Patient case: 62-year-old male with cholangiocarcinoma; genetic feature: PIK3CA (1047H)

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

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 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
  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

Eligibility: -  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 in the expansion cohort undergoing tumor biopsies may not be on anticoagulants due to risk of thrombocytopenia on treatment and risk for bleeding.
  -  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.

Relevance to patient case: not relevant