Phase I Study of Veliparib (ABT-888), an Oral PARP Inhibitor, and VX-970, an ATR Inhibitor in Combination With Cisplatin in Patients With Refractory Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 53
- 试验地点
- 3
- 主要终点
- Number of Participants With Worst Grade 2 or Higher Adverse Events Occurring in >5% of Participants at Least Possibly Related to Study Drugs
研究概览
简要总结
Background:
The drug cisplatin treats certain cancers when given with other chemotherapy drugs. Researchers think combining cisplatin with 2 other drugs could block proteins that support cancer cell growth. The other drugs are ABT-888 (veliparib) and M6620 (VX-970). They want to test if this drug combination slows the growth of cancer and is safe.
Objectives:
To test the safety and tolerability of VX-970 and veliparib combined with cisplatin in people with advanced refractory solid tumors. To determine the maximum tolerated dose of these drugs.
Eligibility:
People ages 18 and older with:
- Solid tumors that have progressed after treatment or for which no treatment exists
- Normal organ and marrow function
Design:
Participants will be screened with:
- Medical history
- Physical exam
- Computed tomography (CT) scan or magnetic resonance imaging (MRI)
- Blood and urine tests
Participants will get the study drugs in 3-week cycles:
- Cisplatin in a vein on 1 or 2 days
- VX-970 in a vein on 2 days
- Veliparib by mouth twice a day on 6 days
In each cycle, participants will have 5 physical exams and blood tests 5 times.
In some cycles, participants will have CT scans or MRIs.
In cycle 1, participants may have 2 tumor biopsies. A small piece of tissue is removed by needle.
Participants will keep a study diary. They will write when they take the drugs and if they have side effects.
Participants will stay in the study as long as they tolerate the drugs and their tumors are not getting worse.
Participants will have a phone call about a month after their last dose.
详细描述
Background:
- Ataxia-telangiectasia-related (ATR) protein kinase is central to the deoxyribonucleic acid (DNA) damage response and homologous recombination, activating a series of phosphorylation cascades, culminating in cell cycle arrest to allow time for deoxyribonucleic acid (DNA) repair. ATR additionally facilitates homologous recombination repair through modulation of the p53-replication protein A (p53-RPA) complex bound to single-stranded deoxyribonucleic acid (ssDNA) during the DNA repair process.
- Poly (ADP-ribose) polymerase-1 (PARP-1) plays a pivotal role in base-excision repair of single strand breaks formed either due to direct genotoxic stress or during the processing of double strand breaks. PARP also plays a role in alternative end joining, which may contribute to combination activity. PARP-1 binding to sites of DNA damage results in activation of its catalytic activity and generation of chains of poly (ADP-ribosyl)ated polymers, which serve as docking sites for recruitment of DNA repair proteins.
- Veliparib (ABT-888) is a potent PARP 1/2 inhibitor with clinical evidence of potentiation of antitumor activity in combination with cisplatin in breast cancer gene (BRCA) mutation carriers and patients with sporadic triple-negative breast cancer.
- M6620 (VX-970) is a potent ATR inhibitor, with half maximal inhibitory concentration (IC(50) of 20 nanomolar and antitumor activity across a broad range of cell lines in combination with DNA damaging agents. Preclinical studies show M6620 (VX-970) synergizes with cisplatin to induce DNA damage and antitumor activity. The addition of PARP inhibitor veliparib with ATR inhibitor M6620 (VX-970) allows for impairment of DNA repair, the induction of a BRCA null phenotype, and potentiation of the antitumor activity of cisplatin.
Primary Objective:
-To establish the safety, tolerability, and the maximum tolerated dose (MTD) of the combination of M6620 (VX-970) and veliparib in combination with cisplatin in patients with advanced refractory solid tumors
Secondary Objectives:
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
- 未提供
排除标准
- 未提供
研究组 & 干预措施
M6620 (VX-970)
M6620 will be administered intravenous (IV) on Days 2 and 9 of each 21-day cycle; Veliparib will be administered orally twice a day (BID) Days 1-3 and 8-10 of each cycle; Cisplatin will be administered at 40 mg/m^2 IV Day 1 (and Day 8 from dose level 3 onwards) of each cycle
干预措施: Veliparib + VX-970 + Cisplatin (Drug)
结局指标
主要结局
Number of Participants With Worst Grade 2 or Higher Adverse Events Occurring in >5% of Participants at Least Possibly Related to Study Drugs
时间窗: Cycle 1 (i.e., one cycle = 21 days)
Adverse events were assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Grade 2 is moderate, Grade 3 is severe or medically significant but not immediately life threatening, and Grade 4 is life threatening.
次要结局
- Number of Participants With RAD51 Recombinase (Rad51), Phosphorylated Histone H2AX (γH2AX), Phosphorylated at Serine 343 (pS343)-Nibrin (Nbs1), and Phosphorylated KRAB-associated Protein 1 (pKAP-1) Induced After Treatment(Cycle 1 Day 1, and Cycle 1 Day 9 (i.e., one cycle = 21 days))
- Number of Participants With a Best Response to the Antitumor Activity of Veliparib (ABT-888), an Oral PARP Inhibitor, and VX-970, an ATR Inhibitor, in Combination With Cisplatin(4 cycles (i.e., one cycle = 21 days))
研究者
Alice Chen, M.D.
Principal Investigator
National Cancer Institute (NCI)