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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

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


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%.


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%.


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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  • 05 June 2019

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


  1. Smith JS, Wang XY, Qian J, Hosek SM, Scheithauer BW, Jenkins RB, James CD (2000) Amplification of the platelet-derived growth factor receptor -A (PDGFRA) gene occurs in oligodendrogliomas with Grade IV anaplastic features. J Neuropathol Exp Neurol 59:495–503

    Article  CAS  Google Scholar 

  2. DiRocco F, Carroll RS, Zhang J, Black PM (1998) Platelet-derived growth factor and its receptor expression in human oligodendrogliomas. Neurosurgery 42:341–346

    Article  CAS  Google Scholar 

  3. Ranza E, Mazzini G, Facoetti A, Nano R (2010) In-vitro effects of the tyrosine kinase inhibitor imatinib on glioblastoma cell proliferation. J Neurooncol 96:349–357

    Article  CAS  Google Scholar 

  4. Fleming TR (1982) One-sample multiple testing procedure for phase II clinical trials. Biometrics 38:143–151

    Article  CAS  Google Scholar 

  5. Duffy D, Santner T (1987) Confidence intervals for a binomial parameter based on multistage tests. Biometrics 43:81–93

    Article  Google Scholar 

  6. Clopper C, Pearson ES (1934) The use of confidence or fiducial limits illustrated in the case of the binomial. Biometrika 26:404–413

    Article  Google Scholar 

  7. Altman DG (1991) Practical statistics for medical research. Chapman and Hall, London

    Google Scholar 

  8. Moses LE, Emerson JD, Hosseini H (1984) Analyzing data from ordered categories. New Engl J Med 311:442–448

    Article  CAS  Google Scholar 

  9. Rajkumar SV, Buckner JC, Schomberg PJ, Reid JM, Bagniewski PJ, Ames MM, Cascino TL, Marks PS (1998) Phase I and pharmacokinetic study of preirradiation chemotherapy with BCNU, cisplatin and etoposide and accelerated radiotherapy in patients with high-grade gliomas. Int J Radiat Oncol Biol Phys 42:969–975

    Article  CAS  Google Scholar 

  10. Appollini I, Calzolari F, Barilari M, Terrile M, Daga A, Malatesta P (2012) Antagonistic modulation of gliomagenesis by Pax6 and Olig2 in PDGF-induced oligodendroglioma. Int J Cancer 131:1078–1087

    Article  Google Scholar 

  11. Dai C, Lyustikman Y, Shih A, Hu X, Fuller GN, Rosenblum M, Holland EC (2005) The characteristics of astrocytomas and oligodendrogliomas are caused by two distinct and interchangeable signaling formats. Neoplasia 7:397–406

    Article  CAS  Google Scholar 

  12. Doucette T, Yang Y, Zhang W, Fuller GN, Suki D, Fults DW, Rao G (2011) Bcl-2 promotes malignant progression in a PDGF-B-dependent murine model of oligodendroglioma. Int J Cancer 129:2093–2103

    Article  CAS  Google Scholar 

  13. Hassler MR, Vedadinejad M, Flechl B (2014) Response to imatinib as a function of target kinase expression in recurrent glioblastoma. Springerplus 25:1–9

    Google Scholar 

  14. Sugiura J, Fujiwara Y, Ando M, Kawai A, Ogose A, Ozaki T, Yokoyama R, Hiruma T, Ishii T, Morioka H, Mugishima H (2010) Multicenter phase II trial assessing effectiveness of imatinib mesylate on relapsed or refractory KIT-positive or PDGFR-positive sarcoma. J Orthop Sci 15:654–660

    Article  CAS  Google Scholar 

  15. Shingu T, Fujiwara K, Bogler O, Akiyama Y, Moritake K, Shinojima N, Tamada Y, Yoyoyama T, Kondo S (2009) Inhibition of autophagy at a late stage enhances imatinib-induced cytotoxicity in human malignant glioma cells. Int J Cancer 124:1060–1071

    Article  CAS  Google Scholar 

  16. Johnson JR, Bross P, Cohen M, Rothmann M, Chen G, Zajicek A, Gobburu J, Rahman A, Staten A, Pazdur R (2003) Approval summary: imatinib mesylate capsules for treatment of adult patients with newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase. Clin Cancer Res 9:1972–1979

