An Open-Label, Multicenter, Phase 1b/2 Study of Rebastinib (DCC-2036) in Combination With Paclitaxel to Assess Safety, Tolerability, and Pharmacokinetics in Patients With Advanced or Metastatic Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 177
- 试验地点
- 14
- 主要终点
- Number of Participants With Adverse Events
研究概览
简要总结
This is an open-label Phase 1b/2 multicenter study of rebastinib (DCC-2036) in combination with paclitaxel designed to evaluate the safety, tolerability, and pharmacokinetics (PK) in patients with advanced or metastatic solid tumors.
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
- •Male or female patients ≥18 years of age at the time of informed consent
- •Part 1 Histologically confirmed diagnosis of a locally advanced or metastatic solid tumor for which paclitaxel is considered appropriate treatment
- •Triple-negative and Stage IV inflammatory breast cancer
- •Recurrent ovarian cancer
- •Recurrent, metastatic or high-risk endometrial cancer
- •Advanced (stage III or IV), or recurrent gynecological carcinosarcoma
- •Homologous or heterologous type carcinosarcoma (malignant mixed Mullerian tumor [MMMT] allowed
- •Eastern Cooperative Oncology Group Performance Status (ECOG PS) of ≤2
- •Able to provide an archival tumor tissue sample
- •Adequate organ function and bone marrow reserve
- •If a female of childbearing potential, must have a negative pregnancy test prior to enrollment
- •Patient must provide signed consent to participate in the study and is willing to comply with study-specific procedures
排除标准
- •Received prior anticancer or other investigational therapy within 28 days or 5× the half-life prior to the first dose
- •Not recovered from prior-treatment toxicities to Grade ≤1
- •Peripheral neuropathy of any etiology >Grade 1
- •Concurrent malignancy
- •Known active central nervous system (CNS) metastases
- •Use of systemic corticosteroids
- •Known retinal neovascularization, macular edema or macular degeneration
- •History or presence of clinically relevant cardiovascular abnormalities
- •QT interval corrected by Fridericia's formula (QTcF) >450 ms in males or >470 ms in females
- •Left ventricular ejection fraction (LVEF) <50% at screening
- •Arterial thrombotic or embolic events
- •Venous thrombotic event
- •Active infection ≥Grade 3
- •Human immunodeficiency virus (HIV) or hepatitis C (HCV) infection only if taking medications excluded per protocol, active hepatitis B (HBV), or active HCV infection
- •Use of proton pump inhibitors
- •If female, the patient is pregnant or lactating
- •Major surgery 4 weeks prior to the first dose of study drug
- •Malabsorption syndrome or other illness which could affect oral absorption
- •Known allergy or hypersensitivity to any component of rebastinib or any of its excipients.
- •Any other clinically significant comorbidities
研究组 & 干预措施
Part 2 Cohort 2 Rebastinib 50 mg + Paclitaxel 80 mg/m^2
Dose expansion in inflammatory breast cancer. Rebastinib 50 mg BID PO in combination with paclitaxel IV infusion at 80 mg/m^2 on days 1, 8, and 15 of repeated 28-day cycles.
干预措施: Rebastinib (Drug)
Part 2 Cohort 2 Rebastinib 50 mg + Paclitaxel 80 mg/m^2
Dose expansion in inflammatory breast cancer. Rebastinib 50 mg BID PO in combination with paclitaxel IV infusion at 80 mg/m^2 on days 1, 8, and 15 of repeated 28-day cycles.
干预措施: Paclitaxel (Drug)
Part 2 Cohort 2 Rebastinib 100 mg + Paclitaxel 80 mg/m^2
Dose expansion in inflammatory breast cancer. Rebastinib 100 mg BID PO in combination with paclitaxel IV infusion at 80 mg/m^2 on days 1, 8, and 15 of repeated 28-day cycles.
干预措施: Rebastinib (Drug)
Part 2 Cohort 2 Rebastinib 100 mg + Paclitaxel 80 mg/m^2
Dose expansion in inflammatory breast cancer. Rebastinib 100 mg BID PO in combination with paclitaxel IV infusion at 80 mg/m^2 on days 1, 8, and 15 of repeated 28-day cycles.
