Efficacy and safety results of ABT-414 in combination with radiation and temozolomide in newly diagnosed glioblastoma

David A. Reardon, Andrew B. Lassman, Martin Van Den Bent, Priya Kumthekar, Ryan Merrell, Andrew M. Scott, Lisa Fichtel, Erik P. Sulman, Erica Gomez, Judee Fischer, Ho Jin Lee, Wijith Munasinghe, Hao Xiong, Helen Mandich, Lisa Roberts-Rapp, Peter Ansell, Kyle D. Holen, Hui K Gan

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Abstract

Background. The purpose of this study was to determine the maximum tolerated dose (MTD), recommended phase II dose (RPTD), safety, and pharmacokinetics of ABT-414 plus radiation and temozolomide in newly diagnosed glioblastoma. ABT-414 is a first-in-class, tumor-specific antibody-drug conjugate that preferentially targets tumors expressing overactive epidermal growth factor receptor (EGFR). Methods. In this multicenter phase I study, patients received 0.5-3.2 mg/kg ABT-414 every 2 weeks by intravenous infusion. EGFR alterations, O 6 -methylguanine-DNA methyltransferase (MGMT) promoter hypermethylation, and isocitrate dehydrogenase (IDH1) gene mutations were assessed in patient tumors. Distinct prognostic classes were assigned to patients based on a Molecular Classification Predictor model. Results. As of January 7, 2016, forty-five patients were enrolled to receive ABT-414 plus radiation and temozolomide. The most common treatment emergent adverse events were ocular: blurred vision, dry eye, keratitis, photophobia, and eye pain. Ocular toxicity at any grade occurred in 40 patients and at grades 3/4 in 12 patients. RPTD and MTD were set at 2 mg/kg and 2.4 mg/kg, respectively. Among 38 patients with pretreatment tumor tested centrally, 39% harbored EGFR amplification, of which 73% had EGFRvIII mutation. Among patients with available tumor tissue (n = 30), 30% showed MGMT promoter methylation and none had IDH1 mutations. ABT-414 demonstrated an approximately dose proportional pharmacokinetic profile. The median duration of progression-free survival was 6.1 months; median overall survival has not been reached. Conclusion. ABT-414 plus chemoradiation demonstrated an acceptable safety and pharmacokinetic profile in newly diagnosed glioblastoma. Randomized studies are ongoing to determine efficacy in newly diagnosed (NCT02573324) and recurrent glioblastoma (NCT02343406).

Original languageEnglish
Pages (from-to)965-975
Number of pages11
JournalNeuro-Oncology
Volume19
Issue number7
DOIs
Publication statusPublished - 1 Jul 2017
Externally publishedYes

