Metastatic Castration-resistant Prostate Cancer, Prostate Cancer
Conditions
Keywords
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
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.
Interventions
DRUGacapatamab
Investigational immunotherapy for the treatment of metastatic castration-resistant prostate cancer
DRUGPembrolizumab
Combined with acapatamab for investigational treatment of mCRPC
DRUGEtanercept
Prophylaxis for acapatamab-related cytokine release syndrome.
DRUGCytochrome P450 (CYP) Cocktail
Evaluate the effect of co-administration of multiple dosing of acapatamab on plasma
Sponsors
Amgen
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| Accumulation ratio 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. |
| Other PCWG3-recommended endpoints - urine N-telopeptide levels | 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 |
| 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. |
| Change in time to progression (radiographic and PSA) | 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. |
| Other PCWG3-recommended endpoints - neutrophil-to-lymphocyte ratio | 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 |
Countries
Australia, Austria, Belgium, Canada, France, Japan, Netherlands, Singapore, Taiwan, United States
Outcome results
None listed