NCT02608229终止1 期
Phase Ib Study of BVD-523 Plus Nab-paclitaxel and Gemcitabine in Patients With Metastatic Pancreatic Cancer
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- Maximum Tolerated Dose (MTD) of BVD-523
研究概览
简要总结
In light of the central role of extracellular signal-regulated kinases (ERK) in pancreatic cancer, the investigators propose a phase I study to evaluate the ERK inhibitor BVD-523 at the recommended phase 2 dose in combination with nab-paclitaxel plus gemcitabine in patients with newly diagnosed metastatic pancreatic cancer. The primary endpoint will be maximum tolerated dose (MTD) or RP2D and safety. The secondary endpoints include safety, response rate, biochemical response, progression-free survival (PFS) and overall survival (OS). The exploratory endpoints include the assessing the impact of BVD-523 on the MEK/ERK pathway and other major pathway pertain to pancreatic cancer.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 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
- •Histologically or cytologically confirmed newly diagnosed treatment-naïve metastatic adenocarcinoma of the pancreas with metastatic disease diagnosed no more than 6 weeks prior to enrollment. Patients with advanced pancreatic cancer progressed on 5-FU (or capecitabine) based regimen will be allowed in the expansion cohort.
- •Measurable disease defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan or MRI, as ≥ 20 mm by chest x-ray, or ≥ 10 mm with calipers by clinical exam.
- •At least 18 years of age.
- •Life expectancy > 3 months.
- •ECOG performance status ≤ 1
- •Normal bone marrow and organ function as defined below:
- •Absolute neutrophil count ≥ 1,500/mcL
- •Platelets ≥ 100,000/mcL
- •Hemoglobin ≥ 9.0 g/dL
- •Total bilirubin ≤ IULN
- •AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN, unless there are liver metastases in which case AST and ALT ≤ 5.0 x IULN
- •Creatinine ≤ 1.5 x IULN OR GFR of ≥ 50 mL/min
- •Cardiac function ≥ ILLN, e.g., LVEF of > 50% as assessed by MUGA or ECHO, QTc < 470 ms
- •Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry, for the duration of study participation, and for three months following study discontinuation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.
- •Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).
排除标准
- •Current use or anticipated need for alternative, holistic, naturopathic, or botanical formulations used for the purpose of cancer treatment.
- •A history of other malignancy with the exception of those treated with curative intent with no evidence of disease for 2 years.
- •Currently receiving any other investigational agents.
- •Known brain metastases or CNS involvement.
- •Significant ascites that require therapeutic paracentesis.
- •A history of allergic reactions attributed to compounds of similar chemical or biologic composition to BVD-523, gemcitabine, nab-paclitaxel, or other agents used in the study.
- •Neuropathy ≥ grade
- •History or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR).
- •History of interstitial lung disease or pneumonitis.
- •Concurrent therapy with drugs known to be strong inhibitors of CYP1A2, CYP2D6, and CYP3A4, or strong inducers of CYP3A4 (see Appendix B).
- •Gastrointestinal condition which could impair absorption of BVD-523 or inability to ingest BVD-
- •Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
- •Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 7 days of study entry.
- •Known HIV-positivity.
研究组 & 干预措施
Dose De-escalation: BVD-523/Nab-paclitaxel/Gemcitabine
Experimental
- Treatment will be given in a 28-day cycle.
- BVD-523 600 mg on a twice daily basis (at approximately 12-hour intervals).
- BVD-523 at 600 mg twice daily on its own for two weeks before initiating Cycle 1 treatment with gemcitabine and nab-paclitaxel.
- Nab-paclitaxel 125 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes.
- Gemcitabine 1000 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes.
- Mandatory biopsy at baseline and baseline at end of 2 week BVD-523 lead in.
干预措施: BVD-523 (Drug)
Dose De-escalation: BVD-523/Nab-paclitaxel/Gemcitabine
Experimental
- Treatment will be given in a 28-day cycle.
- BVD-523 600 mg on a twice daily basis (at approximately 12-hour intervals).
- BVD-523 at 600 mg twice daily on its own for two weeks before initiating Cycle 1 treatment with gemcitabine and nab-paclitaxel.
- Nab-paclitaxel 125 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes.
- Gemcitabine 1000 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes.
- Mandatory biopsy at baseline and baseline at end of 2 week BVD-523 lead in.
干预措施: Nab-paclitaxel (Drug)
Dose De-escalation: BVD-523/Nab-paclitaxel/Gemcitabine
Experimental
- Treatment will be given in a 28-day cycle.
- BVD-523 600 mg on a twice daily basis (at approximately 12-hour intervals).
