Adavosertib With or Without Olaparib in Treating Participants With Recurrent Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

PRIMARY OBJECTIVES:

I. To determine the objective response rate (ORR) as determined by Response Evaluation
Criteria in Solid Tumors version 1.1 (RECIST 1.1) of adavosertib (AZD1775) alone or in
combination with olaparib in women with recurrent ovarian cancer in whom progression has been
documented following poly ADP-ribose polymerase (PARP) inhibitor therapy.

SECONDARY OBJECTIVES:

I. To evaluate the overall safety and tolerability of AZD1775 alone or in combination with
olaparib in this population.

II. To evaluate the disease control rate (DCR) = overall response rate (ORR) plus stable
disease rate for 16 weeks.

III. To evaluate the progression free survival (PFS) and overall survival (OS) of this
population following AZD1775 alone or in combination with olaparib.

IV. To evaluate the duration of response by RECIST version (v)1.1.

EXPLORATORY OBJECTIVES:

I. To evaluate the efficacy of each arm by BRCA-mutation status (BRCA-mt) and homologous
recombination deoxyribonucleic acid (DNA) repair deficiencies (HRD).

II. To describe endogenous and dynamic markers of DNA damage response in tumor tissue and
circulating surrogates, such as circulating tumor cells (CTC), circulating tumor DNA (ctDNA),
exosomes (cellular/nuclear), cell cycle kinetics (CDKs), and immunophenotype.

III. To examine genomic alterations associated with response and mechanisms of resistance to
olaparib and/or AZD1775.

OUTLINE: Participants are randomized to 1 of 2 arms.

ARM I: Participants receive adavosertib orally (PO) once daily (QD) on days 1-5 and 8-12.
Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

ARM II: Participants receive olaparib PO twice daily (BID) on days 1-21 and adavosertib PO QD
on days 1-3 and 8-10. Courses repeat every 21 days in the absence of disease progression or
unacceptable toxicity.

Inclusion Criteria:

- Has read and understands the informed consent form and has given written informed
consent prior to any study procedures.

- Histologically confirmed recurrent epithelial ovarian, primary peritoneal, or
fallopian tube cancer for which there is no known or established treatment available
with curative intent.

- Have demonstrated progressive disease while taking a PARP inhibitor as a previous
therapy or within 6 months of completing PARP inhibitor therapy. Response to prior
PARPi is not required.

- Prior PARP therapy could have been administered as either treatment for recurrent
disease or as maintenance following prior treatment.

- Measurable disease according to RECIST v1.1.

- Adequate archived primary or metastatic tumor tissue collected before the prior PARP
therapy.

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0-1.

- Absolute neutrophil count (ANC) >=1500/L (within 14 days of study drug(s) initiation).

- Hemoglobin (Hgb) >= 10 g/dL with no blood transfusion in the past 14 days (within 14
days of study drug(s) initiation).

- Platelets >= 100,000/L (within 14 days of study drug(s) initiation).

- Alanine transaminase (ALT) and aspartate transaminase (AST) =< 2.5 x upper limit of
normal (ULN) or =< 5 x ULN if known hepatic metastases (within 14 days of study
drug(s) initiation).

- Serum bilirubin within normal limits (WNL) or =< 1.5 x ULN in patients with liver
metastases; or total bilirubin =< 3.0 x ULN with direct bilirubin WNL in patients with
well documented Gilbert's syndrome (within 14 days of study drug(s) initiation).

- Patients should have serum creatinine < 1.5 x ULN and calculated or measured
glomerular filtration rate (GFR) of > 50 mL/min.

- Women who are not of child-bearing potential and fertile females of childbearing
potential who agree to use adequate contraceptive measures, who are not breastfeeding,
and who have a negative serum pregnancy test within 3 days prior to the start of study
treatment.

- Predicted life expectancy >= 16 weeks.

- Willingness and ability to comply with study and follow-up procedures.

Exclusion Criteria:

- Prior Treatment:

- PARP inhibitor: Most oral PARP inhibitors (the immediate prior therapy) have a
half-life for which 5 half-lives is between termination of the prior treatment and administration of olaparib and/or
AZD1775 treatment is required. In the event a PARP inhibitor has a longer
half-life where 5 half-lives is >= 21 days, treatment of olaparib and/or AZD1775
should not begin for 5 half-lives or at least 21 days, whichever is shorter.

- Any hormonal therapy directed at the malignant tumor must be discontinued at
least one week prior to registration (study enrollment). Continuation of hormone
replacement therapy is permitted.

- Any other prior therapy directed at the malignant tumor, including immunologic
agents, must be discontinued at least three weeks prior to first dose of study
drug (6 weeks for nitrosoureas or mitomycin C).

- Major surgical procedures =< 28 days of beginning study treatment, or minor surgical
procedures =< 7 days. No waiting period required following port-a-cath placement.

- Grade > 1 toxicity from prior therapy (except alopecia or anorexia).

- Patient has an inability to swallow oral medications and patients with
gastrointestinal disorders likely to interfere with absorption of the study
medication. Note: Patient may not have a percutaneous endoscopic gastrostomy (PEG)
tube or be receiving total parenteral nutrition (TPN).

- Known central nervous system (CNS) disease other than neurologically stable, treated
brain metastases - defined as metastasis having no evidence of progression or
hemorrhage for at least 2 weeks after treatment (including brain radiotherapy). Must
be off any systemic corticosteroids for the treatment of brain metastases for at least
14 days prior to enrollment.

- Patient has had a prescription or non-prescription drugs or other products known to be
sensitive to CYP3A4 substrates or CYP3A4 substrates with a narrow therapeutic index,
or to be moderate to strong inhibitors/inducers of CYP3A4 which cannot be discontinued
2 weeks prior to day -3 of dosing and withheld throughout the study until 2 weeks
after the last dose of study drug. Co-administration of aprepitant or fosaprepitant
during this study is prohibited.

- Herbal preparations are not allowed throughout the study. These herbal medications
include but are not limited to: St. John's wort, kava, ephedra (mahung), gingko
biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto and ginseng. Patients
should stop using these herbal medications 7 days prior to first dose of study
treatment.

- Any known hypersensitivity or contraindication to the components of the study drug
AZD1775 or olaparib.

- Any of the following cardiac diseases currently or within the last 6 months as defined
by New York Heart Association (NYHA) >= class 2. a. Unstable angina pectoris; b.
Congestive heart failure; c. Acute myocardial infarction; d. Conduction abnormality
not controlled with pacemaker or medication; e. Significant ventricular or
supraventricular arrhythmias (patients with chronic rate- controlled atrial
fibrillation in the absence of other cardiac abnormalities are eligible).

- AZD1775 should not be given to patients who have a history of Torsades de pointes
unless all risk factors that contributed to Torsades have been corrected. AZD1775 has
not been studied in patients with ventricular arrhythmias or recent myocardial
infarction.

- Patients with resting corrected QT interval (specifically QTc calculated using the
Fridericia formula [QTcF]) > 470 msec from a single electrocardiogram (ECG) performed
at study entry or congenital long QT syndrome.

- Pregnant or breast-feeding.

- Serious active infection at the time of study entry, or another serious underlying
medical condition that would impair the ability of the patient to receive study
treatment.

- Presence of other active invasive cancers.

- Psychological, familial, sociological, or geographical conditions that do not permit
compliance with protocol.

- Patients with myelodysplastic syndrome(MDS)/acute myeloid leukemia (AML) or with
features suggestive of MDS/AML.

- Previous allogenic bone marrow transplant or double umbilical cord blood
transplantation (dUCBT).