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)

Kurt Jaeckle, S. K. Anderson, Erin L. Twohy, Jesse G. Dixon, Caterina Giannini, Robert Jenkins, Merrill J. Egorin, Jann N. Sarkaria, Paul D. Brown, P. J. Flynn, John Schwerkoske, Jan C. Buckner, Evanthia Galanis

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)573-581
Number of pages9
JournalJournal of Neuro-Oncology
Volume143
Issue number3
DOIs
StatePublished - Jul 1 2019

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Oligodendroglioma
Astrocytoma
Neoplasms
Therapeutics
Anticonvulsants
Hypophosphatemia
Survival
Maximum Tolerated Dose
Imatinib Mesylate
Disease-Free Survival
Fatigue
Pharmacokinetics
Hemorrhage
Drug Therapy
Enzymes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Neurology
  • Clinical Neurology
  • Cancer Research

Cite this

Jaeckle, Kurt ; Anderson, S. K. ; Twohy, Erin L. ; Dixon, Jesse G. ; Giannini, Caterina ; Jenkins, Robert ; Egorin, Merrill J. ; Sarkaria, Jann N. ; Brown, Paul D. ; Flynn, P. J. ; Schwerkoske, John ; Buckner, Jan C. ; Galanis, Evanthia. / 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). In: Journal of Neuro-Oncology. 2019 ; Vol. 143, No. 3. pp. 573-581.
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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.",
author = "Kurt Jaeckle and Anderson, {S. K.} and Twohy, {Erin L.} and Dixon, {Jesse G.} and Caterina Giannini and Robert Jenkins and Egorin, {Merrill J.} and Sarkaria, {Jann N.} and Brown, {Paul D.} and Flynn, {P. J.} and John Schwerkoske and Buckner, {Jan C.} and Evanthia Galanis",
year = "2019",
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Jaeckle, K, Anderson, SK, Twohy, EL, Dixon, JG, Giannini, C, Jenkins, R, Egorin, MJ, Sarkaria, JN, Brown, PD, Flynn, PJ, Schwerkoske, J, Buckner, JC & Galanis, E 2019, '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)', Journal of Neuro-Oncology, vol. 143, no. 3, pp. 573-581. https://doi.org/10.1007/s11060-019-03194-z

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). / Jaeckle, Kurt; Anderson, S. K.; Twohy, Erin L.; Dixon, Jesse G.; Giannini, Caterina; Jenkins, Robert; Egorin, Merrill J.; Sarkaria, Jann N.; Brown, Paul D.; Flynn, P. J.; Schwerkoske, John; Buckner, Jan C.; Galanis, Evanthia.

In: Journal of Neuro-Oncology, Vol. 143, No. 3, 01.07.2019, p. 573-581.

Research output: Contribution to journalArticle

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T1 - 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)

AU - Jaeckle, Kurt

AU - Anderson, S. K.

AU - Twohy, Erin L.

AU - Dixon, Jesse G.

AU - Giannini, Caterina

AU - Jenkins, Robert

AU - Egorin, Merrill J.

AU - Sarkaria, Jann N.

AU - Brown, Paul D.

AU - Flynn, P. J.

AU - Schwerkoske, John

AU - Buckner, Jan C.

AU - Galanis, Evanthia

PY - 2019/7/1

Y1 - 2019/7/1

N2 - 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.

AB - 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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