Safety, Tolerability, Pharmacokinetics, and Efficacy of Acapatamab in Subjects With mCRPC

• ClinicalTrials.gov Identifier: NCT03792841
• Recruitment Status: Active, not recruiting
• First Posted: January 3, 2019
• Last Update Posted: July 27, 2022
• Sponsor: Amgen
• Information provided by (Responsible Party): Amgen

Study Description

Brief Summary:

A phase 1 study evaluating the safety, tolerability, pharmacokinetics, and efficacy of prostate specific membrane antigen half-life extended bispecific T-cell engager acapatamab in subjects with metastatic castration-resistant prostate cancer, and to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D).

Condition or disease	Intervention/treatment	Phase
Metastatic Castration-resistant Prostate Cancer; Prostate Cancer	Drug: acapatamab; Drug: Pembrolizumab; Drug: Etanercept; Drug: Cytochrome P450 (CYP) Cocktail	Phase 1

Detailed Description:

This is a phase I, first-in-human study to evaluate the safety and tolerability of acapatamab; a half-life extended (HLE) bispecific T-cell engager (BiTE®) construct, alone and in combination with pembrolizumab, etanercept prophylaxis and cytochrome P450 (CYP) phenotyping cocktail in subjects with metastatic castration-resistant prostate cancer.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 212 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1 Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy of Prostate Specific Membrane Antigen Half-life Extended Bispecific T-cell Engager Acapatamab in Subjects With Metastatic Castration-resistant Prostate Cancer
• Actual Study Start Date: February 5, 2019
• Estimated Primary Completion Date: May 16, 2025
• Estimated Study Completion Date: May 16, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part 1 Dose-exploration: acapatamab treatment; Part 1 dose-exploration: acapatamab is administered intravenously. The dose-exploration phase of the study will estimate the MTD of acapatamab. RP2D may be identified based on emerging safety, efficacy, and pharmacodynamic data prior to reaching an MTD.	Drug: acapatamab; Investigational immunotherapy for the treatment of metastatic castration-resistant prostate cancer; Other Name: PSMA Targeted Therapy
Experimental: Part 1 Dose-expansion: acapatamab treatment; Part 1 dose-expansion: acapatamab is administered intravenously at the MTD/RP2D.	Drug: acapatamab; Investigational immunotherapy for the treatment of metastatic castration-resistant prostate cancer; Other Name: PSMA Targeted Therapy
Experimental: Part 2: acapatamab + Pembrolizumab; Part 2: acapatamab is administered intravenously at the MTD/RP2D. Pembrolizumab will be administered intravenously.	Drug: acapatamab; Investigational immunotherapy for the treatment of metastatic castration-resistant prostate cancer; Other Name: PSMA Targeted Therapy; Drug: Pembrolizumab; Combined with acapatamab for investigational treatment of mCRPC; Other Name: PD-1 inhibitor
Experimental: Part 3: acapatamab + Etanercept Prophylaxis; Part 3: acapatamab is administered intravenously at RP2D/MTD levels. Etanercept will be administered subcutaneously in cycle 1 only.	Drug: acapatamab; Investigational immunotherapy for the treatment of metastatic castration-resistant prostate cancer; Other Name: PSMA Targeted Therapy; Drug: Etanercept; Prophylaxis for acapatamab-related cytokine release syndrome.; Other Name: TNF-alpha inhibitor
Experimental: Part 4: acapatamab 24 Hour Monitoring; Part 4: acapatamab is administered intravenously at RP2D/MTD with 24-hour monitoring.	Drug: acapatamab; Investigational immunotherapy for the treatment of metastatic castration-resistant prostate cancer; Other Name: PSMA Targeted Therapy
Experimental: Part 5: acapatamab Outpatient Cohort; Part 5: acapatamab is administered intravenously at RP2D/MTD in an outpatient setting with 8-hour monitoring.	Drug: acapatamab; Investigational immunotherapy for the treatment of metastatic castration-resistant prostate cancer; Other Name: PSMA Targeted Therapy
Experimental: Part 6: acapatamab + Cytochrome P450 (CYP) Cocktail Drug Interaction; Part 6: acapatamab is administered intravenously at RP2D/MTD. A CYP phenotyping cocktail will be administered orally.	Drug: acapatamab; Investigational immunotherapy for the treatment of metastatic castration-resistant prostate cancer; Other Name: PSMA Targeted Therapy; Drug: Cytochrome P450 (CYP) Cocktail; Evaluate the effect of co-administration of multiple dosing of acapatamab on plasma; Other Name: Cooperstown 5+1 CYP phenotyping cocktail

