Gemcitabine Hydrochloride With or Without WEE1 Inhibitor MK-1775 in Treating Patients With Recurrent Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

PRIMARY OBJECTIVES:

I. To evaluate the progression free survival (PFS) of subjects with recurrent
platinum-resistant ovarian, fallopian tube or primary peritoneal cancer receiving gemcitabine
(gemcitabine hydrochloride) in combination with AZD 1775 (MK-1775 [WEE1 inhibitor MK-1775])
compared to subjects receiving gemcitabine in combination with placebo.

SECONDARY OBJECTIVES:

I. To evaluate the objective response by Response Evaluation Criteria in Solid Tumors
(RECIST) 1.1 of patients receiving gemcitabine combined with AZD 1775 (MK-1775) compared to
patients receiving gemcitabine in combination with placebo.

II. To evaluate the Gynecologic Cancer Intergroup (GCIG) cancer antigen (CA)125 response rate
of patients receiving gemcitabine combined with AZD 1775 (MK-1775) compared to patients
receiving gemcitabine in combination with placebo.

III. To evaluate the overall survival of patients (max 1-year [yr] follow-up) receiving
gemcitabine combined with AZD 1775 (MK-1775) compared to patients receiving gemcitabine in
combination with placebo.

IV. To evaluate the safety and tolerability of the combination of gemcitabine combined with
AZD 1775 (MK-1775) in patients with recurrent, platinum-resistant ovarian, fallopian tube or
primary peritoneal cancer.

V. To evaluate tumor protein p53 (TP53) mutations (presence of mutation and type of mutation)
as potential predictive factors of benefit (defined as response or progression-free survival
[PFS] prolongation) to AZD 1775 (MK-1775) and gemcitabine treatment.

VI. To evaluate p53 protein expression by immunohistochemistry as potential predictive
factors of benefit (defined as response or PFS prolongation) to AZD 1775 (MK-1775) and
gemcitabine treatment.

TERTIARY OBJECTIVES:

I. To evaluate patient reported outcomes using Patient-Reported Outcomes (PRO)-Common
Terminology Criteria for Adverse Events (CTCAE).

II. To evaluate the concordance of TP53 mutations in the tumor specimen and TP53 mutations
determined by tagged-amplicon deep sequencing (Tam-Seq) in circulating tumor DNA.

III. To correlate the levels circulating DNA TP53 mutations by Tam-Seq with response.

IV. Validation of phosphorylated-cyclin-dependent cycle 2 (pCDC2) and gamma-H2A histone
family, member X (H2AX) in skin and tumor tissue as a pharmacodynamic marker of therapy.

V. To correlate changes in pCDC2 and gamma-H2AX with survival outcomes and response rate.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive WEE1 inhibitor MK-1775 orally (PO) on days 1, 2, 8, 9, 15, and 16 and
gemcitabine hydrochloride intravenously (IV) over 30 minutes on days 1, 8, and 15. Courses
repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive placebo PO on days 1, 2, 8, 9, 15, and 16 and gemcitabine
hydrochloride as patients in Arm I. Courses repeat every 28 days in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6-8 weeks (after the
30-37 day safety visit) for up to 1 year.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed epithelial ovarian,
primary peritoneal and fallopian tube carcinoma; all histologic subtypes of epithelial
ovarian cancer are eligible, but only patients with high grade serous ovarian cancer
will be considered for the statistical analysis; non-high grade serous cancers will be
allowed in an exploratory cohort

- Patients must be platinum-resistant (platinum-free interval < 6 months) or have
platinum-refractory disease as per Gynecologic Cancer Intergroup Committee (GCIC)
criteria; disease progression has to be radiologic or clinical; biomarker progression
with CA125 after a platinum based regimen would not be sufficient evidence of disease
progression; the patients must have had radiological progression to that regimen

- 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 > 10 mm with computed
tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam

