Spots Global Cancer Trial Database for Veliparib (ABT-888), an Oral PARP Inhibitor, and VX-970, an ATR Inhibitor, in Combination With Cisplatin in People With Refractory Solid Tumors

Study Description

Brief Summary: 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.

Detailed Description: 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: * To assess the effect of the combination of M6620 (VX-970), veliparib, and cisplatin on markers of DNA damage and apoptosis * To assess antitumor activity of the combination Exploratory Objective: -To investigate tumor genomic alterations potentially associated with acquired resistance to the combination of M6620 (VX-970), veliparib, and cisplatin Eligibility: * Patients must have histologically confirmed solid tumors for which all standard therapy known to prolong survival has failed in the metastatic setting, or for which standard therapies do not exist * Patients must have had no major surgery, radiation, or chemotherapy within 3 weeks prior to entering the study * Patients must have adequate organ function Study Design: * Initially, M6620 (VX-970) will be administered intravenously on Days 2 and 9 of each 21-day cycle. Veliparib will be administered orally twice a day (every (q)12 hours +/- 1 hour) for Days 1-3 and 8-10 of each 21-day cycle. Cisplatin will be administered at 40 mg/m\^2 intravenously on Day 1 (and Day 8 from dose level 3 (DL3) onwards) of each 21-day cycle. * As of Amendment I (12/7/2017), patients who have been on study for at least 6 cycles may have cisplatin administration held or discontinued at the discretion of the Principal Investigator (PI), Dr. Chen, in recognition of the cumulative neurotoxicity seen with cisplatin treatment. If cisplatin is not administered during a cycle M6620 (VX-970) will be administered on Days 1 and 8 of that cycle. * The escalation portion of the trial will follow a standard 3+3 design, whereby patients will be dose escalated in cohorts of 3 until dose-limiting toxicity is observed * Once the maximum tolerated dose (MTD) is established, up to 15 additional patients will be enrolled to an expansion phase at the MTD. Mandatory tumor biopsies will be obtained in the expansion phase to assess pharmacodynamic (PD) endpoints

Keywords

Eligibility

Minimum Age: 18 Years

Eligible Ages: ADULT, OLDER_ADULT

Sex: ALL

Healthy Volunteers: No

Locations

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