Veliparib (ABT-888), an Oral PARP Inhibitor, and VX-970, an ATR Inhibitor, in Combination With Cisplatin in People With Refractory Solid Tumors

NCT02723864 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 16008716-C-0087
• Study Type: interventional
• Target: 53
• Locations: 1 country
• Sites: 3

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.

Conditions

Neoplasms

Keywords

Pharmacodynamic; DNA Damage Repair; BRCA Null; Apoptosis; Combination Therapy

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Worst Grade 2 or Higher Adverse Events Occurring in >5% of Participants at Least Possibly Related to Study Drugs

  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.

  Cycle 1 (i.e., one cycle = 21 days)

Secondary Outcomes (2)

• 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)

Other Outcomes (1)

• Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)

  Date treatment consent signed to date off study, approximately 6 months and 20 days, 3 months and 17 days, 24 months and 13 days, 9 months and 8 days, 5 months and 18 days, 35 months and 20 days, and 5 months and 22 days for each Arm/Group respectively.

Study Arms (1)

M6620 (VX-970)

EXPERIMENTAL

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

Drug: Veliparib + VX-970 + Cisplatin

Interventions

Veliparib + VX-970 + Cisplatin DRUG

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 DNA repair. Poly (ADP-ribose) polymerase (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 M6620 (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 breast cancer gene (BRCA) null phenotype, and potentiation of the antitumor activity of cisplatin.

Also known as: ABT-888 + M6620 (berzosertib) + Cisplatinum

M6620 (VX-970)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have histologically confirmed solid tumors for which standard therapy known to prolong survival has failed in the metastatic setting or for which standard therapies do not exist.
• Tumor amenable to biopsy and willingness to undergo tumor biopsies before and after M6620 (VX-970) treatment during the expansion phase of the trial (biopsies optional during the escalation phase).
• Patients must have completed any chemotherapy, radiation therapy, surgery, or biologic therapy greater than or equal to 3 weeks (or greater than or equal to 5 half-lives, whichever is shorter) prior to entering the study. Patients must be greater than or equal to 2 weeks since any prior administration of a study drug in an exploratory investigational new drug (IND)/Phase 0 study and greater than or equal to 1 week since any palliative radiation therapy. Patients must have recovered to eligibility levels from prior toxicity or adverse events.
• Age greater than or equal to 18 years of age.
• Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2.
• Life expectancy \> 3 months.
• Patients must have normal organ and marrow function as defined below:
• absolute neutrophil count greater than or equal to 1,500/mcL
• hemoglobin greater than or equal to 10 g/dL
• platelets greater than or equal to 100,000/mcL
• total bilirubin less than or equal to 1.5 X institutional upper limit of normal
• Aspartate aminotransferase (AST) Serum glutamic oxaloacetic transaminase(SGOT)/alanine aminotransferase (ALT) Serum glutamic pyruvic transaminase (SGPT) less than or equal to 1.5 X institutional upper limit of normal (OR \< 3X upper limit of normal (ULN) in the setting of liver metastases)
• creatinine less than or equal to 1.5X institutional upper limit of normal
• creatinine clearance greater than or equal to 60 mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal
• The effects of M6620 (VX-970) and veliparib on the developing human fetus are unknown. For this reason and because cisplatin is known to be teratogenic, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 6 months after completing study treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and for 6 months after completion of administration of study agents.

You may not qualify if:

• Patients who are receiving any other investigational agents.
• Patients with known active brain metastases or carcinomatous meningitis are excluded from this clinical trial. Patients whose brain metastatic disease status has remained stable for greater than or equal to 4 weeks following treatment of brain metastases are eligible to participate at the discretion of the principal investigator.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active untreated infection, or psychiatric illness/social situations that would limit compliance with study requirements.
• Patients required to be on any of the concomitant medications are excluded.
• Pregnant women and women who are breastfeeding are excluded from this study because the effects of the study drugs on the developing fetus are unknown.
• Patients who have had prior platinum-based therapy who have \> Grade 1 neurotoxicity or ototoxicity at the time of enrollment will not be permitted on study.
• Patients with a seizure history will not be permitted on protocol due to association of veliparib with seizure activity in animal toxicology studies at higher doses. Patients on anticonvulsant medications will not be permitted on study due to the potential to lower plasma levels of anticonvulsants and risk for seizure activity.
• Patients with treatment-related acute myeloid leukemia (AML) (t-AML)/Myelodysplastic syndromes (MDS), or with features suggestive of AML/MDS, or who have had prior allogeneic bone marrow transplant or double umbilical cord blood transplantation, should not receive Veliparib due to reports of MDS and leukemia secondary to oncology therapy on Cancer Therapy Evaluation Program (CTEP)-sponsored studies utilizing Veliparib.
• Both men and women of all races and ethnic groups are eligible for this trial.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (3)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030-4096, United States

