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

• ClinicalTrials.gov Identifier: NCT04631601
• Recruitment Status: Active, not recruiting
• First Posted: November 17, 2020
• Last Update Posted: March 9, 2023
• Sponsor: Amgen
• Information provided by (Responsible Party): Amgen

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Metastatic Castration-resistant Prostate Cancer	Drug: Acapatamab; Drug: Enzalutamide; Drug: Abiraterone; Drug: AMG 404	Phase 1; Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 136 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Master Protocol Evaluating the Safety and Efficacy of Therapies for Metastatic Castration-resistant Prostate Cancer (mCRPC)
• Actual Study Start Date: January 15, 2021
• Estimated Primary Completion Date: November 7, 2023
• Estimated Study Completion Date: November 7, 2023

Arms and Interventions

Arm	Intervention/treatment
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.	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
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.	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
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.	Drug: Acapatamab; Acapatamab will be administered as an intravenous (IV) infusion.; Other Name: PSMA targeted therapy; Drug: Abiraterone; Abiraterone will be administered orally.; Other Name: Cytochrome P450 (CYP)17 inhibitor
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.	Drug: Acapatamab; Acapatamab will be administered as an intravenous (IV) infusion.; Other Name: PSMA targeted therapy; Drug: Abiraterone; Abiraterone will be administered orally.; Other Name: Cytochrome P450 (CYP)17 inhibitor
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.	Drug: Acapatamab; Acapatamab will be administered as an intravenous (IV) infusion.; Other Name: PSMA targeted therapy; Drug: AMG 404; AMG 404 will be administered as an intravenous (IV) infusion.; Other Name: PD-1 inhibitor
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.	Drug: Acapatamab; Acapatamab will be administered as an intravenous (IV) infusion.; Other Name: PSMA targeted therapy; Drug: AMG 404; AMG 404 will be administered as an intravenous (IV) infusion.; Other Name: PD-1 inhibitor
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.	Drug: AMG 404; AMG 404 will be administered as an intravenous (IV) infusion.; Other Name: PD-1 inhibitor
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.	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
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.	Drug: Acapatamab; Acapatamab will be administered as an intravenous (IV) infusion.; Other Name: PSMA targeted therapy; Drug: Abiraterone; Abiraterone will be administered orally.; Other Name: Cytochrome P450 (CYP)17 inhibitor
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.	Drug: Acapatamab; Acapatamab will be administered as an intravenous (IV) infusion.; Other Name: PSMA targeted therapy; Drug: AMG 404; AMG 404 will be administered as an intravenous (IV) infusion.; Other Name: PD-1 inhibitor
Experimental: Acapatamab Monotherapy; Acapatamab monotherapy is being conducted to evaluate safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and efficacy of Acapatamab in subjects with mCRPC.	Drug: Acapatamab; Acapatamab will be administered as an intravenous (IV) infusion.; Other Name: PSMA targeted therapy

Outcome Measures

Primary Outcome Measures :

1. 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.

2. Number of participants who experience one or more treatment-emergent adverse events (TEAEs) [ Time Frame: Up to 3 years ]
3. Number of participants who experience one or more treatment-related adverse events [ Time Frame: Up to 3 years ]
4. Number of participants who experience a clinically significant change in vital signs [ Time Frame: Up to 3 years ]
5. Number of participants who experience a clinically significant change in clinical laboratory tests [ Time Frame: Up to 3 years ]

Secondary Outcome Measures :

1. 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 ]
2. Number of participants who experience circulating tumor cell (CTC) response [ Time Frame: Up to 3 years ]
3. Number of participants who experience prostate-specific antigen (PSA) response rate [ Time Frame: Up to 3 years ]
4. Duration of response [ Time Frame: Up to 3 years ]
5. Overall survival (OS) [ Time Frame: Up to 3 years ]
6. Progression-free survival [ Time Frame: Up to 3 years ]
7. Time to progression [ Time Frame: Up to 3 years ]
8. Time to subsequent therapy [ Time Frame: Up to 3 years ]
9. Maximum plasma concentration (Cmax) [ Time Frame: Up to 3 years ]
10. Minimum plasma concentration (Cmin) [ Time Frame: Up to 3 years ]
11. Area under the concentration-time curve (AUC) [ Time Frame: Up to 3 years ]
12. Accumulation ratio based on area under the concentration-time curve (AUC) [ Time Frame: Up to 3 years ]
13. Half-life (t1/2) [ Time Frame: Up to 3 years ]
14. 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 ]
15. 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 ]
16. Time to symptomatic skeletal events [ Time Frame: Up to 3 years ]
17. Concentration of alkaline phosphatase [ Time Frame: Up to 3 years ]
18. Concentration of lactate dehydrogenase (LDH) [ Time Frame: Up to 3 years ]
19. Concentration of hemoglobin [ Time Frame: Up to 3 years ]
20. Neutrophil-to-lymphocyte ratio [ Time Frame: Up to 3 years ]
21. Concentration of N-telopeptide in the urine [ Time Frame: Up to 3 years ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 99 Years (Adult, Older Adult)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, Alabama

University of Alabama at Birmingham

Birmingham, Alabama, United States, 35294

United States, California

University of California at Irvine Medical Center

Orange, California, United States, 92868

University of California San Francisco Mission Bay Campus

San Francisco, California, United States, 94158

United States, Illinois

University of Chicago

Chicago, Illinois, United States, 60637

United States, Kentucky

Norton Cancer Institute

Louisville, Kentucky, United States, 40207

United States, Texas

University of Texas Southwestern Medical Center

Dallas, Texas, United States, 75390

University of Texas MD Anderson Cancer Center

Houston, Texas, United States, 77030

Australia, New South Wales

St Vincents Hospital Sydney

Darlinghurst, New South Wales, Australia, 2010

Denmark

Rigshospitalet

Kobenhavn O, Denmark, 2100

Spain

Clinica Universidad de Navarra

Pamplona, Navarra, Spain, 31008

Sweden

Skanes universitetssjukhus

Lund, Sweden, 221 85

Karolinska Universitetssjukhuset Solna

Stockholm, Sweden, 171 76

Akademiska sjukhuset

Uppsala, Sweden, 75185

United Kingdom

Royal Marsden Hospital

Sutton, United Kingdom, SM2 5PT

Sponsors and Collaborators

Amgen

Investigators

• Study Director: MD; Amgen

More Information

Additional Information:

AmgenTrials clinical trials website 

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT04631601
• Other Study ID Numbers: 20190505; 2020-001305-23 ( EudraCT Number )
• First Posted: November 17, 2020
• Last Update Posted: March 9, 2023
• Last Verified: March 2023

Individual Participant Data (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; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); 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

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

Keywords provided by Amgen:

Acapatamab; HALF-LIFE EXTENDED (HLE) BITE; mCRPC; Metastatic Castration-resistant Prostate Cancer; 68; 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

Additional relevant MeSH terms:

Prostatic Neoplasms; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Prostatic Diseases; Immune Checkpoint Inhibitors; Androgens; Androgen Receptor Antagonists; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Androgen Antagonists; Hormone Antagonists