Phase I/randomized phase II study of afatinib, an irreversible ErbB family blocker, with or without protracted temozolomide in adults with recurrent glioblastoma

on behalf of the BI 1200.36 Trial Group, the Canadian Brain Tumour Consortium

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Background. This phase I/II trial evaluated the maximum tolerated dose (MTD) and pharmacokinetics of afatinib plus temozolomide as well as the efficacy and safety of afatinib as monotherapy (A) or with temozolomide (AT) vs temozolomide monotherapy (T) in patients with recurrent glioblastoma (GBM). Methods. Phase I followed a traditional 3 + 3 dose-escalation design to determine MTD. Treatment cohorts were: afatinib 20, 40, and 50 mg/day (plus temozolomide 75 mg/m2/day for 21 days per 28-day cycle). In phase II, participants were randomized (stratified by age and KPS) to receive A, T or AT; A was dosed at 40 mg/day and T at 75 mg/m2for 21 of 28 days. Primary endpoint was progression-free survival rate at 6 months (PFS-6). Participants were treated until intolerable adverse events (AEs) or disease progression. Results. Recommended phase II dose was 40 mg/day (A) + T based on safety data from phase I (n = 32). Most frequent AEs in phase II (n = 119) were diarrhea (71% [A], 82% [AT]) and rash (71% [A] and 69% [AT]). Afatinib and temozolomide pharmacokinetics were unaffected by coadministration. Independently assessed PFS-6 rate was 3% (A), 10% (AT), and 23% (T). Median PFS was longer in afatinib-treated participants with epidermal growth factor receptor (EFGR) vIII-positive tumors versus EGFRvIII-negative tumors. Best overall response included partial response in 1 (A), 2 (AT), and 4 (T) participants and stable disease in 14 (A), 14 (AT), and 21 (T) participants. Conclusions. Afatinib has a manageable safety profile but limited single-agent activity in unselected recurrent GBM patients.

Original languageEnglish (US)
Pages (from-to)430-439
Number of pages10
JournalNeuro-oncology
Volume17
Issue number3
DOIs
StatePublished - Jan 1 2015

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temozolomide
Glioblastoma
Maximum Tolerated Dose
Safety
Dihydrotachysterol
Pharmacokinetics
Exanthema
Epidermal Growth Factor Receptor
Disease-Free Survival
Disease Progression
BIBW 2992
Diarrhea
Neoplasms
Survival Rate

All Science Journal Classification (ASJC) codes

  • Oncology
  • Clinical Neurology
  • Cancer Research

Cite this

Phase I/randomized phase II study of afatinib, an irreversible ErbB family blocker, with or without protracted temozolomide in adults with recurrent glioblastoma. / on behalf of the BI 1200.36 Trial Group; the Canadian Brain Tumour Consortium.

In: Neuro-oncology, Vol. 17, No. 3, 01.01.2015, p. 430-439.

Research output: Contribution to journalArticle

on behalf of the BI 1200.36 Trial Group ; the Canadian Brain Tumour Consortium. / Phase I/randomized phase II study of afatinib, an irreversible ErbB family blocker, with or without protracted temozolomide in adults with recurrent glioblastoma. In: Neuro-oncology. 2015 ; Vol. 17, No. 3. pp. 430-439.
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title = "Phase I/randomized phase II study of afatinib, an irreversible ErbB family blocker, with or without protracted temozolomide in adults with recurrent glioblastoma",
abstract = "Background. This phase I/II trial evaluated the maximum tolerated dose (MTD) and pharmacokinetics of afatinib plus temozolomide as well as the efficacy and safety of afatinib as monotherapy (A) or with temozolomide (AT) vs temozolomide monotherapy (T) in patients with recurrent glioblastoma (GBM). Methods. Phase I followed a traditional 3 + 3 dose-escalation design to determine MTD. Treatment cohorts were: afatinib 20, 40, and 50 mg/day (plus temozolomide 75 mg/m2/day for 21 days per 28-day cycle). In phase II, participants were randomized (stratified by age and KPS) to receive A, T or AT; A was dosed at 40 mg/day and T at 75 mg/m2for 21 of 28 days. Primary endpoint was progression-free survival rate at 6 months (PFS-6). Participants were treated until intolerable adverse events (AEs) or disease progression. Results. Recommended phase II dose was 40 mg/day (A) + T based on safety data from phase I (n = 32). Most frequent AEs in phase II (n = 119) were diarrhea (71{\%} [A], 82{\%} [AT]) and rash (71{\%} [A] and 69{\%} [AT]). Afatinib and temozolomide pharmacokinetics were unaffected by coadministration. Independently assessed PFS-6 rate was 3{\%} (A), 10{\%} (AT), and 23{\%} (T). Median PFS was longer in afatinib-treated participants with epidermal growth factor receptor (EFGR) vIII-positive tumors versus EGFRvIII-negative tumors. Best overall response included partial response in 1 (A), 2 (AT), and 4 (T) participants and stable disease in 14 (A), 14 (AT), and 21 (T) participants. Conclusions. Afatinib has a manageable safety profile but limited single-agent activity in unselected recurrent GBM patients.",
author = "{on behalf of the BI 1200.36 Trial Group} and {the Canadian Brain Tumour Consortium} and Reardon, {David A.} and Nabors, {Louis B.} and Mason, {Warren P.} and Perry, {James R.} and William Shapiro and Petr Kavan and David Mathieu and Surasak Phuphanich and Agnieszka Cseh and Yali Fu and Julie Cong and Sven Wind and Eisenstat, {David D.} and Patrick Wen and Tom Mikkelson and Jana Portnow and Pierre Giglio and Rose Lai and Pamela New and Karen Fink and Sajeel Chowdhary and Michael Madison and Lynn Taylor and Lattimore Michael and Yolanda Madarnas and Jacob Easaw and Isabelle Valli{\`e}res and Hal Hirte and Pierre Whitlock and MacNeil, {Mary V.}",
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T1 - Phase I/randomized phase II study of afatinib, an irreversible ErbB family blocker, with or without protracted temozolomide in adults with recurrent glioblastoma

