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

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

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).

Study Overview

• Status: Completed
• Conditions: Prostate Cancer; Metastatic Castration-resistant Prostate Cancer
• Intervention / Treatment: Drug: acapatamab; Drug: Pembrolizumab; Drug: Etanercept; Drug: Cytochrome P450 (CYP) Cocktail

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 Type: Interventional
• Enrollment (Actual): 212
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Chris OBrien Lifehouse
    • Randwick, New South Wales, Australia, 2031
      • Scientia Clinical Research Ltd
  • Victoria
    • Parkville, Victoria, Australia, 3050
      • Peter MacCallum Cancer Centre
• Austria
  • Linz, Austria, 4020
    • Ordensklinikum Linz Elisabethinen
  • Salzburg, Austria, 5020
    • Landeskrankenhaus Salzburg
  • Wien, Austria, 1090
    • Universitaetsklinikum Allgemeines Krankenhaus Wien
  • Wien, Austria, 1020
    • Krankenhaus der Barmherzigen Brueder Wien
• Belgium
  • Bruxelles, Belgium, 1200
    • Universite Catholique de Louvain Cliniques Universitaires Saint Luc
  • Gent, Belgium, 9000
    • Universitair Ziekenhuis Gent
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • BC Cancer Vancouver
• France
  • Villejuif Cedex, France, 94805
    • Institut Gustave Roussy
• Japan
  • Chiba
    • Kashiwa-shi, Chiba, Japan, 277-8577
      • National Cancer Center Hospital East
  • Kanagawa
    • Yokohama-shi, Kanagawa, Japan, 232-0024
      • Yokohama City University Medical Center
• Netherlands
  • Rotterdam, Netherlands, 3015 GD
    • Erasmus Medisch Centrum
• Singapore
  • Singapore, Singapore, 119074
    • National University Hospital
  • Singapore, Singapore, 169610
    • National Cancer Centre Singapore
• Taiwan
  • Taoyuan, Taiwan, 33305
    • Linkou Chang Gung Memorial Hospital of Chang Gung Medical Foundation
• United States
  • California
    • Campbell, California, United States, 95008
      • El Camino Hospital
    • Duarte, California, United States, 91010
      • City of Hope National Medical Center
    • Long Beach, California, United States, 90813
      • City of Hope at Long Beach Elm
    • Los Angeles, California, United States, 90095
      • University of California Los Angeles
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane Medical center
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University
  • Nevada
    • Las Vegas, Nevada, United States, 89169
      • Comprehensive Cancer Centers of Nevada
  • New York
    • New York, New York, United States, 10065
      • Weill Cornell Medical College
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

7

Arms and Interventions

Participant Group / 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 Names: 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 Names: 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 Names: PSMA Targeted Therapy; Drug: Pembrolizumab; Combined with acapatamab for investigational treatment of mCRPC; Other Names: 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 Names: PSMA Targeted Therapy; Drug: Etanercept; Prophylaxis for acapatamab-related cytokine release syndrome.; Other Names: 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 Names: 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 Names: 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 Names: PSMA Targeted Therapy; Drug: Cytochrome P450 (CYP) Cocktail; Evaluate the effect of co-administration of multiple dosing of acapatamab on plasma; Other Names: Cooperstown 5+1 CYP phenotyping cocktail

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum serum concentration (Cmax) of acapatamab	Parts 1, 2, 3, 4, 5, and 6 of the study	Up to 3 years
Minimum serum concentration (Cmin) of acapatamab	Parts 1, 2, 3, 4, 5, and 6 of the study	Up to 3 years
Area under the concentration-time curve (AUC) over the dosing interval of acapatamab	Parts 1, 2, 3, 4, 5, and 6 of the study	Up to 3 years
Accumulation ratio of acapatamab	Parts 1, 2, 3, 4, 5, and 6 of the study	Up to 3 years
Half-life of acapatamab	Parts 1, 2, 3, 4, 5, and 6 of the study	Up to 3 years
Objective response (OR)	Parts 1, 2, 3, 4, 5, and 6 of the study	Up to 3 years
Prostate-specific antigen (PSA) response	Parts 1, 2, 3, 4, 5, and 6 of the study	Up to 3 years
Duration of response (DOR) (radiographic and PSA)	Parts 1, 2, 3, 4, 5, and 6 of the study	Up to 3 years
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	Parts 1, 2 and 3 only.	Up to 3 years
Percentage of participants experiencing a response based on 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) response evaluations	Parts 1, 2 and 3 only.	Up to 3 years
Change in time to progression (radiographic and PSA)	Parts 1, 2, 3, 4, 5, and 6 of the study	Up to 3 years
Progression-free survival (PFS) (radiographic and PSA)	Parts 1, 2, 3, 4, 5, and 6 of the study.	Up to 3 years
1, 2 and 3-year overall survival (OS)	Parts 1, 2, 3, 4, 5, and 6 of the study	Up to 3 years
Percentage of participants experiencing circulating tumor cells (CTC) response	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)	Up to 3 years
Other PCWG3-recommended endpoints - time to symptomatic skeletal events	Parts 1, 2, 3, 4, 5, and 6 of the study	Up to 3 years
Other PCWG3-recommended endpoints - lactate dehydrogenase [LDH] levels	Parts 1, 2, 3, 4, 5, and 6 of the study	Up to 3 years
Other PCWG3-recommended endpoints - hemoglobin levels	Parts 1, 2, 3, 4, 5, and 6 of the study	Up to 3 years
Other PCWG3-recommended endpoints - neutrophil-to-lymphocyte ratio	Parts 1, 2, 3, 4, 5, and 6 of the study	Up to 3 years
Other PCWG3-recommended endpoints - urine N-telopeptide levels	Parts 1, 2, 3, 4, 5, and 6 of the study	Up to 3 years
Other PCWG3-recommended endpoints - alkaline phosphatase [total, bone] levels	Parts 1, 2, 3, 4, 5, and 6 of the study	Up to 3 years
Maximum serum concentration (Cmax) of acapatamab when administered with CYP enzymes	Part 6 only.	Up to 3 years
Area under the concentration-time curve over a 24-hour period (AUC24) of acapatamab when administered with CYP enzymes	Part 6 only.	Up to 3 years
Half-life of acapatamab when administered with CYP enzymes	Part 6 only.	Up to 3 years

Collaborators and Investigators

• Sponsor: Amgen
• Investigators: Study Director: MD, Amgen

Publications and helpful links

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start (Actual): February 5, 2019
• Primary Completion (Actual): July 3, 2023
• Study Completion (Actual): July 3, 2023

Study Registration Dates

• First Submitted: January 2, 2019
• First Submitted That Met QC Criteria: January 2, 2019
• First Posted (Actual): January 3, 2019

Study Record Updates

• Last Update Posted (Actual): October 18, 2023
• Last Update Submitted That Met QC Criteria: October 16, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Immunotherapy; Prostate cancer; Solid tumor; mCRPC; PSMA; Immuno-oncology; Immunooncology; Metastatic Castration-resistant Prostate Cancer; acapatamab; HLE-BiTE®; BiTE®; Bispecific T-Cell engager; PSMA Targeted Therapy
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Prostatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Gastrointestinal Agents; Antineoplastic Agents, Immunological; Etanercept; Pembrolizumab; Immune Checkpoint Inhibitors
• Other Study ID Numbers: 20180101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request
• IPD Sharing 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.
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No