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A randomized phase II trial of standard dose bevacizumab versus low dose bevacizumab plus lomustine (CCNU) in adults with recurrent glioblastoma

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Abstract

Antiangiogenic therapy can rapidly reduce vascular permeability and cerebral edema but high doses of bevacizumab may induce selective pressure to promote resistance. This trial evaluated the efficacy of low dose bevacizumab in combination with lomustine (CCNU) compared to standard dose bevacizumab in patients with recurrent glioblastoma. Patients (N = 71) with recurrent glioblastoma who previously received radiation and temozolomide were randomly assigned 1:1 to receive bevacizumab monotherapy (10 mg/kg) or low dose bevacizumab (5 mg/kg) in combination with lomustine (90 mg/m2). The primary end point was progression-free survival (PFS) based on a blinded, independent radiographic assessment of post-contrast T1-weighted and non-contrast T2/FLAIR weighted magnetic resonance imaging (MRI) using RANO criteria. For 69 evaluable patients, median PFS was not significantly longer in the low dose bevacizumab + lomustine arm (4.34 months, CI 2.96–8.34) compared to the bevacizumab alone arm (4.11 months, CI 2.69–5.55, p = 0.19). In patients with first recurrence, there was a trend towards longer median PFS time in the low dose bevacizumab + lomustine arm (4.96 months, CI 4.17–13.44) compared to the bevacizumab alone arm (3.22 months CI 2.5–6.01, p = 0.08). The combination of low dose bevacizumab plus lomustine was not superior to standard dose bevacizumab in patients with recurrent glioblastoma. Although the study was not designed to exclusively evaluate patients at first recurrence, a strong trend towards improved PFS was seen in that subgroup for the combination of low dose bevacizumab plus lomustine. Further studies are needed to better identify such subgroups that may most benefit from the combination treatment.

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Funding

National Institutes of Health [1R21CA152024-01] to J. D. National Institutes of Health [CCSG-P30 CA016672] to R. D.

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Author notes

  1. Charles A. Conrad

    Present address: Texas Oncology, 901 W. 38th Street, Austin, TX, 78705, USA

  2. Mark R. Gilbert

    Present address: National Institutes of Health, 9030 Old Georgetown Rd., Bethesda, MD, 20892, USA

  3. Ivo Tremont-Lukats

    Present address: Department of Neurosurgery, Houston Methodist Hospital, 6560 Fannin, Scurlock Suite 900, Houston, TX, 77030, USA

Authors and Affiliations

  1. Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 431, Houston, TX, 77030, USA

    Shiao-Pei Weathers, Charles A. Conrad, Mark R. Gilbert, Monica E. Loghin, Barbara J. O’Brien, Marta Penas-Prado, Vinay K. Puduvalli, Ivo Tremont-Lukats, W. K. Alfred Yung & John F. de Groot

  2. University of Alabama at Birmingham, 1020 Faculty Office Tower, 510 20th Street South, Birmingham, AL, 35294, USA

    Xiaosi Han

  3. Department of Biostatistics, University of MD Anderson Cancer Center, 1400 Pressler St., Houston, TX, 77030, USA

    Diane D. Liu

  4. Department of Neuroradiology, University of Texas MD Anderson Cancer Center, 1400 Pressler St Unit 1482, Houston, TX, 77030, USA

    Rivka R. Colen

  5. M410 Starling Loving Hall, 320 W., 10th Avenue, Columbus, OH, 43210, USA

    Vinay K. Puduvalli

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  1. Shiao-Pei Weathers
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  2. Xiaosi Han
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Corresponding author

Correspondence to Shiao-Pei Weathers.

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Conflict of interest

S. W. serves on the advisory board for Actelion. X. H. has no disclosures. D. L. has no disclosures. C. C. has consultant relationships with Actelion, DNAtrix, Reata Pharma, Newlink Genetics and Cytrx Corp. M. G. has no disclosures. M. L. has no disclosures. B. O. has no disclosures. M. P-P. has no disclosures. V. P. is a consultant for Orbus Therapeutics, Foundation Medicine, Celgene, Genetech, and Merck. I. T-L. has no disclosures. R. C. has no disclosures. W. Y. is a consultant and serves on the advisory board for Actelion, DNATrix, Merck, and Novartis. J. D. serves on the advisory board for Genentech, Inc., Novartis, Celldex Therapeutics, and Foundation Medicine, Inc. J. D. serves on the DSMB for VBL Therapeutics and is a consultant for Celldex Therapeutics, OXiGENE, Omniox, Inc. and Deciphera Pharmaceuticals. J. D. receives research support from Sanofi-Aventis, AstraZeneca, EMD-Serono, Eli Lilly, Novartis, and Deciphera Pharmaceuticals.

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Weathers, SP., Han, X., Liu, D.D. et al. A randomized phase II trial of standard dose bevacizumab versus low dose bevacizumab plus lomustine (CCNU) in adults with recurrent glioblastoma. J Neurooncol 129, 487–494 (2016). https://doi.org/10.1007/s11060-016-2195-9

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  • DOI: https://doi.org/10.1007/s11060-016-2195-9

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