Dataset Information

A Bayesian adaptive randomized phase II multicenter trial of bevacizumab with or without vorinostat in adults with recurrent glioblastoma.

ABSTRACT:

Background

Bevacizumab 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.

Methods

This 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.

Results

Ninety 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).

Conclusions

Bevacizumab 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.

SUBMITTER: Puduvalli VK

PROVIDER: S-EPMC7686463 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Publications

A Bayesian adaptive randomized phase II multicenter trial of bevacizumab with or without vorinostat in adults with recurrent glioblastoma.

Puduvalli Vinay K VK Wu Jing J Yuan Ying Y Armstrong Terri S TS Vera Elizabeth E Wu Jimin J Xu Jihong J Giglio Pierre P Colman Howard H Walbert Tobias T Raizer Jeffrey J Groves Morris D MD Tran David D Iwamoto Fabio F Avgeropoulos Nicholas N Paleologos Nina N Fink Karen K Peereboom David D Chamberlain Marc M Merrell Ryan R Penas Prado Marta M Yung W K Alfred WKA Gilbert Mark R MR

Neuro-oncology 20201001 10

<h4>Background</h4>Bevacizumab 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.<h4>Methods</h4>This multicenter phase II trial used a Bayesian adaptive design to randomize patients with recurrent GBM to bevacizumab alone or bevacizumab plus vorinostat with the pri ...[more]

PMID: 32166308

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Project description:BackgroundGlioblastoma (GBM), the most lethal primary brain tumor, has limited treatment options upon recurrence after chemoradiation and bevacizumab. TRC105 (carotuximab), a chimeric anti-endoglin (CD105) antibody, inhibits angiogenesis and potentiates activity of VEGF inhibitor bevacizumab in preclinical models. This study sought to assess safety, pharmacokinetics, and efficacy of TRC105 for bevacizumab-refractory GBM.MethodsWe conducted a pre-registered (NCT01564914), multicenter, open-label phase II clinical trial (ENDOT). We administered 10 mg/kg TRC105 monotherapy (first cohort) in adults with GBM and radiographic progression following radiation, temozolomide and bevacizumab therapy. Primary outcome was median time-to-progression (TTP), amended after first cohort's enrollment to median overall survival (mOS). Secondary outcomes were objective response rate, safety and tolerability, and progression-free survival (PFS).Results6 patients were enrolled in TRC105 monotherapy cohort. Median TTP and PFS of 5 evaluable patients receiving monotherapy was 1.4 months, in whom plasma VEGF-A levels were elevated post-therapy. Lack of response led to protocol amendment, and second cohort's addition of bevacizumab+TRC105 with primary endpoint of mOS. 16 patients were enrolled in bevacizumab+TRC105 cohort. mOS of 15 evaluable patients was 5.7 (95%CI: 4.2-9.8) months. All 22 patients had measurable disease at baseline. Median PFS of 14 evaluable patients receiving bevacizumab+TRC105 was 1.8 months (95%CI 1.2-2.1). Serum TRC105 was measurable above target concentration of 25 ug/mL in all evaluable patients. Study medications were well-tolerated in both cohorts. Combined administration did not potentiate known toxicities of either medication, with cerebral hemorrhage not observed.ConclusionsSingle-agent TRC105 lacks activity in bevacizumab-refractory GBM, possibly secondary to upregulated VEGF-A expression. Meaningful mOS in bevacizumab+TRC105 cohort warrants further trials to investigate efficacy of combination therapy.

Dataset Information

A Bayesian adaptive randomized phase II multicenter trial of bevacizumab with or without vorinostat in adults with recurrent glioblastoma.

Background

Methods

Results

Conclusions

Publications

A Bayesian adaptive randomized phase II multicenter trial of bevacizumab with or without vorinostat in adults with recurrent glioblastoma.

Similar Datasets

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