Olaparib and Cediranib Maleate in Treating Patients With Recurrent Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

PRIMARY OBJECTIVES:

I. To evaluate the association of BROCA-homologous recombination (HR) with the clinical
activity of cediranib maleate (cediranib)/olaparib, as measured by progression-free survival
(PFS), in women with recurrent platinum-sensitive ovarian cancer.

II. To assess the clinical activity of cediranib/olaparib, as measured by objective response,
in women with recurrent platinum-resistant ovarian cancer.

SECONDARY OBJECTIVES:

I. To assess overall survival (OS), objective response, and clinical benefit (stable disease
[SD] or response >= 16 weeks) in women with platinum-sensitive ovarian cancer, and PFS, OS,
and clinical benefit in women with platinum-resistant ovarian cancer.

II. To assess the safety of cediranib/olaparib in women with recurrent platinum-sensitive and
-resistant ovarian cancer.

III. To evaluate the association of circulating endothelial cells at baseline and day 3 with
the clinical activity of cediranib/olaparib, as measured by PFS, in women with
platinum-sensitive and -resistant ovarian cancer.

IV. To evaluate changes in BROCA-HR status between archival and pre-treatment biopsy samples.

V. To evaluate the associate of BROCA-HR with the clinical activity of cediranib/olaparib as
measured by PFS, in women with platinum-resistant ovarian cancer.

VI. To characterize genomic alteration by whole exome sequencing in women with
platinum-sensitive and -resistant ovarian cancer.

VII. To identify biomarker signatures that correlate with the clinical activity of
cediranib/olaparib in women with recurrent platinum-sensitive and -resistant ovarian cancer,
including changes in gene expression or acquired mutations in on-treatment tumor biopsies
that are associated with clinical activity, and changes in gene expression or acquired
mutations in post-progression biopsies that are associated with clinical resistance.

VIII. To explore changes in biomarker signatures and candidate angiogenic markers from
pre-treatment to post-progression in women with platinum-sensitive and -resistant ovarian
cancer.

IX. To evaluate the population pharmacokinetics (PK) of the combination of cediranib and
olaparib (tablets) in platinum-sensitive and platinum-resistant ovarian cancer.

EXPLORATORY OBJECTIVES:

I. To determine the feasibility of a mobile phone application (app) ecediranib-olaparib (eCO)
to collect patient-generated blood pressure and symptom data based upon study protocol
recommendations.

II. Assess patient and health care professional perceived usability and satisfaction of the
eCO app (for patients) and of a connected web portal (for health care providers).

III. Assess the number of generated alerts to the study team (via the web portal and email
"high" alerts) based on pre-determined severity levels.

OUTLINE:

Patients receive olaparib orally (PO) twice daily (BID) and cediranib maleate PO once daily
(QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Inclusion Criteria:

- Participants must have histologically or cytologically confirmed ovarian cancer,
peritoneal cancer or fallopian tube cancer and must have a histological diagnosis of
either high grade serous or high grade endometrioid cancer based on local
histopathological findings; participants with a deleterious BRCA-mutation on a
commercial Clinical Laboratory Improvement Amendments (CLIA) assay with other
high-grade histologies are also eligible

- Myriad testing will be accepted as documentation of a deleterious mutation; if
testing for BRCA is done by other organizations, documentation from a qualified
medical professional (e.g., ovarian cancer specialty physician involved in the
field, high risk genetics physician, genetics counselor) listing the mutation and
confirming that the laboratory results show a recognized germline deleterious
BRCA1 or BRCA2 mutation or BRCA rearrangements is required to document the
presence of a deleterious mutation

- Participants must have measurable disease via Response Evaluation Criteria in Solid
Tumors (RECIST) 1.1, 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 with conventional techniques or as >= 10 mm
with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or
calipers by clinical exam

- Patients may not have received prior poly ADP ribose polymerase (PARP) inhibitors

- Patients may have received but may not have progressed on prior anti-angiogenic
therapy in the upfront setting

- For platinum sensitive cohort

- Cancer that has not progressed within 6 months of the last receipt of
platinum-based chemotherapy

- No limit on the number of platinum-based lines

- No more than one prior non-platinum based line of therapy in the recurrent
setting

- For platinum-resistant or -refractory cohort

- Disease that has progressed within 6 months of the last receipt of platinum-based
chemotherapy

- No more than 1 prior line of therapy in the platinum-resistant/-refractory
setting

- No limit on number of prior lines received in the platinum-sensitive setting
prior to development of platinum-resistance (defined as disease progression
within 6 months of platinum-based chemotherapy)

- Hormonal therapies used as single agents (i.e. tamoxifen, aromatase inhibitors) will
not count towards line limit considerations

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Hemoglobin >= 10 g/dL

- Platelets >= 100,000/mcL

- Total bilirubin =< 1.5 x the institutional upper limit of normal (ULN)

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

- Creatinine less than or equal to the institutional upper limit of normal or creatinine
clearance >= 60 mL/min/1.73 m^2 for participants with creatinine levels above
institutional normal

- Proteinuria less than or equal to 1+ proteinuria on two consecutive dipsticks taken no
less than week apart, or a urine protein:creatinine (UPC) ration of =< 1

- Coagulation parameters (international normalized ratio [INR], activated partial
thromboplastin time [aPTT]) =< 1.25 x ULN institutional limits, except where a lupus
anti-coagulant has been confirmed

- Presence of biopsiable disease and willingness to undergo pre-treatment biopsy

- Women of child-bearing 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 up to 3 months after end of 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

- Adequately controlled thyroid function, with no symptoms of thyroid dysfunction and
thyroid stimulating hormone (TSH) within normal limits

