Summary

for people ages 18 years and up (full criteria)
at La Jolla, California and other locations
study started
estimated completion:
David E. Piccioni

Description

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. Cediranib maleate and olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread.

Official Title

A Randomized Phase 2 Trial of Cediranib and Olaparib Compared to Bevacizumab in Patients With Recurrent Glioblastoma Who Have Not Received Prior VEGF Therapy

Details

PRIMARY OBJECTIVES:

  1. 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:

  1. 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.

  1. 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, courses 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.

Keywords

Recurrent Glioblastoma Glioblastoma Bevacizumab Olaparib Cediranib Endothelial Growth Factors Antibodies Immunoglobulins Antibodies, Monoclonal Immunoglobulin G Maleic acid Cediranib Maleate Laboratory Biomarker Analysis

Eligibility

You can join if…

Open to people ages 18 years and up

  • 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 within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal

  • 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

You CAN'T join if...

  • 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

Locations

  • UC San Diego Moores Cancer Center accepting new patients
    La Jolla California 92093 United States
  • Siteman Cancer Center at Saint Peters Hospital accepting new patients
    Saint Peters Missouri 63376 United States
  • Siteman Cancer Center at West County Hospital accepting new patients
    Creve Coeur Missouri 63141 United States
  • Siteman Cancer Center-South County accepting new patients
    Saint Louis Missouri 63129 United States
  • Washington University School of Medicine accepting new patients
    Saint Louis Missouri 63110 United States
  • Siteman Cancer Center at Christian Hospital accepting new patients
    Saint Louis Missouri 63136 United States
  • University of Kentucky/Markey Cancer Center accepting new patients
    Lexington Kentucky 40536 United States
  • Ohio State University Comprehensive Cancer Center accepting new patients
    Columbus Ohio 43210 United States
  • Moffitt Cancer Center accepting new patients
    Tampa Florida 33612 United States
  • University of Pittsburgh Cancer Institute (UPCI) accepting new patients
    Pittsburgh Pennsylvania 15232 United States
  • Rutgers Cancer Institute of New Jersey accepting new patients
    New Brunswick New Jersey 08903 United States
  • Smilow Cancer Hospital Care Center-Fairfield currently not accepting new patients, but might later
    Fairfield Connecticut 06824 United States
  • Smilow Cancer Hospital Care Center-Trumbull currently not accepting new patients, but might later
    Trumbull Connecticut 06611 United States
  • Smilow Cancer Hospital-Torrington Care Center currently not accepting new patients, but might later
    Torrington Connecticut 06790 United States
  • Smilow Cancer Hospital-Derby Care Center currently not accepting new patients, but might later
    Derby Connecticut 06418 United States
  • Smilow Cancer Hospital-Waterbury Care Center currently not accepting new patients, but might later
    Waterbury Connecticut 06708 United States
  • Smilow Cancer Hospital-Orange Care Center currently not accepting new patients, but might later
    Orange Connecticut 06477 United States
  • Smilow Cancer Center/Yale-New Haven Hospital accepting new patients
    New Haven Connecticut 06510 United States
  • Yale University accepting new patients
    New Haven Connecticut 06520 United States
  • Smilow Cancer Hospital Care Center at Saint Francis currently not accepting new patients, but might later
    Hartford Connecticut 06105 United States
  • Yale-New Haven Shoreline Medical Center currently not accepting new patients, but might later
    Guilford Connecticut 06437 United States
  • Lawrence and Memorial Cancer Center currently not accepting new patients, but might later
    Waterford Connecticut 06385 United States
  • Dana-Farber Cancer Institute accepting new patients
    Boston Massachusetts 02215 United States
  • Massachusetts General Hospital Cancer Center accepting new patients
    Boston Massachusetts 02114 United States

Details

Status
accepting new patients
Start Date
Completion Date
(estimated)
Sponsor
National Cancer Institute (NCI)
ID
NCT02974621
Phase
Phase 2
Lead Scientist
David E. Piccioni
Study Type
Interventional
Last Updated
August 2, 2018