Cediranib Maleate and Olaparib Compared to Bevacizumab in Treating Patients With Recurrent Glioblastoma

PRIMARY OBJECTIVES:

I. To compare the antitumor activity of cediranib maleate (cediranib)/olaparib versus
reference bevacizumab monotherapy, as measured by progression-free survival at 6 months
(PF6), in patients with recurrent glioblastoma (GBM).

SECONDARY OBJECTIVES:

I. To compare overall survival (OS), progression free survival (PFS) and objective response
(ORR) in patients with recurrent GBM treated with cediranib/olaparib versus bevacizumab.

II. To assess the safety of the combination of olaparib and cediranib in patients with
recurrent GBM.

III. To evaluate the association of blood based biomarkers involved with angiogenesis using
the Biomarker Review Committee-approved Plasma Angiome Panel (bFGF, Ang-1, Ang-2, Tie-2,
SDF1-alpha, Collagen IV, PlGF, sVEGFR1, sVEGFR2, VEGF, Il-1beta, Il-6, Il-8, TNF-alpha, CAIX)
with the clinical activity of cediranib/olaparib.

IV. To evaluate the association of tissue biomarkers involved with deoxyribonucleic acid
(DNA) repair using the Biomarker Review Committee-approved BROCA panel with the clinical
activity of cediranib/olaparib.

V. To identify genomic alteration by whole exome sequencing in GBM tumor specimens that
correlate with the clinical activity of cediranib/olaparib.

VI. To evaluate the association of magnetic resonance imaging (MRI) imaging parameters (tumor
perfusion and oxygenation, brain tumor cellularity) with the biological response of
cediranib/olaparib.

VII. To contribute genetic analysis data from de-identified biospecimens to Genomic Data
Commons (GDC), a well annotated cancer molecular and clinical data repository, for current
and future research; specimens will be annotated with key clinical data, including
presentation, diagnosis, staging, summary treatment, and if possible, outcome.

VIII. To bank formalin-fixed, paraffin-embedded (FFPE) tissue, blood (for cell-free DNA
analysis), and nucleic acids obtained from patients at the Experimental Therapeutics Clinical
Trials Network (ETCTN) Biorepository at Nationwide Children's Hospital.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive olaparib orally (PO) twice daily (BID) and cediranib maleate PO once
daily (QD) on days 1-28.

ARM B: Patients receive bevacizumab intravenously (IV) over 30 minutes every 2 weeks.

In both arms, cycles repeat every 28 days in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then
periodically for 3 years.

Inclusion Criteria:

- Unequivocal evidence of progressive disease on contrast-enhanced brain computed
tomography (CT) or MRI as defined by Response Assessment in Neuro-Oncology (RANO)
criteria, or have documented recurrent glioblastoma on diagnostic biopsy

- Previous therapy with at least radiotherapy and temozolomide

- Must be 12 weeks from radiotherapy; if patients are within 12 weeks of radiotherapy,
then the progressive lesion must be outside of the high-dose radiation target volume
or have unequivocal evidence of progressive tumor on a biopsy specimen

- Only first and second recurrences of GBM are eligible

- From the projected start of scheduled study treatment, the following time periods must
have elapsed: 5 half-lives from investigational agents, 4 weeks from cytotoxic therapy
(except 23 days for temozolomide and 6 weeks from nitrosoureas), 6 weeks from
antibodies, or 4 weeks (or 5 half-lives, whichever is shorter) from other systemic
anti-tumor therapies; treatment on study may start one day after discontinuation of
the optune device

- All adverse events grade > 1 related to prior therapies (chemotherapy, radiotherapy,
and/or surgery) must be resolved, except for alopecia

- Willingness to release archival tissue sample for research purposes, if available

- Karnofsky performance status >= 60

- Life expectancy of at least 3 months

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Hemoglobin >= 10.0 g/dL and no blood transfusions in the 28 days prior to
entry/randomization

- Total bilirubin =< 1.5 x 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 upper limit of normal

- Creatinine should not exceed the institutional upper limit of normal OR creatinine
clearance >= 60 mL/min/1.73 m^2

- Urine protein: creatinine (UPC) ratio < 1 or urine dipstick for proteinuria =< 2+
(note: if the UPC ratio is >= 1.0 then a 24-hour urine collection should be performed
and this must demonstrate =< 1g of protein in 24 hours)

- CT or MRI within 14 days prior to start of study drug

- Corticosteroid dose must be stable or decreasing for at least 5 days prior to the
baseline MRI scan

