Study of Ifinatamab Deruxtecan in De Novo or Treatment-Emergent Neuroendocrine Prostate Cancer

1. Age ≥18 years

2. Documentation of Histologic or molecular evidence of neuroendocrine prostate cancer (NEPC), defined by at least one of the following:

   1. Small cell or large cell neuroendocrine cancer by morphology
   2. ≥20% tumor expression of Insulinoma-Associated Protein 1(INSM1), synaptophysin, or Cluster of Differentiation 56 (CD56)
   3. Genomic alterations in ≥2 of RB Transcriptional Corepressor 1(RB1), Tumor Protein p53 (TP53), or phosphatase and tensin homolog (PTEN).

   Patients only meeting criterion 2(c) will be capped at no more than 30% of the efficacy-evaluable study population.

3. Presence of one or more metastatic lesions by conventional imaging with measurable soft tissue disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.
4. Availability of archival formalin-fixed paraffin-embedded (FFPE) tumor tissue obtained at time of or following initial Neuroendocrine Prostate Cancer (NEPC) diagnosis and/or the provision of a fresh tumor biopsy obtained during Screening. In patients without available archival FFPE tissue and no safely accessible lesion for fresh tumor biopsy, waiver of biopsy requirement may be permitted upon determination of the Principal Investigator.
5. Patients with de novo neuroendocrine prostate cancer must have received prior treatment with platinum-based chemotherapy.

6. Patients with treatment-emergent neuroendocrine prostate cancer must meet all of the following criteria:

   1. Ongoing androgen deprivation therapy with castrate level of testosterone (\< 50 nanograms per deciliter (ng/dL)) at study entry.
   2. Prior treatment with at least one prior androgen pathway inhibitor.
   3. Prior treatment with at least one line of cytotoxic chemotherapy unless patient refuses chemotherapy.

   No more than 10 efficacy-evaluable patients with treatment-emergent neuroendocrine prostate cancer who are naïve to platinum-based chemotherapy may be enrolled.

7. Eastern Cooperative Oncology Group (ECOG) status of ≤ 2

8. Demonstrates adequate organ function as defined below:

   Adequate bone marrow function:

   Absolute neutrophil count ≥1,500/microliter (mcL) Platelets Hemoglobin ≥100,000/mcL

   ≥ 9 grams of a substance per deciliter of fluid (g/dL) without transfusion in the 14 days prior to screening lab assessment.

   Adequate hepatic function:

   total bilirubin ≤ 1.5 × institutional upper limit of normal if no liver metastases or ≤3.0 × upper limit of normal (ULN) if liver metastases at baseline or documented Gilbert's Syndrome (unconjugated hyperbilirubinemia) aspartate aminotransferase (AST) (Serum Glutamic-Oxaloacetic Transaminase (SGOT)) ≤ 3 X institutional upper limit of normal or ≤5.0 × ULN with liver metastasis at baseline alanine aminotransferase (ALT)(Serum Glutamic-Pyruvic Transaminase (SGPT)) ≤ 3 X institutional upper limit of normal ≤5.0 × ULN with liver metastasis at baseline

   Adequate renal function:

   Creatinine clearance (CrCl) ≥30 milliliters per minute (mL/min), as calculated using the Cockcroft-Gault equation

   Adequate blood clotting function:

   Prothrombin Time /International Normalized Ratio (PT/INR) and either a-Partial Thromboplastin Time (PTT) OR PTT ≤1.5 × institutional upper limit of normal unless the participant is receiving anticoagulant therapy, as long as PT/INR or activated partial thromboplastin time (aPTT) or PTT is within the therapeutic range of intended use of anticoagulant (if applicable)

9. Ability to understand and the willingness to sign a written informed consent document.

10. Patients must use appropriate method s of contraception at time of diagnosis of NEPC and/ during study treatment and for at least 5 months for males and their partners of childbearing potential after last study treatment 5 months for males and their partners of child bearing potential. Patients who are sexually active should consider their partner to be of childbearing potential if they experienced menarche and are not postmenopausal (defined as amenorrhea > 24 consecutive months) or have not undergone successful surgical sterilization. Even those who use contraceptive hormones (oral, implanted, or injected), an intrauterine device, or barrier methods (diaphragms, condoms, spermicide) should be considered to be of childbearing potential.

    Patients who have undergone vasectomy themselves should also be considered to be of childbearing potential.

    Acceptable methods of contraception include continuous total abstinence, or the double-barrier method of birth control (e.g., condoms used with spermicide, or condoms used with oral contraceptives). Periodic abstinence and withdrawal are not acceptable methods of contraception.

11. Patients must not freeze or donate sperm starting at enrollment and throughout the study period, and at least 5 months after the final study drug administration. Preservation of sperm may be considered prior to enrollment in this study.