- There is no limitation in the number of prior lines of therapy

- Patients must have completed any prior chemotherapy, radiotherapy or major surgery at
least 4 weeks before receiving study treatment; ongoing toxicities related to
treatment must be =< grade 1 and patients with grade 2 alopecia or peripheral
neuropathy can also be included; palliative radiation to < 10% of bone marrow is
permissible if completed within one week of commencing study treatment as long as the
toxicities secondary to palliative radiotherapy are limited to grade 1; the lesions
that have received radiation treatment immediately before will be excluded as target
lesions; previously irradiated lesions can be considered as targeted lesions, as long
as there is prove of radiological progression

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

- Life expectancy of greater than 3 months

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Hemoglobin >= 90 g/L

- Blood transfusions are allowed at any time during the screening, treatment or
follow-up period, according to the center recommendations

- Prothrombin time (PT), partial thromboplastin time (PTT) and international normalized
ratio (INR) =< 1.5 upper limit of normal (ULN)

- Total bilirubin =< 1.5 x institutional upper limit of normal; unless due to Gilbert's
syndrome

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x
institutional upper limit of normal (5 x if liver metastases)

- Creatinine =< 1.5 × institutional upper limit of normal OR creatinine clearance >= 40
mL/min/1.73 m^2 for patients with creatinine levels above 1.5 x institutional limit of
normal

- Patients must be able to tolerate oral medication and not have evidence of active
bowel obstruction

- Note: patients can have a history of prior bowel obstruction, provided the
patient is not having symptoms of bowel obstruction at the time of enrolment and
the bowel obstruction is not anticipated to recur during the participation in the
study

- Patients must have disease amenable to biopsy and must be willing to undergo a paired
biopsy for correlative analyses (the first biopsy within 28 days prior to start of
treatment and the second biopsy while on treatment)

- Women of child-bearing potential must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry and for the duration
of study participation; should a woman become pregnant or suspect she is pregnant
while she is participating in this study, she should inform her treating physician
immediately

- Women of childbearing potential include women who have experienced menarche and
who have not undergone successful surgical sterilization (hysterectomy, bilateral
tubal ligation, or bilateral oophorectomy) or are not postmenopausal;
postmenopause is defined as amenorrhea >= 12 consecutive months; Note: women who
have been amenorrheic for 12 or more months are still considered to be of
childbearing potential if the amenorrhea is possibly due to prior chemotherapy,
anti-estrogens, ovarian suppression or any other reversible reason

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

Exclusion Criteria:

- Patients who previously received gemcitabine for the treatment of recurrent disease

- Patients who are receiving any other investigational agents

- Patients with clinically or radiologically unstable brain metastases are excluded from
this clinical trial

- Note: patients with stable brain metastases after treatment, for at least 3
months prior to enrolling on this trial, could participate in the study; patients
should be off, or on a stable dose of steroids

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to AZD 1775 (MK-1775) or gemcitabine

- Patients taking the following prescription or non-prescription drugs or other products
(i.e. grapefruit juice) are ineligible: sensitive cytochrome P450 family 3, subfamily
A, polypeptide 4 (CYP3A4) substrates, CYP3A4 substrates with a narrow therapeutic
index, moderate to potent inhibitors/inducers of CYP3A4; patients would be eligible if
the medications can be discontinued two weeks prior to day 1 of dosing and withheld
throughout the study until 2 weeks after the last dose of study medication

- Pregnant and breastfeeding women are excluded from this study

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible

- Uncontrolled intercurrent illness including, but not limited to, myocardial infarction
within 6 months, congestive heart failure, symptomatic congestive heart failure,
unstable angina pectoris, active cardiomyopathy, unstable ventricular arrhythmia,
uncontrolled hypertension, uncontrolled psychotic disorders, serious infections,
active peptic ulcer disease, active liver disease or cerebrovascular disease with
previous stroke, or psychiatric illness/social situations that would limit compliance
with study requirements