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

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ClinicalTrials.gov Identifier: NCT02974621
Recruitment Status : Suspended (Other - Awaiting CTEP Approval of Amendment v.10/15/18)
First Posted : November 28, 2016
Last Update Posted : November 14, 2018
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief 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.

Condition or disease Intervention/treatment Phase
Recurrent Glioblastoma Biological: Bevacizumab Drug: Cediranib Maleate Other: Laboratory Biomarker Analysis Drug: Olaparib Phase 2

Detailed Description:

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, 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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 70 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : September 15, 2017
Estimated Primary Completion Date : October 31, 2019
Estimated Study Completion Date : October 31, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm A (olaparib, cediranib maleate)
Patients receive olaparib PO BID and cediranib maleate PO once QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: Cediranib Maleate
Given PO
Other Names:
  • AZD2171
  • AZD2171 Maleate
  • Recentin

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Olaparib
Given PO
Other Names:
  • AZD2281
  • KU-0059436
  • Lynparza
  • PARP Inhibitor AZD2281

Experimental: Arm B (bevacizumab)
Patients receive bevacizumab IV over 90 minutes every 2 weeks. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Biological: Bevacizumab
Given IV
Other Names:
  • Anti-VEGF
  • Anti-VEGF Humanized Monoclonal Antibody
  • Anti-VEGF rhuMAb
  • Avastin
  • Bevacizumab Biosimilar BEVZ92
  • Bevacizumab Biosimilar BI 695502
  • Bevacizumab Biosimilar CBT 124
  • Bevacizumab Biosimilar FKB238
  • Bevacizumab Biosimilar MIL60
  • Bevacizumab Biosimilar QL 1101
  • BEVACIZUMAB, LICENSE HOLDER UNSPECIFIED
  • Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer
  • Recombinant Humanized Anti-VEGF Monoclonal Antibody
  • rhuMab-VEGF

Other: Laboratory Biomarker Analysis
Correlative studies




Primary Outcome Measures :
  1. Progression-free survival [ Time Frame: Time from randomization to the earlier of progression or death due to any cause, assessed at 6 months ]
    Defined as the proportion of subjects in the analysis population who remain progression-free for at least 6 months following initiation of study therapy. Will be calculated with the Kaplan-Meier method and the log-rank test will be conducted to compare between the study arms. 95% confidence interval (CI) will be provided for proportion outcomes.


Secondary Outcome Measures :
  1. Overall survival (OS) [ Time Frame: Time from randomization to death due to any cause or censored at date last known alive, assessed up to 3 years ]
    OS will be calculated with the Kaplan-Meier method and the log-rank test will be conducted to compare between the study arms.

  2. Incidence of adverse events (AE) assessed by National Cancer Institute Common Terminology Criteria for Adverse Events 5.0 [ Time Frame: Up to 3 years ]
    Maximum grade AE during treatment will be reported using 95% binomial confidence intervals.

  3. Levels of circulating cytokines involved with angiogenesis [ Time Frame: Up to 3 years ]
    Descriptive statistics will be provided for all continuous biomarkers outcomes. Contingency tables will be provided for categorical data. All comparisons between study arms will be adjusted for multiplicity and in particular false discovery rate (FDR) (Hochberg and Binaymini) will be used for genome data. Binary endpoints will be reported using 95% binomial confidence intervals.

  4. Levels of serial circulating biomarkers involved with deoxyribonucleic acid (DNA) repair [ Time Frame: Up to 3 years ]
    Descriptive statistics will be provided for all continuous biomarkers outcomes. Contingency tables will be provided for categorical data. All comparisons between study arms will be adjusted for multiplicity and in particular FDR (Hochberg and Binaymini) will be used for genome data. Binary endpoints will be reported using 95% binomial confidence intervals.

  5. Tumor genomic alteration by whole exome sequencing [ Time Frame: Up to 3 years ]
    Descriptive statistics will be provided for all continuous biomarkers outcomes. Contingency tables will be provided for categorical data. All comparisons between study arms will be adjusted for multiplicity and in particular FDR (Hochberg and Binaymini) will be used for genome data. Binary endpoints will be reported using 95% binomial confidence intervals.

  6. Imaging correlates (vascular permeability, tumor perfusion and oxygenation, brain tumor cellularity) [ Time Frame: Up to 3 years ]
    Descriptive statistics will be provided for all continuous biomarkers outcomes. Contingency tables will be provided for categorical data. All comparisons between study arms will be adjusted for multiplicity and in particular FDR (Hochberg and Binaymini) will be used for genome data. Binary endpoints will be reported using 95% binomial confidence intervals.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 =< 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02974621


  Show 27 Study Locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Isabel Arrillaga-Romany Dana-Farber - Harvard Cancer Center LAO

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02974621     History of Changes
Other Study ID Numbers: NCI-2016-01769
NCI-2016-01769 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
17-735
10067 ( Other Identifier: Dana-Farber - Harvard Cancer Center LAO )
10067 ( Other Identifier: CTEP )
UM1CA186709 ( U.S. NIH Grant/Contract )
First Posted: November 28, 2016    Key Record Dates
Last Update Posted: November 14, 2018
Last Verified: November 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Bevacizumab
Olaparib
Cediranib
Endothelial Growth Factors
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Immunoglobulin G
Maleic acid
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents
Immunologic Factors
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Protein Kinase Inhibitors