmaceutical compound is Compound 1 and the additional therapeutic agent comprises quavonlimab.

[0164] Administration and Dosage

[0165] In some embodiments of the method disclosed herein, the radiopharmaceutical compound is administered intravenously.

[0166] In some embodiments of the method disclosed herein, the additional therapeutic agent is administered orally, subcutaneously, and / or intravenously. In one embodiment, the additional therapeutic agent is administered orally. In another embodiment, the additional therapeutic agent is administered subcutaneously. In another embodiment, the additional therapeutic agent is administered intravenously. In another embodiment, the additional therapeutic agent is more than one therapeutic agent, and each therapeutic agent is administered by the same, or by different, routes of administration.PAT060054-PCT-SEC01

[0167] In some embodiments, the additional therapeutic agent and the radiopharmaceutical compound are administered simultaneously. In some embodiments, the additional therapeutic agent and the radiopharmaceutical compound are administered concurrently. In some embodiments, the additional therapeutic agent and the radiopharmaceutical compound are administered sequentially.

[0168] In some embodiments, the administration of the additional therapeutic agent commences prior to the administration of the radiopharmaceutical compound. In some embodiments, the administration of the radiopharmaceutical compound commences prior to the administration of the additional therapeutic agent.

[0169] In some embodiments, the radiopharmaceutical compound is administered to the subject once every 2 weeks to once every 10 weeks. For example, the radiopharmaceutical compound (e.g., Compound 1) may be administered to the subject once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, or once every 10 weeks. In a particular embodiment, the radiopharmaceutical compound is administered to the subject once every 6 weeks.

[0170] The radiopharmaceutical compound may be administered for 1 or more cycles. For example, the radiopharmaceutical compound may be administered for 1 cycle, for 2 cycles, for 3 cycles, for 4 cycles, for 5 cycles, for 6 cycles, for 7 cycles, for 8 cycles, for 9 cycles, or for 10 cycles. In a particular embodiment, the radiopharmaceutical compound is administered for 4 cycles.

[0171] In some embodiments, the additional therapeutic agent is administered to the subject once every 2 weeks to once every 10 weeks.

[0172] In some embodiments, the total dose (over the course of a treatment regimen) of the radiopharmaceutical compound comprising an a-emitter, e.g.,225Ac, is from about 1 MBq to about 100 MBq, e.g., about 4 MBq to about 80 MBq, e.g., about 5 MBq to about 77 MBq, e.g., about 5 MBq, about 6MBq, about 8 MBq, about 10 MBq, about 13 MBq, and about 76 MBq . In some embodiments, the radiopharmaceutical compound comprising an a-emitter is administered in a total dose of from about 20 to about 80 MBq of radiation. In some embodiments, the radiopharmaceutical compound comprising an a-emitter, e.g.,225Ac, is administered in a single dose (once within a 24-hour period) to deliver from about 1 to about 40 MBq of radiation. In some embodiments, the radiopharmaceutical compound comprising an a-emitter e.g.,225Ac, isPAT060054-PCT-SEC01

[0173] administered in a single dose (once within a 24-hour period) to deliver from about 5 to about 40 MBq of radiation. In some embodiments, the radiopharmaceutical compound comprising an a-emitter e.g.,225Ac, is administered in a single dose (once within a 24-hour period) to deliver from about 5 to about 25 MBq of radiation. In some embodiments, the radiopharmaceutical compound comprising an a-emitter e.g.,225Ac, is administered in a single dose (once within a 24-hour period) to deliver from about 2 to about 6 MBq of radiation, for example, about 2 MBq, about 3 MBq, about 4 MBq, about 5 MBq, or about 6 MBq of radiation.

[0174] In some embodiments of the method disclosed herein, the radiopharmaceutical compound comprises225Ac and has a specific molar activity in the range of 60-13200 pCi per nmol compound. In an embodiment, the radiopharmaceutical compound comprising225Ac (e.g., Compound 1) has a specific molar activity in the range of 60-13000 pCi per nmol compound. In certain embodiments, for example, the radiopharmaceutical compound comprising225Ac has a specific molar activity in the range of 60-500 pCi per nmol compound, 500-1000 pCi per nmol compound, 1000-2000 pCi per nmol compound, 2000-3000 pCi per nmol compound, 3000-4000 pCi per nmol compound, 4000-5000 pCi per nmol compound, 5000-6000 pCi per nmol compound, 6000-7000 pCi per nmol compound, 7000-8000 pCi per nmol compound, 8000-9000 pCi per nmol compound, 9000-10000 pCi per nmol compound, 10000-11000 pCi per nmol compound, 11000-12000 pCi per nmol compound, or 12000-13000 pCi per nmol compound.

[0175] In some embodiments, the radioisotope is225Ac and the total activity of the radiopharmaceutical compound is in the range of 0.01-5 mCi, for example, 0.1-5 mCi, 1-5 mCi, 2-5 mCi, 3-5 mCi, 4-5 mCi, 0.01-4 mCi. 0.1-4 mCi, 1-4 mCi, 2-4 mCi, 3-4 mCi, 0.01-3 mCi. 0.1-3 mCi, 1-3 mCi, 2-3 mCi, 0.01-2 mCi. 0.1-2 mCi, 1-2 mCi, 2-3, 0.01-1 mCi, or 0.1-1 mCi.

