A Phase 1 Study of ABT-888 (Veliparib) in Combination With Weekly Carboplatin and Paclitaxel in Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 22
- 试验地点
- 3
- 主要终点
- MTD defined as the dose level one level below the lowest dose where greater than or equal to 2 patients experience a DLT assessed by National Cancer Institute (NCI) CTCAE v. 4.0
研究概览
简要总结
This phase I clinical trial studies the side effects and the best dose of veliparib when given together with carboplatin and paclitaxel in treating patients with locally advanced or metastatic solid tumors. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by blocking them from dividing. Giving veliparib with carboplatin and paclitaxel may work better in treating patients with solid tumors.
详细描述
PRIMARY OBJECTIVE:
I. To determine the maximum-tolerated dose (MTD) of the combination of weekly carboplatin, paclitaxel, and veliparib.
SECONDARY OBJECTIVES:
I. To assess the safety, tolerability, and MTD of the combination of weekly carboplatin, paclitaxel, and veliparib.
II. To assess the safety and toxicity of this combination as determined by the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v. 4.0) and to determine the dose-limiting toxicity (DLT).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 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
- •Histologically or cytologically confirmed solid tumor that has evidence of metastatic spread (stage IV) or is locally advanced and unresectable
- •Patients with breast cancer may have estrogen receptor positive or negative (ER+ or ER-) disease
- •Patients with breast cancer may not be human epidermal growth receptor -2 (HER2)-positive ( 3+), or fluorescent in situ hybridization (FISH) ratio > 2.2
- •Patients in the biopsy expansion cohort must have "triple negative" breast cancer defined as:
- •Estrogen receptor staining < 10%; progesterone receptor staining <10%; Her 2 < 2.2 by FISH, or immunohistochemistry (IHC) 0-2+
- •Patients may have been previously treated
- •In the dose escalation cohort, there is no limit to prior therapies
- •In the expansion cohort, patients may have only had 1-3 prior regimens for metastatic disease
- •Patients may have received prior carboplatin, paclitaxel, or poly (ADP-ribose) polymerase (PARP) inhibitor therapy as part of their previous treatment regimens
- •However, patients may NOT have received prior therapy with paclitaxel, carboplatin, and PARP inhibitor in combination
- •Patients must not have received chemotherapy within 4 weeks of starting study (or 6 weeks if prior treatment was with carmustine [BCNU] or mitomycin C)
- •Patients must not have received radiation within 2 weeks of starting study
- •Eastern Cooperative Oncology Group (ECOG) performance status (PS)< 2 (Karnofsky > 60%)
- •Life expectancy > 2 months
- •Absolute neutrophil count (ANC) >= 1,500/mcL
- •Platelet count >= 100,000/mcL
- •Total bilirubin =< 1.5 times upper limit of normal (ULN)
- •Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 times ULN
- •Creatinine normal within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73m^2 for patients with creatinine levels above institutional normal
- •Must able to swallow pills
- •Pregnant women are excluded from this study
- •Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
- •Ability to understand and the willingness to sign a written informed consent document
- •Patients enrolled in the expanded cohort with mandatory biopsies must:
- •Have accessible tumors
- •Not be on therapeutic anticoagulation
- •Have signed informed consent form
排除标准
- •Patients who have had chemotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) or radiotherapy within 2 weeks (4 weeks for central nervous system [CNS] metastases) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
- •Patients may not be receiving any other investigational agents
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to veliparib or other agents used in study
- •Concurrent treatment with bisphosphonates, or other bone anti-resorptive agent such as denosumab is allowed; concurrent treatment with hormonal therapy (tamoxifen, ovarian suppression with gonadotropin-releasing hormone [GNRH] agonists, aromatase inhibitors) or trastuzumab therapy is NOT allowed in breast cancer patients; prostate cancer patients may continue GNRH agents
- •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 women are excluded from this study; breastfeeding should be discontinued if the mother is treated with veliparib
- •Active seizure or history of seizure disorder
