Dataset Information

Marizomib alone or in combination with bevacizumab in patients with recurrent glioblastoma: Phase I/II clinical trial data.

ABSTRACT:

Background

This phase I/II trial in patients with recurrent glioblastoma (GBM) evaluates the safety and preliminary efficacy of marizomib, an irreversible pan-proteasome inhibitor that crosses the blood-brain barrier.

Methods

Part A assessed the safety and efficacy of marizomib monotherapy. In Part B, escalating doses of marizomib (0.5-0.8 mg/m²) in combination with bevacizumab were evaluated. Part C explored intra-patient dose escalation of marizomib (0.8-1.0 mg/m²) for the combination.

Results

In Part A, 30 patients received marizomib monotherapy. The most common AEs were fatigue (66.7%), headache (46.7%), hallucination (43.3%), and insomnia (43.3%). One patient (3.3%) achieved a partial response. In Part B, the recommended phase II dose of marizomib was 0.8 mg/m² when combined with bevacizumab 10 mg/kg. In Part C, dose escalation to 1.0 mg/m² was not tolerated. Pooled analysis of 67 patients treated with marizomib ≤0.8 mg/m² and bevacizumab showed a nonoverlapping safety profile consistent with the known safety profile of each agent: the most common grade ≥3 AEs were hypertension (16.4%), confusion (13.4%), headache (10.4%), and fatigue (10.4%). The overall response rate was 34.3%, including 2 patients with complete response. Six-month progression-free survival was 29.8%; median overall survival was 9.1 months.

Conclusions

The safety profile of marizomib as monotherapy and in combination with bevacizumab was consistent with previous observations that marizomib crosses the blood-brain barrier. Preliminary efficacy did not demonstrate a meaningful benefit of the addition of marizomib to bevacizumab for the treatment of recurrent GBM.

SUBMITTER: Bota DA

PROVIDER: S-EPMC8557653 | biostudies-literature | 2021 Jan-Dec

REPOSITORIES: biostudies-literature

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Publications

Marizomib alone or in combination with bevacizumab in patients with recurrent glioblastoma: Phase I/II clinical trial data.

Bota Daniela A DA Mason Warren W Kesari Santosh S Magge Rajiv R Winograd Benjamin B Elias Ileana I Reich Steven D SD Levin Nancy N Trikha Mohit M Desjardins Annick A

Neuro-oncology advances 20210101 1

<h4>Background</h4>This phase I/II trial in patients with recurrent glioblastoma (GBM) evaluates the safety and preliminary efficacy of marizomib, an irreversible pan-proteasome inhibitor that crosses the blood-brain barrier.<h4>Methods</h4>Part A assessed the safety and efficacy of marizomib monotherapy. In Part B, escalating doses of marizomib (0.5-0.8 mg/m<sup>2</sup>) in combination with bevacizumab were evaluated. Part C explored intra-patient dose escalation of marizomib (0.8-1.0 mg/m<sup> ...[more]

PMID: 34729484

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Project description:BackgroundBevacizumab has promising activity against recurrent glioblastoma (GBM). However, acquired resistance to this agent results in tumor recurrence. We hypothesized that vorinostat, a histone deacetylase (HDAC) inhibitor with anti-angiogenic effects, would prevent acquired resistance to bevacizumab.MethodsThis multicenter phase II trial used a Bayesian adaptive design to randomize patients with recurrent GBM to bevacizumab alone or bevacizumab plus vorinostat with the primary endpoint of progression-free survival (PFS) and secondary endpoints of overall survival (OS) and clinical outcomes assessment (MD Anderson Symptom Inventory Brain Tumor module [MDASI-BT]). Eligible patients were adults (≥18 y) with histologically confirmed GBM recurrent after prior radiation therapy, with adequate organ function, KPS ≥60, and no prior bevacizumab or HDAC inhibitors.ResultsNinety patients (bevacizumab + vorinostat: 49, bevacizumab: 41) were enrolled, of whom 74 were evaluable for PFS (bevacizumab + vorinostat: 44, bevacizumab: 30). Median PFS (3.7 vs 3.9 mo, P = 0.94, hazard ratio [HR] 0.63 [95% CI: 0.38, 1.06, P = 0.08]), median OS (7.8 vs 9.3 mo, P = 0.64, HR 0.93 [95% CI: 0.5, 1.6, P = 0.79]) and clinical benefit were similar between the 2 arms. Toxicity (grade ≥3) in 85 evaluable patients included hypertension (n = 37), neurological changes (n = 2), anorexia (n = 2), infections (n = 9), wound dehiscence (n = 2), deep vein thrombosis/pulmonary embolism (n = 2), and colonic perforation (n = 1).ConclusionsBevacizumab combined with vorinostat did not yield improvement in PFS or OS or clinical benefit compared with bevacizumab alone or a clinical benefit in adults with recurrent GBM. This trial is the first to test a Bayesian adaptive design with adaptive randomization and Bayesian continuous monitoring in patients with primary brain tumor and demonstrates the feasibility of using complex Bayesian adaptive design in a multicenter setting.

Dataset Information

Marizomib alone or in combination with bevacizumab in patients with recurrent glioblastoma: Phase I/II clinical trial data.

Background

Methods

Results

Conclusions

Publications

Marizomib alone or in combination with bevacizumab in patients with recurrent glioblastoma: Phase I/II clinical trial data.

Similar Datasets

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