Safety, Tolerability, Pharmacokinetics, and Efficacy of Acapatamab in Subjects With mCRPC
- Conditions
- Metastatic Castration-resistant Prostate CancerProstate Cancer
- Interventions
- Registration Number
- NCT03792841
- Lead Sponsor
- Amgen
- 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).
- 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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- Male
- Target Recruitment
- 212
- 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
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Part 1 Dose-expansion: acapatamab treatment acapatamab Part 1 dose-expansion: acapatamab is administered intravenously at the MTD/RP2D. Part 5: acapatamab Outpatient Cohort acapatamab Part 5: acapatamab is administered intravenously at RP2D/MTD in an outpatient setting with 8-hour monitoring. Part 6: acapatamab + Cytochrome P450 (CYP) Cocktail Drug Interaction acapatamab Part 6: acapatamab is administered intravenously at RP2D/MTD. A CYP phenotyping cocktail will be administered orally. Part 6: acapatamab + Cytochrome P450 (CYP) Cocktail Drug Interaction Cytochrome P450 (CYP) Cocktail Part 6: acapatamab is administered intravenously at RP2D/MTD. A CYP phenotyping cocktail will be administered orally. Part 1 Dose-exploration: acapatamab treatment acapatamab 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. Part 2: acapatamab + Pembrolizumab acapatamab Part 2: acapatamab is administered intravenously at the MTD/RP2D. Pembrolizumab will be administered intravenously. Part 3: acapatamab + Etanercept Prophylaxis acapatamab Part 3: acapatamab is administered intravenously at RP2D/MTD levels. Etanercept will be administered subcutaneously in cycle 1 only. Part 4: acapatamab 24 Hour Monitoring acapatamab Part 4: acapatamab is administered intravenously at RP2D/MTD with 24-hour monitoring. Part 2: acapatamab + Pembrolizumab Pembrolizumab Part 2: acapatamab is administered intravenously at the MTD/RP2D. Pembrolizumab will be administered intravenously. Part 3: acapatamab + Etanercept Prophylaxis Etanercept Part 3: acapatamab is administered intravenously at RP2D/MTD levels. Etanercept will be administered subcutaneously in cycle 1 only.
- Primary Outcome Measures
Name Time Method Number of participants with dose-limiting toxicity Up to 3 years Parts 1, 2, 3, 4, 5, and 6 of the study
Number of participants with treatment-emergent adverse events Up to 3 years Parts 1, 2, 3, 4, 5, and 6 of the study
Number of participants with treatment-related adverse events Up to 3 years Parts 1, 2, 3, 4, 5, and 6 of the study
Number of participants with clinically significant changes in vital signs Up to 3 years Parts 1, 2, 3, 4, 5, and 6 of the study
Number of participants with clinically significant changes in electrocardiogram (ECG) Up to 3 years Parts 1, 2, 3, 4, 5, and 6 of the study
Number of participants with clinically significant changes in clinical laboratory tests Up to 3 years Parts 1, 2, 3, 4, 5, and 6 of the study
- Secondary Outcome Measures
Name Time Method Accumulation ratio of acapatamab Up to 3 years Parts 1, 2, 3, 4, 5, and 6 of the study
Maximum serum concentration (Cmax) of acapatamab Up to 3 years Parts 1, 2, 3, 4, 5, and 6 of the study
Minimum serum concentration (Cmin) of acapatamab Up to 3 years Parts 1, 2, 3, 4, 5, and 6 of the study
Area under the concentration-time curve (AUC) over the dosing interval of acapatamab Up to 3 years Parts 1, 2, 3, 4, 5, and 6 of the study
Half-life of acapatamab Up to 3 years Parts 1, 2, 3, 4, 5, and 6 of the study
Objective response (OR) Up to 3 years Parts 1, 2, 3, 4, 5, and 6 of the study
Prostate-specific antigen (PSA) response Up to 3 years Parts 1, 2, 3, 4, 5, and 6 of the study
Duration of response (DOR) (radiographic and PSA) Up to 3 years Parts 1, 2, 3, 4, 5, and 6 of the study
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 Up to 3 years Parts 1, 2 and 3 only.
Percentage of participants experiencing a response based on 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) response evaluations Up to 3 years Parts 1, 2 and 3 only.
