Safety and Efficacy of Therapies for Metastatic Castration-resistant Prostate Cancer (mCRPC)

Study Overview
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Brief Summary
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This is a master protocol designed to evaluate the safety and efficacy of investigational therapies in participants with metastatic castration-resistant prostate cancer (mCRPC).

Detailed Description
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This is a master protocol designed to evaluate the safety, tolerability, and maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) and efficacy of Acapatamab, in combination with enzalutamide, abiraterone, or the PD1 inhibitor AMG 404, AMG 404 monotherapy, as well as Acapatamab monotherapy, in participants with metastatic castration-resistant prostate cancer (mCRPC).

Official Title
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A Master Protocol Evaluating the Safety and Efficacy of Therapies for Metastatic Castration-resistant Prostate Cancer (mCRPC)

Conditions
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Metastatic Castration-resistant Prostate Cancer

Intervention / Treatment
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* Drug: Acapatamab
* Drug: Enzalutamide
* Drug: Abiraterone
* Drug: AMG 404


Participation Criteria
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Eligibility Criteria
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All parts Inclusion Criteria: ≥ 18 years of age (or legal adult age within country) Subject has provided informed consent prior to initiation of any study-specific activities/procedures Subjects with mCRPC with histologically or cytologically confirmed adenocarcinoma of the prostate Subjects should have undergone bilateral orchiectomy or should be on continuous androgen deprivation therapy with a gonadotropin releasing hormone agonist or antagonist (testosterone ≤ 50 ng/dL (or 1.7 nmol/L)) Exclusion Criteria: Central nervous system (CNS) metastases or leptomeningeal disease History or presence of clinically relevant CNS pathology Confirmed history or current autoimmune disease or other diseases requiring permanent immunosuppressive therapy Myocardial infarction, uncontrolled hypertension, unstable angina, cardiac arrhythmia requiring medication, and/or symptomatic congestive heart failure (New York Heart Association > class II) within 12 months Prior treatment with a taxane for mCRPC Major surgery and/or Radiation within 4 weeks History or evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection unless agreed upon with medical monitor and meeting the following criteria: Negative test for SARS-CoV-2 RNA by real time polymerase chain reaction (RT-PCR) within 72 hours of first dose of Acapatamab (or AMG 404 in Part 3) No acute symptoms of COVID-19 disease within 10 days prior to first dose of Acapatamab (or AMG 404 in Part 3) (counted from day of positive test for asymptomatic subjects) Prior/Concurrent Clinical Study Experience Currently receiving treatment in another investigational device or drug study, or less than 4 weeks since ending treatment on another investigational device or drug study(ies). Other investigational procedures while participating in this study are excluded with the exception of investigational scans. Subprotocol A only: Inclusion criteria • Subjects planning to receive enzalutamide for the first time for mCRPC Exclusion criteria Use of strong CYP2C8 inhibitors or strong CYP3A4 inducers Use of narrow therapeutic index drugs that are substrates of CYP3A4, CYP2C9 or CYP2C19 Subprotocol B only: Inclusion criteria Subjects planning to receive abiraterone for the first time for mCRPC Exclusion criteria Baseline moderate and severe hepatic impairment (Child-Pugh Class B and C) Presence of uncontrolled hypertension, hypokalemia, or fluid retention History or presence of adrenocortical insufficiency Use of concomitant medications that are sensitive substrates for CYP2D6 with a narrow therapeutic index Use of strong CYP3A4 inducers Subprotocol C only: Inclusion criteria Subjects who are refractory to a novel antiandrogen therapy. Subjects must be ineligible for or refuse taxane therapy. Evidence of progressive disease, defined as 1 or more PCWG3 criteria: PSA level >/=1 ng/mL that has increased on at least 2 successive occasions at least 1 week apart, nodal or visceral progression as defined by RECIST 1.1 with PCGW3 modifications, and/or appearance of 2 or more new lesions in bone scan Exclusion criteria History or evidence of