Veliparib (ABT-888), an Oral PARP Inhibitor, and VX-970, an ATR Inhibitor, in Combination With Cisplatin in People With Refractory Solid Tumors
Condition: Neoplasms
Intervention: Veliparib + VX-970 + Cisplatin
Intervention description: 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.
Intervention MeSH terms: Veliparib
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 53.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Pharmacodynamic; DNA Damage Repair; BRCA Null; Apoptosis; Combination Therapy

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.
    

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
             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

        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.

               -  Human immunodeficiency virus (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
                  gastric (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 hemoglobin (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 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.

        INCLUSION of WOMEN and MINORITIES

        Both men and women of all races and ethnic groups are eligible for this trial.