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

Phase 2TerminatedNCT04631601

Amgen55 enrolled

Overview

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

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).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Metastatic Castration-resistant Prostate Cancer

Interventions

AcapatamabDRUG

Acapatamab will be administered as an intravenous (IV) infusion.

EnzalutamideDRUG

Enzalutamide will be administered orally.

AbirateroneDRUG

Abiraterone will be administered orally.

Eligibility

Sex: MALEMin age: 18 YearsMax age: 99 Years

Medical Language ↔ Plain English

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

Locations (14)

University of Alabama at Birmingham

Birmingham, Alabama, United States

University of California at Irvine Medical Center

Orange, California, United States

University of California San Francisco Mission Bay Campus

Outcomes

Primary Outcomes

Subprotocols A, B and C (Parts 1 and 2): Number of Participants Who Experienced a Dose-limiting Toxicity (DLT)

DLTs were defined as any adverse event (AE) (per Common Terminology Criteria for Adverse Events (CTCAE) v5: Grade 5=Death, Grade 4=Life-threatening, Grade 3=Moderate) occurring within 28 days of the first AMG 160 dose, possibly related to the treatment, including: * Grade 5 toxicity * Grade 4 thrombocytopenia * Grade 3 thrombocytopenia with significant hemorrhage * Grade 4 neutropenia \> 5 days * Febrile neutropenia * Grade 3 anemia requiring transfusion * Grade ≥3 non-hematologic toxicity (with exceptions per protocol) * Aspartate transaminase/alanine transaminase \>3x upper limit of normal (ULN) with serum total bilirubin \>2x ULN without cholestasis or another clear cause * Grade ≥3 non-hematological toxicity delaying treatment \> 2 weeks or resulting in \<75% dose administration. The complete list of DLTs are described in the protocol

Time frame: Cycle 1: Day 1 to Day 28 (28-day cycle)

Subprotocols A, B and C (Parts 1 and 2): Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) and Treatment-related AEs

A TEAE was defined as any untoward medical occurrence in a clinical trial participant irrespective of a causal relationship with the trial treatment that started on or after first dose of investigational product (AMG 160 or AMG 404 for Part 1 and 2; AMG 404 for Part 3). A treatment-related TEAE was defined as a TEAE that had a reasonable possibility of being caused by acapatamab, or AMG 404 (subprotocol C, parts 1 and 2 only). Clinically significant changes from baseline in vital signs and clinical laboratory tests were also recorded as TEAEs.

Time frame: From first dose of acapatamab/AMG 404 to the first of 30 days after last dose of acapatamab/AMG404, end of trial date or the initiation of a new anticancer therapy; median (min, max) duration was 4.665 (0.33, 25.17) months

Subprotocol D: Number of Participants Who Experienced TEAEs and Treatment-related AEs

A TEAE was defined as any untoward medical occurrence in a clinical trial participant irrespective of a causal relationship with the trial treatment that started after the first dose of acapatamab. A treatment-related TEAE was defined as a TEAE that had a reasonable possibility of being caused by acapatamab. Clinically significant changes from baseline in vital signs and clinical laboratory tests were also recorded as TEAEs.

Data from ClinicalTrials.gov

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Secondary Outcomes

Subprotocols A. B, C (Parts 1 and 2) and D: ORR

Objective Response is defined as a CR or PR per RECIST 1.1, confirmed by a repeat assessment at least 4 weeks later. Participants who did not experience a confirmed CR or PR, or did not have any follow-up tumor assessments were regarded as non-responders.

Time frame: From Cycle 1 Day 1 until progression, start of new anticancer therapy, or until end of trial (each cycle was 28 days, maximum duration of acapatamab treatment was 98.43 weeks/AMG 404 treatment was 105.14 weeks)

Subprotocols A, B, C (Parts 1 and 2) and D: Percentage of Participants Who Experienced a CTC0 Response

CTC0 response was defined as CTC0 (reduction of CTCs \> 0 to 0 at any post-baseline measurement). The baseline was defined as the last non-missing value on or prior to the pre-dose of acapatamab assessments on Cycle 1 Day 1 \> 0.

Subprotocols A, B, C (Parts 1 and 2) and D: Percentage of Participants Who Experienced a CTC Conversion Response

CTC conversion response was defined as ≥ 5 CTCs/7.5 mL blood at baseline that converted to ≤ 4 CTCs/7.5 mL blood at any post-baseline measurement. The baseline was defined as the last non-missing value on or prior to the pre-dose of acapatamab assessments on Cycle 1 Day 1.