Outcome Measures

Primary Outcome Measures :

1. Number of participants with dose-limiting toxicity [ Time Frame: Up to 3 years ]
   Parts 1, 2, 3, 4, 5, and 6 of the study
2. Number of participants with treatment-emergent adverse events [ Time Frame: Up to 3 years ]
   Parts 1, 2, 3, 4, 5, and 6 of the study
3. Number of participants with treatment-related adverse events [ Time Frame: Up to 3 years ]
   Parts 1, 2, 3, 4, 5, and 6 of the study
4. Number of participants with clinically significant changes in vital signs [ Time Frame: Up to 3 years ]
   Parts 1, 2, 3, 4, 5, and 6 of the study
5. Number of participants with clinically significant changes in electrocardiogram (ECG) [ Time Frame: Up to 3 years ]
   Parts 1, 2, 3, 4, 5, and 6 of the study
6. Number of participants with clinically significant changes in clinical laboratory tests [ Time Frame: Up to 3 years ]
   Parts 1, 2, 3, 4, 5, and 6 of the study

Secondary Outcome Measures :

1. Maximum serum concentration (Cmax) of acapatamab [ Time Frame: Up to 3 years ]
   Parts 1, 2, 3, 4, 5, and 6 of the study
2. Minimum serum concentration (Cmin) of acapatamab [ Time Frame: Up to 3 years ]
   Parts 1, 2, 3, 4, 5, and 6 of the study
3. Area under the concentration-time curve (AUC) over the dosing interval of acapatamab [ Time Frame: Up to 3 years ]
   Parts 1, 2, 3, 4, 5, and 6 of the study
4. Accumulation ratio of acapatamab [ Time Frame: Up to 3 years ]
   Parts 1, 2, 3, 4, 5, and 6 of the study
5. Half-life of acapatamab [ Time Frame: Up to 3 years ]
   Parts 1, 2, 3, 4, 5, and 6 of the study
6. Objective response (OR) [ Time Frame: Up to 3 years ]
   Parts 1, 2, 3, 4, 5, and 6 of the study
7. Prostate-specific antigen (PSA) response [ Time Frame: Up to 3 years ]
   Parts 1, 2, 3, 4, 5, and 6 of the study
8. Duration of response (DOR) (radiographic and PSA) [ Time Frame: Up to 3 years ]
   Parts 1, 2, 3, 4, 5, and 6 of the study
9. Percentage of participants experiencing a response based on 68Gallium (68Ga)-prostate-specific membrane antigen (PSMA)-11 positron emission tomography (PET)/computed tomography (CT) response evaluations [ Time Frame: Up to 3 years ]
   Parts 1, 2 and 3 only.
10. Percentage of participants experiencing a response based on 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) response evaluations [ Time Frame: Up to 3 years ]
    Parts 1, 2 and 3 only.
11. Change in time to progression (radiographic and PSA) [ Time Frame: Up to 3 years ]
    Parts 1, 2, 3, 4, 5, and 6 of the study
12. Progression-free survival (PFS) (radiographic and PSA) [ Time Frame: Up to 3 years ]
    Parts 1, 2, 3, 4, 5, and 6 of the study.
13. 1, 2 and 3-year overall survival (OS) [ Time Frame: Up to 3 years ]
    Parts 1, 2, 3, 4, 5, and 6 of the study
14. Percentage of participants experiencing circulating tumor cells (CTC) response [ Time Frame: Up to 3 years ]
    Parts 1, 2, 3, 4, 5, and 6 of the study. CTC response defined as CTC0 (reduction of CTCs > 0 to 0) or CTC conversion (≥ 5 CTCs/7.5 mL blood to ≤ 4 CTCs/7.5 mL blood)
15. Other PCWG3-recommended endpoints - time to symptomatic skeletal events [ Time Frame: Up to 3 years ]
    Parts 1, 2, 3, 4, 5, and 6 of the study
16. Other PCWG3-recommended endpoints - lactate dehydrogenase [LDH] levels [ Time Frame: Up to 3 years ]
    Parts 1, 2, 3, 4, 5, and 6 of the study
17. Other PCWG3-recommended endpoints - hemoglobin levels [ Time Frame: Up to 3 years ]
    Parts 1, 2, 3, 4, 5, and 6 of the study
18. Other PCWG3-recommended endpoints - neutrophil-to-lymphocyte ratio [ Time Frame: Up to 3 years ]
    Parts 1, 2, 3, 4, 5, and 6 of the study
19. Other PCWG3-recommended endpoints - urine N-telopeptide levels [ Time Frame: Up to 3 years ]
    Parts 1, 2, 3, 4, 5, and 6 of the study
20. Other PCWG3-recommended endpoints - alkaline phosphatase [total, bone] levels [ Time Frame: Up to 3 years ]
    Parts 1, 2, 3, 4, 5, and 6 of the study
21. Maximum serum concentration (Cmax) of acapatamab when administered with CYP enzymes [ Time Frame: Up to 3 years ]
    Part 6 only.
22. Area under the concentration-time curve over a 24-hour period (AUC24) of acapatamab when administered with CYP enzymes [ Time Frame: Up to 3 years ]
    Part 6 only.
23. Half-life of acapatamab when administered with CYP enzymes [ Time Frame: Up to 3 years ]
    Part 6 only.

