Cediranib Maleate and Olaparib in Treating Patients With Recurrent Ovarian, Fallopian Tube, or Peritoneal Cancer or Recurrent Triple-Negative Breast Cancer

PRIMARY OBJECTIVES:

I. Assess the maximum tolerated dose (MTD) of cediranib (cediranib maleate) in combination
with olaparib in the treatment of recurrent ovarian, fallopian tube, or peritoneal cancer or
metastatic triple-negative breast cancer. (Phase I) II. Assess the efficacy (as measured by
progression-free survival [PFS]) of the combination of cediranib and olaparib compared to
olaparib alone in recurrent grade 2 or 3 platinum-sensitive papillary-serous or endometrioid
ovarian, fallopian tube, or peritoneal cancer. (Phase II) III. Assess the MTD of cediranib in
combination with olaparib tablet formulation in the treatment of recurrent ovarian, fallopian
tube, or peritoneal cancer. (Phase I-T)

SECONDARY OBJECTIVES:

I. Assess the toxicities of the combination of cediranib and olaparib in the treatment of
recurrent ovarian, fallopian tube, or peritoneal cancer or metastatic triple-negative breast
cancer. (Phase I) II. Assess clinical benefit, progression-free survival, and overall
survival for patients treated with cediranib and olaparib. (Phase I) III. Assess tumor
response, clinical response benefit (response or stable disease as defined by Response
Evaluation Criteria in Solid Tumors [RECIST] response criteria x 16 weeks), and overall
survival (OS) for patients treated with cediranib and olaparib at the recommended phase II
dose (RP2D) as compared with patients receiving olaparib alone. (Phase II) IV. Assess the
toxicities of the combination of cediranib and olaparib (tablet formulation) in the treatment
of recurrent ovarian, fallopian tube, or peritoneal cancer. (Phase I-T) V. Assess clinical
benefit, progression-free survival, and overall survival for patients treated with cediranib
and olaparib (tablet formulation). (Phase I-T) VI. Assess the pharmacokinetic profile of
cediranib and olaparib (tablet formulation) when administered in combination. (Phase I-T)

TERTIARY OBJECTIVES:

I. To evaluate the prognostic and predictive role of measured changes in functional vascular
imaging using dynamic contrast-enhanced (DCE)-magnetic resonance imaging (MRI) between
pre-study and day 3. (Phase II) II. To evaluate in an exploratory fashion the predictive or
prognostic value of single nucleotide polymorphisms (SNPs) in key genes involved in
angiogenesis and deoxyribonucleic acid (DNA) repair. (Phase II) III. To evaluate the
predictive value of baseline peripheral blood mononuclear cells (PBMC) poly adenosine
diphosphate (ADP) ribose (PAR) incorporation on response to therapy. (Phase II) IV. To
measure early changes in vascular cytokine production and evaluate in an exploratory fashion
that these changes may be predictive or prognostic, or differentially affected by the
combination of agents. (Phase II) V. To evaluate early changes to circulating endothelial
cells and if these changes are predictive or prognostic. (Phase II) VI. To assess changes in
measures of DNA damage and repair and angiogenesis in tumor cells (tissue and/or malignant
effusions) and correlate to drug/drug/combination. (Phase II)

OUTLINE: This is a phase I, dose-escalation study followed by a randomized phase II study.

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

PHASE II: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive cediranib maleate PO QD and olaparib PO BID on days 1-28.

ARM II: Patients receive olaparib PO BID on days 1-28.

In both arms, 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 months for up to 3
years.

Inclusion Criteria:

- PHASE I: Participants must have histologically or cytologically confirmed epithelial
ovarian cancer, primary peritoneal serous cancer, fallopian tube cancer, or
triple-negative breast cancer

- PHASE II: Participants must have histologically or cytologically grade 2 or 3
(high-grade) papillary-serous or endometrioid epithelial ovarian cancer, primary
peritoneal serous cancer, or fallopian tube cancer; participants with epithelial
ovarian, primary peritoneal, or fallopian tube cancers of other high-grade histologies
who carry a known deleterious breast cancer gene (BRCA) germline mutation by standard
clinical testing (Myriad BRAC Analysis) will also be considered eligible

- PHASE I-T: Participants must have histologically or cytologically confirmed epithelial
ovarian cancer, primary peritoneal serous cancer, or fallopian tube cancer

- Ovarian cancer, primary peritoneal, and fallopian tube participants in the Phase 1 and
Phase 1-T portions of this trial must have either measurable cancer by RECIST 1.1
criteria or an elevated cancer antigen (CA)125 level at least twice the upper limit of
normal on two separate occasions at least 1 day but not more than 3 months apart; at
least one of the samples should be within 1 week of starting treatment; patients with
both an elevated CA125 and measurable cancer will be followed by RECIST 1.1 criteria;
patients with only an elevated CA125 level will be followed by modified Gynecologic
Cancer Intergroup (GCIG) criteria

- Participants in the Phase II portion of the trial must have measurable disease by
RECIST 1.1 criteria

- Breast cancer participants must have measurable disease by RECIST criteria

- PRIOR THERAPY PHASE I and PHASE I-T:

- Prior chemotherapy for ovarian cancer patients must have included a first-line
platinum-based regimen with or without intravenous consolidation chemotherapy

- Breast cancer patients must have recurred post both an Adriamycin- and
taxane-containing regimen

- Prior hormonal-based therapy for ovarian, primary peritoneal serous, fallopian
tube cancer, or breast cancer is acceptable

- Patients may not have had a prior PAR polymerase (PARP)-inhibitor in the
recurrent or metastatic setting; prior treatment with BSI-201 (iniparib) is
allowed