[0176] In some embodiments of the method disclosed herein, the additional therapeutic agent is a PD-1 inhibitor and is administered to the subject once every 2-6 weeks (e.g., once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks) at a dose in the range of 100 mg to 1000 mg (e.g., about 100 mg, about 200 mg, about 300 mg, about 400 g, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg).

[0177] In some embodiments of the method disclosed herein, the additional therapeutic agent is a PD-L1 inhibitor and is administered to the subject once every 2-6 weeks (e.g., once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks) atPAT060054-PCT-SEC01

[0178] a dose in the range of 400 mg to 2000 mg (e.g., about 400 mg, about 500 mg, about 600 mg, about 700 g, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, or about 2000 mg).

[0179] In some embodiments of the method disclosed herein, the additional therapeutic agent is a CTLA-4 inhibitor and is administered to the subject once every 2-6 weeks (e.g., once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks) at a dose in the range of 100 mg to 1000 mg (e.g., about 100 mg, about 200 mg, about 300 mg, about 400 g, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg).

[0180] In some embodiments of the method disclosed herein, the additional therapeutic agent comprises a platinum-based compound (e.g., cisplatin) which is administered to the subject once every 2-4 weeks (e.g., once every 2 weeks, once every 3 weeks, or once every 4 weeks) at a dose in the range of 50-100 mg / m2(e.g., about 50 mg / m2, about 60 mg / m2, about 70 mg / m2, about 80 mg / m2, about 90 mg / m2, or about 100 mg / m2).

[0181] In some embodiments of the method disclosed herein, the additional therapeutic agent comprises a topoisomerase inhibitor (e.g., etoposide) which is administered to the subject once every 2-6 weeks (e.g., once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks) at a dose in the range of 50-400 mg / m2(e.g., about 50 mg / m2, about 100 mg / m2, about 150 mg / m2, about 200 mg / m2, about 300 mg / m2, or about 400 mg / m2).

[0182] In some embodiments, administration of the additional therapeutic agent is characterized by a route and dosage regimen according to Table 1 or Table 2.

[0183] Pharmaceutical Compositions

[0184] In some embodiments, the radiopharmaceutical compound is formulated to exhibit improved properties such as radiochemical stability and radiochemical purity. In some embodiments of the methods disclosed herein, the radiopharmaceutical compound is formulated and administered in the form of a pharmaceutical composition comprising ascorbic acid, or a pharmaceutically acceptable salt thereof, and a polysorbate.

[0185] In some embodiments, the polysorbate is present in the pharmaceutical composition in an amount of <1 mg / mL, optionally 0.3-0.7 mg / mL, optionally 0.4-0.6 mg / mL, optionally about 0.5PAT060054-PCT-SEC01

[0186] mg / mL. In some embodiments, the polysorbate is polyoxyethylene (20) sorbitan monolaurate, optionally wherein the polyoxyethylene (20) sorbitan monolaurate is present in the pharmaceutical composition in an amount of about 0.1 mg / mL to about 1 mg / mL.

[0187] In some embodiments, the mass ratio of ascorbic acid or a pharmaceutically acceptable salt thereof to polysorbate in the pharmaceutical composition is from 50:1 to 150:1, optionally from 80:1 to 120:1, optionally about 100:1.

[0188] In some embodiments, the ascorbic acid or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount of <100 mg / mL, optionally <80 mg / mL, optionally from 30-70 mg / mL, optionally from 40-60 mg / mL, optionally about 50 mg / mL.

[0189] In some embodiments, the pharmaceutical composition further comprises one or more components selected from the group consisting of ethanol, L-methionine, and acetic acid or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition comprises L-methionine, optionally wherein the L-methionine is present in the pharmaceutical composition in a concentration of about 10 mg / mL to about 30 mg / mL. In another embodiment, the pharmaceutical composition comprises acetic acid or a pharmaceutically acceptable salt thereof, optionally wherein the acetic acid or pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in a concentration of about 0.01 M to about 0.15 M. In another embodiment, the pharmaceutical composition comprises ethanol, optionally wherein the ethanol is present in the pharmaceutical composition in an amount of about 1% (v / v) to about 15% (v / v), optionally wherein the ethanol is present in the pharmaceutical composition in an amount of about 5% (v / v) to about 10% (v / v).

[0190] In a particular embodiment, the pharmaceutical composition comprises ethanol, L-methionine, polyoxyethylene (20) sorbitan monolaurate, sodium ascorbate, and ammonium acetate, e.g., in the absolute and / or relative amounts as described herein. In an embodiment, the pharmaceutical composition further comprises di ethylenetriaminepentaacetic acid (DTPA).

[0191] Lurther pharmaceutical compositions and formulations are described in WO

[0192] 2025 / 122615 Al, which is incorporated herein by reference in its entirety.

[0193] In another aspect, provided herein is a pharmaceutical composition comprising a radiopharmaceutical compound targeting DLL3 and an additional therapeutic agent selected from the group consisting of an immunotherapeutic agent, a chemotherapeutic agent, and combinations thereof. In one embodiment, the additional therapeutic agent is an immunePAT060054-PCT-SEC01

[0194] checkpoint inhibitor. In another embodiment, the additional therapeutic agent is a platinum-based compound and / or a topoisomerase inhibitor. In yet another embodiment, the additional therapeutic agent is a combination comprising an immune checkpoint inhibitor, and a platinumbased compound and / or a topoisomerase inhibitor.

