Cediranib Maleate and Olaparib or Standard Chemotherapy in Treating Patients With Recurrent Platinum-Resistant or -Refractory Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

PRIMARY OBJECTIVES:

I. To assess the efficacy and identify (in)active arm(s) of the combination of cediranib
maleate (cediranib) and olaparib, cediranib alone, olaparib alone, and physician's choice
standard of care chemotherapy, as measured by progression-free survival (PFS) in the setting
of recurrent platinum-resistant or-refractory ovarian, primary peritoneal or fallopian tube
cancer. (Phase II) II. To assess the efficacy of the combination of cediranib and olaparib,
and cediranib monotherapy, as measured by overall survival (OS) and PFS, as compared to
physician's choice standard of care chemotherapy in women with recurrent platinum-resistant
or-refractory ovarian, primary peritoneal or fallopian tube cancer. (Phase III)

SECONDARY OBJECTIVES:

I. To assess the efficacy of the combination of cediranib and olaparib, cediranib alone,
olaparib alone, and physician's choice standard of care chemotherapy, as measured by
objective response rate (ORR: partial or complete response) by Response Evaluation Criteria
in Solid Tumors (RECIST) 1.1 criteria, in the setting of recurrent platinum-resistant
or-refractory ovarian, primary peritoneal or fallopian tube cancer. (Phase II and Phase III)
II. To assess safety endpoints, as measured by frequency and severity of adverse events by
Common Terminology Criteria for Adverse Events (CTCAE). (Phase II and Phase III) III. To
assess the efficacy of the combination of cediranib and olaparib, and cediranib monotherapy,
as measured by ORR as compared to physician's choice standard of care chemotherapy in the
setting of recurrent platinum-resistant or-refractory ovarian, primary peritoneal or
fallopian tube cancer. (Phase III)

OBJECTIVES WITH INTEGRATED BIOMARKERS:

I. To assess correlation of homologous recombination deficiency (HRD) status, as assessed via
BROCA-HR assay with response, as measured by PFS and ORR. (Phase II) II. To evaluate the
prognostic and predictive role of circulating endothelial cells (CEC) on comparative
effectiveness of targeted therapies and reference chemotherapy. (Phase II) III. To evaluate
quality of life data compliance, as measured by the 9-item Disease Related Symptoms (DRS-9)
subscale of the National Comprehensive Cancer Network (NCCN)-Functional Assessment of Cancer
Therapy (FACT) Ovarian Symptom Index (NFOSI) for utilization and analysis in the Phase III
study. (Phase II) IV. To assess correlation of HRD status, as assessed via BROCA-HR assay
with response, as measured by OS, PFS and ORR. (Phase III) V. To evaluate the prognostic and
predictive role of circulating endothelial cells (CEC) on comparative effectiveness of
targeted therapies and reference chemotherapy. (Phase III) VI. To assess the effect on
disease-related symptoms (DRS) as measured by the 9-item DRS-P subscale of the NCCN-FACT
Ovarian Symptom Index-18 (NFOSI-18), of single agent cediranib and cediranib/olaparib
combination, compared to standard chemotherapy, in the setting of recurrent
platinum-resistant or-refractory ovarian, primary peritoneal or fallopian tube cancer. (Phase
III)

EXPLORATORY OBJECTIVES:

I. To assess exploratory biomarkers of potential HRD, including genomic scarring, BRCA1
methylation, BRCA1 protein expression, and mutations in NHEJ, and other genes that might
modify HRD. (Phase II and Phase III) II. To evaluate the prognostic and predictive role of
angiogenic biomarkers, as assessed by the Duke plasma angiome. (Phase II and Phase III) III.
To assess the effect on secondary measures of quality of life, as assessed by the treatment
side effects (TSE) and function/well-being (F/WB) subscales of the NFOSI-18, sensory
neuropathy as measured by the FACT/GOG-Ntx-4, and health utility as measured by the EQ-5D, of
single agent cediranib and cediranib/olaparib combination, compared to standard chemotherapy,
in the setting of recurrent platinum-resistant or-refractory ovarian, primary peritoneal or
fallopian tube cancer. (Phase III)

OUTLINE:

PHASE II: Patients are randomized to 1 of 4 treatment arms.

ARM I (REFERENCE REGIMEN): Patients undergo physician's choice of standard of care
chemotherapy, comprising either paclitaxel intravenously (IV) on days 1, 8, 15, and 22 every
28 days (Regimen I); pegylated liposomal doxorubicin hydrochloride IV on day 1 every 28 days
(Regimen II); or topotecan hydrochloride IV on days 1, 8, and 15 every 28 days or days 1-5
every 21 days (Regimen III). Treatment continues in the absence of disease progression or
unacceptable toxicity. No modification of the assigned regimens, such as additional drugs
(gemcitabine, or bevacizumab) is allowed. (12/05/2016)

ARM II (CEDIRANIB MALEATE AND OLAPARIB): Patients receive cediranib maleate orally (PO) and
olaparib PO as determined from an ongoing Phase I study. Courses repeat every 28 days in the
absence of disease progression or unacceptable toxicity.