Change in time to progression (radiographic and PSA) Up to 3 years Parts 1, 2, 3, 4, 5, and 6 of the study
Progression-free survival (PFS) (radiographic and PSA) Up to 3 years Parts 1, 2, 3, 4, 5, and 6 of the study.
1, 2 and 3-year overall survival (OS) Up to 3 years Parts 1, 2, 3, 4, 5, and 6 of the study
Percentage of participants experiencing circulating tumor cells (CTC) response 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)
Other PCWG3-recommended endpoints - time to symptomatic skeletal events Up to 3 years Parts 1, 2, 3, 4, 5, and 6 of the study
Other PCWG3-recommended endpoints - lactate dehydrogenase [LDH] levels Up to 3 years Parts 1, 2, 3, 4, 5, and 6 of the study
Other PCWG3-recommended endpoints - hemoglobin levels Up to 3 years Parts 1, 2, 3, 4, 5, and 6 of the study
Other PCWG3-recommended endpoints - neutrophil-to-lymphocyte ratio Up to 3 years Parts 1, 2, 3, 4, 5, and 6 of the study
Other PCWG3-recommended endpoints - urine N-telopeptide levels Up to 3 years Parts 1, 2, 3, 4, 5, and 6 of the study
Other PCWG3-recommended endpoints - alkaline phosphatase [total, bone] levels Up to 3 years Parts 1, 2, 3, 4, 5, and 6 of the study
Maximum serum concentration (Cmax) of acapatamab when administered with CYP enzymes Up to 3 years Part 6 only.
Area under the concentration-time curve over a 24-hour period (AUC24) of acapatamab when administered with CYP enzymes Up to 3 years Part 6 only.
Half-life of acapatamab when administered with CYP enzymes Up to 3 years Part 6 only.
Trial Locations
- Locations (30)
City of Hope at Long Beach Elm
🇺🇸Long Beach, California, United States
El Camino Hospital
🇺🇸Campbell, California, United States
Indiana University
🇺🇸Indianapolis, Indiana, United States
City of Hope National Medical Center
🇺🇸Duarte, California, United States
University of California Los Angeles
🇺🇸Los Angeles, California, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Universite Catholique de Louvain Cliniques Universitaires Saint Luc
🇧🇪Bruxelles, Belgium
Universitair Ziekenhuis Gent
🇧🇪Gent, Belgium
Erasmus Medisch Centrum
🇳🇱Rotterdam, Netherlands
Institut Gustave Roussy
🇫🇷Villejuif Cedex, France
Emory University
🇺🇸Atlanta, Georgia, United States
Tulane Medical Center
🇺🇸New Orleans, Louisiana, United States
University of Iowa Hospitals and Clinics
🇺🇸Iowa City, Iowa, United States
Washington University
🇺🇸Saint Louis, Missouri, United States
University of Texas Southwestern Medical Center
🇺🇸Dallas, Texas, United States
Comprehensive Cancer Centers of Nevada
🇺🇸Las Vegas, Nevada, United States
Chris OBrien Lifehouse
🇦🇺Camperdown, New South Wales, Australia
Weill Cornell Medical College
🇺🇸New York, New York, United States
Peter MacCallum Cancer Centre
🇦🇺Parkville, Victoria, Australia
Krankenhaus der Barmherzigen Brueder Wien
🇦🇹Wien, Austria
Landeskrankenhaus Salzburg
🇦🇹Salzburg, Austria
Scientia Clinical Research Ltd
🇦🇺Randwick, New South Wales, Australia
Ordensklinikum Linz Elisabethinen
🇦🇹Linz, Austria
Universitaetsklinikum Allgemeines Krankenhaus Wien
🇦🇹Wien, Austria
BC Cancer Vancouver
🇨🇦Vancouver, British Columbia, Canada
National Cancer Center Hospital East
🇯🇵Kashiwa-shi, Chiba, Japan
Yokohama City University Medical Center
🇯🇵Yokohama-shi, Kanagawa, Japan
Linkou Chang Gung Memorial Hospital of Chang Gung Medical Foundation
🇨🇳Taoyuan, Taiwan
National Cancer Centre Singapore
🇸🇬Singapore, Singapore
National University Hospital
🇸🇬Singapore, Singapore