[0195] Listed Embodiments

[0196] 1. A method for treating a cancer characterized by upregulated surface expression of DLL3 in a subject in need thereof, comprising administering to the subject a combination therapy which comprises a radiopharmaceutical compound targeting DLL3 and an additional therapeutic agent selected from the group consisting of an immunotherapeutic agent, a chemotherapeutic agent, and combinations thereof.

[0197] 2. The method of Embodiment 1 , wherein the cancer is a neuroendocrine neoplasm.

[0198] 3. The method of Embodiment 1 or 2, wherein the cancer is small cell lung cancer (SCLC).

[0199] 4. The method of Embodiment 1 or 2, wherein the cancer is neuroendocrine prostate cancer (NEPC).

[0200] 5. The method of Embodiment 1 or 2, wherein the cancer is large cell neuroendocrine carcinoma (LCNEC).

[0201] 6. The method of Embodiment 1 or 2, wherein the cancer is gastroenteropancreatic neuroendocrine tumor (GEP-NET).

[0202] 7. The method of Embodiment 1 , wherein the cancer is a non- neuroendocrine neoplasm. 8. The method of Embodiment 7, wherein the cancer is melanoma.

[0203] 9. The method of any one of Embodiments 1-8, wherein the immunotherapeutic agent is an immune checkpoint inhibitor.

[0204] 10. The method of Embodiment 9, wherein the immune checkpoint inhibitor is a small molecule, antibody or biologically active fragment thereof, fusion protein, or therapeutic oligonucleotide.

[0205] 11. The method of Embodiment 10, wherein the immune checkpoint inhibitor is an inhibitor of PD-1, PD-L1, or CTLA-4.

[0206] 12. The method of Embodiment 11, wherein the immune checkpoint inhibitor is a PD-1 inhibitor.PAT060054-PCT-SEC01

[0207] 13. The method of Embodiment 11, wherein the immune checkpoint inhibitor is a PD-L1 inhibitor.

[0208] 14. The method of Embodiment 11, wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor.

[0209] 15. The method of any one of Embodiments 1-8, wherein the chemotherapeutic agent is one or more agents selected from the group consisting of topoisomerase inhibitors, and platinumbased compounds.

[0210] 16. The method of Embodiment 1, wherein the radiopharmaceutical compound comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0211] 17. The method of Embodiment 16, wherein the radiopharmaceutical compound further comprises a radioisotope selected from the group consisting of:227Th,225Ac,223Ra,213Bi,212Bi,212Pb,211At,203Pb,199AU,188Re,186Re,177Lu,161Tb,153Sm,149Tb,1311,90Y,89Sr,67Cu,64Cu,32P, and47Sc.

[0212] 18. The method of Embodiment 16, wherein the radiopharmaceutical compound is Compound 1, or a pharmaceutically acceptable salt thereof.

[0213] 19. The method of any one of Embodiments 1-18, wherein the additional therapeutic agent is an inhibitor of PD-L1 and the radiopharmaceutical compound is Compound 1.

[0214] 20. The method of Embodiment 19, wherein the inhibitor of PD-L1 is an anti-PD-Ll antibody.

[0215] 21. The method of any one of Embodiments 1-18, wherein the additional therapeutic agent is a platinum-based compound and / or a topoisomerase inhibitor.

[0216] 22. The method of any one of Embodiments 1-21, wherein the additional therapeutic agent is administered orally, subcutaneously, and / or intravenously.

[0217] 23. The method of any one of Embodiments 1-22, wherein the radiopharmaceutical compound is administered intravenously.

[0218] 24. The method of any one of Embodiments 1-23, wherein the additional therapeutic agent and the radiopharmaceutical compound are administered simultaneously.

[0219] 25. The method of any one of Embodiments 1-23, wherein the additional therapeutic agent and the radiopharmaceutical compound are administered concurrently.

[0220] 26. The method of any one of Embodiments 1-23, wherein the additional therapeutic agent and the radiopharmaceutical compound are administered sequentially.PAT060054-PCT-SEC01

[0221] 27. The method of any one of Embodiments 1 -26, wherein administration of the additional therapeutic agent commences prior to administration of the radiopharmaceutical compound. 28. The method of any one of Embodiments 1-26, wherein administration of the radiopharmaceutical compound commences prior to administration of the additional therapeutic agent.

[0222] 29. The method of any one of Embodiments 1 -28, wherein the radiopharmaceutical compound comprises225Ac and is administered at a total dosage in the range of 1 MBq to about 100 MBq.

[0223] 30. The method of any one of Embodiments 1-29, wherein the radiopharmaceutical compound comprises225Ac and has a specific molar activity in the range of 60-13200 pCi per nmol compound.

[0224] 31. The method of any one of Embodiments 1 -30, wherein the radiopharmaceutical compound is administered to the subject once every 2 weeks to once every 10 weeks.

[0225] 32. The method of any one of Embodiments 1-31, wherein the additional therapeutic agent is administered to the subject once every 2 weeks to once every 10 weeks.

[0226] 33. The method of any one of Embodiments 1-32, wherein the radiopharmaceutical compound is administered in the form of a stabilized composition comprising ascorbic acid, or a pharmaceutically acceptable salt thereof, and a polysorbate.