ARM III (CEDIRANIB): Patients receive cediranib maleate PO daily continuously. Courses repeat
every 28 days in the absence of disease progression or unacceptable toxicity.

ARM IV (OLAPARIB): Patients receive olaparib PO twice daily (BID) on days 1-28. Courses
repeat every 28 days in the absence of disease progression or unacceptable toxicity. (In July
2018, the Data Monitoring Committee voted to exclude the olaparib alone regimen).

PHASE III: Patients are randomized to 1 of 3 treatment arms.

ARM I (REFERENCE REGIMEN): Patients undergo physician's choice standard of care chemotherapy
as in Phase II Arm I. No modification of the assigned regimens, such as additional drugs
(gemcitabine or bevacizumab) is allowed. (12/05/2016)

ARM II (CEDIRANIB AND OLAPARIB): Patients receive cediranib maleate PO and olaparib PO as in
Phase II Arm II.

ARM III (SINGLE AGENT): Patients receive cediranib maleate PO as determined by the Phase II
study. Courses repeat every 28 days in the absence of disease progression or unacceptable
toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and
then every 6 months for up to 3 years.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed ovarian cancer,
peritoneal cancer or fallopian tube cancer and must have a histological diagnosis of
either serous or endometrioid cancer based on local histopathological findings; both
endometrioid and serous histology should be high-grade for eligibility of non-mutation
carriers; patients with clear cell, mixed epithelial, undifferentiated carcinoma, or
transitional cell carcinoma histologies are also eligible, provided that the patient
has a known deleterious germline BRCA1 or BRCA2 mutation identified through testing at
a clinical laboratory

- Note: Due to the long acceptance of BRCA testing through Myriad, Myriad testing
will be accepted; 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 showed
a recognized germ line deleterious BRCA 1 or BRCA 2 mutation or BRCA
rearrangement is required; a copy of Myriad or other BRCA mutational analysis
(positive or variants of unknown significance [VUS] or negative) reports will be
requested but not required for study enrollment

- Patients should have recurrent platinum-resistant or- refractory disease - defined as
disease that has progressed by imaging while receiving platinum or had recurrence
within 6 months of the last receipt of platinum-based chemotherapy; rising CA125 only
is not considered as platinum-resistant or refractory disease

- Phase II study: measurable disease by RECIST 1.1 criteria; if archival tumor sample is
not available tumor sample from fresh biopsy is acceptable

- Phase III study: evaluable disease - defined as RECIST 1.1 measurable disease OR
non-measurable disease (defined as solid and/or cystic abnormalities on radiographic
imaging that do not meet RECIST 1.1 definitions for target lesions OR ascites and/or
pleural effusion that has been pathologically demonstrated to be disease-related in
the setting of a cancer antigen [CA]125 >= 2 x upper limit of normal [ULN])

- No more than 3 prior treatment regimens (including primary therapy; no more than 1
prior non-platinum based therapy in the platinum-resistant/-refractory setting);
hormonal therapies used as single agents (i.e. tamoxifen, aromatase inhibitors) will
not count towards this line limit

- Patients may not have had a prior anti-angiogenic agent in the recurrent setting;
prior use of bevacizumab in the upfront or upfront maintenance setting is allowed

- Patients may not have previously received a PARP-inhibitor

- Patient must have provided study specific informed consent prior to study entry

- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 or 2

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Hemoglobin >= 10 g/dL

- Total bilirubin within =< 1.5 times the upper limit of normal (ULN) institutional
limits

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 3 x institutional ULN; if intrahepatic liver metastases are present, AST and ALT
must be =< 5 times institutional ULN

- Creatinine =< 1.5 x the institutional ULN

- Urine protein: creatinine ratio urine protein creatinine (UPC) of =< 1 OR less than or
equal to 2+ proteinuria on two consecutive dipsticks taken no less than 1 week apart;
UPC is the preferred test; patients with 2+ proteinuria on dipstick must also have a
24-hour urine collection demonstrating protein of =< 500 mg over 24 hours

- Toxicities of prior therapy (excepting alopecia) should be resolved to less than or
equal to grade 1 as per CTCAE

- Adequately controlled blood pressure (systolic blood pressure [SBP] =< 140; diastolic
blood pressure [DBP] =< 90 mmHg) on maximum of three antihypertensive medications;
patients must have a BP of =< 140/90 mmHg taken in the clinic setting by a medical
professional within 2 weeks prior to starting study; it is strongly recommended that
patients who are on three antihypertensive medications must be actively followed by a
cardiologist or a primary care physician for management of BP while on protocol;
patients must be willing and able to check and record daily blood pressure readings;
blood pressure cuffs will be provided to patients randomized to cediranib alone and
the combination of olaparib and cediranib arms

