A Randomized Phase II Study of Anti-PD-1 and Limited Metastatic Site Radiation Therapy Versus Anti-PD-1 Alone for Patients With Microsatellite Instability-high (MSI-H) and Mismatch Repair Deficient (dMMR) Metastatic Solid Tumors
试验速览
- 阶段
- 2 期
- 状态
- 撤回
- 试验地点
- 1
- 主要终点
- Out-of-field ORR improvement
研究概览
简要总结
To determine if the out-of-field ORR is improved with the addition of radiation therapy to anti-PD-1 for patients with MSI-H/dMMR metastatic solid tumors. Determine the rates of in-field tumor control, disease control (stable disease, partial response, complete response), durability of disease response, progression-free survival, overall survival, and to assess quality of life and toxicity. Determine the chronology and profile of the radiation-associated immune response.
详细描述
This is a randomized phase II study with a primary objective to compare the objective response rate (ORR) for anti-PD-1 therapy alone versus anti-PD-1 therapy and limited metastatic site radiation, in patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic solid tumors. The anti-PD-1 agent, pembrolizumab, received recent FDA accelerated approval for the use in patients with metastatic MSI-H or dMMR solid tumors that have progressed following prior treatment or without satisfactory alternative treatment options. FDA approval for pembrolizumab was based on the results of five multi-cohort, multi-center, single-arm trials, which together showed an ORR of 39.6% among 149 patients with MSI-H/dMMR cancers. Importantly, there is mounting preclinical and clinic evidence supporting the safety and efficacy of combining radiation therapy with systemic immunotherapy, although no prospective comparative data, to the best of our knowledge. In this study, the investigators will focus on patients with MSI-H/dMMR tumors, given their baseline responsiveness to immune checkpoint inhibition, and test the hypothesis that ORR will be improved with radiation and anti-PD-1 therapy compared to anti-PD-1 therapy alone, through a randomized phase II trial design.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Investigator, Outcomes Assessor)
盲法说明
In an effort to minimize bias, the study will utilize a randomization. The randomization list will be generated by the study biostatistician and provided only to the study personnel who will be responsible for assigning each subject to a cohort of the study.
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.
- •Adult patients, 18-100 years of age.
- •Unresectable or metastatic MSI-H/dMMR tumors eligible to receive pembrolizumab according to FDA-approved indications:
- •Solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options OR
- •Colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan11
- •Confirmation from medical or gynecologic oncology that the patient is eligible to receive pembrolizumab per FDA-approved indication for patients not currently receiving pembrolizumab .
- •At least one site of disease amenable to radiation therapy per the acceptable dosing regimens outlined in section 6.2, and at least one additional site of measurable disease suitable for out-of-field response assessment.
- •Adequate baseline labs for initiation of trial treatment:
- •absolute neutrophil count (ANC) >1,000/µL
- •platelets >75,000/µL
- •hemoglobin >8 g/dL
- •serum creatinine < 1.5 x ULN
- •serum total bilirubin < 1.5 x ULN
- •AST and ALT < 2.5 x ULN, or < 5 x ULN if liver metastasis are present
排除标准
- •Pregnant women. Pregnancy testing is required for all female subjects of childbearing potential.
- •Patients with active collagen vascular disease (CVD), specifically systemic lupus erythematosus or scleroderma. Patients with a history of CVD without evidence of active disease are eligible for enrollment at the discretion of the study PI.
- •History of immunodeficiency, hypersensitivity to pembrolizumab, or other medical contraindication to receipt of pembrolizumab.
- •Active infection.
- •Active CNS metastases. Patients with treated CNS metastases are eligible.
- •Patients with a separate non-cutaneous cancer diagnosis for which the patient has not been without evidence of disease for at least 5 years.
研究组 & 干预措施
RT and Anti-PD-1
In the pembrolizumab + RT arm, pembrolizumab will be started on study within 7 days (+/- 7 days) of start of RT.
Pembrolizumab will be given as standard of care in both arms
干预措施: RT and Anti-PD-1 (Combination Product)
Anti-PD-1
anti-PD-1 therapy alone Pembrolizumab will be given as standard of care in both arms
干预措施: Anti-PD-1 (Drug)
结局指标
主要结局
Out-of-field ORR improvement
时间窗: 12 months
• Out-of-field objective response rate (ORR: CR+PR) according to RECIST 1.1 assessment
次要结局
- Durability of disease response(12 months)
- Progression-free Survival(12 months)
- in-field tumor control and disease control(12 Months)
- Determine the chronology and profile of the radiation-associated immune response.(12 months)
- Overall Survival(12 Months)
- Quality of life score(12 Months)