Olaparib, Cediranib Maleate, and Standard Chemotherapy in Treating Patients With Small Cell Lung Cancer

PRIMARY OBJECTIVES:

I. To determine whether the addition of cediranib maleate (cediranib) plus olaparib as
maintenance therapy, in patients with small cell lung cancer (SCLC) who have stable disease
or better (non-progressive disease or non-PD) after initial therapy, leads to improved median
progression-free survival (PFS), PFS is measured in months from the time of randomization to
maintenance therapy (after completion of initial therapy), compared to standard therapy (no
maintenance treatment.

SECONDARY OBJECTIVES:

I. To evaluate the impact of cediranib plus olaparib maintenance therapy on median overall
survival (OS) in patients with SCLC who have non-PD after initial therapy.

II. To determine whether the addition of cediranib to cisplatin/carboplatin plus etoposide
during initial therapy adds benefit to response rate, median PFS and median OS.

III. To assess safety and tolerability of the combination of cediranib plus olaparib during
maintenance therapy.

IV. To evaluate potential biomarkers of clinical benefit to olaparib/cediranib combination,
including tumor proteomic and genomic markers, and circulating levels of cytokines and
angiogenic factors, that that may be associated with clinical benefit.

OUTLINE:

INITIAL THERAPY PHASE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive carboplatin intravenously (IV) over 60 minutes or cisplatin IV over
60 minutes on day 1 and etoposide IV over 60 minutes on days 1, 2, and 3. Treatment repeats
every 21 days for up to 4 courses in the absence of disease progression or unacceptable
toxicity.

ARM II: Patients receive treatment as in Arm I and also receive cediranib maleate orally (PO)
once daily (QD) on days 1-21. Treatment repeats every 21 days for up to 4 courses in the
absence of disease progression or unacceptable toxicity.

Patients in Arm I who have stable disease, partial, or a complete response are randomized to
receive maintenance therapy or no maintenance therapy. Patients in Arm II are assigned to
receive maintenance therapy.

MAINTENANCE THERAPY: Patients receive cediranib maleate PO QD and olaparib PO twice daily
(BID) on days 1-28.

NO MAINTENANCE THERAPY: Patients are eligible to crossover to receive treatment with
cediranib maleate and olaparib upon disease progression at the treating investigator's
discretion.

After completion of study treatment, patients are followed up every 3-4 months for at least 1
year.

Inclusion Criteria:

- Histologically or cytologically confirmed diagnosis of extensive-stage small cell lung
cancer with no prior systemic treatment

- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded for
non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) with
conventional techniques or as >= 10 mm (>= 1 cm) with spiral computed tomography (CT)
scan, magnetic resonance imaging (MRI), or calipers by clinical exam

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- White blood cell count (WBC) >= 3 x 10^9/L

- No features suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)
on peripheral blood smear

- Within 28 days prior to administration of therapy: Absolute neutrophil count >=
1,500/mcL

- Within 28 days prior to administration of therapy: Platelets >= 100,000/mcL

- Within 28 days prior to administration of therapy: Hemoglobin >= 10 g/dL with no blood
transfusion within 28 days of initiation of therapy

- Within 28 days prior to administration of therapy: Total bilirubin =< 1.5 x
institutional upper limit of normal (ULN)

- Within 28 days prior to administration of therapy: Aspartate aminotransferase (AST)
serum glutamic-oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT) serum
glutamate pyruvate transaminase (SGPT) =< 2.5 x institutional ULN, unless liver
metastases are present and then =< 5 x institutional ULN is acceptable

- Within 28 days prior to administration of therapy: Creatinine clearance >= 50 mL/min

- Within 28 days prior to administration of therapy: Proteinuria - urine
protein:creatinine ratio (UPC) of =< 1 OR =< 2+ proteinuria on two consecutive
urinalysis/dipstick tests taken no less than 1 week apart; patients with 2+
proteinuria on dipstick must also have a UPC of =< 0.5 on 2 consecutive samples

- Urine protein: creatinine ratio (UPC) of =< 1; UPC is the preferred test

- Ability to swallow and retain oral medication

- Women of child-bearing potential and male patients and their partners who are sexually
active must agree to use two highly effective forms of contraception in combination
for the duration of study participation and for 3 months after completion of olaparib
and cediranib administration; 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

- Postmenopausal or evidence of non-pregnant status for women of childbearing potential
as confirmed by a negative urine or serum pregnancy test within 7 days prior to the
start of therapy; postmenopausal status is defined as:

- Age >= 60 years, or

- Age < 60 with any one or more of the conditions below:

- Amenorrheic for >= 1 year in the absence of chemotherapy and/or hormonal
treatments,

- Luteinizing hormone and/or follicle stimulating hormone and/or estradiol
levels in the post-menopausal range,

