Phase 2 trial of dasatinib in target-selected patients with recurrent glioblastoma (RTOG 0627)

Andrew B. Lassman, Stephanie L. Pugh, Mark R. Gilbert, Kenneth D. Aldape, Sandrine Geinoz, Jan H. Beumer, Susan M. Christner, Ritsuko Komaki, Lisa M. Deangelis, Rakesh Gaur, Emad Youssef, Henry Wagner, Minhee Won, Minesh P. Mehta

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

We conducted a phase II trial to evaluate the efficacy of dasatinib, a multitargeted tyrosine kinase inhibitor, for adults with recurrent glioblastoma (GBM). Methods. Eligibility requirements were Karnofsky performance status ≥60%; no concurrent hepatic enzyme-inducing anticonvulsants; prior treatment with surgery, radiotherapy, and temozolomide exclusively; and activation or overexpression of ≥2 putative dasatinib targets in GBM (ie, SRC, c-KIT, EPHA2, and PDGFR). Using a 2-stage design, 77 eligible participants (27 in stage 1, if favorable, and then 50 in stage 2) were needed to detect an absolute improvement in the proportion of patients either alive and progression-free patients at 6 months (6mPFS) or responding (any duration) from a historical 11% to 25%. Results. A high rate of ineligibility (27%) to stage 1 precluded a powered assessment of efficacy, but there was also infrequent treatment-related toxicity at 100 mg twice daily. Therefore, the study was redesigned to allow intrapatient escalation by 50 mg daily every cycle as tolerated (stage 1B) before determining whether to proceed to stage 2. Escalation was tolerable in 10 of 17 (59%) participants evaluable for that endpoint; however, among all eligible patients (stages 1 and 1B, n 50), there were no radiographic responses, median overall survival was 7.9 months, median PFS was 1.7 months, and the 6mPFS rate was 6%. The clinical benefit was insufficient to correlate tested biomarkers with efficacy. The trial was closed without proceeding to stage 2. Conclusions. Intraparticipant dose escalation was feasible, but dasatinib was ineffective in recurrent GBM. Clinical trials.gov identified. NCT00423735 (available at http://clinicaltrials.gov/ct2/show/NCT00423735).

Original languageEnglish (US)
Pages (from-to)992-998
Number of pages7
JournalNeuro-oncology
Volume17
Issue number7
DOIs
StatePublished - Jul 1 2015

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Glioblastoma
temozolomide
Karnofsky Performance Status
Anticonvulsants
Protein-Tyrosine Kinases
Radiotherapy
Biomarkers
Clinical Trials
Survival
Liver
Enzymes
Therapeutics
Dasatinib

All Science Journal Classification (ASJC) codes

  • Oncology
  • Clinical Neurology
  • Cancer Research

Cite this

Lassman, A. B., Pugh, S. L., Gilbert, M. R., Aldape, K. D., Geinoz, S., Beumer, J. H., ... Mehta, M. P. (2015). Phase 2 trial of dasatinib in target-selected patients with recurrent glioblastoma (RTOG 0627). Neuro-oncology, 17(7), 992-998. https://doi.org/10.1093/neuonc/nov011
Lassman, Andrew B. ; Pugh, Stephanie L. ; Gilbert, Mark R. ; Aldape, Kenneth D. ; Geinoz, Sandrine ; Beumer, Jan H. ; Christner, Susan M. ; Komaki, Ritsuko ; Deangelis, Lisa M. ; Gaur, Rakesh ; Youssef, Emad ; Wagner, Henry ; Won, Minhee ; Mehta, Minesh P. / Phase 2 trial of dasatinib in target-selected patients with recurrent glioblastoma (RTOG 0627). In: Neuro-oncology. 2015 ; Vol. 17, No. 7. pp. 992-998.
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abstract = "We conducted a phase II trial to evaluate the efficacy of dasatinib, a multitargeted tyrosine kinase inhibitor, for adults with recurrent glioblastoma (GBM). Methods. Eligibility requirements were Karnofsky performance status ≥60{\%}; no concurrent hepatic enzyme-inducing anticonvulsants; prior treatment with surgery, radiotherapy, and temozolomide exclusively; and activation or overexpression of ≥2 putative dasatinib targets in GBM (ie, SRC, c-KIT, EPHA2, and PDGFR). Using a 2-stage design, 77 eligible participants (27 in stage 1, if favorable, and then 50 in stage 2) were needed to detect an absolute improvement in the proportion of patients either alive and progression-free patients at 6 months (6mPFS) or responding (any duration) from a historical 11{\%} to 25{\%}. Results. A high rate of ineligibility (27{\%}) to stage 1 precluded a powered assessment of efficacy, but there was also infrequent treatment-related toxicity at 100 mg twice daily. Therefore, the study was redesigned to allow intrapatient escalation by 50 mg daily every cycle as tolerated (stage 1B) before determining whether to proceed to stage 2. Escalation was tolerable in 10 of 17 (59{\%}) participants evaluable for that endpoint; however, among all eligible patients (stages 1 and 1B, n 50), there were no radiographic responses, median overall survival was 7.9 months, median PFS was 1.7 months, and the 6mPFS rate was 6{\%}. The clinical benefit was insufficient to correlate tested biomarkers with efficacy. The trial was closed without proceeding to stage 2. Conclusions. Intraparticipant dose escalation was feasible, but dasatinib was ineffective in recurrent GBM. Clinical trials.gov identified. NCT00423735 (available at http://clinicaltrials.gov/ct2/show/NCT00423735).",
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Lassman, AB, Pugh, SL, Gilbert, MR, Aldape, KD, Geinoz, S, Beumer, JH, Christner, SM, Komaki, R, Deangelis, LM, Gaur, R, Youssef, E, Wagner, H, Won, M & Mehta, MP 2015, 'Phase 2 trial of dasatinib in target-selected patients with recurrent glioblastoma (RTOG 0627)', Neuro-oncology, vol. 17, no. 7, pp. 992-998. https://doi.org/10.1093/neuonc/nov011

