VAMANA: A phase 2 study of low-dose bevacizumab plus CCNU in relapsed/recurrent glioblastoma.

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LBA2064 Background: There are limited systemic therapy options for recurrent glioblastomas (rGBM). CCNU and/or Bevacizumab are often used to treat rGBM not amenable to local therapy. The addition of Bevacizumab (10 mg/kg) to CCNU failed to improve overall survival in the EORTC 26101 study. The question is whether the failure was due to the high dose of Bevacizumab used in the study. High doses of Bevacizumab may lead to excessive pruning & destruction of blood vessels, hampering the delivery of CCNU. In vitro & in vivo studies showed that a lower dose of Bevacizumab (1-1.5 mg/kg) has the potential to normalize tumor vasculature leading to improved drug delivery & outcomes. To test this hypothesis, we conducted this study to evaluate the efficacy of low-dose Bevacizumab in combination with CCNU in rGBM. Methods: This was a phase 2 open-label, single-arm trial that included adults with rGBM with an ECOG PS 0-2 and adequate organ & marrow function. The participants received CCNU 110 mg/m2 PO once a day, on day 1 of a 42-day cycle (max. 8 cycles) with Bevacizumab 1.5 mg/kg intravenously every 3 weeks (max.16 cycles). Appropriate anti-emetic prophylaxis was given. Treatment continued until disease progression, clinical deterioration, or development of intolerable side effects. Response assessment was done with MRI Brain +/- spine at 2 monthly intervals till disease progression. The modified RANO criteria were used for response assessment. Safety assessments were done on day 8 of cycle 1, & days 21 & 42 of each cycle. The primary end-point of this study was overall survival (OS) and secondary end-points were progression-free survival (PFS) & safety. A 6-month OS ≥ 40% was the signal to explore this regimen further and if the 6-month OS <20% it would be considered futile. Descriptive statistics were performed and the Kaplan-Meier method was used for time-to-event analysis. Results: Forty-six patients were enrolled in this study. The median age was 42 years (IQR 33-52.75) and 78.3% (36/46) were males. Most patients (76.1%, 35/46) had an ECOG PS of 1. The median follow-up duration was 15.27 months (95% CI 13.47-17.06). The median number of doses of Bevacizumab and CCNU were 4 and 2 respectively. Three (6.5%) patients completed all planned doses of Bevacizumab and CCNU. The objective response rate (ORR) was 15.2 % (7/46). The median OS was 6.133 months (95% CI 5.474-6.793). The 6-month OS was 57.1%. The median PFS was 3.267 months (95% CI 0.850-5.684). The most frequent grade 3 or higher toxicities seen were neutropenia (7/46, 15.2%), thrombocytopenia (5/46,10.8%), elevated ALT levels (3/46, 6.5%), anemia (2/46, 4.3%) and hyponatremia (2/46, 4.3%). Conclusions: This study demonstrates the efficacy of low-dose Bevacizumab in combination with CCNU in rGBM (the median OS exceeded the preplanned cut-off of 40%) with an acceptable toxicity profile and no new safety signals. This combination should be explored further in a phase III randomized study. Clinical trial information: CTRI/2020/07/026696 .