[0227] 34. A pharmaceutical composition comprising a radiopharmaceutical compound targeting DLL3 and an additional therapeutic agent selected from the group consisting of an immunotherapeutic agent, a chemotherapeutic agent, and combinations thereof.

[0228] 35. The pharmaceutical composition of Embodiment 34, wherein the additional therapeutic agent is an immune checkpoint inhibitor.

[0229] 36. The pharmaceutical composition of Embodiment 34, wherein the additional therapeutic agent is a platinum-based compound and / or a topoisomerase inhibitor.

[0230] 37. The pharmaceutical composition of Embodiment 34, wherein the additional therapeutic agent is a combination comprising an immune checkpoint inhibitor, and a platinum-based compound and / or a topoisomerase inhibitor.PAT060054-PCT-SEC01

[0231] EXAMPLES

[0232] Example 1. Efficacy evaluation of Compound 1 and anti-mPD-Ll against CT26 XXX murine colorectal carcinoma in female BALB / c mice.

[0233] The purpose of this study was to evaluate the anti-cancer efficacy of Compound 1 and anti-mPD-Ll against established subcutaneous engineered CT26 XXX murine colorectal carcinoma in a female Balb / c mice. “XXX” indicates that the cell line was engineered to express human DLL3. Such cells have a DLL3 surface density (copies per cell) of 12,326 ± 3566, as compared to a DLL3 surface density of 67 for CR26.WT cells. There were no deaths or body weight loss in the treatment window in the Control Group (Group 1). There was one death in the treatment window (10.0% incidence) and -2.4% mean body weight change in the treatment window in mice treated with Compound 1 at 0.25 pCi and anti-mPD-Ll (Clone 10F.9G2) (Group 5). All other treatments were tolerated, producing no deaths or body weight loss in the treatment window. Several animals in Group 4 and one animal in Groups 5 and 6 were noted with abnormally decreased activity immediately following the anti-mPD-Ll (Clone 10F.9G2) dose on Day 18 or Day 21, indicating the potential for antibody sensitivity. There was a 10.0% incidence of tumor-free survivors (TFS) in the Control Group, likely due to variable disease progression.

[0234] Treatment with the Vehicle and anti-mPD-Ll (Clone 10F.9G2) (Group 4) produced a 40.0% incidence of complete regressions and TFS.

[0235] Treatment with Compound 1 at 0.25 pCi / animal and isotype control (Clone LTF-2) (Group 2) or with Compound 1 at 0.25 pCi / animal or 0.125 pCi / animal and anti-mPD-Ll (Clone 10F.9G2) (Groups 5 and 6, respectively) produced CR incidences ranging from 60.0% to 90.0% and incidences of TFS ranging from 50.0% to 70.0%. Combination therapy produced greater incidences of CRs and TFS when compared to the respective monotherapy groups.

[0236] Treatment with Compound 1 at 0.125 pCi / animal and isotype control (Clone LTF-2) (Group 3) produced a 28.5% incidence of TFS (2 of 7 animals).

[0237] Materials and Methods

[0238] Compound 1:

[0239] • Physical description: Clear, colorless solution

[0240] • Concentration: 1.25 pCi / mLPAT060054-PCT-SEC01

[0241] • Storage (stock) Ambient temperature

[0242] • Vehicle: Formulation buffer

[0243] • High Dose Formulation: 1.25 pCi / mL

[0244] • Formulation pH: 6.0

[0245] • Dose volume: 200 pL / animal

[0246] • Comments: The radiochemical purity (RCP) was 94.56% at the end of synthesis. The concentration of the stock solution was corrected for radioactive decay from the time of original calibration to the time of dosing. The lower dose formulation (0.125 pCi / animal) was dosed at 100 pL / animal.

[0247] Table 1-1. Isotype control (Clone LTF-2)

[0248] Supplier Bio X cell Lot / Cataicg S? 915223J3C / BPOOSO Date received October 17, 2024 Physical description Clear, colorless solution Concentration 9.98 mg / ml Storage (stock; 4T . | Molecular NA Molecular weight / NA / bA

[0249] Formula Formula weight

[0250] Purity Parent NA

[0251] Vehicle DABS High Doss 1.0 mg / mL

[0252] Formulation

[0253] Formulation pH 7 Stability 1 week

[0254] Formulation Clear, colorless solution Formulation Storage Maintained on wet ice Description during preparation and dosing; discarded after use Dose volume 0.01 mt / g Dose expressed as Vendor indicated

[0255]

[0256] concentration (unsorrected) iPAT060054-PCT-SEC01

[0257] Table 1-2. Anti-mPD-Ll (Clone 10F.9G2)

[0258] Supplier Bis X Cell Lot / Catalog A

[0259] Date received October 17,. 2024 Physical description Clear, solo dess solution Concentration 9,85 mg / ml Storage (stock) 4VC

[0260] Molecular NA Molecular weight / NA, NA

[0261] formula Formula weight

[0262] Purity 97 Parent NA

[0263] Vehicle DPSS High dote formulation 1.0 e j 'n L Formulation pH 7.1 Stability 1 week

[0264] Formulation Clear. r.cloriess solution Formulation storage Maintained on wet Ice description during preparation sod dosrn^ dhtarced ?ntefuse Dose volume 0.01 ml / g Dose expressed as Vendor mcife-siU'd

[0265] concentration

[0266]

[0267] (uncorrected)

[0268] All procedures carried out in this experiment were conducted in compliance with the applicable laws, regulations, and guidelines of the National Institutes of Health (NIH) and with the approval of Labcorp Discovery Oncology’s Animal Care and Use Committee. Labcorp (Ann Arbor) is an AAALAC accredited facility.