Subprotocols A, B, C (Parts 1 and 2) and D: Percentage of Participants Who Experienced a PSA Response

A PSA response was defined as the below and must have been confirmed by a second consecutive value 3 weeks later: * PSA 30 response: ≥ 30% reduction from the baseline PSA. * PSA 50 response: ≥ 50% reduction from the baseline PSA. * PSA 70 response: ≥ 70% reduction from the baseline PSA. * PSA 90 response: ≥ 90% reduction from the baseline PSA. The baseline was defined as the last non-missing value on or prior to the pre-dose of acapatamab assessments on Cycle 1 Day 1.

Time frame: Cycle 1 Day 1 to 5 months post-last dose of acapatamab/AMG 404 (each cycle was 28 days, maximum duration of acapatamab treatment was 98.43 weeks/AMG 404 treatment was 105.14 weeks)

Subprotocols A, B, C (Parts 1, 2 and 3) and D: Duration of CTC0 Response

Duration of CTC0 response was defined as the time from the date of initial CTC0 response to the earlier of CTC0 progression or death. Participants who had not ended their response at the time of analysis had duration of CTC0 response censored on the date of their last CTC0 or CTC conversion assessment.

Time frame: From date of initial CTC0 response to the earlier of CTC0 progression or death (maximum duration of acapatamab treatment was 98.43 weeks/AMG 404 treatment was 105.14 weeks)

Subprotocols A, B, C (Parts 1, 2 and 3) and D: Duration of CTC Conversion Response

Duration of CTC conversion response was defined as the time from the date of an initial CTC conversion response to the earlier of CTC conversion progression or death. Participants who had not ended their response at the time of analysis had duration of CTC response censored on the date of their last CTC0 or CTC conversion assessment.

Time frame: From the date of an initial CTC conversion response to the earlier of CTC conversion progression or death (maximum duration of acapatamab treatment was 98.43 weeks/AMG 404 treatment was 105.14 weeks)

Subprotocols A, B, C (Parts 1, 2 and 3) and D: Duration of PSA Response

Duration of PSA response was defined as the time of an initial PSA response (PSA 50) to the earlier of PSA progression or death. Participants who had not ended their response at the time of analysis had duration of PSA response censored on the date of their last PSA measurement.

Time frame: From date of an initial PSA response (PSA 50) to the earlier of PSA progression or death (maximum duration of acapatamab treatment was 98.43 weeks/AMG 404 treatment was 105.14 weeks)

Subprotocols A, B, C (Parts 1, 2 and 3) and D: Duration of Response Per RECIST 1.1

Duration of response per RECIST 1.1 was defined as the time from the date of an initial objective response (CR/PR) per RECIST 1.1 to the earlier of soft-tissue progression per RECIST 1.1 or death. CR/PR must have been confirmed at least 4 weeks later. Participants who had not ended their response at the time of analysis had duration of response censored at their last evaluable tumor assessment by computed tomography (CT)/magnetic resonance imaging (MRI) scan.

Time frame: From date of an initial objective response per RECIST 1.1 to the earlier of soft-tissue progression per RECIST 1.1 or death (maximum duration of acapatamab treatment was 98.43 weeks/AMG 404 treatment was 105.14 weeks)

Subprotocols A, B, C (Parts 1, 2 and 3) and D: Overall Survival (OS)

OS was defined as the time from the date of trial Day 1 until death due to any cause. OS time (months) = (date of death - trial Day 1 + 1) x 12/365.25. Any participant not known to have died at the time of analysis was censored based on the last recorded date on which the participant was alive. The median was estimated using the Kaplan-Meier method and the 95% confidence interval was estimated using the method by Kalbfleisch and Prentice.

Time frame: From the date of study Day 1 until death due to any cause (maximum duration of acapatamab treatment was 98.43 weeks/AMG 404 treatment was 105.14 weeks)

Subprotocols A, B, C (Parts 1, 2 and 3) and D: Radiographic Progression Free Survival (rPFS)

rPFS was defined as the time from trial Day 1 to radiographic progression. If a participant had no evaluable post-baseline and on-trial disease assessment and was on trial without disease progression (PD) or death recorded, rPFS was censored on the date of the first dose of the investigational product (IP). rPFS was censored at the last evaluable radiographic tumor assessment date for participants who had no PD, death or new anti-cancer therapy reported, started a new anti-cancer therapy prior to PD or death, if death recorded without new anti-cancer therapy and without PD, if death or PD immediately after more than one consecutively missed tumor assessment occurred. The median was estimated using the Kaplan-Meier method and the 95% confidence interval was estimated using the method by Brookmeyer and Crowley.

