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

• ClinicalTrials.gov Identifier: NCT04631601
• Recruitment Status: Terminated
• First Posted: November 17, 2020
• Last Update Posted: November 7, 2023
• Sponsor: Amgen
• Information provided by (Responsible Party): Amgen

Tracking Information

• First Submitted Date: November 13, 2020
• First Posted Date: November 17, 2020
• Last Update Posted Date: November 7, 2023
• Actual Study Start Date: January 15, 2021
• Actual Primary Completion Date: October 23, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 14, 2021)

• Dose exploration only: Number of participants who experience dose limiting toxicities (DLTs) [ Time Frame: Up to 3 years ]
  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.
• Number of participants who experience one or more treatment-emergent adverse events (TEAEs) [ Time Frame: Up to 3 years ]
• Number of participants who experience one or more treatment-related adverse events [ Time Frame: Up to 3 years ]
• Number of participants who experience a clinically significant change in vital signs [ Time Frame: Up to 3 years ]
• Number of participants who experience a clinically significant change in clinical laboratory tests [ Time Frame: Up to 3 years ]

Original Primary Outcome Measures (submitted: November 13, 2020)

• Number of participants who experience dose limiting toxicities (DLTs) [ Time Frame: Up to 3 years ]
  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 AMG 160. 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 AMG 160 with an evaluable DLT endpoint. 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.
• Number of participants who experience one or more treatment-emergent adverse events (TEAEs) [ Time Frame: Up to 3 years ]
  Parts 1, 2 and 3 of the study
• Number of participants who experience one or more treatment-related adverse events [ Time Frame: Up to 3 years ]
  Parts 1, 2 and 3 of the study
• Number of participants who experience a clinically significant change in vital signs [ Time Frame: Up to 3 years ]
  Parts 1, 2 and 3 of the study
• Number of participants who experience a clinically significant change in clinical laboratory tests [ Time Frame: Up to 3 years ]
  Parts 1, 2 and 3 of the study

Current Secondary Outcome Measures (submitted: September 15, 2021)

• Objective response rate per response evaluation criteria in solid tumors (RECIST) 1.1 with prostate cancer working group 3 (PCWG3) modifications [ Time Frame: Up to 3 years ]
• Number of participants who experience circulating tumor cell (CTC) response [ Time Frame: Up to 3 years ]
• Number of participants who experience prostate-specific antigen (PSA) response rate [ Time Frame: Up to 3 years ]
• Duration of response [ Time Frame: Up to 3 years ]
• Overall survival (OS) [ Time Frame: Up to 3 years ]
• Progression-free survival [ Time Frame: Up to 3 years ]
• Time to progression [ Time Frame: Up to 3 years ]
• Time to subsequent therapy [ Time Frame: Up to 3 years ]
• Maximum plasma concentration (Cmax) [ Time Frame: Up to 3 years ]
• Minimum plasma concentration (Cmin) [ Time Frame: Up to 3 years ]
• Area under the concentration-time curve (AUC) [ Time Frame: Up to 3 years ]
• Accumulation ratio based on area under the concentration-time curve (AUC) [ Time Frame: Up to 3 years ]
• Half-life (t1/2) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: Baseline to 3 years ]
• Time to symptomatic skeletal events [ Time Frame: Up to 3 years ]
• Concentration of alkaline phosphatase [ Time Frame: Up to 3 years ]
• Concentration of lactate dehydrogenase (LDH) [ Time Frame: Up to 3 years ]
• Concentration of hemoglobin [ Time Frame: Up to 3 years ]
• Neutrophil-to-lymphocyte ratio [ Time Frame: Up to 3 years ]
• Concentration of N-telopeptide in the urine [ Time Frame: Up to 3 years ]

Original Secondary Outcome Measures (submitted: November 13, 2020)

• Objective response rate per response evaluation criteria in solid tumors (RECIST) 1.1 with prostate cancer working group 3 (PCWG3) modifications [ Time Frame: Up to 3 years ]
  Parts 1, 2 and 3 of the study
• Number of participants who experience circulating tumor cell (CTC) response [ Time Frame: Up to 3 years ]
  Parts 1, 2 and 3 of the study
• Number of participants who experience prostate-specific antigen (PSA) response rate [ Time Frame: Up to 3 years ]
  Parts 1, 2 and 3 of the study
• Duration of response [ Time Frame: Up to 3 years ]
  Parts 1, 2 and 3 of the study
• Overall survival (OS) [ Time Frame: Up to 3 years ]
  Parts 1, 2 and 3 of the study
• Progression-free survival [ Time Frame: Up to 3 years ]
  Parts 1, 2 and 3 of the study
• Time to progression [ Time Frame: Up to 3 years ]
  Parts 1, 2 and 3 of the study
• Time to subsequent therapy [ Time Frame: Up to 3 years ]
  Parts 1, 2 and 3 of the study
• Maximum plasma concentration (Cmax) [ Time Frame: Up to 3 years ]
  Parts 1, 2 and 3 of the study
• Minimum plasma concentration (Cmin) [ Time Frame: Up to 3 years ]
  Parts 1, 2 and 3 of the study
• Area under the concentration-time curve (AUC) [ Time Frame: Up to 3 years ]
  Parts 1, 2 and 3 of the study
• Accumulation ratio based on area under the concentration-time curve (AUC) [ Time Frame: Up to 3 years ]
  Parts 1, 2 and 3 of the study
• Half-life (t1/2) [ Time Frame: Up to 3 years ]
  Parts 1, 2 and 3 of the study
• 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) [ Time Frame: Baseline up to 3 years ]
  Parts 1, 2 and 3 of the study
• 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) [ Time Frame: Baseline to 3 years ]
  Parts 1, 2 and 3 of the study
• Time to symptomatic skeletal events [ Time Frame: Up to 3 years ]
  Parts 1, 2 and 3 of the study
• Concentration of alkaline phosphatase [ Time Frame: Up to 3 years ]
  Parts 1, 2 and 3 of the study
• Concentration of lactate dehydrogenase (LDH) [ Time Frame: Up to 3 years ]
  Parts 1, 2 and 3 of the study
• Concentration of hemoglobin [ Time Frame: Up to 3 years ]
  Parts 1, 2 and 3 of the study
• Neutrophil-to-lymphocyte ratio [ Time Frame: Up to 3 years ]
  Parts 1, 2 and 3 of the study
• Concentration of N-telopeptide in the urine [ Time Frame: Up to 3 years ]
  Parts 1, 2 and 3 of the study

