A Phase 2 Study of Cediranib in Combination With Olaparib in Advanced Solid Tumors

PRIMARY OBJECTIVES:

I. To determine the objective response rate (ORR) of cediranib (cediranib maleate) plus
olaparib in combination in patients with advanced or metastatic solid tumors of the following
tumor types: non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC),
pancreatic ductal adenocarcinoma (PDAC), and small cell lung cancer (SCLC).

SECONDARY OBJECTIVES:

I. To assess the safety and tolerability of oral administration of cediranib in combination
with olaparib in patients with select advanced solid tumors.

II. To estimate progression free survival (PFS) in each tumor cohort.

EXPLORATORY OBJECTIVES:

I. To estimate the prevalence of the mutations of deoxyribonucleic acid (DNA) repair genes in
tumors using the BROCA panel and to correlate tumor regression with mutations status.
(Integrated) II. To evaluate changes in tumor hypoxia on cediranib treatment compared to
baseline by [F-18] fluoromisonidazole (FMISO) positron emission tomography/computed
tomography (PET/CT) in patients with NSCLC.

III. To evaluate levels of angiogenesis/inflammatory markers including VEGF at baseline and
on treatment.

IV. To evaluate levels of circulating tumor deoxyribonucleic acid (ctDNA) at baseline and on
treatment.

OUTLINE:

Patients receive cediranib maleate orally (PO) once daily (QD) on day 1. Patients undergoing
FMISO scan also receive olaparib PO twice daily (BID) beginning the day after the second
FMISO scan and the rest of the patients receive olaparib PO BID beginning day 4 of course 1.
Courses repeat every 28 days (35 days for course 1) in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 weeks and then every 4
weeks thereafter.

Inclusion Criteria:

- Patients must have histologically confirmed, metastatic or unresectable malignancy of
the following types: (a) non-small cell lung cancer (NSCLC), (b) triple-negative
breast cancer (TNBC; defined by estrogen receptor [ER] < 1%, progesterone receptor
[PR] < 1% and HER2 1+ or less by immunohistochemistry [IHC]; if HER-2 expression is
2+, a negative fluorescence in situ hybridization [FISH] testing is required) (c)
pancreatic adenocarcinoma (PDAC), or (d) small cell lung cancer (SCLC)

- Must have received at least one line of standard systemic treatment for locally
advanced or metastatic disease setting of the respective tumor type; for NSCLC, it is
either PD-1/PD-L1 inhibitor, or platinum-containing chemotherapy, or an EGFR tyrosine
kinase inhibitor or an ALK inhibitor if sensitizing mutation present; TNBC:
platinum-containing chemotherapy; PDAC: fluorouracil (5-FU-), gemcitabine-, or
taxane-containing chemotherapy either with or without radiation therapy; SCLC:
platinum-containing chemotherapy for limited or extensive stage disease

- Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors
(RECIST) version (v)1.1

- Toxicities of prior therapy (except alopecia) should be resolved to =< grade 1 as per
National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE)
version (v)5.0; patients with long-standing stable grade 2 neuropathy may be
considered after discussion with the study principal investigator (PI)

- Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2 (Karnofsky >=
50%)

- Life expectancy of >= 4 months

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Hemoglobin > 9 g/dL

- 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])
=< 2.5 x institutional ULN

- Creatinine =< 1.5 x ULN OR

- Creatinine clearance >= 45 mL/min/1.73 m^2 for patients with creatinine levels above
institutional normal; the creatinine clearance is calculated using Cockcroft-Gault
formula

- A urine protein: creatinine ratio of < 1 or < 1 g protein on 24-hour urine collection

- International normalized ration (INR) within 1.25 x ULN institutional limits, except
where a lupus anti-coagulant has been confirmed

- Activated partial thromboplastin time (aPTT) within 1.25 x ULN institutional limits,
except where a lupus anti-coagulant has been confirmed

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

- Adequately controlled thyroid function, with no symptoms of thyroid dysfunction;
elevated thyroid stimulating hormone (TSH) with normal T3 and T4 are allowed; patients
on thyroid replacement therapy are allowed

- Adequately controlled blood pressure (BP) < 140 mmHg (systolic) and < 90 mmHg
(diastolic) 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 3
antihypertensive medications; patients who are on 3 antihypertensive medications are
highly recommended to be followed by a cardiologist or blood pressure specialist for
management of BP while on protocol

- Patients who have the following risk factors are considered to be at increased risk
for cardiac toxicities, and must have documented left ventricular ejection fraction
(LVEF) by echocardiogram greater than institution's lower limit of normal (or 55% if
threshold for normal not otherwise specified by institutional guidelines) obtained
within 3 months

