Veliparib With or Without Mitomycin C in Treating Patients With Metastatic, Unresectable, or Recurrent Solid Tumors
ABT-888 as Monotherapy and in Combination With Mitomycin C in Patients With Solid Tumors With Deficiency in Homologous Recombination Repair
研究概览
详细说明
PRIMARY OBJECTIVES:
I. To screen cancer patients across different histological sites to identify those with functional defects in the Fanconi anemia (FA) pathway in their tumors.
II. To establish the safety and practicality of treating patients with FA deficient tumors with the poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor ABT-888 (veliparib) as protracted monotherapy.
III. To establish the safety and practicality of treating patients with FA deficient tumors with the combination of mitomycin C (MMC) and ABT-888.
IV. To select a dose of ABT-888 protracted monotherapy and a dose-schedule of the combination of mitomycin C and ABT-888 in patients with FA deficient tumors for phase 2 trials.
SECONDARY OBJECTIVES:
I. To evaluate for germ-line FA repair deficiency and BRCA mutations in peripheral blood mononuclear (PBMC) in patients receiving ABT-888 treatment.
II. To evaluate in PBMC samples for foci produced by the histone variant gamma-H2A histone family, member X (H2AX) in patients receiving mitomycin C with or without ABT-888 in order to assess any possible effect of ABT-888 in the cellular sensing and processing of mitomycin C-induced deoxyribonucleic acid (DNA) double strand breaks.
III. Quantify the number of patients with antitumor responses.
OUTLINE: This is a dose-escalation study of veliparib. Patients are assigned to 1 of 2 treatment arms.
ARM I: Patients receive veliparib orally (PO) twice daily (BID) in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive veliparib PO BID on days 1-7, 1-14, or 1-21. Patients also receive mitomycin C intravenously (IV) over 10-20 minutes on day 1. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 12 weeks.
研究类型
注册 (实际的)
阶段
- 阶段1
联系人和位置
学习地点
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Kentucky
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Georgetown、Kentucky、美国、40324
- Georgetown Cancer Treatment Center
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Ohio
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Columbus、Ohio、美国、43210
- Ohio State University Comprehensive Cancer Center
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参与标准
资格标准
适合学习的年龄
接受健康志愿者
有资格学习的性别
描述
Inclusion Criteria:
- Patients must have a histologically confirmed solid malignancy that is metastatic, or unresectable, or recurrent, for which no curative or standard of care exist, or this standard of care is no longer effective
- Tumors have been shown to be deficient for the FA pathway, based on Fanconi anemia triple stain immunofluorescence (FATSI) screening
- Patients will be consented to have their existing, or about to be obtained, paraffin embedded tumor tissue screened for FA deficiency; screening will be performed on an ongoing basis on the breast, thoracic, gastrointestinal (GI), Georgetown University (GU), and gynecologic (GYN) Ohio State University (OSU) clinics, anteceding and concurrently with the clinical trial; it will continue until the numbers of patients required for the clinical trial are identified and enrolled; based on the estimation from our preliminary data of 15 to 30% of patients, depending on the primary organ site, having tumors deficient for the FA pathway we will need to screen around 300 patients' samples to identify 40-50 patients; none of the eligibility criteria defined above or below will need to be met for the screening portion, since FA deficient patients identified by screening may meet eligibility criteria for the clinical trial at a later time; (e.g., patient is undergoing standard of care treatment at the time of the screening); separate written consents for screening and for the clinical trial will be obtained from patients
- Up to two chemotherapy regimens for metastatic disease are allowed; in addition, prior adjuvant/neo-adjuvant chemotherapy, hormonal therapy, molecular targeted therapy or estrogen receptor B (Erb) inhibitor treatments (e.g., erlotinib, Herceptin, sorafenib, sunitinib) will be allowed and will not count towards eligibility; at least 4 weeks must elapse since prior chemotherapy or radiation therapy (two weeks for erlotinib, hormonal therapy, or limited field palliative radiation to bone, brain, or radiosurgery), 6 weeks if the last regimen included nitrosoureas or mitomycin C; previous use of mitomycin C would be restricted to topical applications (bladder cancer) or chemoembolization (e.g., liver tumors)
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
- Life expectancy of greater than 3 months
- Leukocytes >= 3,000/mcL
- Absolute neutrophil count (ANC) >= 1,500/mcL
- Hemoglobin >= 9 g/dL
- Platelets >= 100,000/mcL
- Total bilirubin within normal institutional limit
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal
- Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
- 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 should be able to swallow capsules
EXPANSION COHORT:
- Diagnosis of colorectal malignancy
- Absence of Fanconi anemia, complementation group D2 (FANCD2) foci by FATSI screening
- Presence of biopsiable lesion by imaging
- Consent to a baseline (prior to treatment) tumor biopsy and for a repeat biopsy at the time of progression on the event that an antitumor response is demonstrated on the MMC-ABT-888 regimen
- Same eligibility as above, except that they will have no limitations related prior number of chemotherapy regimens given; patients could have received prior treatment with PARP inhibitors if used as single agent
Exclusion Criteria:
- Patients may not be receiving any other investigational agents
- Patients with known central nervous system (CNS) metastases (unless previously resected or irradiated and not clinically active); patients with CNS metastases must be stable after therapy for > 3 months and off steroid treatment prior to study enrollment
- History of allergic reactions attributed to compounds of similar chemical or biologic composition as ABT-888 or Mitomycin C
- 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
- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
- Patients with active seizure or a history of seizures
- Patients previously treated with PARP inhibitors; with the exception of patients enrolled on Arm 2 who may have had prior treatment with PARP inhibitors as monotherapy
学习计划
研究是如何设计的?
