Phase I/II Study of Cediranib and Olaparib in Combination for Treatment of Recurrent Papillary-Serous Ovarian, Fallopian Tube, or Peritoneal Cancer or for Treatment of Recurrent Triple-Negative Breast Cancer

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 BRCA germline mutation by standard clinical
testing (Myriad BRAC Analysis) will also be considered eligible

- Ovarian cancer, primary peritoneal, and fallopian tube participants in the Phase 1
portion of this trial must have either measurable cancer by RECIST 1.1 criteria or an
elevated CA125 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 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:

- 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 PARP-inhibitor in the recurrent or metastatic
setting; prior treatment with BSI-201 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

- ECOG performance status 0 or 1 (Karnofsky > 60%)

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Hemoglobin >= 9 g/dL

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

- AST (SGOT)/ALT (SGPT) =< 2.5 X institutional upper limit of normal

- Creatinine =< the institutional upper limit of normal or creatinine clearance >= 60
mL/min/1.73 m2 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 (INR, aPTT) within 1.25 x upper limit of normal institutional
limits, except where a Lupus anti-coagulant has been confirmed

- Toxicities of prior therapy (excepting alopecia) should be resolved to less than or
equal to Grade 1 as per NCI-CTCAE v4.0; Patients with long-standing stable grade 2
neuropathy may be considered after discussion with the overall 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 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 (see
Appendix E)

- 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 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 CT or MRI scans
should not be included on this study, since neurologic dysfunction may confound the
evaluation of neurologic and other adverse events; 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 or olaparib

- Participants receiving any medications or substances that are strong inhibitors or
inducers of 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 QTc prolongation > 500 msec or other significant ECG abnormality
noted within 14 days of treatment

- NYHA classification of III or IV

- If cardiac function assessment is clinically indicated or performed: 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, and must have a normal blood pressure 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 IV hydration or 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 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

- Known 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

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