[0269] Table 1-3. Animals and Husbandry

[0270] Spades Mouse Sax Female

[0271] Source inotlv (Envigo) Barrier 2.DSA

[0272] Strain BAlB / c (BALB / cAnNHsd)

[0273] Age at implant 7-8 weeks On study / lotsl 60 / 120

[0274] Diet Teklad 2918 Rodent Diet Water innovive acidified water

[0275] ard (pH 25-3.9), t?d ijbstym Supplements Hydrogel provided at >I£As Acclimation 6 days

[0276] body weight loss

[0277] Housing innovive dispussbie An^nais / cage 5 or fewer

[0278] ventilated caging with corn

[0279] cob bedding Inside

[0280]

[0281] Biobubble® Clean RoomsPAT060054-PCT-SEC01

[0282] I am para sc re ?0>?T Lght cycle ' <" ? hm -r

[0283] Hurnsdity 3Q-7W ID methoc Ear punch

[0284] Meas<x e d / wsek Weigh frequency 3 / week

[0285] frequency

[0286] Staged fey Calipers Minimum 16.9 g

[0287] individual weight

[0288] (Dll)

[0289] Overall mesn 20.2 g Overall mean 196 mm5

[0290] body weight tumor burden

[0291] (DLL) (Dll)

[0292] Necropsy Yes Health checks 2? lx

[0293] Euthanasia Study termination, >2000 mmstumor burden and >20% body weight loss

[0294]

[0295] cf:ier:a

[0296] Table 1-4. Cell Preparation / Implantation

[0297] Morses •'T26 x / X Histatype i Murine colorectal carcinoma Source Mariana Oncology, inc Implant type i Cells

[0298] Media RPMI 1640 medium, Dissociation:F f uvess Enzyme (LX),

[0299] 10% non-heaWnsctlvated 17BS< sofotkm ; no phenol red 1% peoidllin-strepiQmydn- L-glutamine

[0300] Route / lscatic n Subcutaneous / Right axilla (high)

[0301] j noculum 5.00E+05 trypan-excluding cells implant media i Serum-free RPMI 1540

[0302] 1 medium

[0303] Extra cellular 5W Injection volume i 200 pl

[0304] matrix

[0305] Viability (pre) VishiUty (post) i

[0306] Comments H-Tlb XXX Is an engineered cel! line that expresses ti ' t t t of interest.

[0307] Ail thiogiyccslate cultures of ceils used for imphntsticsn were negative for grass

[0308]

[0309] bacterial contamination.PAT060054-PCT-SEC01

[0310] Table 1-5. Study Groups

[0311] Group Treatment Dose PDA Regimen Treatment dayis) 1 w VebiGe 200 pl / lnjection i IV ; QDxl 11. :

[0312] Isotype contra I W mg / kg i IF i (Q3Dx2, 3 11, .14, 18, 21 (Gans LTF-2) i days ©if) x 2

[0313] 3 Compound 1 O,25^G / animal i iV : QDxl 11

[0314] isotype control 10 mg / kg i IF i (Q3Dx2, 3 11, 14., M 21 (done LTF-2| i days off] x 2

[0315] 3 r Campound "I 0,125 pG / animal i IV i QDxi 11

[0316] isatype control lO mg / kg 1 IP i (Q30x2, 3 11, 14, M 21 (Ctons LTF-2) i days off) x 2

[0317] 4 IS Vehicle 200 pl / lnfection ; IV i QDxl 11

[0318] ents-mPD-ll 10 mg / kg i IP (Q3Dx2, 3 11, 14., IS. 21 (Choe I0F.FG2] : days off] x 2

[0319] 5 w Caftqrottnd 1 0,25pG / animal i IV : QDxl 11

[0320] anti-mPD-ll 10 mg / kg i IP (030x2. 3 11, 14, 18, 21 (dsns W.9S21 : days off] x 2

[0321] S w 0.125 pCi / animal i IV i QDxi 11

[0322] anti-mPD-ll IP mg / kg : IP : (CBDxX 3 11, 14, IS. 21 (Gone WAG2} i days off] x 2

[0323] Comments ’ nor- -'{AM doses were administered prior to RAPP dores.

[0324] •‘Group 3 Mice § (male) end Mice 4 and 7 (pregnant femalesl were euthanized nrisr to

[0325]

[0326] the completion of the prescribed dosing regimen.