- Radiation-induced oophorectomy with last menses > 1 year ago,

- Chemotherapy-induced menopause with > 1 year interval since last menses,

- Surgical sterilization (bilateral oophorectomy or hysterectomy)

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

- Participants must have archival tumor tissue available for analysis (minimum 20 5 um
slide) or be able to undergo a baseline fresh tumor tissue biopsy

- Adequately controlled blood pressure; (defined as systolic blood pressure [SBP] of <
140 mmHg and diastolic blood pressure [DBP] of < 90 mmHg) on maximum of three
antihypertensive medications; participants must have a blood pressure (BP) of < 140/90
taken in the clinic or hospital setting by a medical professional within 2 weeks prior
to starting on study; it is strongly recommended that participants who are on 3
antihypertensive medications be followed by a cardiologist or a primary care physician
for management of BP while on study

- Adequately controlled thyroid function, with no symptoms of thyroid dysfunction;
patients can be on thyroid hormone replacement medication; asymptomatic patients with
elevated thyroid stimulating hormone (TSH) with normal T4/T3 are allowed to enroll,
and recommended to follow with routine thyroid function test

Exclusion Criteria:

- Patients who have had major surgery or trauma within 28 days prior to entering the
study; patients must have recovered from any effects of any major surgery and surgical
wound should have healed prior to starting treatment

- Patients who have had radiotherapy within 14 days prior to entering the study

- Patients with a non-healing wound, fracture, or ulcer

- Patients who have not recovered from adverse events due to prior anti-cancer therapy
(i.e., have residual toxicities > Common Terminology Criteria for Adverse Events
[CTCAE] grade 1 or baseline, with the exception of alopecia)

- Patients who are receiving any other investigational agents

- Patients with symptomatic central nervous system (CNS) metastases or leptomeningeal
carcinomatosis should be excluded from this clinical trial because of their poor
prognosis and because they often develop progressive neurologic dysfunction that would
confound the evaluation of neurologic and other adverse events; exceptions include
patients with previously-treated CNS metastases or those with are asymptomatic,
subcentimeter metastases, and have no requirement for steroids or anti-seizure
medication for at least one week prior to study entry; screening with CNS imaging
studies (CT scan or MRI) is required

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to olaparib, cediranib, carboplatin, cisplatin, or etoposide

- Patients with a history of myelodysplastic syndrome (MDS)

- Patients with a history of acute myeloid leukemia (AML), or patients with a history of
any other primary malignancy within 3 years prior to initiation of treatment on this
study; exceptions include: patients with a history of malignancies (other than AML)
that were treated curatively and have not recurred within 3 years prior to study
entry; resected basal and squamous cell carcinomas of the skin; and completely
resected carcinoma in situ of any type

- Patients with clinically significant gastrointestinal abnormalities including, but not
limited to:

- Clinically significant signs and/or symptoms of bowel obstruction within 3 months
prior to starting treatment

- History of intra-abdominal abscess within 3 months prior to starting treatment

- History of gastrointestinal (GI) perforation within 6 months prior to starting
treatment

- Evidence of abdominal fistula within 6 months prior to starting treatment;
history of abdominal fistula will be considered eligible if the fistula was
surgically repaired, and there has been no evidence of fistula for at least 6
months prior to starting treatment, and patient is deemed to be at low risk of
recurrent fistula

- Patients with a history of cerebrovascular accident including transient ischemic
attack (TIA), pulmonary embolism or insufficiently treated deep venous thrombosis
(DVT) within the past 3 months; Note: Participants with recent DVT who have been
treated with therapeutic anti-coagulants for at least 6 weeks are eligible, with the
exception of participants being treated with warfarin, which is prohibited on this
study; other oral anti-coagulants may be allowed after discussion with overall
principle investigator (PI), but short half-life low molecular weight heparins are
strongly preferred

- Patients with evidence of active bleeding diathesis

- Patients with hemoptysis in excess of 2.5 mL within 6 weeks prior to the first dose of
study medication

- Patients receiving any medications or substances that are potent inhibitors or
inducers of CYP3A4 are ineligible; the required washout period for strong inhibitors
is 2 weeks and at least one week for moderate inhibitors; the required washout period
prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 4 weeks
for other agents

- Patients requiring concomitant therapy with phenytoin, phenobarbital, carbamazepine,
or valproic acid

- 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; specifically, patients with any of the following within 6 months
prior to starting treatment are excluded:

- Acute myocardial infarction

- Unstable angina

- New York Heart Association functional classification of III or IV

- Left ventricular ejection fraction (LVEF) < lower limit of normal (LLN) per
institutional guidelines, or 55%

- Prior allogeneic bone marrow transplant or double umbilical cord blood
transplantation

- Patients with active hepatitis (B or C)

- Patients with active pneumonitis

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with olaparib or cediranib

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible

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