A Phase 1, Open-Label, Dose Escalation and Dose Expansion Study Evaluating the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Effects of Orally Administered CB-5083 in Subjects With Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- 入组人数
- 62
- 试验地点
- 6
- 主要终点
- Dose Escalation Stage - the dose limiting toxicities (DLTs), using NCI CTCAE v4.0, of oral CB-5083 in subjects with advanced tumors
研究概览
简要总结
This is a multicenter, open-label, Phase 1 study of orally administered CB-5083 in adult subjects with advanced metastatic solid tumors. The study will be conducted in 2 parts: an initial Dose Escalation Phase (Phase 1a) of CB-5083 in subjects with advanced metastatic solid tumors who have progressed or are non-responsive to available therapies and for which no standard therapy exists, followed by a Dose Expansion Phase (Phase 1b) which will include 1 to 4 arms: one arm in subjects with RAS mutated mCRC; optionally, at sponsors discretion, 3 additional arms may be added for subjects with advanced RCC, advanced pNET, or solid tumors with mutations in the RAS-MAPK pathway.
详细描述
The objectives of the Dose Escalation Phase are to determine the safety, tolerability, PK and pharmacodynamic profiles, the MTD and/or RP2D, and the effect of fed vs. fasted state on the bioavailability of orally administered CB-5083. The objectives of the dose expansion phase are to confirm the safety and tolerability of the RP2D, to further assess the PK and pharmacodynamic profiles and to evaluate the preliminary anti-tumor activity of CB-5083 in subjects with tumors for which there is biologic plausibility of unique sensitivity to CB-5083 mechanism of action (MOA) based on pre-clinical data. The objectives of the Food Effect Stage is to determine the effect of fed vs. fasted state on the bioavailability of orally administered CB-5083.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 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
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Dose Escalation Stage - CB-5083
CB-5083 will be orally administered daily, 4 days on and 3 days off, for 28 day cycles; subjects who have completed at least one cycle may optionally participate in a food effect week, wherein CB-5083 will be orally administered once daily, on days 1 and 4, and thereafter return to the original dosing schedule
干预措施: CB-5083 (Drug)
Dose Expansion Stage - CB-5083
CB-5083 will be orally administered daily, 4 days on and 3 days off, for 28 day cycles
干预措施: CB-5083 (Drug)
Food Effect Stage - CB-5083
CB-5083 will be orally administered once daily, on days 1 and 4 of week 1, cycle 1, and orally administered daily, 4 days on and 3 days off, for the remaining 3 weeks of cycle 1; for subsequent 28 day cycles, CB-5083 will be orally administered daily, 4 days on and 3 days off
干预措施: CB-5083 (Drug)
结局指标
主要结局
Dose Escalation Stage - the dose limiting toxicities (DLTs), using NCI CTCAE v4.0, of oral CB-5083 in subjects with advanced tumors
时间窗: the first 28 days of treatment with CB-5083
Dose Escalation Stage - the pharmacokinetic profile (PK) of oral CB-5083 in subjects with advanced solid tumors; parameters include AUC, Cmax, Tmax and T1/2
时间窗: day 1 to day 5 of Cycle 1 and day 1 and day 2 of Cycle 2
Dose Expansion Stage - safety and tolerability of oral CB-5083 administered to subjects with RAS mutated metastatic colorectal cancer (mCRC) at the RP2D, using NCI CTCAE v4.0
时间窗: day 1 of Cycle 1 through 28 days after the subjects's last treatment
Dose Expansion Stage - safety and tolerability of CB-5083 in subjects with advanced renal-cell carcinoma (RCC), pancreatic neuroendocrine tumors (pNET) or solid tumors with RAS-MAPK mutations, if such arms are opened per Sponsor, using NCI CTCAE v4.0
时间窗: from day 1 of Cycle 1 through 28 days after the subjects's last treatment
Food Effect Stage - the effect of a standard meal on the plasma concentration of oral CB-5083 in subjects with advanced solid tumors
时间窗: from day 1 of Cycle 1 through day 5 of Cycle 1
次要结局
- Dose Escalation Stage - the pharmacodynamic (PD)effects of CB-5083 through the measurement of polyubiquitin accumulation (PUA) in peripheral blood mononuclear cells (PBMCs)(day 1 through day 5 of Cycle 1)
- Dose Expansion Stage - PK and PD profiles of CB-5083; PK parameters to include AUC, Cmax, Tmax and T1/2; PD effects through the measurement of PUA in PBMCs(day 1 through day 5 of Cycle 1; day 1 and day 2 of Cycle 2 (PK only))
- Dose Expansion Stage - anti-tumor activity in certain subjects, using the Response Evaluation Criteria in Solid Tumors (RECIST), v1.1(from the pre-study visit though the end of the last cycle on treatment, an expected average of 14 weeks)
- Food Effect Stage - safety and tolerability of oral CB-5083 in subjects with advanced solid tumors using NCI CTCAE v4.0, of oral CB-5083(From day 1 of Cycle 1 through 28 days after the subjects's last treatment)