A Phase 1/2 Study of the Concomitant Administration of Indoximod Plus Immune Checkpoint Inhibitors for Adult Patients With Advanced or Metastatic Melanoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 131
- 试验地点
- 12
- 主要终点
- Overall Incidence of Adverse Events as a Measure of Safety and Tolerability
研究概览
简要总结
To evaluate the preliminary efficacy of the established dose of indoximod in combination with immune checkpoint inhibition as measured by the best overall response rate (ORR) (complete response (CR) + partial response (PR))across both standard of care agents administered sequentially in patients with unresectable stage III or stage IV melanoma
详细描述
The incidence of melanoma is increasing. Based upon data obtained between 2004 and 2006, the lifetime probability of developing melanoma in the United States is estimated to be 1 in 37 for men and 1 in 56 for women. In the United States, melanoma is the fifth leading cancer in men and the seventh in women. Locally confined, fully-resectable disease may be curable with current therapy; but Stage IV metastatic disease (or relapsed/recurrent disease) is highly refractory to therapy. Thus, experimental clinical trials provide an accepted treatment option for metastatic or relapsed/refractory melanoma.
The current study is designed as a prospective trial to evaluate the combination of indoximod and checkpoint inhibitors in adult patients with metastatic melanoma. Ipilimumab, pembrolizumab and nivolumab will be used at the recommended approved doses for this indication.
The current trial will be done in two phases: a Phase 1b dose escalation of indoximod in combination with ipilimumab, starting at half the recommended single-agent dose, to establish the recommended Phase 2 dose for the combination.
This will be followed by a three arm expansion study testing a fixed dose of indoximod (at the recommended Phase 2 dose) combined with standard-dose ipilimumab, pembrolizumab or nivolumab.
Treatment will be administered on an outpatient basis. No investigational or commercial cancer directed agents or therapies other than those described below may be administered.
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
- All
- 接受健康志愿者
- 否
入选标准
- •Unresectable Stage III or Stage IV melanoma.
- •Patients must have measurable disease, defined as lesions that can be accurately measure in in 2 perpendicular diameters with at least one diameter > 20mm and the other >10mm on conventional CT or MRI or 10mm x 10 mm by spiral CT.
- •No systemic treatment in the previous 28 days.
- •Age ≥18 years. Because no dosing or adverse event data are currently available on the use of ipilimumab or indoximod in patients <18 years of age, children are excluded from this study.
- •ECOG performance status ≤2 (Karnofsky ≥60% )
- •Patients with known brain metastases will only be eligible after their tumors have been treated with definitive resection and/or radiotherapy and they are neurologically stable for at least 1 month off steroids.
排除标准
- •Patients who have had molecular targeted therapy (including vemurafenib) or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.
- •Patients who have had prior therapy with immune checkpoint inhibition or or indoximod are excluded from the trial.
- •Any other cancer, unless the patient has been disease-free for ≥5 years
- •Patients with laboratory evidence of pancreatitis are excluded.
- •Patients with autoimmune disease
- •Chronic use of immune-suppressive drugs (ie, systemic corticosteroids used in the management of cancer or non-cancer related illnesses, eg, COPD).
研究组 & 干预措施
Indoximod + Ipilimumab
Indoximod will be administered at 1200mg BID by mouth.
Ipilimumab administered intravenously at 3 mg/kg every three weeks for a total of four doses.
Indoximod and ipilimumab will be dosed concurrently. Indoximod will be dosed twice daily on all days of each 21 day cycles (segment 1). Ipilimumab will be dosed on the 1st day of each 21 day cycle for the first 4 cycles. Indoximod dosing will continue after all 4 doses of ipilimumab are administered (segment 2, 28-day cycles).
Patients will continue until they experience disease progression or limiting toxicity.
干预措施: Ipilimumab (Drug)
Indoximod + Ipilimumab
Indoximod will be administered at 1200mg BID by mouth.
Ipilimumab administered intravenously at 3 mg/kg every three weeks for a total of four doses.
Indoximod and ipilimumab will be dosed concurrently. Indoximod will be dosed twice daily on all days of each 21 day cycles (segment 1). Ipilimumab will be dosed on the 1st day of each 21 day cycle for the first 4 cycles. Indoximod dosing will continue after all 4 doses of ipilimumab are administered (segment 2, 28-day cycles).
Patients will continue until they experience disease progression or limiting toxicity.
干预措施: Indoximod (Drug)
Indoximod + Pembrolizumab
Indoximod will be administered at 1200mg BID by mouth.
Pembrolizumab administered intravenously at 2 mg/kg every three weeks.
干预措施: Indoximod (Drug)
Indoximod + Pembrolizumab
Indoximod will be administered at 1200mg BID by mouth.
Pembrolizumab administered intravenously at 2 mg/kg every three weeks.
干预措施: Pembrolizumab (Drug)
Indoximod + Nivolumab
Indoximod will be administered at 1200mg BID by mouth.
Nivolumab administered intravenously at 240 mg every 2 weeks.
干预措施: Indoximod (Drug)
Indoximod + Nivolumab
Indoximod will be administered at 1200mg BID by mouth.
Nivolumab administered intravenously at 240 mg every 2 weeks.
干预措施: Nivolumab (Drug)
结局指标
主要结局
Overall Incidence of Adverse Events as a Measure of Safety and Tolerability
时间窗: 17 months
Phase 1 component: Evaluate the safety (adverse events - type, incidence, severity, duration, causality and treatment intervention) of the combination of indoximod and ipilimumab when given concomitantly. The safety and tolerability ipilimumab followed by Indoximod will be assessed by listing the overall incidence of AEs. The AEs will be summarized and classified by body system and by treatment group. The type, incidence, severity, and causality of each AE, the duration of the event, and any required treatment interventions will be tabulated. Physical examination results will be presented in the patient data listings. The DLT will be listed per dose level and treatment along with overall frequencies. The data from the expansion part (Phase II) will be used for this part of safety and tolerability assessment.
Phase 2 Dosing
时间窗: 22 months
Phase 1 component: To determine the recommended Phase 2 dose of indoximod in combination with ipilimumab in patients with unresectable melanoma. A minimum of nine patients will be treated depending on DLT. Each dose will be administered to a cohort of 3 patients. If 0 out of 3 or less than 2 out of 6 patients experienced a DLT at any given dose level, the dose escalation will proceed to the next dose level. The MTD is generally the largest dose level at which at most 1 out of 6 patients experiences a DLT. IF DLT is not reached at the highest dose level (1200mg twice daily), no further escalation will proceed and this dose level will be declared the recommended Phase II dose
Overall Response Rate
时间窗: 22 months
Phase 2 component: To evaluate the preliminary efficacy of the established dose of indoximod in combination with immune checkpoint inhibition as measured by the best overall response rate in patients with unresectable Stage III or Stage IV melanoma.
次要结局
- Mechanisms of activity/resistance to IDO/CTLA-4 inhibitor therapy(24 months)
- Number of Participants with Adverse Events as a Measure of Safety and Tolerability(22 months)
- Progression Free Survival(22 months)
- Disease control rate(22 months)
- Overall Survival(24 months)