Clinical Trial 19385

Cancer Type:
Interventions:AZD2171 (Cediranib); Avastin (Bevacizumab); Bevacizumab; Cediranib (Recentin); FMISO; Olaparib (Lynparza)

Study Type: Treatment
Phase of Study: Phase II

  • Solmaz Sahebjam


Study 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


The main purpose of this study is to compare the safety and effects of the study drugs called cediranib and olaparib.


Primary Objectives: 1. To compare the anitumor activity of cediranib/olaparib versus reference bevacizumab monotherapy, as measured by progression-free survival at 6 months (PF6), in patients with recurrent GBM. 1.2 Secondary Objectives: 1. To compare overall survival (OS), and objective response (ORR) in patients with recurrent GBM treated with cediranib/olaparib versus bevacizumab. 2. To assess the safety of the combination of olaparib and cediranib in patients with recurrent GBM. 3. 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. 4. To evaluate the association of tissue biomarkers involved with DNA repair using the Biomarker Review Committee-approved BROCA panel with the clinical activity of cediranib/olaparib. 5. To identify genomic alteration by whole exome sequencing in GBM tumor specimens that correlate with the clinical activity of cediranib/olaparib. 6. To evaluate the association of MRI and PET imaging parameters ( tumor perfusion and oxygenation, brain tumor cellularity) with the biological response of cediranib/olaparib.

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 glioblastoma (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
  • Adequate organ and marrow function
  • 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 scan
  • Females 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 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 4 months after completion of olaparib + cediranib administration
  • Ability to understand and the willingness to sign a written informed consent document

  • Exclusion Criteria

  • Have received any other investigational agents or participated in an investigational trial within the past 4 weeks
  • Prior use of PARP inhibitors; have received prior treatment affecting the VEGF pathway in the recurrent setting, including but not limited to thalidomide, bevacizumab, sunitinib, or sorafenib
  • Receiving any other investigational agents
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to olaparib, cediranib or bevacizumab
  • Any evidence of ongoing inadequately controlled; patients with hypertension may not be on more than three antihypertensive medications for management of their blood pressure;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
  • Any prior history of hypertensive crisis or hypertensive encephalopathy
  • History of abdominal fistula or gastrointestinal perforation within the past 6 months
  • History of intra-abdominal abscess within the past 6 months
  • Known or confirmed history of pneumonitis
  • Current signs and/or symptoms of bowel obstruction or signs and/or symptoms of bowel obstruction within 3 months prior to starting study drugs
  • 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 6 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 > Corrected QT (QTc) > 470 msec or family history of long QT syndrome
  • A major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to starting cediranib
  • 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
  • Receiving any medications or substances that are strong inhibitors or inducers of CYP3A4 or moderate inhibitors of CYP3A4
  • Pregnant or breastfeeding
  • HIV-positive patients on combination antiretroviral therapy
  • Current use of a prohibited medication as outlined in the study documentation
  • Evidence of coagulopathy or bleeding diathesis; therapeutic anticoagulation for prior thromboembolic events is permitted
  • Invasive procedures defined as follows: Anticipation of need for major surgical procedures during the course of the study. Core biopsy within 7 days prior to day 1 (D1) therapy