Exclusion Criteria:

1. Patients with other active malignancies. requiring active treatment at the time of study entry. Exceptions include patients receiving radical treatment for any in-situ carcinomas: Non-melanoma skin cancer, non-muscle invasive bladder cancer, or melanoma-in-situ.
2. Receipt of more than two prior lines of cytotoxic chemotherapy. Note: The addition of platinum to ongoing taxane-based chemotherapy will not be considered a separate line of systemic therapy, nor will re-treatment with the same chemotherapy regimen separated by a treatment break.
3. Prior treatment with B7-H3-targeted agents, including I-DXd, orlotamab, or enoblituzumab.
4. Prior treatment with topotecan, irinotecan, or an antibody-drug conjugate with topoisomerase 1 inhibitor payload.
5. Chronic steroid treatment (dose of greater than 10 mg daily oral prednisone equivalent), except for low-dose inhaled steroids (for asthma/Chronic Obstructive Pulmonary Disease (COPD)), topical steroids (for mild skin conditions), or intra-articular steroid injections.

6. Has received any of the following treatments:

   1. Major surgery \< 4 weeks from cycle 1 Day 1 (C1D1) Note: placement of vascular access will not be regarded as a major surgery.
   2. Radiation therapy within 7 days
   3. Radioligand therapy or antibody-based treatment \< 4 weeks from C1D1
   4. Cranial irradiation, including whole brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS) ≤ 2 weeks from C1D1
   5. Small molecule inhibitor within 2 weeks from C1D1
   6. Hormonal therapy (except for Luteinizing hormone-releasing hormone (LHRH) agonists/antagonists) within 2 weeks from C1D1.
   7. within Chloroquine/Hydroxychloroquine ≤2 weeks from C1D1

   Inadequate treatment washout period before randomization/enrollment, defined in the table below:

   Treatment Washout Period Major surgery (placement of vascular access will not be regarded as a major surgery) \<4 weeks Surgery for low-invasive cases (eg, colostomy) \< 2 wks Radiation therapy \<4 weeks Palliative stereotactic radiation therapy without abdominal radiation ≤2 weeks Palliative radiation to the bone only > 7 days Cranial irradiation, including whole brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS)radiosurgery (SRS) ≤ 2 weeks

   Systemic anticancer therapy (including immunotherapy [other than antibodies]) \<3 weeks or 5 half-lives, whichever is longer.

   Note: Treatment with monoclonal antibodies (mAbs) will require at least a 4-week washout period or recovery to Grade ≤1 or baseline for AEs due to mAbs.

   Treatment with denosumab as standard of care for bone metastases is permitted if the participant has been on a stable dose for ≥4 weeks prior to randomization.

   Hormonal therapy except for LHRH agonists/ antagonists \<2 weeks

   Antibody-based anticancer therapy \<4 weeks Chloroquine/Hydroxychloroquine ≤14 days 5α reductase inhibitors (e.g., finasteride or dutasteride), estrogens, and/or cyproterone \<4 weeks Herbal products that may have hormonal antiprostate cancer activity and/or are known to decrease PSA levels (e.g., saw palmetto) \<4 weeks

7. Any of the following conditions within the past 6 months: cerebrovascular accident, transient ischemic attack, or another arterial thromboembolic event
8. Clinically significant corneal disease in the judgment of the treating investigator.

9. Uncontrolled or significant cardiovascular disease, including:

   1. QT interval corrected with Fridericia's formula (QTcF) interval >450 ms (males) based on average of the screening triplicate 12-lead electrocardiogram (ECG) determinations.
   2. Diagnosed or suspected long QT syndrome.
   3. History of clinically relevant ventricular arrhythmias, such as ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes.
   4. Clinically relevant bradycardia of less than 50 beats per minute (bpm) unless the subject has a pacemaker.
   5. History of second- or third-degree heart block. Candidates with a history of heart block may be eligible if they currently have a pacemaker and have no history of fainting or clinically relevant arrhythmia with the pacemaker.
   6. Acute myocardial infarction within 6 months prior to Screening.
   7. Uncontrolled angina pectoris within 6 months prior to Screening
   8. Symptomatic congestive heart failure (CHF) defined as New York Heart Association (NYHA) Class II to IV.
   9. Coronary/peripheral artery bypass graft within 6 months prior to Screening.
   10. Uncontrolled hypertension (blood pressure (BP) ≥ 160/100 mm Hg). Treatment and repeating blood pressure assessment is permitted during screening.
   11. Complete left or right bundle branch block.
   12. Left ventricular ejection fraction (LVEF) \<50% by either an echocardiogram (ECHO) or a multigated acquisition (MUGA) scan.

