NCT01390571

Olaparib and Temozolomide in Treating Patients With Relapsed Glioblastoma

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

• Status: Completed
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 34 (estimated)
• Sponsor: Cancer Research UK · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

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.

Detailed description

OBJECTIVES: Primary * 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) Secondary * 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) Tertiary * 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). Stage 1 is complete and it was proven that olaparib can cross the BBB and achieve tumour penetration in glioblastoma patients. * 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.

Conditions

• Brain and Central Nervous System Tumors

Interventions

Type	Name	Description
DRUG	olaparib
DRUG	temozolomide
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

Timeline

• Start date: 2011-07-01
• Primary completion: 2017-06-20
• Completion: 2017-06-20
• First posted: 2011-07-11
• Last updated: 2018-02-05

Locations

7 sites across 1 country: United Kingdom