Cediranib Maleate and Olaparib Compared to Bevacizumab in Treating Patients With Recurrent Glioblastoma
Condition: Recurrent Glioblastoma
MeSH terms: Glioblastoma; Recurrence
Intervention: Bevacizumab; Cediranib; Cediranib Maleate; Olaparib
Intervention description: Given IV; Given PO; Given PO; Given PO
Intervention MeSH terms: Bevacizumab; Antineoplastic Agents, Immunological; Olaparib; Cediranib; Endothelial Growth Factors; Antibodies; Immunoglobulins; Antibodies, Monoclonal; Immunoglobulin G; Maleic acid
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 70.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This randomized phase II trial studies how well cediranib maleate and olaparib work compared
      to bevacizumab in treating patients with glioblastoma that has come back (recurrent).
      Cediranib maleate and olaparib may stop the growth of tumor cells by blocking some of the
      enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as
      bevacizumab, may help the body's immune system attack the cancer, and may interfere with the
      ability of tumor cells to grow and spread.
    

Eligibility criteria:

        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

               -  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 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