Clinical Trials /

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

NCT02723864

Description:

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 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 - 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.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 160087
  • SECONDARY ID: 16-C-0087
  • NCT ID: NCT02723864

Conditions

  • Neoplasms

Interventions

DrugSynonymsArms
Veliparib + VX-970 + Cisplatin1

Purpose

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 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 - 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.

Detailed Description

      Background:

        -  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.

        -  M6620 (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 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 (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.

        -  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 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 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
    

Trial Arms

NameTypeDescriptionInterventions
1ExperimentalVX-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
  • Veliparib + VX-970 + Cisplatin

Eligibility Criteria

        -  INCLUSION CRITERIA:

          -  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
             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.

          -  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

               -  AST(SGOT)/ALT(SGPT) less than or equal to 1.5 X institutional upper limit of
                  normal (OR < 3X ULN in the setting of liver metastases)

               -  creatinine less than or equal to 1.5X institutional upper limit of normal

        OR

          -  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.

               -  HIV-positive subjects on combination antiretroviral therapy are ineligible
                  because of the potential for pharmacokinetic interactions with M6620 (VX-970). In
                  addition, these subjects are at increased risk of lethal infections when treated
                  with marrow-suppressive therapy.

               -  Patients must be able to swallow whole tablets or capsules. Nasogastric or G-tube
                  administration is not allowed. Any gastrointestinal disease which would impair
                  ability to swallow, retain, or absorb drug is not allowed.

               -  Ability to understand and the willingness to sign a written informed consent
                  document.

               -  During the expansion phase of the protocol, patients must have disease amenable
                  to biopsy and be willing to undergo pre- and post-treatment biopsies.

               -  Patients must have greater than or equal to 10.0 g/dL Hb and no blood transfusion
                  in the past 28 days to receive Veliparib.

        EXCLUSION CRITERIA:

          -  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 AML (t-AML)/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 CTEP-sponsored studies utilizing Veliparib.

        INCLUSION of WOMEN and MINORITIES

        Both men and women of all races and ethnic groups are eligible for this trial.
      
Maximum Eligible Age:110 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description:Adverse event descriptions and grading scales from the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting.

Secondary Outcome Measures

Measure: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
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

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

Last Updated

December 6, 2019