Keywords

  • ABT-414
  • antibody-drug conjugate
  • EGFR
  • glioblastoma
  • phase

Cite this

Reardon, David A. ; Lassman, Andrew B. ; Van Den Bent, Martin ; Kumthekar, Priya ; Merrell, Ryan ; Scott, Andrew M. ; Fichtel, Lisa ; Sulman, Erik P. ; Gomez, Erica ; Fischer, Judee ; Lee, Ho Jin ; Munasinghe, Wijith ; Xiong, Hao ; Mandich, Helen ; Roberts-Rapp, Lisa ; Ansell, Peter ; Holen, Kyle D. ; Gan, Hui K. / Efficacy and safety results of ABT-414 in combination with radiation and temozolomide in newly diagnosed glioblastoma. In: Neuro-Oncology. 2017 ; Vol. 19, No. 7. pp. 965-975.
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title = "Efficacy and safety results of ABT-414 in combination with radiation and temozolomide in newly diagnosed glioblastoma",
abstract = "Background. The purpose of this study was to determine the maximum tolerated dose (MTD), recommended phase II dose (RPTD), safety, and pharmacokinetics of ABT-414 plus radiation and temozolomide in newly diagnosed glioblastoma. ABT-414 is a first-in-class, tumor-specific antibody-drug conjugate that preferentially targets tumors expressing overactive epidermal growth factor receptor (EGFR). Methods. In this multicenter phase I study, patients received 0.5-3.2 mg/kg ABT-414 every 2 weeks by intravenous infusion. EGFR alterations, O 6 -methylguanine-DNA methyltransferase (MGMT) promoter hypermethylation, and isocitrate dehydrogenase (IDH1) gene mutations were assessed in patient tumors. Distinct prognostic classes were assigned to patients based on a Molecular Classification Predictor model. Results. As of January 7, 2016, forty-five patients were enrolled to receive ABT-414 plus radiation and temozolomide. The most common treatment emergent adverse events were ocular: blurred vision, dry eye, keratitis, photophobia, and eye pain. Ocular toxicity at any grade occurred in 40 patients and at grades 3/4 in 12 patients. RPTD and MTD were set at 2 mg/kg and 2.4 mg/kg, respectively. Among 38 patients with pretreatment tumor tested centrally, 39{\%} harbored EGFR amplification, of which 73{\%} had EGFRvIII mutation. Among patients with available tumor tissue (n = 30), 30{\%} showed MGMT promoter methylation and none had IDH1 mutations. ABT-414 demonstrated an approximately dose proportional pharmacokinetic profile. The median duration of progression-free survival was 6.1 months; median overall survival has not been reached. Conclusion. ABT-414 plus chemoradiation demonstrated an acceptable safety and pharmacokinetic profile in newly diagnosed glioblastoma. Randomized studies are ongoing to determine efficacy in newly diagnosed (NCT02573324) and recurrent glioblastoma (NCT02343406).",
keywords = "ABT-414, antibody-drug conjugate, EGFR, glioblastoma, phase",
author = "Reardon, {David A.} and Lassman, {Andrew B.} and {Van Den Bent}, Martin and Priya Kumthekar and Ryan Merrell and Scott, {Andrew M.} and Lisa Fichtel and Sulman, {Erik P.} and Erica Gomez and Judee Fischer and Lee, {Ho Jin} and Wijith Munasinghe and Hao Xiong and Helen Mandich and Lisa Roberts-Rapp and Peter Ansell and Holen, {Kyle D.} and Gan, {Hui K}",
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Reardon, DA, Lassman, AB, Van Den Bent, M, Kumthekar, P, Merrell, R, Scott, AM, Fichtel, L, Sulman, EP, Gomez, E, Fischer, J, Lee, HJ, Munasinghe, W, Xiong, H, Mandich, H, Roberts-Rapp, L, Ansell, P, Holen, KD & Gan, HK 2017, 'Efficacy and safety results of ABT-414 in combination with radiation and temozolomide in newly diagnosed glioblastoma', Neuro-Oncology, vol. 19, no. 7, pp. 965-975. https://doi.org/10.1093/neuonc/now257

Efficacy and safety results of ABT-414 in combination with radiation and temozolomide in newly diagnosed glioblastoma. / Reardon, David A.; Lassman, Andrew B.; Van Den Bent, Martin; Kumthekar, Priya; Merrell, Ryan; Scott, Andrew M.; Fichtel, Lisa; Sulman, Erik P.; Gomez, Erica; Fischer, Judee; Lee, Ho Jin; Munasinghe, Wijith; Xiong, Hao; Mandich, Helen; Roberts-Rapp, Lisa; Ansell, Peter; Holen, Kyle D.; Gan, Hui K.

In: Neuro-Oncology, Vol. 19, No. 7, 01.07.2017, p. 965-975.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Efficacy and safety results of ABT-414 in combination with radiation and temozolomide in newly diagnosed glioblastoma

AU - Reardon, David A.

AU - Lassman, Andrew B.

AU - Van Den Bent, Martin

AU - Kumthekar, Priya

AU - Merrell, Ryan

AU - Scott, Andrew M.

AU - Fichtel, Lisa

AU - Sulman, Erik P.

AU - Gomez, Erica

AU - Fischer, Judee

AU - Lee, Ho Jin

AU - Munasinghe, Wijith

AU - Xiong, Hao

AU - Mandich, Helen

AU - Roberts-Rapp, Lisa

AU - Ansell, Peter

AU - Holen, Kyle D.