[0327] Results

[0328] Study validation: The mean estimated tumor burden for all groups in the experiment on the first day of treatment was 196 mm3. All animals weighed at least 16.9 g at the initiation of therapy with an overall mean body weight of 20.2 g. Tumor burden and body weights for all groups in the experiment were well-matched (within 10% of overall mean). Tumor growth kinetics and parameters (clinical signs, body weight change, and time on study) in the Control Group (Group 1) were within historical norms.PAT060054-PCT-SEC01

[0329] Table 1-6: Group Tolerance and Response

[0330] Median AT / Increase in

[0331] Weight Deaths AC Regression Time to Partial Complete Tumor-free Group change Regression Regression

[0332] Day 25 (%) Day 25 (%) Progression Survivors (%) (%) (%)

[0333] (%) (%) (%)

[0334] 1 12.3 0.0 NA NA NA 0.0 10.0 10.0 2 6.8 0.0 NA 80.0 >136.8 10.0 60.0 50.0 3 8.0 0.0 35.9 NA 15.7 0.0 28.5 28.5 4 7.2 0.0 15.7 NA 78.9 0.0 40.0 40.0 5 -2.4 10.0 NA 80.4 >136.8 0.0 90.0 70.0 6 4.7 0.0 NA 93.5 >136.8 0.0 70.0 60.0

[0335]

[0336] Example 2. Efficacy evaluation of Compound 1 alone or in combination with etoposide and cisplatin against established subcutaneous SHP-77 human small cell lung carcinoma in female nude mice.

[0337] The purpose of this study was to evaluate the anti-cancer efficacy of Compound 1 against established SHP-77 human small cell lung cancer (DLL3 surface density of 3,466 ± 1,331) in female nude mice. Treatment in Groups 1-4 was tolerated, producing incidences of deaths in the treatment window ranging from 0.0% to 10.0% and mean body weight change in the treatment window ranging from -12.3% to 3.1%. In Group 4, body weight loss nadir occurred on Day 17 and showed signs of recovery reaching a final weight loss of -5.1% by Day 31. Treatment with Compound 1 in combination with cisplatin (CDDP) and etoposide (Group 5) produced a 20.0% incidence of deaths and -14.6% mean body weight change in the treatment window. Similar to Group 4, mean body weight loss nadir in this group was reached on Day 17, but moderate to severe group body weight loss (=10%) persisted through Day 28 before notable recovery occurred.

[0338] Treatment with Compound 1 alone at 1.0 pCi / animal or 0.25 pCi / animal (Groups 2 and 3, respectively) produced anti-cancer activity in a dose dependent manner. Treatment in Groups 2 and 3 produced a Day 26 regression value of 12% (Group 2) or Day 26 median .T / .C value of 6% (Group 3) and increase in time to progression (ITP) values of >141.6%. There was a 90.0% incidence of tumor-free survivors (TFS) in Group 2, and a 10.0% incidence of partial regression (PR) in Group 3.PAT060054-PCT-SEC01

[0339] Treatment with cisplatin (CDDP) and etoposide (Group 4) produced a Day 26 median .T / .C value of 61% and an ITP value of 41.6%. There were no tumor regressions. The addition of treatment with Compound 1 at 0.25 pCi / animal (Group 5) produced greater anti-cancer activity than Group 3 or Group 4. Treatment in Group 5 produced a Day 26 median .T / .C value of 0%, an ITP value of >141.6%, and 20.0% incidence of TFS. All groups treated with Compound 1 exhibited extended survival as demonstrated by the ITP values of >141.6%.

[0340] Treatment with Compound 1 at 1.0 pCi induced sustained tumor regression and prolonged survival and that a low dose (0.25 pCi) of Compound 1 administered in combination with standard of care (SOC) agents was superior to either respective treatment alone.

[0341] Materials and Methods

[0342] i. Compound 1.

[0343] o Physical description: Clear, colorless solution

[0344] o Concentration: 4.85 pCi / mL

[0345] o Storage (stock) Ambient temperature

[0346] o Vehicle: Formulation buffer (70 mg / mL sodium ascorbate, 10.5 mg / mL L- methionine, 37.92 mM ammonium acetate, 5.25 % (v / v) ethanol, 0.44 % (w / v) saline, 0.05 % (w / v) Tween-20, 0.05 mg / mL DTPA)

[0347] o High Dose Formulation: 4.85 pCi / mL

[0348] o Formulation pH: 6.0

[0349] o Dose volume: Group 2: 200 pL / animal; Groups 3, 5: 50 pL / animal

[0350] ii. Etoposide was purchased from Selleck Chemicals (Lot / Catalog number S122511 / S1225) iii. Cisplatin was purchased from Fischer Scientific (Lot / Catalog number 6A / 287253 / 22- 515-0)

[0351] All procedures carried out in this experiment were conducted in compliance with the applicable laws, regulations, and guidelines of the National Institutes of Health (NIH) and with the approval of Labcorp Preclinical Oncology (PCO)’s Animal Care and Use Committee.

