An Open-Label, Phase II Efficacy Trial of Doxorubicin in Combination With Dual Checkpoint Blockade Using Zalifrelimab (AGEN1884) or Botensilimab (AGEN1181) With Balstilimab (AGEN2034) for Advanced or Metastatic Soft Tissue Sarcomas
概览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 65
- 试验地点
- 1
- 主要终点
- Determine the progression-free survival rate
概览
简要总结
This is an open-label, non-randomized, single-institution, single arm Phase II study conducted using a Simon two-stage design with an additional safety lead-in. The overall objective is to determine the efficacy of combination doxorubicin with dual checkpoint blockade with anti-CTLA-4 antibody AGEN1884 and anti-PD-1 antibody AGEN2034. The investigators will estimate the progression-free survival rate at 6 months (PFS6mo) of doxorubicin plus AGEN1884/AGEN2034 in comparison to historical PFS6mo with doxorubicin monotherapy, calculated as the mean from two large randomized Phase 3 clinical trials.
详细描述
The primary endpoint for the study is PFS6mo by RECIST 1.1. The sample size calculation is based on a Simon Two-Stage design with incorporation of early stopping rules for safety and futility (See section 9 for statistical considerations). The Investigators will enroll up to 35 patients on the study to obtain 28 evaluable patients for the primary endpoint. Safety of the combination will be evaluated after the first six patients complete the DLT observation period of 9 weeks. This lengthy DLT period is designed to capture safety and toxicity profile, understanding that immune-related toxicities from checkpoint inhibitors may not emerge immediately. This will also ensure adequate evaluation of potential cardiac and hepatic toxicity from combination doxorubicin and checkpoint inhibitor therapy. If two or more patients experience DLT in the initial safety lead-in cohort, the regimen will be declared intolerable. Any patients who do not complete study therapy through the 9-week DLT observation period for any reasons other than toxicity will be replaced for safety lead-in assessment. If fewer than two patients experience DLT, the investigators will proceed to expansion to complete enrollment of 15 patients in Stage 1. Following enrollment of stage one, accrual will pause for analysis of efficacy. If 6 or fewer of the 15 patients are progression-free at 6 months, the investigators will halt the study for futility. If 7 or more patients are free from progression, then the investigators will proceed with enrollment of 13 additional patients to complete stage 2. the investigators are powered to detect improvement in 6-month PFS rate to 63.4% with the combination over the 43.4% historical PFS6mo.
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 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Provision to sign and date the consent form.
- •Stated willingness to comply with all study procedures and be available for the duration of the study.
- •Be male or female aged 18-100 years at the time of signing informed consent.
- •Have a histological diagnosis of advanced or metastatic soft tissue sarcoma (STS) (by local pathology review), not curable by surgery, for which treatment with doxorubicin is deemed appropriate by the investigator.
- •Has one of the following histologies:
- •synovial sarcoma,
- •malignant peripheral nerve sheath tumors,
- •dedifferentiated, pleomorphic or myxoid/round cell liposarcoma,
- •uterine or soft tissue leiomyosarcoma,
- •malignant phylloides tumor,
排除标准
- •Prior therapy with anthracycline or checkpoint inhibitors.
- •Hypersensitivity to doxorubicin or any excipients.
- •Patients may not be receiving any other investigational agents (within 4 weeks prior to Cycle 1, Day 1).
- •Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to Cycle 1, Day 1 or has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
- •Patient has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to Cycle 1, Day 1 or has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier. Subjects with ≤ Grade 2 neuropathy or alopecia are an exception to this criterion and may qualify for the study. Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
- •Additional known malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, or squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in situ cervical cancer.
- •Patients with underlying immune deficiency, chronic infections including HIV, hepatitis, or tuberculosis (TB) or autoimmune disease.
- •Patients with underlying hematologic issues including bleeding diathesis, such as known previous GI bleeding requiring intervention within the past 6 months. Newly diagnosed pulmonary emboli or deep venous thrombosis must be clinically stable on anticoagulation regimen for ≥ 2 weeks as of Cycle 1 Day
- •Has known history of non-infectious pneumonitis that required oral corticosteroid therapy for resolution within 12 months prior to study entry, or evidence by imaging or symptoms of active non-infectious pneumonitis.
- •Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis or leptomeningeal disease. Subjects with previously treated brain metastases may participate provided they are stable based on the following: 1) MRI brain obtained during screening evaluations shows no radiographic evidence of progression or new lesions, 2) any neurologic symptoms have returned to baseline, 3) no requirement for steroids for at least 28 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability. Patients without a known history of brain metastases do not require screening brain MRI prior to study enrollment.
