Olaparib and Temozolomide in Treating Patients With Relapsed Glioblastoma
RATIONALE: Olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Olaparib may help temozolomide kill more tumor cells by making tumor cells more sensitive to the drug.
PURPOSE: This phase I trial is studying the side effects and best dose of olaparib and temozolomide in treating patients with relapsed glioblastoma.
Brain and Central Nervous System Tumors
Genetic: gene expression analysis
Genetic: protein expression analysis
Other: laboratory biomarker analysis
Other: pharmacological study
Procedure: diffusion-weighted magnetic resonance imaging
Procedure: dynamic contrast-enhanced magnetic resonance imaging
Procedure: therapeutic conventional surgery
|Study Design:||Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Cancer Research UK Phase I Trial of Olaparib (AZD2281), an Oral PARP Inhibitor, in Combination With Extended Low-Dose Oral Temozolomide in Patients With Relapsed Glioblastoma|
- Detection of olaparib in tumor tissue using liquid chromatography mass spectrometry (LC-MS) seen in at least 1 out of the 6 patients treated in stage 1 of the study [ Designated as safety issue: No ]
- Maximum-tolerated dose of olaparib in combination with temozolomide (stage 2) [ Designated as safety issue: Yes ]
- Toxicity profile and dose-limiting toxicity as assessed by NCI CTCAE Version 4.02 (stage 2) [ Designated as safety issue: Yes ]
- Measurement of blood-brain barrier (BBB) disruption and permeability biomarkers by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted imaging (DWI) (stage 1 and stage 2 MTD expansion cohort) [ Designated as safety issue: No ]
- Progression-free survival at 6 months post-surgery as assessed by the Response Assessment in Neuro-Oncology Working Group (RANO) criteria from conventional MRI and clinical assessment (stage 2) [ Designated as safety issue: No ]
- Gene copy number analysis of DNA repair genes [ Designated as safety issue: No ]
- Quantification of DNA repair gene expression [ Designated as safety issue: No ]
- Measurement of methylation of the MGMT promoter gene by bisulfite modification of DNA and pyrosequencing [ Designated as safety issue: No ]
- Measurement of microsatellite instability by Multiplex PCR [ Designated as safety issue: No ]
- Measurement of mismatch repair (MMR) gene expression by quantitative real time polymerase chain reaction (QRT-PCR) analysis [ Designated as safety issue: No ]
- Measurement of phosphatase and tensin homolog (PTEN) protein and gene expression [ Designated as safety issue: No ]
- Quantification of global DNA strand breaks in tumour tissue by Immunostaining for γH2AX [ Designated as safety issue: No ]
- Measurement of Rad51 foci and nuclear staining intensity as markers of homologous recombination (HR) repair activity [ Designated as safety issue: No ]
- Plasma levels of olaparib measured by LC-MS [ Designated as safety issue: No ]
- PARP inhibition measured by validated assays [ Designated as safety issue: No ]
|Study Start Date:||July 2011|
|Estimated Primary Completion Date:||September 2016 (Final data collection date for primary outcome measure)|
- To determine whether olaparib crosses the blood-brain barrier (BBB) and achieves tumor penetration in patients with relapsed glioblastoma. (Stage 1)
- To determine the safety and tolerability of the combination of olaparib and temozolomide in patients with relapsed glioblastoma. (Stage 2)
- To assess BBB disruption and BBB permeability in patients with relapsed glioblastoma. (Stage 1 and stage 2 maximum-tolerated dose [MTD] expansion cohort)
- To assess the possible anti-tumor activity of the combination of olaparib and temozolomide in patients with relapsed glioblastoma. (Stage 2)
- To assess biological markers as possible predictors of olaparib efficacy in patients with glioblastoma.
- To optimize techniques for measuring DNA damage responses to PARP inhibition in tumor tissue.
- To determine plasma concentration of olaparib at the time of surgery in patients with glioblastoma.
- To evaluate the PARP inhibition at the time of surgery in peripheral blood mononuclear cells (PBMCs).
OUTLINE: This is a multicenter, dose-escalation study.
- Stage 1: Patients receive fixed-dose oral olaparib twice daily for 3 days prior to resection and then receive a dose of oral olaparib on the morning of the resection. After the surgical resection, patient receive standard of care treatment. Patients undergo dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted imaging (DWI) scans to assess the disruption and permeability of the blood-brain barrier (BBB).
If it is proven that olaparib can cross the BBB and achieve tumor penetration as measured by liquid chromatography mass spectrometry (LC-MS) in at least one out of six patients, then new patients are recruited to stage 2 of the study.
- Stage 2: Patients receive escalating doses of oral olaparib once or twice daily for 3 days prior to resection and then receive a dose of oral olaparib on the morning of the resection. After recovery from surgery, patients receive oral olaparib once or twice daily and oral temozolomide once daily on days 1-42. Treatment repeats every 8 weeks for up to 3 courses in the absence of disease progression or unacceptable toxicity. Patients may receive 3 additional courses of treatment in the absence of disease progression.
Once the maximum tolerated dose (MTD) is established, 10 more patients are treated at the MTD as stage 2 MTD expansion cohort. These patients also undergo DCE-MRI and DWI scans.
All patients undergo blood collection periodically for pharmacokinetic and pharmacodynamic studies.
After completion of study treatment, patients are followed up for 28 days and then monthly until resolution of study drug-related adverse events.
Peer Reviewed and Funded or Endorsed by Cancer Research UK.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01390571
|Bristol Haematology and Oncology Centre||Recruiting|
|Bristol, England, United Kingdom, BS2 8ED|
|Contact: Contact Person 01173423008 Kristen.Hopkins@UHBristol.nhs.uk|
|Principal Investigator: Kristen Hopkins, Dr|
|Cambridge, England, United Kingdom, CB2 0QQ|
|Contact: Contact Person 01223586705 email@example.com|
|Principal Investigator: Sarah Jefferies, Dr|
|Manchester, England, United Kingdom|
|Contact: Contact Person 0161 446 3495 firstname.lastname@example.org|
|Principal Investigator: Catherine McBain, Dr|
|Royal Marsden Hospital||Recruiting|
|Sutton, England, United Kingdom|
|Contact: Contact Person 020 8661 3988 Rhoda.email@example.com|
|Principal Investigator: Rhoda Molife, Dr|
|Beatson West of Scotland Cancer Centre||Recruiting|
|Glasgow, Scotland, United Kingdom|
|Contact: Contact Person 0141 301 7097 firstname.lastname@example.org|
|Principal Investigator: Anthony Chalmers, Prof|
|Queen Elizabeth Hospital||Recruiting|
|Birmingham, United Kingdom, B15 2TH|
|Contact: Contact Person 0121 697 8231 Garth.Cruickshank@uhb.nhs.uk|
|Principal Investigator: Garth Cruikshank, Dr|
|Western General Hospital||Recruiting|
|Edinburgh, United Kingdom, EH4 2XU|
|Contact: Contact Person 0131 537 1052 email@example.com|
|Principal Investigator: Sara Erridge, Dr|
|Principal Investigator:||Anthony Chalmers, Prof||Beatson West of Scotland Cancer Centre|