Phase 2 trial of dasatinib in target-selected patients with recurrent glioblastoma (RTOG 0627). / Lassman, Andrew B.; Pugh, Stephanie L.; Gilbert, Mark R.; Aldape, Kenneth D.; Geinoz, Sandrine; Beumer, Jan H.; Christner, Susan M.; Komaki, Ritsuko; Deangelis, Lisa M.; Gaur, Rakesh; Youssef, Emad; Wagner, Henry; Won, Minhee; Mehta, Minesh P.

In: Neuro-oncology, Vol. 17, No. 7, 01.07.2015, p. 992-998.

Research output: Contribution to journalArticle

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T1 - Phase 2 trial of dasatinib in target-selected patients with recurrent glioblastoma (RTOG 0627)

AU - Lassman, Andrew B.

AU - Pugh, Stephanie L.

AU - Gilbert, Mark R.

AU - Aldape, Kenneth D.

AU - Geinoz, Sandrine

AU - Beumer, Jan H.

AU - Christner, Susan M.

AU - Komaki, Ritsuko

AU - Deangelis, Lisa M.

AU - Gaur, Rakesh

AU - Youssef, Emad

AU - Wagner, Henry

AU - Won, Minhee

AU - Mehta, Minesh P.

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Y1 - 2015/7/1

N2 - We conducted a phase II trial to evaluate the efficacy of dasatinib, a multitargeted tyrosine kinase inhibitor, for adults with recurrent glioblastoma (GBM). Methods. Eligibility requirements were Karnofsky performance status ≥60%; no concurrent hepatic enzyme-inducing anticonvulsants; prior treatment with surgery, radiotherapy, and temozolomide exclusively; and activation or overexpression of ≥2 putative dasatinib targets in GBM (ie, SRC, c-KIT, EPHA2, and PDGFR). Using a 2-stage design, 77 eligible participants (27 in stage 1, if favorable, and then 50 in stage 2) were needed to detect an absolute improvement in the proportion of patients either alive and progression-free patients at 6 months (6mPFS) or responding (any duration) from a historical 11% to 25%. Results. A high rate of ineligibility (27%) to stage 1 precluded a powered assessment of efficacy, but there was also infrequent treatment-related toxicity at 100 mg twice daily. Therefore, the study was redesigned to allow intrapatient escalation by 50 mg daily every cycle as tolerated (stage 1B) before determining whether to proceed to stage 2. Escalation was tolerable in 10 of 17 (59%) participants evaluable for that endpoint; however, among all eligible patients (stages 1 and 1B, n 50), there were no radiographic responses, median overall survival was 7.9 months, median PFS was 1.7 months, and the 6mPFS rate was 6%. The clinical benefit was insufficient to correlate tested biomarkers with efficacy. The trial was closed without proceeding to stage 2. Conclusions. Intraparticipant dose escalation was feasible, but dasatinib was ineffective in recurrent GBM. Clinical trials.gov identified. NCT00423735 (available at http://clinicaltrials.gov/ct2/show/NCT00423735).

AB - We conducted a phase II trial to evaluate the efficacy of dasatinib, a multitargeted tyrosine kinase inhibitor, for adults with recurrent glioblastoma (GBM). Methods. Eligibility requirements were Karnofsky performance status ≥60%; no concurrent hepatic enzyme-inducing anticonvulsants; prior treatment with surgery, radiotherapy, and temozolomide exclusively; and activation or overexpression of ≥2 putative dasatinib targets in GBM (ie, SRC, c-KIT, EPHA2, and PDGFR). Using a 2-stage design, 77 eligible participants (27 in stage 1, if favorable, and then 50 in stage 2) were needed to detect an absolute improvement in the proportion of patients either alive and progression-free patients at 6 months (6mPFS) or responding (any duration) from a historical 11% to 25%. Results. A high rate of ineligibility (27%) to stage 1 precluded a powered assessment of efficacy, but there was also infrequent treatment-related toxicity at 100 mg twice daily. Therefore, the study was redesigned to allow intrapatient escalation by 50 mg daily every cycle as tolerated (stage 1B) before determining whether to proceed to stage 2. Escalation was tolerable in 10 of 17 (59%) participants evaluable for that endpoint; however, among all eligible patients (stages 1 and 1B, n 50), there were no radiographic responses, median overall survival was 7.9 months, median PFS was 1.7 months, and the 6mPFS rate was 6%. The clinical benefit was insufficient to correlate tested biomarkers with efficacy. The trial was closed without proceeding to stage 2. Conclusions. Intraparticipant dose escalation was feasible, but dasatinib was ineffective in recurrent GBM. Clinical trials.gov identified. NCT00423735 (available at http://clinicaltrials.gov/ct2/show/NCT00423735).

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Lassman AB, Pugh SL, Gilbert MR, Aldape KD, Geinoz S, Beumer JH et al. Phase 2 trial of dasatinib in target-selected patients with recurrent glioblastoma (RTOG 0627). Neuro-oncology. 2015 Jul 1;17(7):992-998. https://doi.org/10.1093/neuonc/nov011