A Phase 1b Study of the Safety and Tolerability of Ruxolitinib in Combination With Gemcitabine With or Without Nab-Paclitaxel in Subjects With Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 42
- 主要终点
- Percentage of Participants With Adverse Events That Are Defined as Dose Limiting Toxicities (DLTs)
研究概览
简要总结
This is a study of ruxolitinib in combination with gemcitabine with or without nab-paclitaxel administered to patients with advanced or metastatic pancreatic cancer. The study will be conducted in two parts.
Part 1 of the study will evaluate the safety, tolerability and pharmacokinetics (PK) of ruxolitinib when given as described to patients with advanced or metastatic pancreatic cancer. A goal of Part 1 will be to identify the maximally tolerated dose (MTD) of ruxolitinib when given with gemcitabine with or without nab-paclitaxel. This dose will be selected for use in Part 2 of the study.
Part 2 of the study will further evaluate the safety, tolerability, PK and preliminary clinical activity of ruxolitinib at the dose defined in Part 1 used in combination with gemcitabine with or without nab-paclitaxel in subjects with advanced or metastatic pancreatic cancer.
After multiple challenges of trial conduct, by mutual agreement between investigators and sponsor, dose escalation ended after Cohort B1, RUX 10 mg twice daily (BID) - GCSF in October 2014. Therefore, the MTD was not reached. No safety issues led to the decision to stop further enrollment.
Because of the early study termination, samples for pharmacokinetics and pharmacodynamics, and computed tomography for tumor burden were collected, but not analyzed; analysis data are not available. The data cutoff for this posting is 22 SEP 2015. As of the data cutoff, 1 subject was receiving treatment in the study and had been enrolled for 47 weeks. This subject had their end of treatment visit in AUG 2016. A comparison of this subjects' safety data after the cutoff date showed no clinically meaningful differences (eg, adverse events) compared with safety results that are summarized here.
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
- •Male or female, 18 years or older
- •Histologically or cytologically confirmed adenocarcinoma of the pancreas
- •Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
- •Requirements for prior therapy as outlined below:
- •Enrollment into Regimen A: received no more than 1 prior chemotherapy regimen for advanced or metastatic disease (not including neoadjuvant and/or adjuvant therapy)
- •Enrollment into Regimen B: received no prior chemotherapy for advanced or metastatic disease (not including neoadjuvant and/or adjuvant therapy)
- •Adequate renal, hepatic, and bone marrow function without blood product or hematopoietic growth factor support:
- •Able to swallow and retain oral medication
排除标准
- •Any known contraindications to the use of gemcitabine (for enrollment in Regimen A or B) or nab-paclitaxel (for enrollment into Regimen B).
- •Evidence of uncontrolled brain metastases or history of uncontrolled seizures.
- •Ongoing radiation therapy and/or radiation therapy administered within 28 days of enrollment. Subjects who have received radiation to the spine, pelvis, ribs, or femur should be discussed with the sponsor, as extensive radiation to marrow forming region may compromise a subject's ability to tolerate myelosuppressive chemotherapy. Subjects who have ongoing radiotherapy-related toxicities are not eligible.
- •Subjects who participated in any other study in which receipt of an investigational study drug occurred within 28 days or 5 half-lives (whichever is longer) prior to first dose.
- •Current or previous other malignancy within 2 years of study entry, except cured basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix, or other noninvasive malignancy without sponsor approval.
- •Inability to swallow food or any condition of the upper GI tract that precludes administration of oral medications.
- •Recent (≤ 3 months) history of partial or complete bowel obstruction.
- •Unwilling to be transfused with blood components.
- •Known history of Hepatitis B or C infection or HIV infection.
- •Presence of ≥ Grade 2 neuropathy
研究组 & 干预措施
Regimen A -ruxolitinib, gemcitabine
Ruxolitinib (RUX) was self-administered by the subject orally in the morning and evening, approximately 12 hours apart, without regard to food. The morning dose of RUX was to be taken before the chemotherapy infusion, Gemcitabine IV, on days when they were given together (Days 1, 8, and 15 of each cycle).
干预措施: ruxolitinib (Drug)
Regimen A -ruxolitinib, gemcitabine
Ruxolitinib (RUX) was self-administered by the subject orally in the morning and evening, approximately 12 hours apart, without regard to food. The morning dose of RUX was to be taken before the chemotherapy infusion, Gemcitabine IV, on days when they were given together (Days 1, 8, and 15 of each cycle).
