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: December 8, 2022
• Sponsor: Amgen
• Information provided by (Responsible Party): Amgen

Tracking Information

• First Submitted Date: January 2, 2019
• First Posted Date: January 3, 2019
• Last Update Posted Date: December 8, 2022
• Actual Study Start Date: February 5, 2019
• Estimated Primary Completion Date: May 16, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 15, 2020)

• Number of participants with dose-limiting toxicity [ Time Frame: Up to 3 years ]
  Parts 1, 2, 3, 4, 5, and 6 of the study
• 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
• 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
• 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
• 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
• 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

Original Primary Outcome Measures (submitted: January 2, 2019)

Subject incidence of dose-limiting toxicity [ Time Frame: Up to 3 years ]

Number of dose limiting toxicities

Current Secondary Outcome Measures (submitted: September 29, 2021)

• Maximum serum concentration (Cmax) of acapatamab [ Time Frame: Up to 3 years ]
  Parts 1, 2, 3, 4, 5, and 6 of the study
• Minimum serum concentration (Cmin) of acapatamab [ Time Frame: 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 [ Time Frame: Up to 3 years ]
  Parts 1, 2, 3, 4, 5, and 6 of the study
• Accumulation ratio of acapatamab [ Time Frame: Up to 3 years ]
  Parts 1, 2, 3, 4, 5, and 6 of the study
• Half-life of acapatamab [ Time Frame: Up to 3 years ]
  Parts 1, 2, 3, 4, 5, and 6 of the study
• Objective response (OR) [ Time Frame: Up to 3 years ]
  Parts 1, 2, 3, 4, 5, and 6 of the study
• Prostate-specific antigen (PSA) response [ Time Frame: Up to 3 years ]
  Parts 1, 2, 3, 4, 5, and 6 of the study
• Duration of response (DOR) (radiographic and PSA) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Up to 3 years ]
  Parts 1, 2 and 3 only.
• 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
• Progression-free survival (PFS) (radiographic and PSA) [ Time Frame: Up to 3 years ]
  Parts 1, 2, 3, 4, 5, and 6 of the study.
• 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
• 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)
• 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
• 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
• Other PCWG3-recommended endpoints - hemoglobin levels [ Time Frame: Up to 3 years ]
  Parts 1, 2, 3, 4, 5, and 6 of the study
• 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
• 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
• 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
• Maximum serum concentration (Cmax) of acapatamab when administered with CYP enzymes [ Time Frame: 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 [ Time Frame: Up to 3 years ]
  Part 6 only.
• Half-life of acapatamab when administered with CYP enzymes [ Time Frame: Up to 3 years ]
  Part 6 only.

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Safety, Tolerability, Pharmacokinetics, and Efficacy of Acapatamab in Subjects With mCRPC
• 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
• 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.
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Metastatic Castration-resistant Prostate Cancer
• Prostate Cancer

Intervention

• 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
• Drug: Etanercept
  Prophylaxis for acapatamab-related cytokine release syndrome.
  Other Name: TNF-alpha inhibitor
• 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

Study Arms

• 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.
  Intervention: Drug: acapatamab
• Experimental: Part 1 Dose-expansion: acapatamab treatment
  Part 1 dose-expansion: acapatamab is administered intravenously at the MTD/RP2D.
  Intervention: Drug: acapatamab
• Experimental: Part 2: acapatamab + Pembrolizumab
  Part 2: acapatamab is administered intravenously at the MTD/RP2D. Pembrolizumab will be administered intravenously.
  Interventions:

  • Drug: acapatamab
  • Drug: Pembrolizumab
• 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.
  Interventions:

  • Drug: acapatamab
  • Drug: Etanercept
• Experimental: Part 4: acapatamab 24 Hour Monitoring
  Part 4: acapatamab is administered intravenously at RP2D/MTD with 24-hour monitoring.
  Intervention: Drug: acapatamab
• Experimental: Part 5: acapatamab Outpatient Cohort
  Part 5: acapatamab is administered intravenously at RP2D/MTD in an outpatient setting with 8-hour monitoring.
  Intervention: Drug: acapatamab
• 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.
  Interventions:

  • Drug: acapatamab
  • Drug: Cytochrome P450 (CYP) Cocktail

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: July 26, 2022): 212
• Original Estimated Enrollment (submitted: January 2, 2019): 60
• Estimated Study Completion Date: May 16, 2025
• Estimated Primary Completion Date: May 16, 2025 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Austria, Belgium, Canada, France, Japan, Netherlands, Singapore, Taiwan, United States

Administrative Information

• NCT Number: NCT03792841
• Other Study ID Numbers: 20180101
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

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

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
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: 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

• Current Responsible Party: Amgen
• Original Responsible Party: Same as current
• Current Study Sponsor: Amgen
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: MD; Amgen

• PRS Account: Amgen
• Verification Date: December 2022