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Phase I-II trial of imatinib mesylate (Gleevec; STI571) in treatment of recurrent oligodendroglioma and mixed oligoastrocytoma. North central cancer treatment group study N0272 (ALLIANCE/NCCTG)

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A Correction to this article was published on 05 June 2019

This article has been updated

Abstract

Purpose

To evaluate the pharmacokinetics and efficacy of imatinib in patients with recurrent oligodendroglial tumors.

Methods

Patients with progressive WHO grade II-III recurrent tumors after prior RT and chemotherapy were eligible. A phase I dose-escalation study was conducted for patients on enzyme-inducing anticonvulsants (EIAC). A phase II study for non-EIAC patients utilized a fixed dose of 600 mg/D. Primary efficacy endpoint was 6-month progression-free survival (PFS6). A 2-stage design was utilized, with 90% power to detect PFS6 increase from 25 to 45%.

Results

In the Phase I, maximum tolerated dose was not reached at 1200 mg/D. For phase II patients, overall PFS6 was 33% and median PFS 4.0 months (95% CI 2.1, 5.7). Median overall survival (OS) was longer in imatinib-treated patients compared with controls (16.6 vs. 8.0 months; HR = 0.64, 95% CI 0.41,1.0, p = 0.049), and longer in patients with 1p/19q-codeleted tumors (19.2 vs. 6.2 months, HR = 0.43, 95% CI 0.21,0.89, p = 0.019). Confirmed response rate was 3.9% (PR = 1; REGR = 1), with stable disease observed in 52.9%. At 600 mg/D, mean steady-state imatinib plasma concentration was 2513 ng/ml (95% CI 1831,3195). Grade 3–4 adverse events (hematologic, fatigue, GI, hypophosphatemia, or hemorrhage) occurred in 61%.

Conclusions

Although adequate plasma levels were achieved, the observed PFS6 of 33% did not reach our pre-defined threshold for success. Although OS was longer in imatinib-treated patients than controls, this finding would require forward validation in a larger cohort. Imatinib might show greater activity in a population enriched for PDGF-dependent pathway activation in tumor tissue.

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Change history

  • 05 June 2019

    The last author's first name was truncated in the initial online publication. The original article has been corrected.

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Acknowledgements

The following institutional networks participated in this study: Cancer Alliance of Nebraska, Omaha, NE, Gamini Soori; Carle Cancer Center NCI Community Oncology Research Program, Urbana, IL, Kendrith Rowland, UG1CA189861; Geisinger Cancer Institute NCI Community Oncology Research Program, Danville, PA, Srilatha Hosur, UG1CA189847; Iowa Oncology Research Assoc.; Mayo Clinic LAPS, Rochester, MN, Steven Alberts, U10CA180790; Metro Minnesota Community Oncology Research Consortium, Saint Louis Park, MN, Daniel Anderson, UG1CA189863; Michigan Cancer Research Consortium NCORP, Ann Arbor, MI, Philip Stella, UG1CA189971; Montana Cancer Consortium NCORP, Billings, MT, Benjamin Marchello, UG1CA189872; Sanford NCI Community Oncology Research Program of the North Central Plains, Sioux Falls, SD, Preston Steen, UG1CA189825; Toledo Community Hospital Oncology Program CCOP, Toledo, OH, Rex Mowat; and Wichita NCI Community Oncology Research Program, Wichita, KS, Shaker Dakhil, UG1CA189808.

Funding

Research was supported by the National Cancer Institute of the National Institutes of Health under Award Numbers U10CA180821, U10CA180882, and U24CA196171 to the Alliance (Alliance for Clinical Trials in Oncology), and U10CA180790, U10CA180844, and UG1CA189863. Content is solely the responsibility of the authors and does not necessarily represent official views of the National Institutes of Health. Supported in part by Novartis Pharmaceuticals, Florham Park, NJ.

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Author notes

  1. Merrill J. Egorin—Deceased

Authors and Affiliations

  1. Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL, 32224, USA

    Kurt A. Jaeckle

  2. Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN, USA

    S. K. Anderson, Erin L. Twohy & Jesse G. Dixon

  3. Mayo Clinic Rochester, Rochester, MN, USA

    Caterina Giannini, Robert Jenkins, Jann N. Sarkaria, Paul D. Brown, Jan C. Buckner & Evanthia Galanis

  4. University of Pittsburgh, Pittsburgh, PA, USA

    Merrill J. Egorin

  5. Minnesota Oncology, Minneapolis, MN, USA

    P. J. Flynn & John Schwerkoske

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  1. Kurt A. Jaeckle
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Correspondence to Kurt A. Jaeckle.

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The following institutional networks participated in this study are listed in Acknowledgement.

The original version of this article has been revised: The last author’s name has been corrected.

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Jaeckle, K.A., Anderson, S.K., Twohy, E.L. et al. Phase I-II trial of imatinib mesylate (Gleevec; STI571) in treatment of recurrent oligodendroglioma and mixed oligoastrocytoma. North central cancer treatment group study N0272 (ALLIANCE/NCCTG). J Neurooncol 143, 573–581 (2019). https://doi.org/10.1007/s11060-019-03194-z

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