interstitial lung disease or active, non-infectious pneumonitis Subjects on a prior PD-1 or PD-L1 inhibitor who experienced a grade 3 or higher immune-related adverse event prior to first day of dose Subprotocol D only: Inclusion criteria Subjects may have had novel hormonal therapies (NHT; eg, abiraterone, enzalutamide, apalutamide, or darolutamide) for prostate cancer, but no more than 1 NHT for metastatic prostate cancer Ineligible for or refuse taxane therapy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Acapatamab and Enzalutamide: Dose Exploration<br>The dose-exploration part of the study will estimate the MTD/recommended phase 2 dose (RP2D) of Acapatamab in combination with enzalutamide. | Drug: Acapatamab<br>* Acapatamab will be administered as an intravenous (IV) infusion.<br>* Other names: PSMA targeted therapy;Drug: Enzalutamide<br>* Enzalutamide will be administered orally.<br>* Other names: Androgen receptor inhibitor;|
| Experimental: Acapatamab and Enzalutamide: Dose Expansion<br>Following dose exploration, dose expansion will be conducted to confirm the safety and tolerability of the selected dose and to further evaluate the efficacy of Acapatamab in combination with enzalutamide. | Drug: Acapatamab<br>* Acapatamab will be administered as an intravenous (IV) infusion.<br>* Other names: PSMA targeted therapy;Drug: Enzalutamide<br>* Enzalutamide will be administered orally.<br>* Other names: Androgen receptor inhibitor;|
| Experimental: Acapatamab and Abiraterone: Dose Exploration<br>The dose exploration part of the study will estimate the MTD/recommended phase 2 dose (RP2D) of Acapatamab in combination with abiraterone. | Drug: Acapatamab<br>* Acapatamab will be administered as an intravenous (IV) infusion.<br>* Other names: PSMA targeted therapy;Drug: Abiraterone<br>* Abiraterone will be administered orally.<br>* Other names: Cytochrome P450 (CYP)17 inhibitor;|
| Experimental: Acapatamab and Abiraterone: Dose Expansion<br>Following dose exploration, dose expansion will be conducted to confirm the safety and tolerability of the selected dose and to further evaluate the efficacy of Acapatamab in combination with abiraterone. | Drug: Acapatamab<br>* Acapatamab will be administered as an intravenous (IV) infusion.<br>* Other names: PSMA targeted therapy;Drug: Abiraterone<br>* Abiraterone will be administered orally.<br>* Other names: Cytochrome P450 (CYP)17 inhibitor;|
| Experimental: Acapatamab and AMG 404: Dose Exploration<br>The dose-exploration part of the study will estimate the MTD/RP2D of Acapatamab in combination with AMG 404. | Drug: Acapatamab<br>* Acapatamab will be administered as an intravenous (IV) infusion.<br>* Other names: PSMA targeted therapy;Drug: AMG 404<br>* AMG 404 will be administered as an intravenous (IV) infusion.<br>* Other names: PD-1 inhibitor;|
| Experimental: Acapatamab and AMG 404: Dose Expansion<br>Following dose exploration, dose expansion will be conducted to confirm the safety and tolerability of the selected dose and to further evaluate the efficacy of Acapatamab in combination with AMG 404. | Drug: Acapatamab<br>* Acapatamab will be administered as an intravenous (IV) infusion.<br>* Other names: PSMA targeted therapy;Drug: AMG 404<br>* AMG 404 will be administered as an intravenous (IV) infusion.<br>* Other names: PD-1 inhibitor;|
| Active Comparator: AMG 404 Monotherapy<br>AMG 404 monotherapy is being conducted to evaluate the preliminary anti-tumor activity of PD-1 inhibition in the mCRPC population. | Drug: AMG 404<br>* AMG 404 will be administered as an intravenous (IV) infusion.<br>* Other names: PD-1 inhibitor;|
| Experimental: Acapatamab and Enzalutamide: Dose Expansion Asia Cohort<br>Following dose exploration, dose expansion will be conducted in the Asia cohort at the combination MTD/RP2D determined in dose exploration to confirm the safety, tolerability and PK of Acapatamab in combination with enzalutamide for subjects in Asia. | Drug: Acapatamab<br>* Acapatamab will be administered as an intravenous (IV) infusion.<br>* Other names: PSMA targeted therapy;Drug: Enzalutamide<br>* Enzalutamide will be administered orally.<br>* Other names: Androgen receptor inhibitor;|
| Experimental: Acapatamab and Abiraterone: Dose Expansion Asia Cohort<br>Following dose exploration, dose expansion will be conducted in the Asia cohort at the combination MTD/RP2D determined in dose exploration to confirm the safety, tolerability and PK of Acapatamab in combination with abiraterone for subjects in Asia. | Drug: Acapatamab<br>* Acapatamab will be administered as an intravenous (IV) infusion.<br>* Other names: PSMA targeted therapy;Drug: Abiraterone<br>* Abiraterone will be administered orally.<br>* Other names: Cytochrome P450 (CYP)17 inhibitor;|