设计细节
- 主要用途:治疗
- 分配:非随机化
- 介入模型:并行分配
- 屏蔽:无(打开标签)
武器和干预
参与者组/臂 |
干预/治疗 |
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实验性的:Arm I (veliparib)
Patients receive veliparib PO BID in the absence of disease progression or unacceptable toxicity.
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相关研究
给定采购订单
其他名称:
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实验性的:Arm II (veliparib and mitomycin C)
Patients receive veliparib PO BID on days 1-7, 1-14, or 1-21.
Patients also receive mitomycin C IV over 10-20 minutes on day 1.
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
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相关研究
给定采购订单
其他名称:
鉴于IV
其他名称:
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研究衡量的是什么?
主要结果指标
结果测量 |
大体时间 |
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Ability to safely deliver the combination of mitomycin C and veliparib
大体时间:Up to 12 weeks post-treatment
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Up to 12 weeks post-treatment
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Ability to safely deliver veliparib in a continuous dose as monotherapy
大体时间:Up to 12 weeks post-treatment
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Up to 12 weeks post-treatment
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Feasibility of screening for FA deficiency across different tumor types, defined as adequate number of patients deficient on this pathway
大体时间:Up to 12 weeks post-treatment
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Up to 12 weeks post-treatment
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Selection of a dose schedule of the combination of mitomycin C and veliparib for phase II trials
大体时间:Up to 12 weeks post-treatment
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Up to 12 weeks post-treatment
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Selection of a dose schedule of veliparib monotherapy for phase II trials
大体时间:Up to 12 weeks post-treatment
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Up to 12 weeks post-treatment
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次要结果测量
结果测量 |
措施说明 |
大体时间 |
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BRCA mutations
大体时间:Baseline
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Descriptive statistics will be provided: proportions for categorical variables; mean and standard deviation for the continuous variables.
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Baseline
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FancD2 foci formation in peripheral blood mononuclear cells
大体时间:Up to week 5
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Descriptive statistics will be provided: proportions for categorical variables; mean and standard deviation for the continuous variables.
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Up to week 5
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Foci produced by the histone variant gamma-H2AX
大体时间:Up to week 5
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Descriptive statistics will be provided: proportions for categorical variables; mean and standard deviation for the continuous variables.
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Up to week 5
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Tumor shrinkage as assessed by radiological means
大体时间:Up to 12 weeks post-treatment
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Up to 12 weeks post-treatment
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合作者和调查者
调查人员
- 首席研究员:Sameh Mikhail、Ohio State University Comprehensive Cancer Center
研究记录日期
研究主要日期
学习开始
初级完成 (实际的)
研究注册日期
首次提交
首先提交符合 QC 标准的
首次发布 (估计)
研究记录更新
最后更新发布 (估计)
上次提交的符合 QC 标准的更新
最后验证
更多信息
与本研究相关的术语
其他研究编号
- NCI-2012-01473 (注册表标识符:CTRP (Clinical Trial Reporting Program))
- P30CA016058 (美国 NIH 拨款/合同)
- N01CM62207 (美国 NIH 拨款/合同)
- N01CM00070 (美国 NIH 拨款/合同)
- OSU-09100
- OSU# 09100
- 2009C0069
- 09100
- NCI 8472
- CDR0000656393
- OSU 09100 (其他标识符:Ohio State University Comprehensive Cancer Center)
- 8472 (其他标识符:CTEP)
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