Phase II Randomized Trial of ABT-888 in Combination With Metronomic Oral Cyclophosphamide in Refractory BRCA-Positive Ovarian, Primary Peritoneal, Ovarian High-Grade Serous Carcinoma, Fallopian Tube Cancer, or Triple-Negative Breast Cancer
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 124
- 试验地点
- 10
- 主要终点
- Percentage of Participants With an Overall Response Rate
研究概览
简要总结
Background:
- The experimental cancer treatment drug ABT-888 (Veliparib) works by preventing deoxyribonucleic acid (DNA) repair in tumor cells. Cyclophosphamide is a cancer treatment drug that works by causing DNA damage in cells, including cancer cells, resulting in cell death. However, because cyclophosphamide has strong and unpleasant side effects, researchers are interested in finding drugs that can be given in combination with cyclophosphamide that will allow a lower dose of cyclophosphamide to be given with similar effects. The combination of ABT-88 and cyclophosphamide may be an effective treatment for some types of cancer, such as certain kinds of breast or ovarian cancer and non-Hodgkin's lymphoma that often do not respond to standard therapies.
Objectives:
- To evaluate the safety and effectiveness of ABT-888 and cyclophosphamide in ovarian and breast cancer and in non-Hodgkin's lymphoma that have not responded to standard treatments.
Eligibility:
- Individuals at least 18 years of age who have been diagnosed with (1) (Breast cancer 1/2) BRCA1/2 ovarian cancer, primary peritoneal or ovarian high-grade carcinoma, or fallopian tube cancer; (2) triple-negative breast cancer (not responsive to hormone-related therapy); or (3) low grade non-Hodgkin's lymphoma.
Design:
- Participants will be screened with a full medical history and physical examination, blood and urine tests, and tumor imaging studies. Participants will be divided into two groups with different treatment subgroups.
- Group 1: Participants who have BRCA-positive ovarian cancer, primary peritoneal or ovarian high-grade serous carcinoma, or fallopian tube cancer
- Participants will receive either the combination of ABT-888 and cyclophosphamide, or cyclophosphamide alone.
- Participants will take the study drug by mouth once a day for 21-day cycles of treatment, and will keep a diary to record drug doses and any side effects.
- Participants will have clinic visits with blood and urine tests, imaging studies, and other examinations on days 1, 2, 7, and 14 of cycle 1, and on the first day of all other cycles.
- Group 2: Participants who have triple-negative breast cancer or non-Hodgkin's lymphoma
- Participants will receive either the combination of ABT-888 and cyclophosphamide, or cyclophosphamide alone.
- Participants will take the study drug by mouth once a day for 21-day cycles of treatment, and will keep a diary to record drug doses and any side effects.
- Participants will have clinic visits with blood and urine tests, imaging studies, and other examinations on days 1, 2, 7, and 14 of cycle 1, and on the first day of all other cycles.
- Participants receiving only cyclophosphamide who show signs of disease progression after tumor imaging studies can receive the combination of ABT-888 with cyclophosphamide.
- Treatment will continue as long as participants tolerate the drugs and the disease does not progress.
详细描述
Background:
- The poly (ADP-ribose) polymerase (PARP) family of enzymes is critical for maintaining genomic stability by regulating a variety of DNA repair mechanisms.
- Individuals with deleterious mutations in the BRCA1 or BRCA2 tumor suppressor genes have an increased risk of developing breast and ovarian cancers due to impaired or defective DNA damage repair; these individuals have an increased susceptibility to DNA-damaging agents and PARP inhibitors. Inhibition of PARP inhibits the repair of DNA damage caused by alkylating agents such as cyclophosphamide.
- Metronomic cyclophosphamide has demonstrated efficacy in several tumor types. The PARP inhibitor ABT-888 has been shown to potentiate the action of cyclophosphamide in xenograft models. This combination is well tolerated in a Phase I study and showing promising activity.
Objectives:
- Compare the response rate (complete response (CR) + partial response (PR)) of the combination of ABT-888 with metronomic oral cyclophosphamide to the response rate (CR+PR) of metronomic oral cyclophosphamide in patients with deleterious BRCA mutations and refractory ovarian cancer or patients with primary peritoneal or ovarian high-grade serous carcinoma or fallopian tube cancer.