AU - Gan, Hui K

PY - 2017/7/1

Y1 - 2017/7/1

N2 - Background. The purpose of this study was to determine the maximum tolerated dose (MTD), recommended phase II dose (RPTD), safety, and pharmacokinetics of ABT-414 plus radiation and temozolomide in newly diagnosed glioblastoma. ABT-414 is a first-in-class, tumor-specific antibody-drug conjugate that preferentially targets tumors expressing overactive epidermal growth factor receptor (EGFR). Methods. In this multicenter phase I study, patients received 0.5-3.2 mg/kg ABT-414 every 2 weeks by intravenous infusion. EGFR alterations, O 6 -methylguanine-DNA methyltransferase (MGMT) promoter hypermethylation, and isocitrate dehydrogenase (IDH1) gene mutations were assessed in patient tumors. Distinct prognostic classes were assigned to patients based on a Molecular Classification Predictor model. Results. As of January 7, 2016, forty-five patients were enrolled to receive ABT-414 plus radiation and temozolomide. The most common treatment emergent adverse events were ocular: blurred vision, dry eye, keratitis, photophobia, and eye pain. Ocular toxicity at any grade occurred in 40 patients and at grades 3/4 in 12 patients. RPTD and MTD were set at 2 mg/kg and 2.4 mg/kg, respectively. Among 38 patients with pretreatment tumor tested centrally, 39% harbored EGFR amplification, of which 73% had EGFRvIII mutation. Among patients with available tumor tissue (n = 30), 30% showed MGMT promoter methylation and none had IDH1 mutations. ABT-414 demonstrated an approximately dose proportional pharmacokinetic profile. The median duration of progression-free survival was 6.1 months; median overall survival has not been reached. Conclusion. ABT-414 plus chemoradiation demonstrated an acceptable safety and pharmacokinetic profile in newly diagnosed glioblastoma. Randomized studies are ongoing to determine efficacy in newly diagnosed (NCT02573324) and recurrent glioblastoma (NCT02343406).

AB - Background. The purpose of this study was to determine the maximum tolerated dose (MTD), recommended phase II dose (RPTD), safety, and pharmacokinetics of ABT-414 plus radiation and temozolomide in newly diagnosed glioblastoma. ABT-414 is a first-in-class, tumor-specific antibody-drug conjugate that preferentially targets tumors expressing overactive epidermal growth factor receptor (EGFR). Methods. In this multicenter phase I study, patients received 0.5-3.2 mg/kg ABT-414 every 2 weeks by intravenous infusion. EGFR alterations, O 6 -methylguanine-DNA methyltransferase (MGMT) promoter hypermethylation, and isocitrate dehydrogenase (IDH1) gene mutations were assessed in patient tumors. Distinct prognostic classes were assigned to patients based on a Molecular Classification Predictor model. Results. As of January 7, 2016, forty-five patients were enrolled to receive ABT-414 plus radiation and temozolomide. The most common treatment emergent adverse events were ocular: blurred vision, dry eye, keratitis, photophobia, and eye pain. Ocular toxicity at any grade occurred in 40 patients and at grades 3/4 in 12 patients. RPTD and MTD were set at 2 mg/kg and 2.4 mg/kg, respectively. Among 38 patients with pretreatment tumor tested centrally, 39% harbored EGFR amplification, of which 73% had EGFRvIII mutation. Among patients with available tumor tissue (n = 30), 30% showed MGMT promoter methylation and none had IDH1 mutations. ABT-414 demonstrated an approximately dose proportional pharmacokinetic profile. The median duration of progression-free survival was 6.1 months; median overall survival has not been reached. Conclusion. ABT-414 plus chemoradiation demonstrated an acceptable safety and pharmacokinetic profile in newly diagnosed glioblastoma. Randomized studies are ongoing to determine efficacy in newly diagnosed (NCT02573324) and recurrent glioblastoma (NCT02343406).

KW - ABT-414

KW - antibody-drug conjugate

KW - EGFR

KW - glioblastoma

KW - phase

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U2 - 10.1093/neuonc/now257

DO - 10.1093/neuonc/now257

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