    CAS  PubMed  Google Scholar 

  17. Peng B, Lloyd P, Schran H (2005) Clinical pharmacokinetics of imatinib. Clin Pharmacokinet 44:879–894

    Article  CAS  Google Scholar 

  18. Czyzewski K, Styczynski J (2009) Imatinib is a substrate for various multidrug resistance proteins. Neoplasma 5:202–207

    Article  Google Scholar 

  19. Razis E, Selviaridis P, Labropoulos S, Norris JL, Zhu MJ, Song DD, Kalebic T, Torrens M, Kalogera-Founzila A, Karkavelas G, Karanastasi S, Fletcher JA, Fountzilas G (2009) Phase II study of neoadjuvant imatinib in glioblastoma: evaluation of clinical and molecular effects of treatment. Clin Cancer Res 15:6258–6566

    Article  CAS  Google Scholar 

  20. Desjardins A, Quinn JA, Vredenburgh JJ, Sathornsumetee S, Friedman AH, Herndon JE, McLendon RE, Provenzale JM, Rich JN, Sampson JH, Gururangan S, Dowell JM, Salvado A, Friedman HS, Reardon DA (2007) Phase II study of imatinib mesylate and hydroxyurea for recurrent grade III gliomas. J Neurooncol 83:53–60

    Article  CAS  Google Scholar 

  21. Reardon DA, Dresemann G, Campone Taillibert S, M, van den Bent M, Clement P, Blomquist E, Gordower L, Schultz H, Raizer J, Hau P, Easaw J, Gil M, Tonn J, Gijtenbeek A, Schlegel U, Bergstrom P, Green S, Weir A, Nikolova Z, (2009) Multicentre phase II studies evaluating imatinib plus hydroxyurea in patients with progressive glioblastoma. Br J Cancer 101:1995–2004

    Article  CAS  Google Scholar 

  22. Wen PY, Yung WK, Norden Lamborn KR, AD, Cloughesy TF, Abrey LE, Fine HA, Chang SM, Robins HI, Fink K, Deangelis LM, Mehta M, Di Tomaso E, Drappatz J, Kesari S, Ligon KL, Aldape K, Jain RK, Stiles CD, Egorin MJ, Prados MD, (2006) Phase I/II study of imatinib mesylate for recurrent malignant gliomas. North American Brain Tumor Consortium Study 99–08. Clin Cancer Res 12:4899–4907

    Article  CAS  Google Scholar 

  23. Reardon DA, Desjardins A, Vredenburgh JJ, Herndon JE, Coan A, Gururangan S, Peters KB, McLendon R, Sathornsumettee S, Rich JN, Lipp ES, Janney D, Friedman HS (2012) Phase II study of Gleevec plus hydroxyurea in adults with progressive or recurrent low-grade glioma. Cancer 118:4759–4767

    Article  CAS  Google Scholar 

  24. Raymond E, Brandes AA, Dittrich C, Fumoleau P, Coudert G, Clement PM, Frenay M, Rampling R, Stupp R, Kros JM, Heinrich MC, Gorlia T, Lacombe D, van den Bent MJ, European Organisation for Research and Treatment of Cancer Brain Tumor Group Study (2008) Phase II study of imatinib in patients with recurrent gliomas of various histologies: a European Organisation for Research and Treatment of Cancer Brain Tumor Group Study. J Clin Oncol 26:4659–4665

    Article  Google Scholar 

  25. Van Obbergh F, Knoops L, Devos T, Beguin Y, Graux C, Benghiat F, Kargar-Samani K, Bauwens D, Efira A, Dubois C, Springael C, Monfort L, Connerotte T, Capron A, Delannoy A, Wallemacq P (2017) The clinical relevance of imatinib trough concentrations in chronic myeloid leukemia. A Belgian Study. Clin Biochem 50:452–454

    PubMed  Google Scholar 

  26. Leis JF, Stepan DE, Curtin PT, Ford JM, Peng B, Schubach S, Druker BJ, Maziarz RT (2004) Central nervous system failure in patients with chronic myelogenous leukemia lymphoid blast crisis and Philadelphia chromosome positive acute lymphoblastic leukemia treated with imatinib (STI-571). Leuk Lymphoma 45:695–698

    Article  CAS  Google Scholar 

  27. Harada K, Kiya K, Matsumura S, Mori S, Uozumi T (1982) Spontaneous intracranial hemorrhage caused by oligodendroglioma—a case report and review of the literature. Neurol Med Chir (Tokyo) 22:81–84

    Article  CAS  Google Scholar 

  28. Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW (2016) The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 131:803–820

    Article  Google Scholar 

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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.


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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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).

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