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

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

- 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.