- Patients may not have had a prior anti-angiogenic agent in the recurrent or
metastatic setting

- PRIOR THERAPY PHASE II:

- Prior chemotherapy must have included a first-line platinum-based regimen with or
without intravenous consolidation chemotherapy

- Prior hormonal-based therapy for ovarian, primary peritoneal serous, or fallopian
tube cancer is acceptable

- Patients may not have previously received a PARP-inhibitor; prior treatment with
BSI-201 is allowed

- Patients may not have had a prior anti-angiogenic agent in the recurrent setting

- Patients may have received up to 1 non-platinum-based line of therapy in the
recurrent setting

- Patients may have received an unlimited number of platinum-based therapies in the
recurrent setting

- Patients should have platinum-sensitive disease, where platinum-sensitive disease
is defined as having had a > 6 month interval since last receiving platinum
therapy prior to disease recurrence; patients must have had a prior response
while on the platinum-containing regimen and cannot have experienced disease
progression while receiving platinum

- Subjects may begin cediranib and olaparib at least 3 weeks after their last dose of
chemotherapy or hormonal therapy, assuming they are otherwise eligible

- Estimated life expectancy of greater than 6 months

- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Karnofsky > 60%)

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Hemoglobin > 9 g/dL

- For patients enrolled to the Phase 1-T portion of the protocol, the hemoglobin
should be >= 10 g/dL

- Total bilirubin within 1.5 times the upper limit of normal institutional limits

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional upper limit of normal

- Creatinine =< the institutional upper limit of normal or creatinine clearance >= 60
mL/min/1.73 m^2 for subjects with creatinine levels above institutional normal

- Less than or equal to 1+ proteinuria on two consecutive dipsticks taken no less than 1
week apart, OR < 1 gm protein on 24-hour urine collection or a urine protein:
creatinine ratio of < 1

- Troponin T or I within normal institutional limits

- Coagulation parameters (international normalized ratio [INR], activated partial
thromboplastin time [aPTT]) within 1.25 x upper limit of normal institutional limits,
except where a Lupus anti-coagulant has been confirmed

- Toxicities of prior therapy (except alopecia) should be resolved to less than or equal
to grade 1 as per National Cancer Institute Common Terminology Criteria for Adverse
Events version 4.0 (NCI-CTCAE v4.0); patients with long-standing stable grade 2
neuropathy may be considered after discussion with the overall principal investigator
(PI)

- Subjects with treated limited stage basal cell or squamous cell carcinoma of the skin
or carcinoma in situ of the breast or cervix are eligible; subjects with 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 are eligible;
subjects with any other concomitant or prior invasive malignancies are ineligible

- Patients who have the following risk factors are considered to be at increased risk
for cardiac toxicities; these patients should have increased monitoring:

- Prior treatment with anthracyclines

- Prior treatment with trastuzumab

- A New York Heart Association classification of II controlled with treatment

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

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

- 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 for 3 months following treatment
discontinuation; should a woman become pregnant or suspect she is pregnant while
participating in this study, she should inform her treating physician immediately

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

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

- Patients must be willing and able to check and record daily blood pressure readings

Exclusion Criteria:

- Participants who have had chemotherapy or radiotherapy within 3 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 3 weeks earlier

- Participants may not be receiving any other investigational agents nor have
participated in an investigational trial within the past 4 weeks; subjects may not
have received prior treatment affecting the vascular endothelial growth factor (VEGF)
pathway in the recurrent setting, including thalidomide, bevacizumab, sunitinib, or
sorafenib; in the Phase I portion of the trial, subjects may not have received prior
treatment with oregovomab (OvaRex) or any other antibodies that may interfere with
CA-125 measurements

- Patients with untreated brain metastases, spinal cord compression, or evidence of
symptomatic brain metastases or leptomeningeal disease as noted on computed tomography
(CT) or MRI scans should not be included on this study; 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 and
resolution of any associated symptoms must demonstrate stable post-therapeutic imaging
for at least 6 months following therapy prior to starting study drug

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to cediranib maleate or olaparib

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

- Patients with any of the following:

- History of myocardial infarction within six months

- Patients with corrected QT (QTc) prolongation > 500 msec or other significant
electrocardiogram (ECG) abnormality noted within 14 days of treatment

- For patients enrolled in the Phase 1-T portion of the protocol, the QTc
should not exceed 470 msec

- New York Heart Association (NYHA) 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

- Condition requiring concurrent use of drugs or biologics with pro-arrhythmic
potential

- History of stroke or transient ischemic attack within six months

- Patients may not have any evidence of pre-existing inadequately controlled
hypertension (defined as a systolic blood pressure [BP] of > 140 mmHg or a diastolic
BP of > 90 mmHg), and must have a normal blood pressure (=< 140/90 mmHg) taken in the
clinic setting by a medical professional within 2 weeks prior to starting study;
patients with hypertension may be managed with up to a maximum of three
antihypertensive medications; patients who are on three antihypertensive medications
must be actively followed by a cardiologist or blood pressure specialist for
management of blood pressure while on protocol

- Any prior history of hypertensive crisis or hypertensive encephalopathy

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

- Unstable angina

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

- History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess

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

- Current dependency on intravenous (IV) hydration or total parenteral nutrition (TPN)

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

- 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 cediranib or olaparib

- Known human immunodeficiency virus (HIV)-positive individuals are ineligible

- Patients may not use natural herbal products or other "folk remedies" while
participating in this study

- No features suggestive of myelodysplastic syndrome (MDS) or acute myelogenous leukemia
(AML) on peripheral blood smear or bone marrow biopsy, if clinically indicated