- BVD-523 at 600 mg twice daily on its own for two weeks before initiating Cycle 1 treatment with gemcitabine and nab-paclitaxel.
- Nab-paclitaxel 125 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes.
- Gemcitabine 1000 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes.
- Mandatory biopsy at baseline and baseline at end of 2 week BVD-523 lead in.
干预措施: Gemcitabine (Drug)
Dose De-escalation: BVD-523/Nab-paclitaxel/Gemcitabine
Experimental
- Treatment will be given in a 28-day cycle.
- BVD-523 600 mg on a twice daily basis (at approximately 12-hour intervals).
- BVD-523 at 600 mg twice daily on its own for two weeks before initiating Cycle 1 treatment with gemcitabine and nab-paclitaxel.
- Nab-paclitaxel 125 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes.
- Gemcitabine 1000 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes.
- Mandatory biopsy at baseline and baseline at end of 2 week BVD-523 lead in.
干预措施: Tumor biopsy (Procedure)
Dose Expansion: BVD-523/Nab-paclitaxel/Gemcitabine
Experimental
- Treatment will be given in a 28-day cycle.
- First 2 patients enrolled: BVD-523 600 mg on a twice daily basis (at approximately 12-hour intervals), nab-paclitaxel 125 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes, and gemcitabine 1000 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes
- Remaining 6 patients enrolled: BVD-523 450 mg on a twice daily basis (at approximately 12-hour intervals), nab-paclitaxel 100 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes, and gemcitabine 800 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes
- Mandatory biopsy at baseline and at end of cycle 2 (if deemed safe for participant and feasible to obtain)
干预措施: BVD-523 (Drug)
Dose Expansion: BVD-523/Nab-paclitaxel/Gemcitabine
Experimental
- Treatment will be given in a 28-day cycle.
- First 2 patients enrolled: BVD-523 600 mg on a twice daily basis (at approximately 12-hour intervals), nab-paclitaxel 125 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes, and gemcitabine 1000 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes
- Remaining 6 patients enrolled: BVD-523 450 mg on a twice daily basis (at approximately 12-hour intervals), nab-paclitaxel 100 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes, and gemcitabine 800 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes
- Mandatory biopsy at baseline and at end of cycle 2 (if deemed safe for participant and feasible to obtain)
干预措施: Nab-paclitaxel (Drug)
Dose Expansion: BVD-523/Nab-paclitaxel/Gemcitabine
Experimental
- Treatment will be given in a 28-day cycle.
- First 2 patients enrolled: BVD-523 600 mg on a twice daily basis (at approximately 12-hour intervals), nab-paclitaxel 125 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes, and gemcitabine 1000 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes
- Remaining 6 patients enrolled: BVD-523 450 mg on a twice daily basis (at approximately 12-hour intervals), nab-paclitaxel 100 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes, and gemcitabine 800 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes
- Mandatory biopsy at baseline and at end of cycle 2 (if deemed safe for participant and feasible to obtain)
干预措施: Gemcitabine (Drug)
Dose Expansion: BVD-523/Nab-paclitaxel/Gemcitabine
Experimental
- Treatment will be given in a 28-day cycle.
- First 2 patients enrolled: BVD-523 600 mg on a twice daily basis (at approximately 12-hour intervals), nab-paclitaxel 125 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes, and gemcitabine 1000 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes
- Remaining 6 patients enrolled: BVD-523 450 mg on a twice daily basis (at approximately 12-hour intervals), nab-paclitaxel 100 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes, and gemcitabine 800 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes
- Mandatory biopsy at baseline and at end of cycle 2 (if deemed safe for participant and feasible to obtain)
干预措施: Tumor biopsy (Procedure)
结局指标
主要结局
Maximum Tolerated Dose (MTD) of BVD-523
时间窗: Completion of cycle 1 for all dose de-escalation patients (1.8 years), the first cycle is 28 days for each individual patient
-The maximum tolerated dose (MTD) is defined as the Dose Level 1 if 0 or 1 dose-limiting toxicities (DLTs) are seen in patients at that dose level or Dose Level -1 if 2+ DLTs are seen in Dose Level 1 but only 0 or 1 DLTs are seen in patients at Dose Level -1.
次要结局
- Overall Survival (OS)(Up to 2 years)
- Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events(30 days after completion of treatment (median time was 67.5 days))
- Response Rate(Through completion of treatment (median time was 37.5 days))
- Time to Tumor Progression (TTP)(Up to 2 years)
- Progression-free Survival (PFS)(Up to 2 years)
- Biochemical Response of Treatment Regimen(Through completion of treatment (median time was 37.5 days))
研究者
研究点 (1)
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