研究组 & 干预措施
Part 1: Stage 1, Safety Lead-In
The safety lead-in will enroll 6 participants. Balstilimab 300mg flat q3 weeks up to 2 years; Zalifrelimab 1mg/kg q6 weeks x 4; Doxorubicin 75mg/m2 q3 weeks x 2, starts at C2 The participants will complete a dose-limiting toxiciy (DLT) observation period of 9 weeks.
干预措施: Doxorubicin (Drug)
Part 1: Stage 2, Expansion
Balstilimab 300mg flat q3 weeks up to 2 years; Zalifrelimab 1mg/kg q6 weeks up to 2 years; Doxorubicin 75mg/m2 q3 weeks x 6
干预措施: Balstilimab (Drug)
Part 1: Stage 2, Expansion
Balstilimab 300mg flat q3 weeks up to 2 years; Zalifrelimab 1mg/kg q6 weeks up to 2 years; Doxorubicin 75mg/m2 q3 weeks x 6
干预措施: Zalifrelimab (Drug)
Part 1: Stage 2, Expansion
Balstilimab 300mg flat q3 weeks up to 2 years; Zalifrelimab 1mg/kg q6 weeks up to 2 years; Doxorubicin 75mg/m2 q3 weeks x 6
干预措施: Doxorubicin (Drug)
Part 1: Stage 1, Safety Lead-In
The safety lead-in will enroll 6 participants. Balstilimab 300mg flat q3 weeks up to 2 years; Zalifrelimab 1mg/kg q6 weeks x 4; Doxorubicin 75mg/m2 q3 weeks x 2, starts at C2 The participants will complete a dose-limiting toxiciy (DLT) observation period of 9 weeks.
干预措施: Balstilimab (Drug)
Stage 2, Dose 3 Combination of Doxorubicin with Botensilimab and Balstilimab
Doxorubicin 75mg/m2 q3 weeks x 6 doses Botensilimab 75mg flat q6 weeks up to 2 years Balstilimab 450mg q3 weeks up to 2 years
干预措施: Balstilimab (Drug)
Stage 2, Dose 2
Doxorubicin 75mg/m2 q3 weeks x 6 doses Botensilimab 75mg q6 weeks up to two years
干预措施: Doxorubicin (Drug)
Stage 2, Dose 3 Combination of Doxorubicin with Botensilimab and Balstilimab
Doxorubicin 75mg/m2 q3 weeks x 6 doses Botensilimab 75mg flat q6 weeks up to 2 years Balstilimab 450mg q3 weeks up to 2 years
干预措施: Botensilimab (Drug)
Part 1: Stage 1, Safety Lead-In
The safety lead-in will enroll 6 participants. Balstilimab 300mg flat q3 weeks up to 2 years; Zalifrelimab 1mg/kg q6 weeks x 4; Doxorubicin 75mg/m2 q3 weeks x 2, starts at C2 The participants will complete a dose-limiting toxiciy (DLT) observation period of 9 weeks.
干预措施: Zalifrelimab (Drug)
Part 2: Stage 2, Dose 1
Doxorubicin 60mg/m2 q3 weeks x 6 doses Botensilimab 75mg q6 weeks up to two years
干预措施: Botensilimab (Drug)
Part 2: Stage 2, Dose 1
Doxorubicin 60mg/m2 q3 weeks x 6 doses Botensilimab 75mg q6 weeks up to two years
干预措施: Doxorubicin (Drug)
Stage 2, Dose 2
Doxorubicin 75mg/m2 q3 weeks x 6 doses Botensilimab 75mg q6 weeks up to two years
干预措施: Botensilimab (Drug)
Stage 2, Dose 3 Combination of Doxorubicin with Botensilimab and Balstilimab
Doxorubicin 75mg/m2 q3 weeks x 6 doses Botensilimab 75mg flat q6 weeks up to 2 years Balstilimab 450mg q3 weeks up to 2 years
干预措施: Doxorubicin (Drug)
结局指标
主要结局
Determine the progression-free survival rate
时间窗: 6 months
Determine the progression-free survival rate at 6 months of combination therapy with doxorubicin, AGEN1884, and AGEN2034 in anthracycline-naïve patients with advanced or metastatic soft tissue sarcomas.
次要结局
- Determine the overall response rate(3 years)
- Determine the clinical benefit rate(3 years)
- Determine the duration of response(3 years)
- Determine the incidence of adverse events(3 years)