干预措施: gemcitabine (Drug)
Regimen B-ruxolitinib, gemcitabine, nab-paclitaxel, filgrastim
Ruxolitinib (RUX) was self-administered by the subject orally in the morning and evening, approximately 12 hours apart, without regard to food.
Gemcitabine was provided as open-label, commercial product and was administered intravenously (IV) over 30 minutes on Days 1, 8, and 15 of each 28-day cycle. Reduced doses of gemcitabine administered IV over 30 minutes on Days 1, 8, and 15 of each 28-day cycle could also be explored.
nab-Paclitaxel, as open-label, commercial product, was administered IV over 30 minutes on Days 1, 8, and 15 of each 28-day cycle.
干预措施: ruxolitinib (Drug)
Regimen B-ruxolitinib, gemcitabine, nab-paclitaxel, filgrastim
Ruxolitinib (RUX) was self-administered by the subject orally in the morning and evening, approximately 12 hours apart, without regard to food.
Gemcitabine was provided as open-label, commercial product and was administered intravenously (IV) over 30 minutes on Days 1, 8, and 15 of each 28-day cycle. Reduced doses of gemcitabine administered IV over 30 minutes on Days 1, 8, and 15 of each 28-day cycle could also be explored.
nab-Paclitaxel, as open-label, commercial product, was administered IV over 30 minutes on Days 1, 8, and 15 of each 28-day cycle.
干预措施: gemcitabine (Drug)
Regimen B-ruxolitinib, gemcitabine, nab-paclitaxel, filgrastim
Ruxolitinib (RUX) was self-administered by the subject orally in the morning and evening, approximately 12 hours apart, without regard to food.
Gemcitabine was provided as open-label, commercial product and was administered intravenously (IV) over 30 minutes on Days 1, 8, and 15 of each 28-day cycle. Reduced doses of gemcitabine administered IV over 30 minutes on Days 1, 8, and 15 of each 28-day cycle could also be explored.
nab-Paclitaxel, as open-label, commercial product, was administered IV over 30 minutes on Days 1, 8, and 15 of each 28-day cycle.
干预措施: nab-paclitaxel (Drug)
Regimen B-ruxolitinib, gemcitabine, nab-paclitaxel, filgrastim
Ruxolitinib (RUX) was self-administered by the subject orally in the morning and evening, approximately 12 hours apart, without regard to food.
Gemcitabine was provided as open-label, commercial product and was administered intravenously (IV) over 30 minutes on Days 1, 8, and 15 of each 28-day cycle. Reduced doses of gemcitabine administered IV over 30 minutes on Days 1, 8, and 15 of each 28-day cycle could also be explored.
nab-Paclitaxel, as open-label, commercial product, was administered IV over 30 minutes on Days 1, 8, and 15 of each 28-day cycle.
干预措施: filgrastim (Drug)
结局指标
主要结局
Percentage of Participants With Adverse Events That Are Defined as Dose Limiting Toxicities (DLTs)
时间窗: Approximately 28 days
Toxicities occurring during the first treatment cycle (Cycle 1) defined tolerability. Within each cohort, subjects were considered evaluable if they had received at least 40 of 56 planned doses of RUX during the 28-day surveillance period and received 2 of the 3 planned doses of chemotherapy (gemcitabine and/or gemcitabine and nab-paclitaxel) at the assigned dose level, or they had experienced a DLT.
次要结局
- Plasma Concentrations Will be Used to Estimate Peak Plasma Concentration (Cmax) and Area Under the Plasma Concentration Curve (AUC).(Day 1 and Day 8)
- Plasma Concentration of Tumor Specific Biomarkers and Cytokines Before and During Treatment.(Up to 6 months)
- Clinical Activity as Measured by the Greatest Decrease in Tumor Burden Compared to Baseline.(Approximately 6 months)
- Percentage of Participants With a Best Response by RECIST Criteria(every 2 cycles starting at Cycle 3 Day 1 up to approximately 4 to 6 months)
- Percentage of Responders(Randomization to clinical cutoff 22Sept2015 (approx 244 days))
- Duration of Response(Randomization to clinical cutoff 22Sept2015 (approx 244 days))