A Phase 2 Study of Cediranib in Combination With Olaparib in Advanced Solid Tumors
A Phase 2 Study of Cediranib in Combination With Olaparib in Advanced Solid Tumors
This phase II trial studies cediranib maleate in combination with olaparib in treating
 patients with solid tumors that have spread to other parts of the body (advanced/metastatic)
 or cannot be removed by surgery (unresectable), including breast cancer, non-small cell lung
 cancer, small cell lung cancer, and pancreatic cancer. Cediranib maleate and olaparib may
 stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
 Cediranib maleate may also block the flow of oxygen to the tumor, and may help make the tumor
 more sensitive to olaparib.
PRIMARY OBJECTIVE:

 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 cycle 1.
 Cycles repeat every 28 days (35 days for cycle 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 or prior grade 2
 treatment-related hypothyroidism requiring treatment, provided free T4 within normal
 range, may be considered eligible 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 defined by free T4 within normal range, with no
 symptoms of thyroid dysfunction

 -  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