干预措施: Paclitaxel (Drug)
Part 2 Cohort 1 Rebastinib 100 mg + Paclitaxel 80 mg/m^2
Dose expansion in TNBC. Rebastinib 100 mg BID PO in combination with paclitaxel IV infusion at 80 mg/m^2 on days 1, 8, and 15 of repeated 28-day cycles.
干预措施: Paclitaxel (Drug)
Part 1 Arm 1 Rebastinib 50 mg + Paclitaxel 80 mg/m^2
Dose escalation of rebastinib 50 milligram (mg) twice daily (BID) orally (PO) in combination with paclitaxel administered by intravenous (IV) infusion at 80 mg/meter squared (m^2) on days 1, 8, and 15 of repeated 28-day cycles.
干预措施: Rebastinib (Drug)
Part 1 Arm 1 Rebastinib 50 mg + Paclitaxel 80 mg/m^2
Dose escalation of rebastinib 50 milligram (mg) twice daily (BID) orally (PO) in combination with paclitaxel administered by intravenous (IV) infusion at 80 mg/meter squared (m^2) on days 1, 8, and 15 of repeated 28-day cycles.
干预措施: Paclitaxel (Drug)
Part 1 Arm 2 Rebastinib 100 mg + Paclitaxel 80 mg/m^2
Dose escalation of rebastinib 100 mg BID PO in combination with paclitaxel IV infusion at 80 mg/m^2 on days 1, 8, and 15 of repeated 28-day cycles.
干预措施: Rebastinib (Drug)
Part 1 Arm 2 Rebastinib 100 mg + Paclitaxel 80 mg/m^2
Dose escalation of rebastinib 100 mg BID PO in combination with paclitaxel IV infusion at 80 mg/m^2 on days 1, 8, and 15 of repeated 28-day cycles.
干预措施: Paclitaxel (Drug)
Part 2 Cohort 1 Rebastinib 50 mg + Paclitaxel 80 mg/m^2
Dose expansion in triple-negative breast cancer (TNBC). Rebastinib 50 mg BID PO in combination with paclitaxel IV infusion at 80 mg/m^2 on days 1, 8, and 15 of repeated 28-day cycles.
干预措施: Rebastinib (Drug)
Part 2 Cohort 1 Rebastinib 50 mg + Paclitaxel 80 mg/m^2
Dose expansion in triple-negative breast cancer (TNBC). Rebastinib 50 mg BID PO in combination with paclitaxel IV infusion at 80 mg/m^2 on days 1, 8, and 15 of repeated 28-day cycles.
干预措施: Paclitaxel (Drug)
Part 2 Cohort 1 Rebastinib 100 mg + Paclitaxel 80 mg/m^2
Dose expansion in TNBC. Rebastinib 100 mg BID PO in combination with paclitaxel IV infusion at 80 mg/m^2 on days 1, 8, and 15 of repeated 28-day cycles.
干预措施: Rebastinib (Drug)
Part 2 Cohort 3 Rebastinib 50 mg + Paclitaxel 80 mg/m^2
Dose expansion in ovarian cancer. Rebastinib 50 mg BID PO in combination with paclitaxel IV infusion at 80 mg/m^2 on days 1, 8, and 15 repeated 28-day cycles.
干预措施: Rebastinib (Drug)
Part 2 Cohort 3 Rebastinib 50 mg + Paclitaxel 80 mg/m^2
Dose expansion in ovarian cancer. Rebastinib 50 mg BID PO in combination with paclitaxel IV infusion at 80 mg/m^2 on days 1, 8, and 15 repeated 28-day cycles.
干预措施: Paclitaxel (Drug)
Part 2 Cohort 3 Rebastinib 100 mg + Paclitaxel 80 mg/m^2
Dose expansion in ovarian cancer. Rebastinib 100 mg BID PO in combination with paclitaxel IV infusion at 80 mg/m^2 on days 1, 8, and 15 of repeated 28-day cycles.