Location

Related Publications (5)

• Chen X, Wu Y, Dong H, Zhang CY, Zhang Y. Platinum-based agents for individualized cancer treatment. Curr Mol Med. 2013 Dec;13(10):1603-12. doi: 10.2174/1566524013666131111125515.

  PMID: 24206132 BACKGROUND

• Huntoon CJ, Flatten KS, Wahner Hendrickson AE, Huehls AM, Sutor SL, Kaufmann SH, Karnitz LM. ATR inhibition broadly sensitizes ovarian cancer cells to chemotherapy independent of BRCA status. Cancer Res. 2013 Jun 15;73(12):3683-91. doi: 10.1158/0008-5472.CAN-13-0110. Epub 2013 Apr 2.

  PMID: 23548269 BACKGROUND

• Donawho CK, Luo Y, Luo Y, Penning TD, Bauch JL, Bouska JJ, Bontcheva-Diaz VD, Cox BF, DeWeese TL, Dillehay LE, Ferguson DC, Ghoreishi-Haack NS, Grimm DR, Guan R, Han EK, Holley-Shanks RR, Hristov B, Idler KB, Jarvis K, Johnson EF, Kleinberg LR, Klinghofer V, Lasko LM, Liu X, Marsh KC, McGonigal TP, Meulbroek JA, Olson AM, Palma JP, Rodriguez LE, Shi Y, Stavropoulos JA, Tsurutani AC, Zhu GD, Rosenberg SH, Giranda VL, Frost DJ. ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin Cancer Res. 2007 May 1;13(9):2728-37. doi: 10.1158/1078-0432.CCR-06-3039.

  PMID: 17473206 BACKGROUND

• O'Sullivan Coyne G, Do KT, Kummar S, Piha-Paul S, Rubinstein L, Kinders R, Parchment RE, Wilsker D, Ferry-Galow K, Miller B, Takebe N, Juwara L, Ong MJ, Bruns A, Hogu M, Naqash AR, Mittra A, Voth AR, Doroshow JH, Chen AP. Safety and Tolerability of Berzosertib, an Ataxia-Telangiectasia-Related Inhibitor, and Veliparib, an Oral Poly (ADP-ribose) Polymerase Inhibitor, in Combination With Cisplatin in Patients With Refractory Solid Tumors. JCO Precis Oncol. 2025 Jul;9:e2500055. doi: 10.1200/PO-25-00055. Epub 2025 Jul 16.

  PMID: 40669022 DERIVED

• Smith G, Alholm Z, Coleman RL, Monk BJ. DNA Damage Repair Inhibitors-Combination Therapies. Cancer J. 2021 Nov-Dec 01;27(6):501-505. doi: 10.1097/PPO.0000000000000561.

  PMID: 34904813 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Neoplasms

Interventions

veliparib; berzosertib; Cisplatin

Intervention Hierarchy (Ancestors)

Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds

Results Point of Contact

• Title: Dr. Alice Chen
• Organization: National Cancer Institute

chenali@mail.nih.gov

240-781-3274

Study Officials

• Alice P Chen, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: March 30, 2016
• First Posted: March 31, 2016
• Study Start: August 9, 2017
• Primary Completion: December 15, 2020
• Study Completion: December 31, 2021
• Last Updated: February 8, 2022
• Results First Posted: January 10, 2022

Record last verified: 2022-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: During the study and indefinitely via subscription to Biomedical Translational Research Information System (BTRIS).
• Access Criteria: IPD will be shared with NIH Intramural investigators who provide a methodologically sound proposal and whose proposed use of the data has been approved by the study PI, for the purpose of achieving the aims in the approved proposals. Proposals should be submitted via subscription to Biomedical Translational Research Information System (BTRIS).

Locations

US (3)