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 A. Jaeckle, S. K. Anderson, Erin L. Twohy, Jesse G. Dixon, Caterina Giannini, Robert Brian Jenkins, Merrill J. Egorin, Jann N Sarkaria, Paul D. Brown, P. J. Flynn, John Schwerkoske, Jan Craig 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

Keywords

  • Alliance
  • imatinib
  • N0272
  • NCCTG
  • Oligodendroglioma
  • PDGF

ASJC Scopus subject areas

  • Oncology
  • Neurology
  • Clinical Neurology
  • Cancer Research

Cite this

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 A.; Anderson, S. K.; Twohy, Erin L.; Dixon, Jesse G.; Giannini, Caterina; Jenkins, Robert Brian; Egorin, Merrill J.; Sarkaria, Jann N; Brown, Paul D.; Flynn, P. J.; Schwerkoske, John; Buckner, Jan Craig; 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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title = "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)",
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.",
keywords = "Alliance, imatinib, N0272, NCCTG, Oligodendroglioma, PDGF",
author = "Jaeckle, {Kurt A.} and Anderson, {S. K.} and Twohy, {Erin L.} and Dixon, {Jesse G.} and Caterina Giannini and Jenkins, {Robert Brian} and Egorin, {Merrill J.} and Sarkaria, {Jann N} and Brown, {Paul D.} and Flynn, {P. J.} and John Schwerkoske and Buckner, {Jan Craig} and Evanthia Galanis",
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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 A.

AU - Anderson, S. K.

AU - Twohy, Erin L.

AU - Dixon, Jesse G.

AU - Giannini, Caterina

AU - Jenkins, Robert Brian

AU - Egorin, Merrill J.

AU - Sarkaria, Jann N

AU - Brown, Paul D.

AU - Flynn, P. J.

AU - Schwerkoske, John

AU - Buckner, Jan Craig

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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KW - imatinib

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KW - NCCTG

KW - Oligodendroglioma

KW - PDGF

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