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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Metastatic Castration-resistant Prostate Cancer, Prostate Cancer

Intervention / Treatment
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* Drug: acapatamab
* Drug: Pembrolizumab
* Drug: Etanercept
* Drug: Cytochrome P450 (CYP) Cocktail


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 Dose-exploration: acapatamab treatment<br>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<br>* Investigational immunotherapy for the treatment of metastatic castration-resistant prostate cancer<br>* Other names: PSMA Targeted Therapy;|
| Experimental: Part 1 Dose-expansion: acapatamab treatment<br>Part 1 dose-expansion: acapatamab is administered intravenously at the MTD/RP2D. | Drug: acapatamab<br>* Investigational immunotherapy for the treatment of metastatic castration-resistant prostate cancer<br>* Other names: PSMA Targeted Therapy;|
| Experimental: Part 2: acapatamab + Pembrolizumab<br>Part 2: acapatamab is administered intravenously at the MTD/RP2D. Pembrolizumab will be administered intravenously. | Drug: acapatamab<br>* Investigational immunotherapy for the treatment of metastatic castration-resistant prostate cancer<br>* Other names: PSMA Targeted Therapy;Drug: Pembrolizumab<br>* Combined with acapatamab for investigational treatment of mCRPC<br>* Other names: PD-1 inhibitor;|
| Experimental: Part 3: acapatamab + Etanercept Prophylaxis<br>Part 3: acapatamab is administered intravenously at RP2D/MTD levels. Etanercept will be administered subcutaneously in cycle 1 only. | Drug: acapatamab<br>* Investigational immunotherapy for the treatment of metastatic castration-resistant prostate cancer<br>* Other names: PSMA Targeted Therapy;Drug: Etanercept<br>* Prophylaxis for acapatamab-related cytokine release syndrome.<br>* Other names: TNF-alpha inhibitor;|
| Experimental: Part 4: acapatamab 24 Hour Monitoring<br>Part 4: acapatamab is administered intravenously at RP2D/MTD with 24-hour monitoring. | Drug: acapatamab<br>* Investigational immunotherapy for the treatment of metastatic castration-resistant prostate cancer<br>* Other names: PSMA Targeted Therapy;|
| Experimental: Part 5: acapatamab Outpatient Cohort<br>Part 5: acapatamab is administered intravenously at RP2D/MTD in an outpatient setting with 8-hour monitoring. | Drug: acapatamab<br>* Investigational immunotherapy for the treatment of metastatic castration-resistant prostate cancer<br>* Other names: PSMA Targeted Therapy;|
| Experimental: Part 6: acapatamab + Cytochrome P450 (CYP) Cocktail Drug Interaction<br>Part 6: acapatamab is administered intravenously at RP2D/MTD. A CYP phenotyping cocktail will be administered orally. | Drug: acapatamab<br>* Investigational immunotherapy for the treatment of metastatic castration-resistant prostate cancer<br>* Other names: PSMA Targeted Therapy;Drug: Cytochrome P450 (CYP) Cocktail<br>* Evaluate the effect of co-administration of multiple dosing of acapatamab on plasma<br>* Other names: Cooperstown 5+1 CYP phenotyping cocktail;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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