Stage 1: Marizomib + Bevacizumab in WHO Gr IV GBM; Stage 2: Marizomib Alone; Stage 3: Combination of Marizomib and Bevacizumab

Official Title

Phase 1, Multicentre, Open-label, Dose-escalation, Combination Study of Marizomib and Bevacizumab in Bevacizumab-Naïve Subjects With WHO Grade IV Malignant Glioma Followed by a Phase 2 Studies of Single Agent Marizomib and Combination Marizomib and Bevacizumab and Phase 1 Dose-Escalation Study of Enterally-administered Marizomib With Bevacizumab

Summary:

This is a Phase 1/2 clinical trial to evaluate a new combination of drugs, marizomib (MRZ) and bevacizumab (BEV; Avastin®), for the treatment of WHO Grade IV malignant glioma. The study population includes subjects who are in first or second relapse and who have not previously received any bevacizumab or other anti-angiogenic agent or proteasome inhibitor for treatment of malignant glioma. Part 1 Phase 1 evaluates the combination of MRZ and BEV, while Part 2 Phase 2 evaluates single-agent MRZ. Part 3 (Phase 2) includes a combination MRZ using intra-patient dose escalation, and BEV at a fixed dose. Part 4 Phase 1 evaluates MRZ through enteral administration, and BEV at a fixed dose.

Trial Description

Primary Outcome:

  • Part 1 (Phase 1): Maximum Tolerated Dose (MTD) / Maximum Administered Dose (MAD)
  • Part 1 (Phase 1): Recommended Phase 2 Dose (RP2D)
  • Part 2 (Phase 2): MRZ single agent tumour activity
  • Part 3 (Phase 2): activity of MRZ + BEV with intra-patient dose escalation
  • Part 4 (Phase 1): Maximum Tolerated Dose (MTD) of enterally administered MRZ
Secondary Outcome:
  • Part 1 (Phase 1): Tumour activity
  • Part 1 (Phase 1): Tumour activity
  • Part 1 (Phase 1): Tumour activity
  • Parts 1, 2, 3 & 4 (Phase 1 and Phase 2): Assess safety and tolerance
  • Part 1 & 4 (Phase 1): MRZ pharmacokinetics
  • PParts 1 & 4 (Phase 1): Proteasome Activity in Packed Whole Blood (PWB) and peripheral blood mononuclear cells (PBMCs)
  • Parts 1, 2 & 3 (Phase 1 and Phase 2): Neurological Coordination Assessment
  • Parts 1, 2 & 3 (Phase 1 and Phase 2): Quality of Life Assessment
One of the few treatment options currently FDA approved for recurrent WHO Grade IV malignant glioma is BEV. Additional treatment options are needed for these subjects. Published literature indicates that targeting the proteasome in glioma cells has shown significant anti-tumour activity. MRZ is a novel, second generation proteasome inhibitor that prevents the breakdown of proteins involved in signal transduction which blocks growth and survival of cancer cells. In-vitro studies of multiple glioma cell lines were highly sensitive to MRZ. MRZ had relatively little effect on neural stem/progenitor cells suggesting minimal neurotoxicity while significantly affecting both malignant glioma stem cells and glioma cell lines. Parts 1 and 2 of this trial have been completed with the Recommended Part 3 (Phase 2) Dose established at 0.8 mg/m2. Part 3 of this trial is enrolling at the MRZ RP2D determined in Phase 1 to assess the combination of MRZ and BEV activity and safety. Parts 1, 2, and 3 of this trial have been completed with the Recommended Dose established at 0.8 mg/m2. Part 4 of this trial is enrolling.

View this trial on ClinicalTrials.gov

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Resources

Canadian Cancer Society

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