Time frame: From trial Day 1 to the earlier of a radiographic progression or death from any cause (maximum duration of acapatamab treatment was 98.43 weeks/AMG 404 treatment was 105.14 weeks)

Subprotocols A, B, C (Parts 1, 2 and 3) and D: PSA PFS

PSA PFS was defined as the interval from trial Day 1 to the earlier of a PSA progression or death from any cause; otherwise, PSA PFS was censored on the date of the last PSA measurement. If a participant had no baseline or post-baseline PSA measurement and a vital status of alive or known, PSA PFS was censored at trial Day 1. The median was estimated using the Kaplan-Meier method and the 95% confidence interval was estimated using the method by Brookmeyer and Crowley.

Time frame: From trial Day 1 to the earlier of a PSA progression or death from any cause (maximum duration of acapatamab treatment was 98.43 weeks/AMG 404 treatment was 105.14 weeks)

Subprotocols A, B, C (Parts 1, 2 and 3) and D: Clinical PFS

Clinical PFS was defined as the time from the first dose to clinical disease progression or death from any cause. If a participant had no evaluable post-baseline or on-trial disease assessment or was on trial without PD or death recorded, clinical PFS was censored on the date of the first dose of the IP. Otherwise, clinical PFS was censored on the date of last assessment. The median was estimated using the Kaplan-Meier method and the 95% confidence interval was estimated using the method by Brookmeyer and Crowley.

Time frame: From first dose of acapatamab or AMG 404 (subprotocol C only) to clinical disease progression or death from any cause (maximum duration of acapatamab treatment was 98.43 weeks/AMG 404 treatment was 105.14 weeks)

Subprotocols A, B, C (Parts 1, 2 and 3) and D: Time to Radiographic Progression

Time to radiographic progression was defined as the interval from Day 1 to radiographic progression in the absence of subsequent anticancer therapy. If a participant had no evaluable post-baseline and on-trial disease assessment and was on trial without PD or death recorded, time to radiographic progression was censored on the date of the first dose of the IP. Time to radiographic progression was censored on the date of last evaluable radiographic tumor assessment for participants who: * had no PD but death recorded without new anti-cancer therapy; * had no PD, death, or new anti-cancer therapy; * had PD or death immediately after more than one consecutively missed tumor assessment; * started new anti-cancer therapy prior to PD or death, or prior to any other disease assessment if there is no PD or death. The median was estimated using the Kaplan-Meier method and the 95% CI was estimated using the method by Brookmeyer and Crowley.

Time frame: From trial Day 1 to radiographic progression in the absence of subsequent anticancer therapy (maximum duration of acapatamab treatment was 98.43 weeks/AMG 404 treatment was 105.14 weeks)

Subprotocols A, B, C (Parts 1, 2 and 3) and D: Time to PSA Progression

Time to PSA progression was defined as the interval from trial Day 1 to PSA progression. If a participant had no evaluable post-baseline or on-trial PSA assessment, time to PSA progression was censored on the date of the first dose of the IP. Otherwise, time to PSA progression was censored on the date of the last PSA assessment. The median was estimated using the Kaplan-Meier method and the 95% confidence interval was estimated using the method by Brookmeyer and Crowley.

Time frame: From trial Day 1 to PSA progression (maximum duration of acapatamab treatment was 98.43 weeks/AMG 404 treatment was 105.14 weeks)

Subprotocols A, B, C (Parts 1, 2 and 3) and D: Time to Subsequent Therapy

Time to subsequent therapy was defined as the interval from trial Day 1 to the time a participant starts/receives the subsequent cancer therapy/subsequent therapy; otherwise, time to subsequent therapy was censored at the last known date of any of the trial assessments prior to initiating the subsequent cancer therapy/subsequent therapy. The median was estimated using the Kaplan-Meier method and the 95% confidence interval was estimated using the method by Brookmeyer and Crowley.

Time frame: From trial Day 1 to the time a participant starts/receives the subsequent cancer therapy/subsequent therapy (maximum duration of acapatamab treatment was 98.43 weeks/AMG 404 treatment was 105.14 weeks)

Subprotocols A, B, C (Parts 1, 2 and 3) and D: Percentage of Participants Who Experienced a Gallium Prostate-specific Membrane Antigen-11 (PSMA-11) Response

A Gallium PSMA-11 response was defined as a ≥ 50% reduction from baseline in the maximum standardized update value (SUV) using 68Gallium (68Ga)-PSMA-11 positron emission tomography (PET)/CT. PSMA-11 response percentages were based on the number of participants with a baseline PSMA assessment (defined as the last non-missing value on or prior to the pre-dose of acapatamab/AMG 404 assessments) on Cycle 1 Day 1. The 95% confidence interval was calculated based on the Clopper-Pearson method.

