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A multi-site phase I trial of Veliparib with standard radiation and temozolomide in patients with newly diagnosed glioblastoma multiforme (GBM)

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Abstract

Purpose

A multi-site Phase I trial was conducted to determine the safety, maximum tolerated dose, and pharmacokinetics (PK) of Veliparib, a Poly (ADP-ribose) polymerase [PARP] enzyme inhibitor, when administered with temozolomide (TMZ) alone and then with temozolomide and radiation (RT) in patients with newly diagnosed glioblastoma.

Methods

Given the potential for myelosuppression when a PARP inhibitor is combined with chemotherapy, the first 6 patients accrued were given Veliparib 10 mg bid and TMZ 75 mg/m2/d daily for six weeks. If this was well tolerated, the same doses of Veliparib and TMZ would be tested along with standard radiation with plans to dose escalate the Veliparib in subsequent patient cohorts. Once a maximal tolerated dose was determined, a 78 patient phase II study was planned. Peripheral blood pharmacokinetics were assessed.

Results

Twenty-four patients were enrolled. In the first 6 patients who received 6 weeks of TMZ with Veliparib only one dose limiting toxicity (DLT) occurred. The next 12 patients received 6 weeks of RT + TMZ + veliparib and 4/12 (33%) had dose limiting hematologic toxicities. As a result, Veliparib was reduced by 50% to 10 mg BID every other week, but again 3/3 patients had dose limiting hematologic toxicities. The trial was then terminated. The mean clearance (± SD) CL/F of Veliparib for the initial dose (27.0 ± 9.0 L/h, n = 16) and at steady-state for 10 mg BID (23.5 ± 10.4 L/h, n = 18) were similar. Accumulation for BID dosing was 56% (± 33%).

Conclusions

Although Veliparib 10 mg BID administered with TMZ 75 mg/m2 for six weeks was well tolerated, when this regimen was combined with standard partial brain irradiation it was severely myelosuppressive even when the dose was reduced by 50%. This study again highlights the potential of localized cranial radiotherapy to significantly increase hematologic toxicity of marginally myelosuppressive systemic therapies.

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Funding

This work was supported by Abvie (Abbot Laboratories) and NIH grant UM1 CA 137443 (Adult Brain Tumor Consortium, Principal Investigators: Stuart A. Grossman, Patrick Wen, Burt Nabors).

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Authors and Affiliations

  1. Radiation Oncology and Radiation Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Lawrence Kleinberg, Emerson Lee & Stuart A. Grossman

  2. Neurosurgery, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Lawrence Kleinberg & Xiaobu Ye

  3. Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Xiaobu Ye

  4. Medicine, Harvard medical School, Boston, MA, USA

    Jeff Supko

  5. Neurology, Cleveland Clinic, Cleveland, OH, USA

    Glen H.J. Stevens

  6. Radiation Oncology, Emory University, Atlanta, Georgia

    Hui-Kuo Shu

  7. Jeffries Precision Medicine Center, Henry Ford Health, Detroit, MI, USA

    Tom Mikkelsen

  8. Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Frank Lieberman

  9. Department of Internal Medicine, Section on Hematology and Oncology, Wake Forest School of Medicine, Winston-Salem, NC, USA

    Glenn J. Lesser

  10. Cyberknife, Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, 401 North Broadway, Suite 1440, Baltimore, MD, 21231, USA

    Lawrence Kleinberg

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  1. Lawrence Kleinberg
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Lawrence Kleinberg, Xiaobu Ye, Jeff Supko, Glenn Stevens; Hui-Khu Shu; Tom Mikkelson; Frank Lieberman and Glen Lesser. The first draft of the manuscript was written by Emerson Lee and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Lawrence Kleinberg.

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Financial interests

Dr. Kleinberg reports research support from BMS. Incyte, Novartis, and Novocure as well as honorarium for a study steering committee for Novocure. Dr. Lieberman reports Research funding from Chimerix and Novocure. Dr Grossman, Dr. Stevens, Dr. Mikkelsen, Dr. Ye, Dr. Lesser, and Dr. Supko declare they have no financial interests.

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Kleinberg, L., Ye, X., Supko, J. et al. A multi-site phase I trial of Veliparib with standard radiation and temozolomide in patients with newly diagnosed glioblastoma multiforme (GBM). J Neurooncol 165, 499–507 (2023). https://doi.org/10.1007/s11060-023-04514-0

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