干预措施: Rebastinib (Drug)
Part 2 Cohort 3 Rebastinib 100 mg + Paclitaxel 80 mg/m^2
Dose expansion in ovarian cancer. Rebastinib 100 mg BID PO in combination with paclitaxel IV infusion at 80 mg/m^2 on days 1, 8, and 15 of repeated 28-day cycles.
干预措施: Paclitaxel (Drug)
Part 2 Cohort 4 Rebastinib 50 mg + Paclitaxel 80 mg/m^2
Dose expansion in endometrial cancer. Rebastinib 50 mg BID PO in combination with paclitaxel IV infusion at 80 mg/m^2 on days 1, 8, and 15 of repeated 28-day cycles.
干预措施: Rebastinib (Drug)
Part 2 Cohort 4 Rebastinib 50 mg + Paclitaxel 80 mg/m^2
Dose expansion in endometrial cancer. Rebastinib 50 mg BID PO in combination with paclitaxel IV infusion at 80 mg/m^2 on days 1, 8, and 15 of repeated 28-day cycles.
干预措施: Paclitaxel (Drug)
Part 2 Cohort 4 Rebastinib 100 mg + Paclitaxel 80 mg/m^2
Dose expansion in endometrial cancer. Rebastinib 100 mg BID PO in combination with paclitaxel IV infusion at 80 mg/m^2 on days 1, 8, and 15 of repeated 28-day cycles.
干预措施: Rebastinib (Drug)
Part 2 Cohort 4 Rebastinib 100 mg + Paclitaxel 80 mg/m^2
Dose expansion in endometrial cancer. Rebastinib 100 mg BID PO in combination with paclitaxel IV infusion at 80 mg/m^2 on days 1, 8, and 15 of repeated 28-day cycles.
干预措施: Paclitaxel (Drug)
Part 2 Cohort 5 Rebastinib 50 mg + Paclitaxel 80 mg/m^2
Dose expansion in gynecological carcinosarcoma (GCS). Rebastinib 50 mg BID PO in combination with paclitaxel IV infusion at 80 mg/m^2 on days 1, 8, and 15 of repeated 28-day cycles.
干预措施: Rebastinib (Drug)
Part 2 Cohort 5 Rebastinib 50 mg + Paclitaxel 80 mg/m^2
Dose expansion in gynecological carcinosarcoma (GCS). Rebastinib 50 mg BID PO in combination with paclitaxel IV infusion at 80 mg/m^2 on days 1, 8, and 15 of repeated 28-day cycles.
干预措施: Paclitaxel (Drug)
结局指标
主要结局
Number of Participants With Adverse Events
时间窗: Baseline up to 2.89 years
Number of participants (pts) who experienced serious adverse events (SAE) and adverse events (AE).
Objective Response Rate (ORR) (Part 2 Expansion)
时间窗: Baseline to PD or Death due to Any Cause (Up to 1.54 years)
Percentage of participants who achieved an objective response of Complete Response (CR) or Partial Response (PR) per Response Evaluation Criteria in Solid Tumor (RECIST) v1.1. CR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had to have reduction in short axis to \<10 mm. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD) is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study including baseline, or the appearance of one or more new lesions.
次要结局
- Objective Response Rate (ORR) (Part 1 Escalation)(Baseline to PD or Death due to Any Cause (Up to 0.92 years))
- Duration of Response (DOR)(Time from CR or PR to PD or Death due to Any Cause (Up to 1.54 years))
- Time to Progression (TTP)(First Dose of Study Drug to PD (Up to 2.61 years))
- Progression-free-survival (PFS)(First Dose of Study Drug to PD or Death due to Any Cause (Up to 2.61 years))
- Overall Survival (OS)(First Dose of Study Drug to Death due to Any Cause (Up to 2.82 years))
- Pharmacokinetics (PK): Maximum Observed Concentration (Cmax) of Rebastinib (Part 1)(Part 1: Cycle 1 Day 1 (C1 D1), C1 D15 (Cycle = 28 days))
- PK: Area Under the Concentration-time Curve (AUC) 0-6 Hours of Rebastinib (Part 1)(Part 1: Cycle 1 Day 1 (C1 D1), C1 D15 (Cycle = 28 days))