Time frame: Cycle 1 Day 1 to 14 days post-last dose of acapatamab or AMG 404 (maximum duration of acapatamab treatment was 98.43 weeks/AMG 404 treatment was 105.14 weeks)

Subprotocols A, B, C (Parts 1, 2 and 3) and D: Time to Symptomatic Skeletal Events

Time to symptomatic skeletal events was defined as time from trial Day 1 to the first symptomatic skeletal event, otherwise time to symptomatic skeletal event was censored at the last dose of acapatamab/AMG 404 or end of safety follow-up date, whichever was later. Symptomatic skeletal events included fracture, spinal cord compression and radiation or surgery to bone. The median was estimated using the Kaplan-Meier method and the 95% confidence interval was estimated using the method by Brookmeyer and Crowley.

Time frame: From trial Day 1 to the first symptomatic skeletal event (maximum duration of acapatamab treatment was 98.43 weeks/AMG 404 treatment was 105.14 weeks)

Subprotocols A, B, C (Parts 1, 2 and 3) and D: Total Alkaline Phosphatase Levels

Alkaline phosphatase levels were collected locally and centrally.

Time frame: Baseline and end of treatment visit (up to 14 days post-last dose of acapatamab/AMG 404. Each cycle was 28 days, maximum duration of acapatamab treatment was 98.43 weeks/AMG 404 treatment was 105.1 weeks).

Subprotocols A, B, C (Parts 1, 2 and 3) and D: Bone Specific Alkaline Phosphatase Levels

Bone specific alkaline phosphatase levels were collected locally and centrally.

Subprotocols A, B, C (Parts 1, 2 and 3) and D: Lactate Dehydrogenase Levels

Lactate dehydrogenase levels were collected locally and centrally.

Subprotocols A, B, C (Parts 1, 2 and 3) and D: Hemoglobin Levels

Hemoglobin levels were collected locally.

Time frame: Baseline, safety follow-up visit (up to 30 days post-last dose of acapatamab/AMG 404), safety follow-up 2 (subprotocol C only, up to 5 months post-dose). Each cycle = 28 days, max acapatamab duration = 98.43 weeks, max AMG 404 duration = 105.1 weeks.

Subprotocols A, B, C (Parts 1, 2 and 3) and D: Neutrophil-to-lymphocyte Ratio

Data for the neutrophil-to-lymphocyte ratio were collected locally. Neutrophil-to-lymphocyte ratio was calculated by dividing the number of absolute neutrophils by the number of lymphocytes.

Subprotocols A, B, C (Parts 1, 2 and 3) and D: Urine N-telopeptide Levels

Urine N-telopeptide levels were collected centrally.

Subprotocol A, B and C (Parts 1 and 2) and D: Maximum Serum Concentration (Cmax) of Acapatamab

Serum concentrations of acapatamab were determined using a validated assay.

Time frame: Cycle 1: Days 1 to 7 and Cycle 2: Days 1 to 14 (each cycle was 28 days)

Subprotocol A, B and C (Parts 1 and 2) and D: Area Under the Curve Over the Dosing Interval (AUCtau)

Serum concentrations of acapatamab were determined using a validated assay.

Time frame: Cycle 1: Days 1 to 7 and Cycle 2: Days 1 to 14 (each cycle was 28 days)

Subprotocol A, B and C (Parts 1 and 2) and D: Time to Reach Cmax (Tmax) of Acapatamab

Serum concentrations of acapatamab were determined using a validated assay.

Time frame: Cycle 1: Days 1 to 7 and Cycle 2: Days 1 to 14 (each cycle was 28 days)

Subprotocol A, B and C (Parts 1 and 2) and D: Terminal Half-life (t1/2z) of Acapatamab

Serum concentrations of acapatamab were determined using a validated assay.

Time frame: Cycle 2: Days 1 to 14 (each cycle was 28 days)

Subprotocol C, Part 3: Number of Participants Who Experienced TEAEs and Treatment-related AEs

Time frame: From first dose of AMG 404 to the first of 30 days after last dose of acapatamab, end of trial date or the initiation of a new anticancer therapy; median (min, max) duration was 6.14 (0.14, 105.14) weeks