Carboplatin and Gemcitabine Hydrochloride With or Without ATR Kinase Inhibitor VX-970 in Treating Patients With Recurrent and Metastatic Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

PRIMARY OBJECTIVES:

I. Assess safety and tolerability of the combination therapy carboplatin, gemcitabine
(gemcitabine hydrochloride) and M6620 (VX-970) (rad3-related [ATR] kinase inhibitor VX-970)
in adult women with platinum sensitive recurrent high grade serous or high grade endometrioid
ovarian, primary peritoneal or fallopian tube cancer. (Phase I Dose Escalation/Safety
Lead-in) II. Determine the dose of the triple therapy to be used in the randomized phase 2
portion of the study. (Phase I Dose Escalation/Safety Lead-in) III. To determine whether the
addition of M6620 (VX-970) to carboplatin and gemcitabine increases the confirmed response
rate (RR) compared to carboplatin and gemcitabine alone in patients with first or second
recurrence of platinum sensitive high grade serous or endometrioid ovarian, primary
peritoneal or fallopian tube carcinoma. (Randomized Phase 2)

SECONDARY OBJECTIVES:

I. To determine whether the addition of M6620 (VX-970) to carboplatin and gemcitabine
increases overall survival (OS) compared to carboplatin and gemcitabine alone in first or
second recurrence platinum sensitive disease.

II. To determine whether the addition of M6620 (VX-970) to carboplatin and gemcitabine
increases the PFS when compared to carboplatin/gemcitabine alone in first or second
recurrence of platinum sensitive disease.

III. To describe and compare adverse events between the two groups.

INTEGRATED CORRELATIVE STUDY OBJECTIVES:

I. To determine whether increased deoxyribonucleic acid (DNA) damage as assessed by multiplex
assay correlates with response to combination therapy with M6620 (VX-970).

II. To determine whether mutations in homologous recombination repair genes correlate with
response to combination therapy with M6620 (VX-970).

III. Assess a limited pharmacokinetic profile of M6620 (VX-970) and gemcitabine when given in
combination with carboplatin.

IV. To ascertain modulation of ATR autophosphorylation and other pharmacodynamic readouts for
ATR inhibition by M6620 (VX-970).

OUTLINE: This is a phase I, dose-escalation study of gemcitabine hydrochloride and ATR kinase
inhibitor VX-970 followed by a phase II study. Patients are randomized to 1 of 2 arms.

ARM I: Patients receive carboplatin intravenously (IV) over 30 minutes on day 1, gemcitabine
hydrochloride IV over 30 minutes on days 1 and 8, and ATR kinase inhibitor VX-970 IV over 60
minutes on days 2 and 9.

ARM II: Patients receive carboplatin IV over 30 minutes on day 1 and gemcitabine
hydrochloride IV over 30 minutes on days 1 and 8.

In both arms, courses repeat every 21 days in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up for 3 years.

Inclusion Criteria:

- Histologically confirmed high grade serous or endometrioid ovarian, peritoneal or
fallopian tube malignancy that is metastatic and for which curative measures do not
exist; the histology can be confirmed from tissue that was taken at the time of
diagnosis; a biopsy at the time of recurrence prior to enrollment on study is not
required

- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded for
non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) with
conventional techniques or as >= 10 mm (>= 1 cm) with spiral computed tomography (CT)
scan, magnetic resonance imaging (MRI), or calipers by clinical exam

- Patients enrolled in the phase 2 portion of the study will be required to have
archival tumor tissue available for analysis and be willing to have a tumor biopsy at
baseline (after registration and prior to starting study treatment) and at cycle 1 day
2; patients must have platinum sensitive disease and be in their first or second
platinum sensitive recurrence; platinum sensitive disease is defined as recurrence
that occurred greater than six months after completion of their last line of platinum
based therapy; no non-platinum regimens allowed; prior therapy with PARP inhibitors as
well as bevacizumab is allowed

- No more than two prior platinum based regimens; one regimen is defined as the interval
of treatment from start of platinum based doublet to finish of that treatment course
for the initial therapy or for the recurrent disease episode; if the nonplatinum agent
is altered due to any reason other than disease progression, it counts as one regimen;
for example, if a patient started on carboplatin and paclitaxel but developed a taxol
reaction and was switched to carboplatin and Abraxane, this counts as one prior
regimen

- Children are excluded from this study, but will be eligible for future pediatric
trials

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- Life expectancy of greater than 6 months

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count (ANC) >= 1,500/mcL

- Platelets >= 100,000/mcL

- Total bilirubin within normal institutional limits

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2 × institutional upper limit of normal (ULN)

- Creatinine within normal institutional limits OR creatinine clearance >= 50
mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

- Negative serum pregnancy test result for females of child bearing potential

- Women of child-bearing potential 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 6 months after completion of VX-970 administration; should a
woman become pregnant or suspect she is pregnant while she is participating in this
study, she should inform her treating physician immediately

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

Exclusion Criteria:

- Patients with platinum resistant disease or platinum sensitive disease that is past
the first or second recurrence

- Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering
the study or those who have not recovered from adverse events due to agents
administered more than 4 weeks earlier, excluding alopecia; patients with treatment
related effects, such as peripheral neuropathy, that are grade 1 or less are eligible

- Prior exposure to gemcitabine

- Patients who are receiving any other investigational agents

- Patients with known brain metastases should be excluded from this clinical trial

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to M6620 (VX-970), carboplatin, gemcitabine or to these specific compounds

- VX-970 is primarily metabolized by cytochrome P450, family 3, subfamily A, polypeptide
4 (CYP3A4); therefore, concomitant administration with strong inhibitors or inducers
of CYP3A4 should be avoided

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant women are excluded from this study, breastfeeding should be discontinued if
the mother is treated with M6620 (VX-970); these potential risks also apply to the
other agents used in this study, such as carboplatin and gemcitabine

- Patients with Li Fraumeni syndrome are excluded from the study