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 =< 1 g 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.
- - The effects of olaparib and cediranib on the developing human fetus are unknown;
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.
- - 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 from this study because cediranib and olaparib agent
with the potential for teratogenic or abortifacient effects; because there is an
unknown but potential risk for 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 and olaparib; these potential
risks may also apply to other agents used in this study.
- - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible because of the potential for pharmacokinetic interactions
with cediranib and olaparib; in addition, these patients are at increased risk of
lethal infections when treated with marrow-suppressive therapy; 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.
- - Because the composition, pharmacokinetics (PK), and metabolism of many herbal
supplements are unknown; 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
