FOR46 in Combination With Enzalutamide in Patients With Metastatic Castration Resistant Prostate Cancer

This is a Phase 1b/2 study evaluating FOR46 in combination with enzalutamide in patients with metastatic castration resistant prostate cancer (mCRPC) after prior progression on abiraterone. FOR46 is designed to target and bind to CD46, a transmembrane cellular protein expressed at moderate or high levels in numerous cancer types. The investigators hypothesize that the combination of FOR46 plus enzalutamide will achieve a clinically significant composite response rate with sufficient durability of response in mCRPC patients.

PRIMARY OBJECTIVES:

Phase 1b:

I. To determine the maximally tolerated dose (MTD) and recommended phase 2 dose (RP2D) of FOR46 in combination with enzalutamide in patients with mCRPC.

Phase 2:

I. To determine the composite response rate of FOR46 plus enzalutamide, defined as:

1. Decline in serum PSA \>= 50% (PSA50) from baseline, confirmed by repeat measurement at least 4 weeks later, and/or
2. Objective response by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria.

SECONDARY OBJECTIVES:

Phase 1b and Phase 2:

I. To determine the PSA50 response rate.

II. To determine the objective response rate by RECIST 1.1 criteria among patients with measurable soft tissue by RECIST 1.1 criteria at baseline.

III. To determine the median duration of objective response.

IIII. To determine the median time to prostate-specific antigen (PSA) progression by Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria.

V. To determine the median radiographic progression-free survival by PCWG3 criteria.

VI. To determine the median overall survival.

VII. To determine the safety of the combination.

OUTLINE:

Participants may continue study treatment from the time of treatment initiation until confirmed radiographic disease progression per PCWG3 / RECIST 1.1 criteria, unequivocal clinical progression, unacceptable toxicity, or patient withdrawal, whichever occurs first. Patients will be followed for overall survival every 90 days (+/- 30 days) from last dose of study treatment, until death, withdrawal of consent, or the end of the study, whichever occurs first.

Eligibility Criteria:
Inclusion Criteria:

1. Histologically confirmed metastatic prostate adenocarcinoma.
2. Disease progression by PCWG3 criteria at study entry.
3. Prior progression by PCWG3 criteria on one or more androgen signaling inhibitors including abiraterone acetate, enzalutamide, apalutamide, and/or darolutamide.
4. No prior taxane-based chemotherapy for the treatment of mCRPC. Prior taxane use in the castration-sensitive prostate cancer (CSPC) setting allowed provided last dose \> 6 months prior to study entry.
5. Patients must be evaluable for the primary endpoint of composite response, and must have either serum PSA ≥ 2 ng/mL during Screening and/or measurable disease by RECIST 1.1 criteria.
6. Participants must be willing to undergo metastatic tumor biopsy during Screening. If there is no safely accessible metastatic lesion, this requirement will be waived.
7. Dose Expansion only: Participants must be willing to undergo CD46-directed Positron Emission Tomography (PET) imaging during Screening (Co-enrolling on NCT05245006, Groups B and C)
8. Castrate level of serum testosterone at study entry (\<50 ng/dL). Patients without prior bilateral orchiectomy are required to remain on Luteinizing hormone-releasing hormone (LHRH) analogue treatment for duration of study.
9. No other systemic anti-cancer therapies administered other than LHRH analogue within 14 days or, 5 half-lives, whichever is shorter, prior to initiation of study treatment. Adverse events related to prior anti-cancer treatment related to therapies other than LHRH analogue must have recovered to Grade ≤ 1 with the exception of any grade alopecia. a. Patients receiving enzalutamide prior to study entry may continue treatment at their current enzalutamide dose level without requirement for wash-out period.
10. Age \>=18 years.
11. Eastern Cooperative Oncology Group (ECOG) performance status \<= 1 (Karnofsky performance status \>= 70 percent (%)).
12. Demonstrates adequate organ function as defined below:

    1. Absolute neutrophil count ≥ 1,500/microliter (mcL).
    2. Platelets \>= 100,000/mcL and no platelet transfusions during the 14 days prior to first dose of FOR46.
    3. Hemoglobin \>= 8.0 grams per deciliter (g/dL) without red blood cell transfusion during the 14 days prior to first dose of FOR46.
    4. Total bilirubin \<=1.5 x institutional upper limit of normal (ULN), unless elevated due to Gilbert's syndrome and direct bilirubin is within normal limits.
    5. Aspartate aminotransferase (AST) /serum glutamic-oxaloacetic transaminase (SGOT) \<=3 x institutional institutional upper limit of normal (ULN).
    6. Alanine aminotransferase (ALT)/serum glutamic-pyruvic transaminase (SGPT) =3 x ULN.
    7. Serum creatinine \<= 1.5 x institutional upper limit of normal OR Calculated creatinine clearance glomerular filtration rate (GFR) \>= 60 mL/min, calculated using the Cockcroft-Gault equation.
    8. Serum sodium level \>=130 mmol/L.
13. Ability to understand a written informed consent document, and the willingness to sign it.
14. Individuals with concurrent second malignancy requiring active treatment at study entry. Nonmelanoma skin cancer, non-muscle invasive bladder cancer, and other carcinomas-in-situ are allowable exceptions.
15. Patients must agree to use adequate contraception prior to the study, for the duration of study participation, and 60 days after last administration of study treatment. Adequate contraception includes:

    1. Patients who are sexually active should consider their female partner to be of childbearing potential if she has experienced menarche and is not postmenopausal (defined as amenorrhea \> 24 consecutive months) or has not undergone successful surgical sterilization. Even women 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.
    2. Acceptable methods of contraception include continuous total abstinence, or 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.

Exclusion Criteria:

1. Has received prior radiotherapy within 2 weeks of first dose of FOR46.
2. Prior treatment with FOR46 or another CD46-targeting therapeutic agent.
3. Prior histologic evidence of de novo or treatment-emergent small cell neuroendocrine prostate cancer. Pathologic assessment of baseline tumor biopsy performed during Screening is not required for determination of study eligibility.
4. Cardiac condition as defined as one or more of the following:

   1. Uncontrolled supraventricular arrhythmia or ventricular arrhythmia requiring treatment.
   2. New York Heart Association (NYHA) congestive heart failure class III or IV.
   3. History of unstable angina, myocardial infarction, or cerebrovascular accident within 6 months prior to Cycle 1, Day 1.
5. History of seizure or pre-disposing condition including:

   1. History of brain metastasis.
   2. Cerebrovascular accident (CVA) within 6 months prior to study entry.
   3. History of intracranial hemorrhage.
6. History of pneumonitis.
7. Is receiving systemic steroid therapy at a prednisone equivalent dose of \> 10 milligram daily or other form of immunosuppressive therapy within 7 days prior to first dose of study drug.
8. Has an active infection requiring intravenous antibiotics within 7 days prior to Cycle 1, Day 1.
9. Use of a prohibited concomitant medication within 7 days of first dose of FOR46, including:

   a. Strong inhibitor of CYP3A4 (boceprevir, clarithromycin, cobicistat, conivaptan, diltiazem, danoprevir/ritonavir, elvitegravir/ritonavir, grapefruit juice, idelalisib, indinavir/ritonavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, paritaprevir/ritonavir/ombitasvir and/or dasabuvir, posaconazole, ritonavir, saquinavir/ritonavir, tipranavir/ritonavir, troleandomycin, and voriconazole).
10. Major surgery within 28 days prior to Cycle 1, Day 1. Minor procedures including biopsies, dental surgery, cataract surgery, or outpatient procedure are allowed.
11. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
12. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.