10. Has any of the following indicators of interstitial lung disease (ILD)/pneumonitis are excluded:

    • Any history of ILD/pneumonitis irrespective of steroid use, except for a history of radiation pneumonitis that did not require steroids
    • Current diagnosis of ILD
    • Clinical or radiographic suspicion of ILD for which the diagnosis of ILD cannot be ruled out. Radiographic findings may include presence of lung parenchymal fibrosis, combined fibrosis and emphysema (CPFE), and/or interstitial lung abnormalities such as reticular opacities, traction bronchiectasis, honeycombing, or extensive ground glass opacities.
11. Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (i.e., pulmonary emboli within 3 months of the study enrollment, severe asthma, severe COPD, restrictive lung disease, pleural effusion, etc.), and any autoimmune, connective tissue or inflammatory disorders with potential pulmonary involvement (i.e., rheumatoid arthritis, Sjogren's syndrome, sarcoidosis etc.), or prior pneumonectomy, or requirement for supplemental oxygen.

12. Clinically active brain metastases, spinal cord compression, or leptomeningeal carcinomatosis, defined as untreated or symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms.

    Note: Subjects with clinically inactive or treated brain metastases who are asymptomatic (i.e., without neurologic signs or symptoms and not requiring treatment with corticosteroids or anticonvulsants) may be included in the study. Subjects must have a stable neurologic status for at least 2 weeks prior to Cycle 1 Day 1.

13. Has an active, known or suspected autoimmune disease.

    Note: The following examples may be enrolled as an exception:

    • Type I diabetes mellitus/hypothyroidism only requiring hormone replacement
    • Skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or
    • Conditions not expected to recur in the absence of an external trigger
14. Any evidence of severe or uncontrolled systemic diseases (including active bleeding diatheses, psychiatric illness/social situations, substance abuse) or other factors that, in the investigator's opinion, makes it undesirable for the subject to participate in the study or would jeopardize compliance with the protocol. Screening for chronic conditions is not required.
15. History of allogeneic bone marrow, stem cell, or solid organ transplant.

16. Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to National Cancer Institute Common Terminology Criteria for Adverse Event (NCI-CTCAE) version (V) 6.0, Grade ≤1 or baseline.

    Note: Subjects may be enrolled with chronic, stable Grade 2 toxicities (defined as no worsening to Grade >2 for at least 3 months prior to enrollment and managed with standard-of-care treatment) that the investigator deems related to previous anticancer therapy, following discussion with the Sponsor-Investigator, such as:

    1. Chemotherapy-induced neuropathy
    2. Endocrinopathies, which may include hypothyroidism, hyperthyroidism, type I diabetes, hyperglycemia, adrenal insufficiency, and/or adrenalitis
    3. Skin hypopigmentation (vitiligo)
17. History of hypersensitivity to the drug substances, inactive ingredients in the drug product, or severe hypersensitivity reactions to other monoclonal antibodies.

18. Evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection.

    Note: Subjects with localized fungal infections of skin or nails are eligible.

19. Has active or uncontrolled human immunodeficiency virus (HIV) infection. Only participants with known HIV infection must be tested for HIV viral load during the Screening Period.

    Note: Participants with a history of HIV are eligible if they meet all the following criteria:

    • Cluster of Differentiation 4 (CD4) + T-cell count ≥350 cells per cubic millimeter (cells/mm3) at the time of Screening, and Virologic suppression defined as confirmed HIV Ribonucleic acid (RNA) level below 50 or the Lower Limit of Quantification (LLOQ; below the limit of detection) at the time of Screening and for at least 12 weeks before Screening, and
    • No opportunistic infections or conditions related to Acquired Immunodeficiency Syndrome (AIDS) within the past 12 months, and
    • On stable antiretroviral therapy (ART) regimen, without changes in drugs or dose modification, for at least 4 weeks prior to initiation of trial intervention, and agree to continue ART throughout the trial.

20. Has active or uncontrolled hepatitis B virus (HBV) infection defined by positive hepatitis B Virus (HBV) viral load. Patients with positive hepatitis B surface antigen (HbsAg) and/or hepatitis B surface antibody (HBcAb) but negative viral load are eligible. Patients who are positive for HBsAg and/or hepatitis B core antibody (HBcAb) should have reactivation prophylaxis or antiviral treatment as per local institutional guidelines.

    Hepatitis B screening tests are not required unless:

    • Known history of HBV infection
    • Mandated by the local health authority

21. Has active or uncontrolled hepatitis C virus infection defined by positive hepatitis C Virus (HCV) viral load.

    Note: Participants with a history of hepatitis C infection are eligible if the HCV viral load is below the level of detection in the absence of antiviral therapy during the previous 4 weeks. Hepatitis C screening tests are not required unless:

    • Known history of HCV infection
    • Mandated by the local health authority
22. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid
23. Seasonal influenza vaccines for injection are generally inactive-virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
24. Is pregnant or breastfeeding or planning to become pregnant
25. Prior or ongoing clinically relevant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the investigator's opinion, could affect the safety of the subject, alter the absorption, distribution, metabolism or excretion of the study drug, or confound the assessment of study results.
26. Is currently receiving any other investigational agents.