Veliparib (ABT-888), an Oral PARP Inhibitor, and VX-970, an ATR Inhibitor, in Combination With Cisplatin in People With Refractory Solid Tumors
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 VX-970. They want to test if this drug combination slows the growth of cancer and is safe.
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.
People ages 18 and older with:
- Solid tumors that have progressed after treatment or for which no treatment exists
- Normal organ and marrow function
Participants will be screened with:
- Medical history
- Physical exam
- CT scan or 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.
|Study Design:||Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Official Title:||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|
- To establish the safety, tolerability, and MTD of the combination of VX 970 and veliparib in combination with cisplatin in patients with advanced refractory solid tumors [ Time Frame: Cycle 1 ]
- To assess the effect of the combination of VX-970, veliparib, and cisplatin on markers of DNA damage and apoptosis [ Time Frame: Cycles 1 and 2 ]
|Study Start Date:||March 22, 2016|
|Estimated Study Completion Date:||December 31, 2017|
|Estimated Primary Completion Date:||December 31, 2017 (Final data collection date for primary outcome measure)|
VX-970 will be administered 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/m2 IV Day 1 (and Day 8 from DL3 onwards) of each cycle
Drug: Veliparib + VX-970 + Cisplatin
ATR protein kinase is central to the DNA damage response and homologous recombination, activating a series of phosphorylation cascades, culminating in cell cycle arrest to allow time for DNA repair. PARP 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. Preclinical studies show ATR inhibitor VX-970 synergizes with cisplatin to induce DNA damage and antitumor activity. The addition of PARP inhibitor veliparib with VX-970 allows for impairment of DNA repair, induction of a BRCA null phenotype, and potentiation of the antitumor activity of cisplatin.
- Ataxia-telangiectasia-related (ATR) protein kinase is central to the DNA damage response and homologous recombination, activating a series of phosphorylation cascades, culminating in cell cycle arrest to allow time for DNA repair. ATR additionally facilitates homologous recombination repair through modulation of the p53-replication protein A (p53-RPA) complex bound to 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 BRCA mutation carriers and patients with sporadic triple-negative breast cancer.
- VX-970 is a potent ATR inhibitor, with IC(50) of 20 nM and antitumor activity across a broad range of cell lines in combination with DNA damaging agents. Preclinical studies show VX-970 synergizes with cisplatin to induce DNA damage and antitumor activity. The addition of PARP inhibitor veliparib with ATR inhibitor VX-970 allows for impairment of DNA repair, the induction of a BRCA null phenotype, and potentiation of the antitumor activity of cisplatin.
-To establish the safety, tolerability, and the maximum tolerated dose (MTD) of the combination of VX-970 and veliparib in combination with cisplatin in patients with advanced refractory solid tumors
- To assess the effect of the combination of VX-970, veliparib, and cisplatin on markers of DNA damage and apoptosis
- To assess antitumor activity of the combination
- 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
- VX-970 will be administered intravenously on Days 2 and 9 of each 21-day cycle. Veliparib will be administered orally twice a day (q12 hours +/- 1 hour) for Days 1-3 and 8-10 of each 21-day cycle. Cisplatin will be administered at 40 mg/m2 intravenously on Day 1 (and Day 8 from DL3 onwards) of each 21-day 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 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 PD endpoints
Please refer to this study by its ClinicalTrials.gov identifier: NCT02723864
|Contact: Nancy Moore, R.N.||(301) firstname.lastname@example.org|
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Recruiting|
|Bethesda, Maryland, United States, 20892|
|Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office 888-624-1937|
|Principal Investigator:||Alice P Chen, M.D.||National Cancer Institute (NCI)|