| Experimental: Acapatamab and AMG 404: Dose Expansion Asia Cohort<br>Following dose exploration, dose expansion will be conducted in the Asia cohort at the combination MTD/RP2D determined in dose exploration to confirm the safety, tolerability and PK of Acapatamab in combination with AMG 404 for subjects in Asia. | Drug: Acapatamab<br>* Acapatamab will be administered as an intravenous (IV) infusion.<br>* Other names: PSMA targeted therapy;Drug: AMG 404<br>* AMG 404 will be administered as an intravenous (IV) infusion.<br>* Other names: PD-1 inhibitor;|
| Experimental: Acapatamab Monotherapy<br>Acapatamab monotherapy is being conducted to evaluate safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and efficacy of Acapatamab in subjects with mCRPC. | Drug: Acapatamab<br>* Acapatamab will be administered as an intravenous (IV) infusion.<br>* Other names: PSMA targeted therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose exploration only: Number of participants who experience dose limiting toxicities (DLTs) | The analysis of all endpoints, unless noted otherwise, will be conducted on the Safety Analysis Set defined as all subjects that are enrolled and receive at least 1 dose of Acapatamab. The analysis of dose-limiting toxicity (DLT) will be conducted on the DLT Analysis Set defined as all subjects that are enrolled and receive at least 1 dose of Acapatamab with an evaluable DLT endpoint. If a single subject experiences more than 1 DLT it will be counted as 1. The DLT endpoint is evaluable if either: 1) the subject experiences a DLT; or 2) the subject does not experience a DLT after receiving all planned doses within the 28-day DLT window in cycle 1. | Up to 3 years | 
| Number of participants who experience one or more treatment-emergent adverse events (TEAEs) |  | Up to 3 years | 
| Number of participants who experience one or more treatment-related adverse events |  | Up to 3 years | 
| Number of participants who experience a clinically significant change in vital signs |  | Up to 3 years | 
| Number of participants who experience a clinically significant change in clinical laboratory tests |  | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate per response evaluation criteria in solid tumors (RECIST) 1.1 with prostate cancer working group 3 (PCWG3) modifications |  | Up to 3 years | 
| Number of participants who experience circulating tumor cell (CTC) response |  | Up to 3 years | 
| Number of participants who experience prostate-specific antigen (PSA) response rate |  | Up to 3 years | 
| Duration of response |  | Up to 3 years | 
| Overall survival (OS) |  | Up to 3 years | 
| Progression-free survival |  | Up to 3 years | 
| Time to progression |  | Up to 3 years | 
| Time to subsequent therapy |  | Up to 3 years | 
| Maximum plasma concentration (Cmax) |  | Up to 3 years | 
| Minimum plasma concentration (Cmin) |  | Up to 3 years | 
| Area under the concentration-time curve (AUC) |  | Up to 3 years | 
| Accumulation ratio based on area under the concentration-time curve (AUC) |  | Up to 3 years | 
| Half-life (t1/2) |  | Up to 3 years | 
| Change from baseline in prostate-specific membrane antigen (PSMA)-positive tumor burden assessed using gallium (GA) 68-labelled PSMA-11 positron emission tomography/computed tomography (PET/CT) |  | Baseline up to 3 years | 
| Change from baseline in prostate-specific membrane antigen (PSMA)-negative disease burden assessed using 18F-fluorodeoxyglucose (F-FDG) positron emission tomography/computed tomography (PET/CT) |  | Baseline to 3 years | 
| Time to symptomatic skeletal events |  | Up to 3 years | 
| Concentration of alkaline phosphatase |  | Up to 3 years | 
| Concentration of lactate dehydrogenase (LDH) |  | Up to 3 years | 
| Concentration of hemoglobin |  | Up to 3 years | 
| Neutrophil-to-lymphocyte ratio |  | Up to 3 years | 
| Concentration of N-telopeptide in the urine |  | Up to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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68, Acapatamab, HALF-LIFE EXTENDED (HLE) BITE, mCRPC, Metastatic Castration-resistant Prostate Cancer, Gallium (68Ga)-prostate-specific membrane, antigen (PSMA)-11 positron emission, tomography(PET)/computed tomography (CT), and, 18, F-fluorodeoxyglucose (FDG) PET/CT, based response evaluation, Bispecific T cell Engager, BITE