- Compare the response rate (CR+PR) of the combination of ABT-888 with metronomic oral cyclophosphamide to the response rate (CR+PR) of single-agent oral cyclophosphamide in patients with triple-negative metastatic breast cancer, stratified for deleterious BRCA mutation.
- Compare the response rate (CR+PR) of the combination of ABT-888 with metronomic oral cyclophosphamide to the response rate (CR+PR) of single-agent metronomic oral cyclophosphamide in patients with refractory low-grade lymphomas.
Secondary Objectives:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 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
- 未提供
研究组 & 干预措施
Triple-negative Breast Cancer: ABT-888 + Cyclophosphamide
Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.
干预措施: ABT-888 (Drug)
Triple-negative Breast Cancer: ABT-888 + Cyclophosphamide
Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.
干预措施: Cyclophosphamide (Drug)
Triple-negative Breast Cancer: Cyclophosphamide Alone
Oral cyclophosphamide 50mg by mouth (PO) for 21 days. Participants in the cyclophosphamide alone arm crossed over to the ABT-888 plus cyclophosphamide arm at time of disease progression.
干预措施: Cyclophosphamide (Drug)
BRCA-positive Ovarian Cancer: ABT-888 + Cyclophosphamide
Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.
干预措施: ABT-888 (Drug)
BRCA-positive Ovarian Cancer: ABT-888 + Cyclophosphamide
Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.
干预措施: Cyclophosphamide (Drug)
BRCA- positive Ovarian Cancer: Cyclophosphamide Alone
Oral cyclophosphamide 50mg by mouth (PO) for 21 days. Participants in the cyclophosphamide alone arm crossed over to the ABT-888 plus cyclophosphamide arm at time of disease progression.
干预措施: Cyclophosphamide (Drug)
Non-Hodgkin's: ABT-888 + Cyclophosphamide
Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.
干预措施: ABT-888 (Drug)
Non-Hodgkin's: ABT-888 + Cyclophosphamide
Oral cyclophosphamide 50mg by mouth (PO) for 21 days and oral ABT-888 60mg by mouth (PO) on a continuous schedule.
干预措施: Cyclophosphamide (Drug)
Non-Hodgkin's: Cyclophosphamide Alone
Oral cyclophosphamide 50mg by mouth (PO) for 21 days. Participants in the cyclophosphamide alone arm crossed over to the ABT-888 plus cyclophosphamide arm at time of disease progression.
干预措施: Cyclophosphamide (Drug)
结局指标
主要结局
Percentage of Participants With an Overall Response Rate
时间窗: an average of 126 days for ovarian; 71 days for TNBC; for crossover intervention, pts stayed on study for an avg of 134 days for ovarian; 50 days for TNBC.
Complete response (CR) + partial response (PR)) of the combination of ABT-888 with metronomic oral cyclophosphamide to the response rate (CR+PR) of metronomic oral cyclophosphamide in patients with deleterious BRCA mutations and refractory ovarian cancer or patients with primary peritoneal or ovarian high-grade serous carcinoma or fallopian tube cancer. CR + PR was determined by the Response Evaluation Criteria in Solid Tumors (RECIST). CR is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm). Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Progression Free Survival
时间窗: Ovarian cancer patients stayed on study for an average of 126 days and triple-negative breast cancer patients for an average of 71 days.
Time to progression for each participant for the initial intervention.
次要结局
- Number of Participants With Adverse Events(up to 30 days following the last dose of study drug.)
- Change in Poly-ADP Ribose (PAR) Concentration Levels From Baseline(At baseline (t=0h) and 4h post drug administration (t=4h))
- Change in ϓH2AX- Positive Circulating Tumor Cells (CTCs) in Whole Blood(At baseline (t=0h) and 24h post drug administration (t=24h))
- Number of Participants With Deleterious Mutations in DNA Repair Genes(Optional tumor biopsies were performed prior to start of treatment (baseline) and 6 months)
研究者
Alice Chen, M.D.
Principal Investigator
National Institutes of Health Clinical Center (CC)