[0352] Labcorp (Ann Arbor) is an AAALAC accredited facility.PAT060054-PCT-SEC01

[0353] Table 2-1. Animals and Husbandry

[0354] SpecierMouse ■^ex Female

[0355] Somxe Envigo Baitiei •71: 7

[0356] am N oude (Hsd Athysmc N«de-F<

[0357] Ase ar implant 6-7 H- wj r- ssfe 0ti Stuih Tul.il 5G7S8

[0358] Diet Teklsdj h* 2918 Rodent Diet Ware i Imiavsve acidified v / ater

[0359] <K( (pM 2 ^-3 0), <?y? Supplements Hydrogel provided at >10% Acclimation ' d" VS

[0360] body weight loss

[0361] Housing hmovive disposable Animals cage 5 or fewer

[0362] ventilated caging with can

[0363] cob bedding inside

[0364] Biobtibble® Clean Rooms

[0365] Tempei ature Licht cscle 12 / 12 hour

[0366] Humidity 30-70% ID method Esr punch

[0367] Measure SAveek Weigh frequency 3.:'week

[0368] fi equenc v

[0369] Staged by Calipers Minimum 19.1 g

[0370] iudhidual weight

[0371] iD12s

[0372] Overall mean 22 >5 S' Overall mean 201 mm;'

[0373] body weight rumor burden

[0374] (DI 2 J iD12s

[0375] Ye< rnpsy Yes Health C heck1; Daily

[0376] Euthanasia Shady termination, Y2&00 aw r' tumor burden and 1 '20% body weight loss

[0377]

[0378] ci tteiia

[0379] Table 2-2. Cell Preparation / Implantation

[0380] Model SHP-77 Histotype Human small cell lung csrcmsma

[0381] *50111 ce ATCC Implant type Cells

[0382] Media RFME 1640 medium. Dissociation XA

[0383] 0.25% glucose, soiuticm

[0384] 1 mM Na pyruvate,

[0385] 1G fflM HEPES,

[0386] H.15. :ion-heat-hiaeth’3ted FBS,

[0387] 1% pensallin-strepiomycin- L-gltsfsmine

[0388] Route.Locatkm Subcufeneou^Riahi axilla (lush)

[0389] Inoculum 5.00 E>06 trypan-excluding Implant media •serum-free RPMI 1640

[0390] cells medium

[0391] Extra cellular 50% Injection Volume 208 pL

[0392] manix

[0393] Viability (pre) 88% Viability (post) 91%

[0394] C nmuwnts All feicslycoiate cultures of cells used for implantation were negative for gross

[0395]

[0396] bacfenstl coistamiaatiois.PAT060054-PCT-SEC01

[0397] Table 2-3. Study Groups

[0398] Group N Treatment Dose ROA Regimen Treatment Day(s)

[0399] 1 10 Vehicle 0.2 mL / 20 g IV QDxl 13

[0400] 2 10 Compound 1 1 IV QDxl (High 13

[0401] pCi / animal dose)

[0402] 3 10 Compound 1 0.25 IV QDxl (Low 13

[0403] gCi / animal dose)

[0404] 4 10 cisplatin (CDDP) 2.5 mg / kg IP QDxl 13

[0405] etoposide 3.5 mg / kg IP QDx3 13, 14, 15 5 10 cisplatin (CDDP) 2.5 mg / kg IP QDxl 13

[0406] etoposide 3.5 mg / kg IP QDx3 13, 14, 15 Compound 1 0.25 IV QDxl (Low 13

[0407] pCi / animal dose)

[0408] Comments The Vehicle, cisplatin (CDDP), and Compound 1 were administered as single doses on Day 13.

[0409] Etoposide was administered once daily on three consecutive days beginning on Day 13 and ending on Day 15.

[0410] Administration of the standard of care agents was completed prior to

[0411]

[0412] administration of Compound 1.

[0413] Results

[0414] Study validation: The mean estimated tumor burden for all groups in the experiment on the day prior to the first day of treatment was 201 mm3. All animals weighed at least 19.1 g on the day prior to the initiation of therapy with an overall mean body weight of 22.5 g. Tumor burden and body weights for all groups in the experiment were well-matched (within 10% of overall mean). Tumor growth kinetics and parameters (clinical signs, body weight change, and time on study) in the Control Group (Group 1) were within historical norms.

Claims

PAT060054-PCT-SEC01Table 2-4. Group Tolerance and Response SummaryMedian AT / Increase inWeight Deaths AC Regression Time to Partial Complete Tumor-free Group change Regression RegressionDay 25 (%) Day 25 (%) Progression Survivors (%) (%) (%)(%) (%) (%)1 3.1 0.0 NA NA NA 0.0 0.0 0.0 2 -8.9 10.0 NA 12 >141.6 0.0 90.0 90.0 3 -5.7 0.0 6 NA >141.6 10.0 0.0 0.0 4 -13.1 10.0 61 NA 41.6 0.0 0.0 0.0 5 -14.6 20.0 0 NA >141.6 10.0 20.0 20.0Example 3. IHC Detection and Quantification of DLL3 Expression in Tumor Tissue Tumor samples (4- pm thick sections mounted on positively charged glass slides) are assessed for DLL3 expression by IHC using a standardized Ventana platform assay (clone SP347, Ventana, Roche, Tucson, AZ). DLL3 expression is quantified on the basis of estimation of the percentage of positive tumor cells (range, 0%-100%) multiplied by staining intensity (weak: 1+, moderate: 2+, strong: 3+) to generate an H-score (range, 0-300). Positive DLL3 expression is found based on pre-defined percentage (e.g., >1%, >10%, >25%, >50%, >75%) of tumor cells having 1+ or higher staining. All staining assessments are completed by board-certified pathologists. See, Brcic et al. 2019.PAT060054-PCT-SEC01CLAIMS1. A method for treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of aradiopharmaceutical compound targeting DLL3 and an effective amount an additional therapeutic agent selected from the group consisting of an immunotherapeutic agent, a chemotherapeutic agent, and combinations thereof.