Eligibility Criteria

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

Criteria

All Parts

Inclusion Criteria:

• Subject has provided informed consent prior to initiation of any study specific activities/procedures
• Subjects with histologically or cytologically confirmed mCRPC who are refractory to a novel antiandrogen therapy (abiraterone, enzalutamide, and/or apalutamide) and have failed at least 1 (but not more than 2) taxane regimens (or who are deemed medically unsuitable to be treated with a taxane regimen or have actively refused treatment with a taxane regimen). Progression on novel antiandrogen therapy may have occurred in the non-metastatic CRPC setting
• Subjects must have undergone bilateral orchiectomy or must be on continuous ADT with a gonadotropin releasing hormone (GnRH) agonist or antagonist
• Total serum testosterone </= 50 ng/dL or 1.7 nmol/L
• 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
• appearance of 2 or more new lesions in bone scan
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 1
• Life expectancy >/= 6months

Exclusion Criteria:

• Any anticancer therapy or immunotherapy within 4 weeks of start of first dose, not including luteinizing hormone-releasing hormone agonist (LHRH)/GnRH analogue (agonist/antagonist). Subjects on a stable bisophosphonate or denosumab regimen for >/= 30 days prior to randomization are eligible
• Prior PSMA-targeted therapy (subjects on prior therapy may be eligible if discussed with Amgen medical monitor prior to enrollment)
• Central nervous system (CNS) metastases, leptomeningeal disease, or spinal cord compression
• Active autoimmune disease or any other diseases requiring immunosuppressive therapy while on study
• Needing chronic systemic corticosteroid therapy (prednisone > 10 mg per day or equivalent) or any other immunosuppressive therapies (including anti-tumor necrosis factor alpha [TNF alpha] therapies) unless stopped 7 days prior to start of first dose
• Myocardial infarction, unstable angina, cardiac arrhythmia requiring medication, and/or symptomatic congestive heart failure (New York Heart Association > class II) within 12 months of first dose of acapatamab

Part 2 only:

• 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 dosing
• History or evidence of interstitial lung disease or active, non-infectious pneumonitis

Part 3 only:

- Evidence of active tuberculosis on chest radiograph within 3 months prior to the first dose of investigational product