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

- Able to swallow and retain oral medications and without gastrointestinal (GI)
illnesses that would preclude absorption of cediranib or olaparib

- Cediranib has been shown to terminate fetal development in the rat, as expected for a
process dependent on VEGF signaling; for this reason, women of child-bearing potential
must have a negative pregnancy test prior to study entry; women of child-bearing
potential must agree to use two reliable forms of contraception (hormonal or barrier
method of birth control; abstinence) prior to study entry, for the duration of study
participation, and for 6 weeks after cediranib discontinuation; should a woman become
pregnant or suspect she is pregnant while participating in this study, she should
inform her treating physician immediately

- Olaparib adversely affects embryofetal survival and development in the rat; for this
reason, women of child-bearing potential must have a negative pregnancy test prior to
study entry; women of child-bearing potential must agree to use must agree to use two
reliable forms of contraception (hormonal or barrier method of birth control;
abstinence) prior to study entry, for the duration of study participation, and for 3
months after the last dose of olaparib; should a woman become pregnant or suspect she
is pregnant while participating in this study, she should inform her treating
physician immediately

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) of starting treatment or those who have not recovered
from adverse events due to agents administered more than 4 weeks earlier; patients may
not have had hormonal therapy within 2 weeks prior to entering the study; patients
receiving raloxifene for bone health as per Food and Drug Administration (FDA)
indication may remain on raloxifene absent other drug interactions

- Any other investigational agents within the past 4 weeks

- Prior treatment affecting the VEGF/VEGFR pathway or the angiopoietin pathway in the
recurrent setting, including but not limited to thalidomide, bevacizumab, sunitinib,
sorafenib, pazopanib, cediranib, nintedanib, and trebananib; bevacizumab used in the
upfront setting in conjunction with chemotherapy and/or as maintenance to treat newly
diagnosed disease will be allowed

- Prior use of PARP-inhibitors

- CA-125 only disease without Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
measurable or otherwise evaluable disease

- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to starting cediranib

- Current signs and/or symptoms of bowel obstruction or signs and/or symptoms of bowel
obstruction within 3 months prior to starting study drugs

- History of intra-abdominal abscess within the past 3 months

- History of gastrointestinal perforation; patients with a history of abdominal fistula
will be considered eligible if the fistula was surgically repaired or has healed,
there has been no evidence of fistula for at least 6 months, and patient is deemed to
be at low risk of recurrent fistula

- Dependency on IV hydration or total parenteral nutrition (TPN)

- Any concomitant or prior invasive malignancies with the following curatively treated
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/serous, clear cell, or other Federation of Gynecology and
Obstetrics (FIGO) grade 3 lesions

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

- 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 should not be included on this study,
since neurologic dysfunction may confound the evaluation of neurologic and other
adverse events; patients with treated brain metastases and resolution of any
associated symptoms must demonstrate stable post-therapeutic imaging for at least 6
months following therapy prior to starting study drug

- Patients with any of the following:

- History of myocardial infarction within six months

- Unstable angina

- Resting electrocardiogram (ECG) with clinically significant abnormal findings

- New York Heart Association functional classification of III or IV

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

- Patients with 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)

- Prior history of impaired cardiac function

- History of stroke or transient ischemic attack within six months

- Clinical significant peripheral vascular disease or vascular disease (aortic aneurysm
or aortic dissection)

- Evidence of coagulopathy or bleeding diathesis; therapeutic anticoagulation for prior
thromboembolic events is permitted

- Evidence suggestive of myelodysplastic syndrome (MDS) or acute myelogenous leukemia
(AML) on peripheral blood smear or bone marrow biopsy, if clinically indicated

- No prior allogeneic bone marrow transplant or double umbilical cord blood
transplantation (dUBCT)

- Patients may not use any complementary or alternative medicines including natural
herbal products or folk remedies as they may interfere with the effectiveness of the
study treatments

- Uncontrolled intercurrent illness including, but not limited to ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia (other than atrial fibrillation with controlled ventricular rate), or
psychiatric illness/social situations that would limit compliance with study
requirements

- Known human immunodeficiency virus (HIV)-positive individuals are ineligible because
of the potential for pharmacokinetic interactions with cediranib or olaparib; in
addition, these individuals are at increased risk of lethal infections when treated
with marrow-suppressive therapy

- Participants receiving any medications or substances that are strong inhibitors or
inducers of CYP3A4 are ineligible

- Strong inhibitors and inducers of UGT/PgP should be used with caution

- Pregnant women are excluded from this study because cediranib and olaparib are agents
with the potential for teratogenic or abortifacient effects; because there is an
unknown but potential risk of adverse events in nursing infants secondary to treatment
of the mother with cediranib and olaparib, breastfeeding should be discontinued if the
mother is treated with cediranib or olaparib; these potential risks may also apply to
other agents used in this study