- •Patients with CNS metastases must be stable after therapy for CNS metastases (such as surgery, radiotherapy or stereotactic radiosurgery) for > 3 months and must be off steroid treatment prior to study enrollment
- •Patients who undergo biopsy as part of the study in the expanded dose cohort should not be on anti-coagulants or have a pre-existing coagulopathy
- •Peripheral neuropathy of severity greater than grade 1
研究组 & 干预措施
Treatment (veliparib, paclitaxel, carboplatin)
DOSE-ESCALATION: Patients receive veliparib PO twice daily BID on days 1-5, 8-12, and 15-19 and paclitaxel IV over 1 hour and carboplatin IV over 30 minutes in course 1 and 3 hours in subsequent courses on days 3, 10, and 17. After 4 courses, patients receive paclitaxel and carboplatin on days 3 and 10 only. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. (Completed as of 12/2012)
EXPANSION COHORT: Patients receive veliparib PO BID on days 1-21 and paclitaxel IV over 1 hour and carboplatin IV over 3 hours on days 3 and 10. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
干预措施: Carboplatin (Drug)
Treatment (veliparib, paclitaxel, carboplatin)
DOSE-ESCALATION: Patients receive veliparib PO twice daily BID on days 1-5, 8-12, and 15-19 and paclitaxel IV over 1 hour and carboplatin IV over 30 minutes in course 1 and 3 hours in subsequent courses on days 3, 10, and 17. After 4 courses, patients receive paclitaxel and carboplatin on days 3 and 10 only. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. (Completed as of 12/2012)
EXPANSION COHORT: Patients receive veliparib PO BID on days 1-21 and paclitaxel IV over 1 hour and carboplatin IV over 3 hours on days 3 and 10. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
干预措施: Laboratory Biomarker Analysis (Other)
Treatment (veliparib, paclitaxel, carboplatin)
DOSE-ESCALATION: Patients receive veliparib PO twice daily BID on days 1-5, 8-12, and 15-19 and paclitaxel IV over 1 hour and carboplatin IV over 30 minutes in course 1 and 3 hours in subsequent courses on days 3, 10, and 17. After 4 courses, patients receive paclitaxel and carboplatin on days 3 and 10 only. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. (Completed as of 12/2012)
EXPANSION COHORT: Patients receive veliparib PO BID on days 1-21 and paclitaxel IV over 1 hour and carboplatin IV over 3 hours on days 3 and 10. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
干预措施: Paclitaxel (Drug)
Treatment (veliparib, paclitaxel, carboplatin)
DOSE-ESCALATION: Patients receive veliparib PO twice daily BID on days 1-5, 8-12, and 15-19 and paclitaxel IV over 1 hour and carboplatin IV over 30 minutes in course 1 and 3 hours in subsequent courses on days 3, 10, and 17. After 4 courses, patients receive paclitaxel and carboplatin on days 3 and 10 only. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. (Completed as of 12/2012)
EXPANSION COHORT: Patients receive veliparib PO BID on days 1-21 and paclitaxel IV over 1 hour and carboplatin IV over 3 hours on days 3 and 10. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
干预措施: Pharmacological Study (Other)
Treatment (veliparib, paclitaxel, carboplatin)
DOSE-ESCALATION: Patients receive veliparib PO twice daily BID on days 1-5, 8-12, and 15-19 and paclitaxel IV over 1 hour and carboplatin IV over 30 minutes in course 1 and 3 hours in subsequent courses on days 3, 10, and 17. After 4 courses, patients receive paclitaxel and carboplatin on days 3 and 10 only. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. (Completed as of 12/2012)
EXPANSION COHORT: Patients receive veliparib PO BID on days 1-21 and paclitaxel IV over 1 hour and carboplatin IV over 3 hours on days 3 and 10. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
干预措施: Veliparib (Drug)
结局指标
主要结局
MTD defined as the dose level one level below the lowest dose where greater than or equal to 2 patients experience a DLT assessed by National Cancer Institute (NCI) CTCAE v. 4.0
时间窗: 21 days
次要结局
- Change in BRCA protein levels by immunohistochemistry(Baseline to day 4 of course 2)
- Change in PAR and g-H2AX in tumor tissue(Baseline to day 4 of course 2)
- Grade >= 3 non-hematological or any grade 5 DLTs as graded by the NCI CTCAE v. 4.0(21 days)
- Incidence of adverse events as graded by the NCI CTCAE v. 4.0(Up to 4 weeks post-treatment)
- Plasma concentration of carboplatin, paclitaxel, and veliparib using liquid chromatography-mass spectrometry (LC-MS) assay and spectrometry assay(Baseline, at 30 minutes and at 1, 2, 4, and 8 hours on day 3 of course 1)
- Response complete response [Cr], partial response [PR], and stable disease [SD]) using the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1)(Up to 4 weeks post-treatment)