- Patients must be able to tolerate oral medications and not have gastrointestinal
illnesses that would preclude absorption of cediranib or olaparib

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

- Willingness to release and confirmed availability of archival tissue sample for
research purposes

- Willingness and ability to check and record daily blood pressure readings; blood
pressure cuffs will be provided to patients

Exclusion Criteria:

- Participants may not have had chemotherapy or radiation therapy (RT) within 3 weeks (6
weeks for nitrosoureas or mitomycin C) prior to entering the study and must have
recovered to =< grade 1 from adverse events due to agents administered more than 3
weeks earlier; patients should not have received hormonal therapy for treatment of
their cancer within 2 weeks of study entry

- Participants should not have received any other investigational agents nor have
participated in an investigational trial within the past 4 weeks

- Participants may not have had prior use of PARP inhibitors; patients may not have
received prior treatment affecting the VEGF pathway in the recurrent setting,
including but not limited to thalidomide, bevacizumab, sunitinib, or sorafenib

- Participants may not have any evidence of ongoing inadequately controlled hypertension
(defined as a systolic blood pressure [BP] of > 140 mmHg or a diastolic BP of > 90
mmHg); patients with hypertension may not be on more than three antihypertensive
medications for management of their blood pressure (medications that combine two
anti-hypertensives into one are considered as two medications); it is strongly
recommended that patients who require three antihypertensive medications for baseline
management of pre-existing hypertension be actively followed by a cardiologist or
blood pressure specialist for management of BP while on protocol

- Participants may not have had any prior history of hypertensive crisis or hypertensive
encephalopathy

- Participants may not have had history of abdominal fistula or gastrointestinal
perforation; patients with a history of abdominal fistula will be considered eligible
if the fistula has healed or was surgically repaired, there has been no evidence of
fistula for at least 6 months, and patient is deemed to be at low risk of recurrent
fistula

- Participants may not have had a history of intra-abdominal abscess within the past 3
months

- Participants may not have current signs and/or symptoms of bowel obstruction or signs
and/or symptoms of bowel obstruction within 3 months prior to starting study drugs

- Participants may not have a dependency on intravenous (IV) hydration or total
parenteral nutrition (TPN)

- Participants with any concomitant or prior invasive malignancies are ineligible with
the following exceptions:

- Treated limited-stage basal cell or squamous cell carcinoma of the skin

- Carcinoma in situ of the breast or cervix

- Primary endometrial cancer meeting the following conditions: stage not greater
than IA, grade 1 or 2, no more than superficial myometrial invasion, without
vascular or lymphatic invasion; no poorly differentiated subtypes, including
papillary serous, clear cell, or other International Federation of Gynecology and
Obstetrics (FIGO) grade 3 lesions

- Prior cancer treated with curative intent with no evidence of recurrent disease 3
years following diagnosis and judged by the investigator to be at low risk of
recurrence

- Participants with any of the following:

- History of myocardial infarction within six months

- Unstable angina

- New York Heart Association (NYHA) classification of III or IV

- If cardiac function assessment is clinically indicated or performed: participants will
be ineligible if left ventricular ejection fraction (LVEF) is less than normal per
institutional guidelines, or < 55%, if the threshold for normal is not otherwise
specified by institutional guidelines

- Patients with any of the following risk factors should have a baseline cardiac
function assessment:

- Prior treatment with anthracyclines

- Prior treatment with trastuzumab

- Prior central thoracic radiation therapy (RT), including RT to the heart

- History of myocardial infarction within 6 to 12 months (patients with history of
myocardial infarction within 6 months are excluded from the study

- A NYHA classification of II controlled with treatment

- Prior history of impaired cardiac function

- Participants may not have had a history of a stroke or transient ischemic attack
within six months

- Participants should not have clinically significant peripheral vascular disease or
vascular disease (including aortic aneurysm or aortic dissection)

- Participants may not have a major surgical procedure, open biopsy, or significant
traumatic injury within 28 days prior to starting cediranib

- Participants should not have any 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

- Patients with untreated brain metastases, spinal cord compression, or evidence of
symptomatic brain metastases or leptomeningeal disease as noted on computed tomography
(CT) or magnetic resonance imaging (MRI) scans are ineligible; screening imaging to
rule out brain metastases is not required for screening, but should be performed prior
to study enrollment if clinically indicated; patients with treated brain metastases
must demonstrate stable post-therapeutic imaging and resolution of any associated
symptoms and must be stably off steroids with no symptoms for at least 6 months
following therapy prior to starting study drug

- Participants may not have a history of allergic reactions attributed to compounds of
similar chemical or biologic composition to cediranib or olaparib

- Participants receiving any medications or substances that are strong inhibitors or
inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) or moderate
inhibitors of CYP3A4 are ineligible; dihydropyridine calcium-channel blockers are
permitted for management of hypertension

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with cediranib and olaparib

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

- Participants should not have evidence of coagulopathy or bleeding diathesis;
therapeutic anticoagulation for prior thromboembolic events is permitted

- Current use of a prohibited medication; the following medications or non-drug
therapies are prohibited:

- Other anti-cancer therapy while on study treatment

- Prophylactic use of bisphosphonates in patients without bone disease, except for
the treatment of osteoporosis

- The concurrent use of all herbal supplements is prohibited during the study
(including, but not limited to, cannabis, St. John's wort, kava, ephedra [ma
huang], ginkgo biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or
ginseng)

- Raloxifene is allowed for patients taking it for bone health

- Participants may not have any features suggestive of myelodysplastic syndrome (MDS) or
acute myelogenous leukemia (AML) on peripheral blood smear or bone marrow biopsy, if
clinically indicated