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NRG oncology RTOG 0625: a randomized phase II trial of bevacizumab with either irinotecan or dose-dense temozolomide in recurrent glioblastoma

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Abstract

Angiogenesis, a hallmark of glioblastoma, can potentially be targeted by inhibiting the VEGF pathway using bevacizumab, a humanized monoclonal antibody against VEGF-A. This study was designed to determine the efficacy and safety of these regimens in the cooperative group setting. Eligibility included age ≥18, recurrent or progressive GBM after standard chemoradiation. Treatment was intravenous bevacizumab 10 mg/kg and either irinotecan (CPT) 125 mg/m2 every 2 weeks or temozolomide (TMZ) 75–100 mg/m2 day 1–21 of 28 day cycle. Accrual goal was 57 eligible patients per arm. Primary endpoint was 6 month progression-free survival (6-m PFS); a predetermined rate of ≥35 % to declare efficacy. 60 eligible patients were enrolled on TMZ arm and 57 patients on CPT arm. Median age was 56, median KPS was 80. For TMZ arm, the 6-m-PFS rate was 39 % (23/59); for the CPT arm, the 6-m-PFS rate was 38.6 % (22/57). Objective responses: TMZ arm had 2 (3 %) CR, 9 (16 %) PR; CPT arm had 2 (4 %) CR, 13 (24 %) PR. Overall there was moderate toxicity: TMZ arm with 33 (55 %) grade 3, 11 (18 %) grade 4, and 1 (2 %) grade 5 (fatal) toxicities; CPT arm had 22 (39 %) grade 3, 7 (12 %) grade 4, and 3 (5 %) grade 5 toxicities. The 6-m-PFS surpassed the predetermined efficacy threshold for both arms, corroborating the efficacy of bevacizumab and CPT and confirming activity for bevacizumab and protracted TMZ for recurrent/progressive GBM, even after prior temozolomide exposure. Toxicities were within anticipated frequencies with a moderately high rate of venous thrombosis, moderate hypertension and one intracranial hemorrhage.

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Acknowledgments

We would like to thank the NRG Oncology RTOG staff including Minhee Won, Kathryn Okrent, Sandrine Geinoz, Barbara Kaiser, and Denise Manfredi for their outstanding work on this clinical trial.

Funding

This project was supported by grants U10CA21661, U10CA180868, U10CA180822, U10CA37422, and U24CA180803 from the National Cancer Institute (NCI).

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Authors and Affiliations

  1. Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bloch Bldg. 82, Rm. 235, 9030 Old George town Road, Bethesda, MD, 20892, USA

    Mark R. Gilbert

  2. NRG Oncology Statistics and Data Management Center, Philadelphia, PA, USA

    Stephanie L. Pugh

  3. University of Toronto, Toronto, Canada

    Ken Aldape

  4. Massachusetts General Hospital, Boston, MA, USA

    A. Gregory Sorensen

  5. Department of Neurology, Henry Ford Hospital, Detroit, MI, USA

    Tom Mikkelsen

  6. University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Marta Penas-Prado

  7. Tel-Aviv Medical Center, Tel-Aviv, Israel

    Felix Bokstein

  8. University of Maryland, Baltimore, MD, USA

    Young Kwok & Minesh Mehta

  9. Intermountain Medical Center, Murray, UT, USA

    R. Jeffrey Lee

Authors
  1. Mark R. Gilbert
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  2. Stephanie L. Pugh
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  3. Ken Aldape
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  4. A. Gregory Sorensen
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  5. Tom Mikkelsen
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  6. Marta Penas-Prado
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  7. Felix Bokstein
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  8. Young Kwok
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  9. R. Jeffrey Lee
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  10. Minesh Mehta
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Corresponding author

Correspondence to Mark R. Gilbert.

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Conflict of interest

Dr. Gilbert reports personal fees and non-financial support from Merck, personal fees from Genentech Roche, personal fees from Abbvie, personal fees from Wellcome Trust, and personal fees from Foundation Medicine, outside the submitted work. Dr. Sorensen reports employment by Siemens Healthcare, outside the submitted work. Dr. Mikkelsen has a consulting or advisory role with Roche Genentech and has received honoraria, travel and research funding from Roche Genentech, outside the submitted work. Dr. Penas-Prado has received research funding from Bayer, Genentech, Glaxo, and Novartis, outside the submitted work. Dr. Mehta has a leadership role with Pharmacyclics, stock or ownership interest in Pharmacyclics, consulting or advisory roles with Cavion, Elekta, Novartis and Novocure, and has received research funding from Novocure and Novellos, outside the submitted work.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Gilbert, M.R., Pugh, S.L., Aldape, K. et al. NRG oncology RTOG 0625: a randomized phase II trial of bevacizumab with either irinotecan or dose-dense temozolomide in recurrent glioblastoma. J Neurooncol 131, 193–199 (2017). https://doi.org/10.1007/s11060-016-2288-5

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  • DOI: https://doi.org/10.1007/s11060-016-2288-5

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