- Prior treatment with anthracyclines

- Prior treatment with trastuzumab

- A New York Heart Association (NYHA) 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)

- The effects of cediranib and olaparib on the developing human fetus are unknown; for
this reason, 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 and for the duration of study participation; 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; men treated or enrolled on this
protocol must also agree to use adequate contraception prior to the study, for the
duration of study participation, and for 4 months after completion of cediranib and
olaparib administration

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

Exclusion Criteria:

- Patients who have had chemotherapy or RT within 3 weeks prior to start of the study
agents, or those who have not recovered from adverse events due to agents administered
more than 3 weeks earlier

- Patients should not have received any other investigational agents within the past 4
weeks

- 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 be excluded from this clinical
trial, since neurologic dysfunction may confound the evaluation of neurologic and
other adverse events (AEs); screening brain MRI (or CT if MRI contraindicated) will be
required for patients with recurrent NSCLC, TNBC, or SCLC; brain MRI (or CT if MRI
contraindicated) is required for PDAC if clinically suspected by patient's symptoms or
neurological exam; should patient found to have brain metastasis, treatment of brain
metastasis must precede the participation in this study; for patients with known and
treated brain metastases is allowed in this study if they fulfill the following
criteria:

- The lesions have improved or remained stable radiographically and clinically for
at least 6 weeks after completion of brain irradiation or stereotactic brain
radiosurgery and off steroids for at least 6 weeks

- Patients who have received prior inhibitor of VEGF signaling and a poly (ADP-ribose)
polymerases (PARP) inhibitor administered in combination; unless administered in
combination, patients who received a prior PARP inhibitor or a prior VEGF-signaling
inhibitor agent are allowed after discussing with the PI

- 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) are
ineligible; dihydropyridine calcium-channel blockers are permitted for management of
hypertension

- Current use of natural herbal products or other complementary alternative medications
(CAM) or "folk remedies"

- Patients with concomitant or prior invasive malignancies within the past 3 years;
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

- 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

- History of myocardial infarction within 6 months prior to registration

- History of stroke or transient ischemic attack within 6 months prior to registration

- NYHA classification of III or IV

- Current cardiac arrhythmia requiring concurrent use of anti-arrhythmic drugs

- History of hypertensive crisis or hypertensive encephalopathy within 3 years prior to
registration

- Clinically significant peripheral vascular disease or abdominal aortic aneurysm (> 5
cm) or aortic dissection; if known history of abdominal aortic aneurysm with >= 4 cm
in diameter, all of the following must be met:

- An ultrasound (US) within the last 6 months prior to registration will be
required to document that it is =< 5 cm

- Patient must be asymptomatic from the aneurysm

- Blood pressure must be well controlled as defined in this protocol

- A major surgical procedure, open biopsy, or significant traumatic injury within 28
days prior to starting cediranib (percutaneous/endobronchial biopsies are allowed)

- History of bowel obstruction within 1 month prior to starting study drugs

- History of hemoptysis or any significant bleeding within the last 1 month prior to
enrollment

- Presence of cavitation of central pulmonary lesion

- History of abdominal fistula, intra-abdominal abscess, or gastrointestinal perforation
within the 3 months prior to enrollment

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

- Patients may not have evidence of coagulopathy or bleeding diathesis; therapeutic
anticoagulation for prior thromboembolic events is permitted; the clinical indication
for therapeutic anticoagulation must be clearly documented prior to enrollment and
must be discussed with the P.I.; given the increases risk of serious bleeding from
cediranib, patients who are on greater than or equal to 2 anti-thrombotic agents,
including but not limited to anti-platelet agents (non-steroidal anti-inflammatory
drugs [NSAIDs]/aspirin, clopidogrel), heparin, low molecular weight heparin (LMWH),
warfarin, and a direct thrombin inhibitor, will be excluded

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

- Pregnant women are excluded from this study because olaparib and cediranib have the
potential for teratogenic or abortifacient effects; due to the fact that there is an
unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with olaparib and cediranib, 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 because of the potential for pharmacokinetic interactions with
cediranib or olaparib; appropriate studies will be undertaken in patients receiving
combination antiretroviral therapy when indicated; HIV-positive patients with
undetectable viral loads and CD4 counts > 300, and not on any antiretroviral therapy
may be allowed after discussing with the principle investigator

- Any condition that, in the opinion of the treating investigator would interfere with
evaluation of the investigational product or interpretation of subject safety or study
results