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Safety and Efficacy of Therapies for Metastatic Castration-resistant Prostate Cancer (mCRPC)
• Official Title: A Master Protocol Evaluating the Safety and Efficacy of Therapies for Metastatic Castration-resistant Prostate Cancer (mCRPC)
• Brief Summary: 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: 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
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Metastatic Castration-resistant Prostate Cancer

Intervention

• Drug: Acapatamab
  Acapatamab will be administered as an intravenous (IV) infusion.
  Other Name: PSMA targeted therapy
• Drug: Enzalutamide
  Enzalutamide will be administered orally.
  Other Name: Androgen receptor inhibitor
• Drug: Abiraterone
  Abiraterone will be administered orally.
  Other Name: Cytochrome P450 (CYP)17 inhibitor
• Drug: AMG 404
  AMG 404 will be administered as an intravenous (IV) infusion.
  Other Name: PD-1 inhibitor

Study Arms

• Experimental: Acapatamab and Enzalutamide: Dose Exploration
  The dose-exploration part of the study will estimate the MTD/recommended phase 2 dose (RP2D) of Acapatamab in combination with enzalutamide.
  Interventions:

  • Drug: Acapatamab
  • Drug: Enzalutamide
• Experimental: Acapatamab and Enzalutamide: Dose Expansion
  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.
  Interventions:

  • Drug: Acapatamab
  • Drug: Enzalutamide
• Experimental: Acapatamab and Abiraterone: Dose Exploration
  The dose exploration part of the study will estimate the MTD/recommended phase 2 dose (RP2D) of Acapatamab in combination with abiraterone.
  Interventions:

  • Drug: Acapatamab
  • Drug: Abiraterone
• Experimental: Acapatamab and Abiraterone: Dose Expansion
  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.
  Interventions:

  • Drug: Acapatamab
  • Drug: Abiraterone
• Experimental: Acapatamab and AMG 404: Dose Exploration
  The dose-exploration part of the study will estimate the MTD/RP2D of Acapatamab in combination with AMG 404.
  Interventions:

  • Drug: Acapatamab
  • Drug: AMG 404
• Experimental: Acapatamab and AMG 404: Dose Expansion
  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.
  Interventions:

  • Drug: Acapatamab
  • Drug: AMG 404
• Active Comparator: AMG 404 Monotherapy
  AMG 404 monotherapy is being conducted to evaluate the preliminary anti-tumor activity of PD-1 inhibition in the mCRPC population.
  Intervention: Drug: AMG 404
• Experimental: Acapatamab and Enzalutamide: Dose Expansion Asia Cohort
  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.
  Interventions:

  • Drug: Acapatamab
  • Drug: Enzalutamide
• Experimental: Acapatamab and Abiraterone: Dose Expansion Asia Cohort
  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.
  Interventions:

  • Drug: Acapatamab
  • Drug: Abiraterone
• Experimental: Acapatamab and AMG 404: Dose Expansion Asia Cohort
  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.
  Interventions:

  • Drug: Acapatamab
  • Drug: AMG 404
• Experimental: Acapatamab Monotherapy
  Acapatamab monotherapy is being conducted to evaluate safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and efficacy of Acapatamab in subjects with mCRPC.
  Intervention: Drug: Acapatamab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: May 19, 2023): 65
• Original Estimated Enrollment (submitted: November 13, 2020): 105
• Actual Study Completion Date: October 23, 2023
• Actual Primary Completion Date: October 23, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 18 Years to 99 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Denmark, Spain, Sweden, United Kingdom, United States

Administrative Information

• NCT Number: NCT04631601
• Other Study ID Numbers: 20190505; 2020-001305-23 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
• Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors. If not approved, a Data Sharing Independent Review Panel will arbitrate and make the final decision. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the URL below.
• URL: http://www.amgen.com/datasharing

• Current Responsible Party: Amgen
• Original Responsible Party: Same as current
• Current Study Sponsor: Amgen
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: MD; Amgen

• PRS Account: Amgen
• Verification Date: November 2023