- Female subjects must either be of non-reproductive potential, not breast-feeding or
must have a negative urine or serum pregnancy test within 28 days of study treatment,
confirmed prior to treatment on day 1; 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 6 months after
completion of olaparib + cediranib administration

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

Exclusion Criteria:

- Participants should not have received any other investigational agents nor have
participated in an investigational trial within the past 4 weeks

- Participants may not have had prior use of PARP inhibitors; patients may not have
received prior treatment affecting the VEGF pathway including but not limited to
thalidomide, bevacizumab, sunitinib, or sorafenib

- Patients who are receiving any other investigational agents

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

- Participants may not have any evidence of ongoing inadequately controlled hypertension
(defined as a systolic blood pressure [BP] of > 140 mmHg or a diastolic BP of > 90
mmHg); patients with hypertension may not be on more than three antihypertensive
medications for management of their blood pressure (medications that combine two
anti-hypertensives into one are considered as two medications); it is strongly
recommended that patients who require three antihypertensive medications for baseline
management of pre-existing hypertension be actively followed by a cardiologist or
blood pressure specialist for management of BP while on protocol

- Participants may not have had any prior history of hypertensive crisis or hypertensive
encephalopathy

- Participants may not have had history of abdominal fistula or gastrointestinal
perforation within the past 6 months

- Participants may not have had a history of intra-abdominal abscess within the past 6
months

- Patients may not have a known or confirmed history of pneumonitis

- Participants may not have current signs and/or symptoms of bowel obstruction or signs
and/or symptoms of bowel obstruction within 3 months prior to starting study drugs

- Participants may not have a dependency on IV hydration or total parenteral nutrition
(TPN)

- Patients with myelodysplastic syndrome/acute myeloid leukemia

- Participants with any concomitant or prior invasive malignancies are ineligible with
the following exceptions:

- Treated limited-stage basal cell or squamous cell carcinoma of the skin

- Carcinoma in situ of the breast or cervix

- Prior cancer treated with curative intent with no evidence of recurrent disease 3
years following diagnosis and judged by the investigator to be at low risk of
recurrence

- Participants with any of the following:

- History of myocardial infarction within six months

- Unstable angina

- History of cerebrovascular accident (CVA) within 6 months

- New York Heart Association grade II or greater congestive heart failure

- Significant vascular disease (e.g. aortic aneurysm, history of aortic dissection)

- Clinically significant peripheral vascular disease

- If cardiac function assessment is clinically indicated or performed: participants will
be ineligible if left ventricular ejection fraction (LVEF) is less than normal per
institutional guidelines, or < 55%, if the threshold for normal is not otherwise
specified by institutional guidelines

- Participants may not have corrected QT (QTc) > 470 msec or family history of long QT
syndrome

- Participants may not have a major surgical procedure, open biopsy, or significant
traumatic injury within 28 days prior to starting cediranib; anticipation of need for
major surgical procedures during the course of the study also excludes patients from
the trial

- Participants should not have any uncontrolled intercurrent illness including, but
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

- Participants receiving any medications or substances that are strong inhibitors or
inducers of CYP3A4 or moderate inhibitors of CYP3A4 are ineligible; the study team
should check a frequently-updated medical reference for a list of drugs to avoid or
minimize use of; as part of the enrollment/informed consent procedures, the patient
will be counseled on the risk of interactions with other agents, and what to do if new
medications need to be prescribed or if the patient is considering a new
over-the-counter medicine or herbal product; dihydropyridine calcium-channel blockers
are permitted for management of hypertension; patient drug information handout and
wallet card should be provided to patients

- Pregnant women are excluded; 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; appropriate studies will be undertaken in patients receiving
combination antiretroviral therapy when indicated

- Current use of a prohibited medication; the following medications or non-drug
therapies are prohibited:

- Other anti-cancer therapy while on study treatment

- Concurrent treatment with bisphosphonates is permitted; however, treatment must
be initiated prior to the first dose of study therapy; prophylactic use of
bisphosphonates in patients without bone disease is not permitted, except for the
treatment of osteoporosis

- The concurrent use of all herbal supplements is prohibited during the study
(including, but not limited to, cannabis, S. John's wort, kava, ephedra [ma
huang], gingko biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto or
ginseng)

- Raloxifene is allowed for patients taking it for bone health

- Participants should not have evidence of coagulopathy or bleeding diathesis;
therapeutic anticoagulation for prior thromboembolic events is permitted