2. The method of claim 1, wherein the cancer is characterized by upregulated surface expression of Delta-like ligand 3 (DLL3).

3. The method of claim 1 or 2, wherein the cancer is a DLL3 positive cancer.

4. The method of any one of claims 1-3, wherein the cancer is a neuroendocrine neoplasm.

5. The method of any one of claims 1-3, wherein the cancer is small cell lung cancer (SCLC).

6. The method of any one of claims 1-3, wherein the cancer is neuroendocrine prostate cancer (NEPC).

7. The method of any one of claims 1-3, wherein the cancer is large cell neuroendocrine carcinoma (LCNEC).

8. The method of any one of claims 1-3, wherein the cancer is gastroenteropancreatic neuroendocrine tumor (GEP-NET).

9. The method of any one of claims 1-3, wherein the cancer is a non- neuroendocrine neoplasm.

10. The method of any one of claims 1-3, wherein the cancer is melanoma.PAT060054-PCT-SEC0111. The method of any one of claims 1-10, wherein the immunotherapeutic agent is an immune checkpoint inhibitor.

12. The method of claim 11, wherein the immune checkpoint inhibitor is a small molecule, antibody or biologically active fragment thereof, fusion protein, or therapeutic oligonucleotide.

13. The method of claim 12, wherein the immune checkpoint inhibitor is an inhibitor of PD-1, PD-L1, or CTLA-4.

14. The method of claim 13, wherein the immune checkpoint inhibitor is a PD-1 inhibitor.

15. The method of claim 13, wherein the immune checkpoint inhibitor is a PD-L1 inhibitor.

16. The method of claim 13, wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor.

17. The method of any one of claims 1-10, wherein the chemotherapeutic agent is one or more agents selected from the group consisting of topoisomerase inhibitors, and platinumbased compounds.

18. The method of claim 1, wherein the radiopharmaceutical compound comprises a compound of Formula (I):PAT060054-PCT-SEC01or a pharmaceutically acceptable salt thereof.

19. The method of 18, wherein the radiopharmaceutical compound further comprises a radioisotope selected from the group consisting of:227Th,225Ac,223Ra,213Bi,212Bi,212Pb,211At,203Pb,199Au,188Re,186Re,177Lu,161Tb,153Sm,149Tb,1311,90Y,89Sr,67Cu,64Cu,32P, and47Sc.

20. The method of claim 18, wherein the radiopharmaceutical compound is Compound 1:or a pharmaceutically acceptable salt thereof.PAT060054-PCT-SEC0121. The method of any one of claims 1-20, wherein the additional therapeutic agent is an inhibitor of PD-L1 and the radiopharmaceutical compound is Compound 1.

22. The method of claim 21, wherein the inhibitor of PD-L1 is an anti-PD-Ll antibody.

23. The method of any one of claims 1-20 wherein the additional therapeutic agent is a platinum-based compound and / or a topoisomerase inhibitor.

24. The method of any one of claims 1-23, wherein the additional therapeutic agent is administered orally, subcutaneously, and / or intravenously.

25. The method of any one of claims 1-25, wherein the radiopharmaceutical compound is administered intravenously.

26. The method of any one of claims 1-25, wherein the additional therapeutic agent and the radiopharmaceutical compound are administered simultaneously.

27. The method of any one of claims 1-25, wherein the additional therapeutic agent and the radiopharmaceutical compound are administered concurrently.

28. The method of any one of claims 1-25, wherein the additional therapeutic agent and the radiopharmaceutical compound are administered sequentially.

29. The method of any one of claims 1-28, wherein administration of the additional therapeutic agent commences prior to administration of the radiopharmaceutical compound.

30. The method of any one of claims 1-28, wherein administration of the radiopharmaceutical compound commences prior to administration of the additional therapeutic agent.PAT060054-PCT-SEC0131. The method of any one of claims 1-30, wherein the radiopharmaceutical compound comprises225Ac and is administered at a total dosage in the range of 1 MBq to about 100 MBq.

32. The method of any one of claims 1-31, wherein the radiopharmaceutical compound comprises225Ac and has a specific molar activity in the range of 60-13200 pCi per nmol compound.

33. The method of any one of claims 1-32, wherein the radiopharmaceutical compound is administered to the subject once every 2 weeks to once every 10 weeks.

34. The method of any one of claims 1-33, wherein the additional therapeutic agent is administered to the subject once every 2 weeks to once every 10 weeks.

35. The method of any one of claims 1-34, wherein the radiopharmaceutical compound is administered in the form of a stabilized composition comprising ascorbic acid, or a pharmaceutically acceptable salt thereof, and a polysorbate.

36. A pharmaceutical composition comprising a radiopharmaceutical compound targeting DLL3 and an additional therapeutic agent selected from the group consisting of an immunotherapeutic agent, a chemotherapeutic agent, and combinations thereof.

37. The pharmaceutical composition of claim 36, wherein the additional therapeutic agent is an immune checkpoint inhibitor.

38. The pharmaceutical composition of claim 36, wherein the additional therapeutic agent is a platinum-based compound and / or a topoisomerase inhibitor.

39. The pharmaceutical composition of claim 36, wherein the additional therapeutic agent is a combination comprising an immune checkpoint inhibitor, and a platinum-based compound and / or a topoisomerase inhibitor.

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