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
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- Amgen
- 入组人数
- 212
- 试验地点
- 30
- 主要终点
- Number of participants with dose-limiting toxicity
研究概览
简要总结
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).
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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.
干预措施: acapatamab (Drug)
Part 1 Dose-expansion: acapatamab treatment
Part 1 dose-expansion: acapatamab is administered intravenously at the MTD/RP2D.
干预措施: acapatamab (Drug)
Part 2: acapatamab + Pembrolizumab
Part 2: acapatamab is administered intravenously at the MTD/RP2D. Pembrolizumab will be administered intravenously.
干预措施: acapatamab (Drug)
Part 2: acapatamab + Pembrolizumab
Part 2: acapatamab is administered intravenously at the MTD/RP2D. Pembrolizumab will be administered intravenously.
干预措施: Pembrolizumab (Drug)
Part 3: acapatamab + Etanercept Prophylaxis
Part 3: acapatamab is administered intravenously at RP2D/MTD levels. Etanercept will be administered subcutaneously in cycle 1 only.
干预措施: acapatamab (Drug)
Part 3: acapatamab + Etanercept Prophylaxis
Part 3: acapatamab is administered intravenously at RP2D/MTD levels. Etanercept will be administered subcutaneously in cycle 1 only.
干预措施: Etanercept (Drug)
Part 4: acapatamab 24 Hour Monitoring
Part 4: acapatamab is administered intravenously at RP2D/MTD with 24-hour monitoring.
干预措施: acapatamab (Drug)
Part 5: acapatamab Outpatient Cohort
Part 5: acapatamab is administered intravenously at RP2D/MTD in an outpatient setting with 8-hour monitoring.
干预措施: acapatamab (Drug)
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.
干预措施: acapatamab (Drug)
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.
干预措施: Cytochrome P450 (CYP) Cocktail (Drug)
结局指标
主要结局
Number of participants with dose-limiting toxicity
时间窗: Up to 3 years
Parts 1, 2, 3, 4, 5, and 6 of the study
Number of participants with treatment-emergent adverse events
时间窗: Up to 3 years
Parts 1, 2, 3, 4, 5, and 6 of the study
Number of participants with treatment-related adverse events
时间窗: 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
时间窗: 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)
时间窗: 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
时间窗: Up to 3 years
Parts 1, 2, 3, 4, 5, and 6 of the study
次要结局
- Accumulation ratio of acapatamab(Up to 3 years)
- Maximum serum concentration (Cmax) of acapatamab(Up to 3 years)
- Minimum serum concentration (Cmin) of acapatamab(Up to 3 years)
- Area under the concentration-time curve (AUC) over the dosing interval of acapatamab(Up to 3 years)
- Half-life of acapatamab(Up to 3 years)
- Objective response (OR)(Up to 3 years)
- Prostate-specific antigen (PSA) response(Up to 3 years)
- Duration of response (DOR) (radiographic and PSA)(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(Up to 3 years)
- Percentage of participants experiencing a response based on 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) response evaluations(Up to 3 years)
- Other PCWG3-recommended endpoints - neutrophil-to-lymphocyte ratio(Up to 3 years)
- Other PCWG3-recommended endpoints - urine N-telopeptide levels(Up to 3 years)
- Change in time to progression (radiographic and PSA)(Up to 3 years)
- Progression-free survival (PFS) (radiographic and PSA)(Up to 3 years)
- 1, 2 and 3-year overall survival (OS)(Up to 3 years)
- Percentage of participants experiencing circulating tumor cells (CTC) response(Up to 3 years)
- Other PCWG3-recommended endpoints - time to symptomatic skeletal events(Up to 3 years)
- Other PCWG3-recommended endpoints - lactate dehydrogenase [LDH] levels(Up to 3 years)
- Other PCWG3-recommended endpoints - hemoglobin levels(Up to 3 years)
- Other PCWG3-recommended endpoints - alkaline phosphatase [total, bone] levels(Up to 3 years)
- Maximum serum concentration (Cmax) of acapatamab when administered with CYP enzymes(Up to 3 years)
- Area under the concentration-time curve over a 24-hour period (AUC24) of acapatamab when administered with CYP enzymes(Up to 3 years)
- Half-life of acapatamab when administered with CYP enzymes(Up to 3 years)