NCT02903069

Study of Marizomib With Temozolomide and Radiotherapy in Patients With Newly Diagnosed Brain Cancer

Phase 1b, Multicenter, Open-Label Study of Marizomib With Temozolomide and Radiotherapy in Patients With Newly Diagnosed WHO Grade IV Malignant Glioma

• Status: Completed
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 66 (actual)
• Sponsor: Celgene · Industry
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

This study is for newly diagnosed WHO Grade IV malignant glioma patients to determine whether an investigational drug known as marizomib (MRZ) will improve the treatment of newly diagnosed glioblastoma patients by delaying the growth of the cancer, reducing the size of the tumor, and/or improving survival. Marizomib (MRZ) is being added to standard-of-care treatments of radiotherapy (RT), temozolomide (TMZ), and Optune.

Detailed description

Gliomas account for \~80% of primary malignant tumors in the Central Nervous System (CNS), with WHO Grade IV malignant glioma (G4 MG; including glioblastoma and gliosarcoma) constituting the majority of gliomas, and are essentially incurable. Currently only surgical resection and radiotherapy (RT) with concomitant and adjuvant temozolomide (TMZ) are standard-of-care treatment strategies for newly diagnosed G4 MG. However, resistance to chemotherapy and RT results in a high recurrence rate, with median survival of \~15-16 months. Since no survival advantage has been demonstrated for the addition of bevacizumab (BEV) to TMZ and RT (Chinot 2014) in newly diagnosed G4 MG, alternative promising investigational agents need to be tested. Targeting the proteasome is a well-validated target for the treatment of multiple myeloma (MM), and preclinical evidence suggests that targeting the proteasome in glioma cells shows significant anti-tumor activity. Proteasome activity is elevated in patient-derived glioblastoma (GBM) tissue in comparison with normal human brain. Importantly, preclinical evidence demonstrates that proteasome inhibition sensitizes GBM cell lines to irradiation and to TMZ. Further, the combination of bortezomib (BTZ, one of three proteasome inhibitors \[PI\] currently approved for the treatment of MM) with TMZ resulted in synergistic glioblastoma cell death in vitro, and BTZ reduces glioma cell survival in vitro in cell lines sensitive and resistant to TMZ. Despite the activity against GBM cells in vitro, BTZ does not cross the blood brain barrier, and thus has proven ineffective in animal models and in the clinic. In contrast, marizomib (MRZ) - a potent and irreversible 20S PI possesses the unique attribute among PIs to cross the blood brain barrier as shown in previous clinical studies. These data prompted examination of the combination of MRZ and BEV in an ongoing clinical trial in patients with recurrent G4 MG. In the dose-escalation portion of this ongoing study (MRZ-108), 12 patients were dosed with MRZ once weekly for 3 weeks (0.55, 0.7, and 0.8 mg/m2 infused intravenously (IV) over 10 minutes) and with BEV on weeks 1 and 3 (10 mg/kg IV) of a 28-day cycle. As of April 2016, of these 12 patients, 7 were on study for over 4 months - 5 with a partial response (including 2 patients with no radiologic evidence of tumor on 2 or more consecutive MRI scans) and 2 patients whose best response was stable disease. Four of these 12 patients were treated for over 6 months, 3 of whom remain on study. The recommended Phase 2 dose (RP2D) of MRZ was determined to be 0.8 mg/m2. Currently, an expansion cohort of 24 patients has been enrolled in the Phase 2 portion of the study. The next phase involves treatment with MRZ alone (no BEV) in patients with recurrent G4 MG, and has begun enrolling patients in the second quarter of 2016. Together, the demonstrated activity of PIs in preclinical glioma models, and the synergistic activity of PIs with TMZ on glioblastoma cells, along with the ability of MRZ to access the CNS, provides compelling rationale to assess the therapeutic benefit of the combination of MRZ with TMZ in patients with G4 MG, for whom no brain-penetrant options for proteasome inhibition are currently available. Very recently, the FDA has approved a novel treatment device using tumor treating fields (Optune) in addition to standard of care RTand TMZ as an option to standard of care. Optune has been shown to significantly improve both progression-free and overall survival in GBM patients. An additional cohort of 12 patients will be treated with Optune in combination with MRZ and TMZ In North America, the Optune arm is offered only for the US trial sites, and is not offered for the Canadian trial sites.

Conditions

• Glioblastoma
• Malignant Glioma

Interventions

Type	Name	Description
DRUG	MRZ	MRZ dose ranges from 0.55 to 1.2 mg/m2 given IV over 10 minutes on Days 1, 8, 15, 29, and 36 during Concomitant Treatment. MRZ dose ranges from 0.55 to 1.2 mg/m2 given IV over 10 minutes on Days 1, 8, 15 every 28 days during Adjuvant Treatment. IV hydration will be given prior to the MRZ infusion.
DRUG	TMZ	TMZ will be administered once daily, 7 days/week, for 6 weeks, starting on Day 1, at a dose of 75 mg/m2 during Concomitant Treatment. TMZ will be administered once daily on Days 1-5 every cycle, dose range 150 to 200 mg/m2 during Adjuvant Treatment.
RADIATION	RT	Focal RT will be administered once daily, 5 days/week, for 30 doses over 6 weeks to a total dose of 60 Gy, starting on Day 1 during Concomitant Treatment.
DEVICE	Optune	Tumor Treating Fields Therapy device to be worn ≥ 18 hours per day.

Timeline

• Start date: 2016-08-17
• Primary completion: 2021-01-25
• Completion: 2021-01-25
• First posted: 2016-09-16
• Last updated: 2021-04-19

Locations

8 sites across 3 countries: United States, Canada, Switzerland