Part 6 only:

Subjects are excluded from this cohort if any of the following additional criteria apply:

• Subjects taking strong OAT3 inhibitors (eg, probenecid) or adjust the dosing to 1 mg PO QD.
• Subjects with latent or active tuberculosis at screening

Contacts and Locations

Locations

United States, California

El Camino Hospital

Campbell, California, United States, 95008

City of Hope National Medical Center

Duarte, California, United States, 91010

City of Hope at Long Beach Elm

Long Beach, California, United States, 90813

University of California Los Angeles

Los Angeles, California, United States, 90095

United States, Georgia

Emory University

Atlanta, Georgia, United States, 30322

United States, Indiana

Indiana University

Indianapolis, Indiana, United States, 46202

United States, Iowa

University of Iowa Hospitals and Clinics

Iowa City, Iowa, United States, 52242

United States, Louisiana

Tulane Medical Center

New Orleans, Louisiana, United States, 70112

United States, Missouri

Washington University

Saint Louis, Missouri, United States, 63110

United States, Nevada

Comprehensive Cancer Centers of Nevada

Las Vegas, Nevada, United States, 89169

United States, New York

Memorial Sloan Kettering Cancer Center

New York, New York, United States, 10065

Weill Cornell Medical College

New York, New York, United States, 10065

United States, Texas

University of Texas Southwestern Medical Center

Dallas, Texas, United States, 75390

Australia, New South Wales

Chris OBrien Lifehouse

Camperdown, New South Wales, Australia, 2050

Scientia Clinical Research Ltd

Randwick, New South Wales, Australia, 2031

Australia, Victoria

Peter MacCallum Cancer Centre

Parkville, Victoria, Australia, 3050

Austria

Ordensklinikum Linz Elisabethinen

Linz, Austria, 4020

Landeskrankenhaus Salzburg

Salzburg, Austria, 5020

Krankenhaus der Barmherzigen Brueder Wien

Wien, Austria, 1020

Universitaetsklinikum Allgemeines Krankenhaus Wien

Wien, Austria, 1090

Belgium

Universite Catholique de Louvain Cliniques Universitaires Saint Luc

Bruxelles, Belgium, 1200

Universitair Ziekenhuis Gent

Gent, Belgium, 9000

Canada, British Columbia

BC Cancer Vancouver

Vancouver, British Columbia, Canada, V5Z 4E6

France

Institut Gustave Roussy

Villejuif Cedex, France, 94805

Japan

National Cancer Center Hospital East

Kashiwa-shi, Chiba, Japan, 277-8577

Yokohama City University Medical Center

Yokohama-shi, Kanagawa, Japan, 232-0024

Netherlands

Erasmus Medisch Centrum

Rotterdam, Netherlands, 3015 GD

Singapore

National University Hospital

Singapore, Singapore, 119074

National Cancer Centre Singapore

Singapore, Singapore, 169610

Taiwan

Linkou Chang Gung Memorial Hospital of Chang Gung Medical Foundation

Taoyuan, Taiwan, 33305

Sponsors and Collaborators

Amgen

Investigators

• Study Director: MD; Amgen

More Information

Additional Information:

AmgenTrials clinical trials website 

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT03792841
• Other Study ID Numbers: 20180101
• First Posted: January 3, 2019
• Last Update Posted: July 27, 2022
• Last Verified: July 2022

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 (or other new use) 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, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. 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: https://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; HLE-BiTE®; mCRPC; Metastatic Castration-resistant Prostate Cancer; Prostate cancer; PSMA; BiTE®; Bispecific T-Cell engager; Immunotherapy; Immuno-oncology; Immunooncology; Solid tumor; PSMA Targeted Therapy

Additional relevant MeSH terms:

Prostatic Neoplasms; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Prostatic Diseases; Etanercept; Pembrolizumab; Immune Checkpoint Inhibitors; Antineoplastic Agents, Immunological; Antineoplastic Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents; Gastrointestinal Agents; Immunosuppressive Agents; Immunologic Factors; Molecular Mechanisms of Pharmacological Action