A Phase I and Randomized Phase II Study of Nab-Paclitaxel/Gemcitabine With or Without AZD1775 for Treatment of Metastatic Adenocarcinoma of the Pancreas
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 8
- 试验地点
- 5
- 主要终点
- Number of Participants With Dose Limiting Toxicities (DLT)
研究概览
简要总结
This partially randomized phase I/II trial studies the side effects and best dose of WEE1 inhibitor AZD1775 when given together with paclitaxel albumin-stabilized nanoparticle formulation and gemcitabine hydrochloride and how well they work in treating patients with previously untreated pancreatic cancer that has spread to another place in the body or cannot be removed by surgery. Drugs used in chemotherapy, such as paclitaxel albumin-stabilized nanoparticle formulation and gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. WEE1 inhibitor AZD1775 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether paclitaxel albumin-stabilized nanoparticle formulation and gemcitabine hydrochloride are more effective with or without WEE1 inhibitor AZD1775 in treating patients with pancreatic cancer.
详细描述
PRIMARY OBJECTIVES:
I. To evaluate the toxicity of combination therapy with nab-paclitaxel (paclitaxel albumin-stabilized nanoparticle formulation), gemcitabine (gemcitabine hydrochloride) and AZD1775 (WEE1 inhibitor MK-1775) in patients with treatment-naive metastatic adenocarcinoma of the pancreas or locally-advanced adenocarcinoma of the pancreas which is not surgically resectable. (Phase I) II. To determine the dose of AZD1775 to be used in combination with nab-paclitaxel and gemcitabine chemotherapy in the phase II portion of the trial. (Phase I) III. To determine the pharmacokinetics of AZD1775 in combination with nab-paclitaxel and gemcitabine. (Phase I) IV. To evaluate progression-free survival (PFS) associated with nab-paclitaxel/gemcitabine/placebo or nab-paclitaxel/gemcitabine/AZD1775 in patients with metastatic adenocarcinoma of the pancreas. (Phase II)
SECONDARY OBJECTIVES:
I. To evaluate overall survival (OS) associated with nab-paclitaxel/gemcitabine/placebo or nab-paclitaxel/gemcitabine/AZD1775 in patients with metastatic adenocarcinoma of the pancreas. (Phase II) II. To evaluate response rate (complete response [CR] + partial response [PR]) associated with nab-paclitaxel/gemcitabine/placebo or nab-paclitaxel/gemcitabine/AZD1775 in patients with metastatic adenocarcinoma of the pancreas. (Phase II) III. To evaluate disease control rate (CR + PR + stable disease [SD]) associated with nab-paclitaxel/gemcitabine/placebo or nab-paclitaxel/gemcitabine/AZD1775 in patients with metastatic adenocarcinoma of the pancreas. (Phase II)
TERTIARY OBJECTIVES:
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
- 未提供
排除标准
- •Prior systemic therapy for metastatic disease
- •Locally advanced disease
- •Major surgical procedures <=28 days of beginning study treatment or minor surgical procedures <=7 days
- •Any of the following cardiac diseases at registration or within the last 6 months as defined by New York Heart Association (NYHA) ≥ Class 2:
- •Unstable angina pectoris
- •Congestive heart failure
- •Acute myocardial infarction
- •Conduction abnormality not controlled with pacemaker or medication
- •Significant ventricular or supraventricular arrhythmias (patients with chronic rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible.)
- •Taking current medications or substances that are inhibitors of CYP3A4, inhibitors or substrates of P-glycoprotein or inhibitors of breast cancer resistance protein (BCRP)
- •Prior Wee1 inhibitors or AZD1775
- •Prior gemcitabine or nab-paclitaxel in a metastatic setting
- •Corrected QT interval QTc > 470 msec (as calculated per institutional standards) at study entry or congenital long QT syndrome).
- •Receiving any other investigational agents concurrently or have received any other investigational agents =< 4 weeks prior to randomization
- •Pre-existing > grade 1 motor or sensory neuropathy
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to nab-paclitaxel, gemcitabine or AZD1775
- •Uncontrolled serious medical illness including, but not limited to, ongoing or active infection, cardiac arrhythmia, or psychiatric illness that would limit compliance with study requirements
- •Previous or concurrent malignancy; exceptions are made for patients who meet any of the following conditions:
- •Non-melanoma skin cancer, in situ cervical cancer, breast cancer in situ, or superficial bladder cancer (noninvasive papillary carcinoma or carcinoma in situ)
- •Prior malignancy completely excised or removed and patient has been continuously disease free for > 5 years
- •Pregnant or breast-feeding
- •Females of childbearing potential must have a blood test or urine study within 5 days prior to randomization to rule out pregnancy; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
- •For participation in the FDG-PET sub-study:
- •Poorly controlled diabetes (defined as fasting glucose level >= 200 mg/dL) despite efforts to improve glucose control by fasting duration and adjustment of medications
- •Weigh more than the maximum weight limit for the PET table
- •For participation in the FLT-PET sub-study:
- •History of allergic reaction attributable to compounds of similar chemical or biologic composition to 18F-fluorothymidine
- •Weigh more than the maximum weight limit for the PET table
研究组 & 干预措施
Arm A
Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Patients also receive WEE1 inhibitor AZD1775 PO daily on days 1, 2, 8, 9, 15, and 16.
干预措施: AZD1775 (Drug)
Arm A
Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Patients also receive WEE1 inhibitor AZD1775 PO daily on days 1, 2, 8, 9, 15, and 16.
干预措施: Gemcitabine (Drug)
Arm A
Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Patients also receive WEE1 inhibitor AZD1775 PO daily on days 1, 2, 8, 9, 15, and 16.
干预措施: Nab-paclitaxel (Drug)
Arm B
Patients receive paclitaxel albumin-stabilized nanoparticle formulation, gemcitabine hydrochloride, and WEE1 inhibitor AZD1775 as in Arm A.
干预措施: AZD1775 (Drug)
Arm B
Patients receive paclitaxel albumin-stabilized nanoparticle formulation, gemcitabine hydrochloride, and WEE1 inhibitor AZD1775 as in Arm A.
干预措施: Gemcitabine (Drug)
Arm B
Patients receive paclitaxel albumin-stabilized nanoparticle formulation, gemcitabine hydrochloride, and WEE1 inhibitor AZD1775 as in Arm A.
干预措施: Nab-paclitaxel (Drug)
结局指标
主要结局
Number of Participants With Dose Limiting Toxicities (DLT)
时间窗: Assessed at 28 days
A dose-limiting toxicity (DLT) was defined by the occurrence of any of the toxicities listed in section 5.1.5 of the protocol that are possibly, probably, or definitely related to study drug(s) within the first cycle (4 weeks = 28 days).
Progression-free Survival
时间窗: Assessed every 3 months for 2 years
To Determine the Pharmacokinetics of AZD1775 in Combination With Nab-paclitaxel and Gemcitabine
时间窗: Assessed at Day 1 and Day 16
Plasma was to be collected on Cycle 1 Day 1 and Cycle 1 Day 16 for the pharmacokinetics analysis.
次要结局
- Disease Control Rate(Assessed every 3 months for 2 years)
- Overall Survival(Assessed every 3 months for 2 years)
- Response Rate(Assessed every 3 months for 2 years)