AU - on behalf of the BI 1200.36 Trial Group

AU - the Canadian Brain Tumour Consortium

AU - Reardon, David A.

AU - Nabors, Louis B.

AU - Mason, Warren P.

AU - Perry, James R.

AU - Shapiro, William

AU - Kavan, Petr

AU - Mathieu, David

AU - Phuphanich, Surasak

AU - Cseh, Agnieszka

AU - Fu, Yali

AU - Cong, Julie

AU - Wind, Sven

AU - Eisenstat, David D.

AU - Wen, Patrick

AU - Mikkelson, Tom

AU - Portnow, Jana

AU - Giglio, Pierre

AU - Lai, Rose

AU - New, Pamela

AU - Fink, Karen

AU - Chowdhary, Sajeel

AU - Madison, Michael

AU - Taylor, Lynn

AU - Michael, Lattimore

AU - Madarnas, Yolanda

AU - Easaw, Jacob

AU - Vallières, Isabelle

AU - Hirte, Hal

AU - Whitlock, Pierre

AU - MacNeil, Mary V.

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Background. This phase I/II trial evaluated the maximum tolerated dose (MTD) and pharmacokinetics of afatinib plus temozolomide as well as the efficacy and safety of afatinib as monotherapy (A) or with temozolomide (AT) vs temozolomide monotherapy (T) in patients with recurrent glioblastoma (GBM). Methods. Phase I followed a traditional 3 + 3 dose-escalation design to determine MTD. Treatment cohorts were: afatinib 20, 40, and 50 mg/day (plus temozolomide 75 mg/m2/day for 21 days per 28-day cycle). In phase II, participants were randomized (stratified by age and KPS) to receive A, T or AT; A was dosed at 40 mg/day and T at 75 mg/m2for 21 of 28 days. Primary endpoint was progression-free survival rate at 6 months (PFS-6). Participants were treated until intolerable adverse events (AEs) or disease progression. Results. Recommended phase II dose was 40 mg/day (A) + T based on safety data from phase I (n = 32). Most frequent AEs in phase II (n = 119) were diarrhea (71% [A], 82% [AT]) and rash (71% [A] and 69% [AT]). Afatinib and temozolomide pharmacokinetics were unaffected by coadministration. Independently assessed PFS-6 rate was 3% (A), 10% (AT), and 23% (T). Median PFS was longer in afatinib-treated participants with epidermal growth factor receptor (EFGR) vIII-positive tumors versus EGFRvIII-negative tumors. Best overall response included partial response in 1 (A), 2 (AT), and 4 (T) participants and stable disease in 14 (A), 14 (AT), and 21 (T) participants. Conclusions. Afatinib has a manageable safety profile but limited single-agent activity in unselected recurrent GBM patients.

AB - Background. This phase I/II trial evaluated the maximum tolerated dose (MTD) and pharmacokinetics of afatinib plus temozolomide as well as the efficacy and safety of afatinib as monotherapy (A) or with temozolomide (AT) vs temozolomide monotherapy (T) in patients with recurrent glioblastoma (GBM). Methods. Phase I followed a traditional 3 + 3 dose-escalation design to determine MTD. Treatment cohorts were: afatinib 20, 40, and 50 mg/day (plus temozolomide 75 mg/m2/day for 21 days per 28-day cycle). In phase II, participants were randomized (stratified by age and KPS) to receive A, T or AT; A was dosed at 40 mg/day and T at 75 mg/m2for 21 of 28 days. Primary endpoint was progression-free survival rate at 6 months (PFS-6). Participants were treated until intolerable adverse events (AEs) or disease progression. Results. Recommended phase II dose was 40 mg/day (A) + T based on safety data from phase I (n = 32). Most frequent AEs in phase II (n = 119) were diarrhea (71% [A], 82% [AT]) and rash (71% [A] and 69% [AT]). Afatinib and temozolomide pharmacokinetics were unaffected by coadministration. Independently assessed PFS-6 rate was 3% (A), 10% (AT), and 23% (T). Median PFS was longer in afatinib-treated participants with epidermal growth factor receptor (EFGR) vIII-positive tumors versus EGFRvIII-negative tumors. Best overall response included partial response in 1 (A), 2 (AT), and 4 (T) participants and stable disease in 14 (A), 14 (AT), and 21 (T) participants. Conclusions. Afatinib has a manageable safety profile but limited single-agent activity in unselected recurrent GBM patients.

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U2 - 10.1093/neuonc/nou160

DO - 10.1093/neuonc/nou160

M3 - Article

VL - 17

SP - 430

EP - 439

JO - Neuro-Oncology

JF - Neuro-Oncology

SN - 1522-8517

IS - 3

ER -