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

Authors: Lassman, A. B.; Pugh, S. L.; Gilbert, M. R.; Aldape, K. D.; Geinoz, S.; Beumer, J. H.; Christner, S. M.; Komaki, R.; Deangelis, L. M.; Gaur, R.; Youssef, E.; Wagner, H.; Won, M.; Mehta, M. P.
Article Title: Phase 2 trial of dasatinib in target-selected patients with recurrent glioblastoma (RTOG 0627)
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 identified. NCT00423735 (available at © 2015 The Author(s).
Keywords: adult; controlled study; human tissue; protein expression; treatment response; aged; major clinical study; overall survival; drug tolerability; drug efficacy; drug withdrawal; patient selection; drug targeting; chemotherapy; temozolomide; cancer staging; biological marker; stem cell factor; progression free survival; multiple cycle treatment; phase 2 clinical trial; dasatinib; platelet derived growth factor receptor; protein tyrosine kinase; drug dose escalation; feasibility study; karnofsky performance status; evening dosage; morning dosage; tumor recurrence; glioblastoma; pleura effusion; ephrin receptor a2; liver enzyme; anticonvulsive agent; tyrosine kinase inhibitor; phase ii; very elderly; human; male; female; article
Journal Title: Neuro-Oncology
Volume: 17
Issue: 7
ISSN: 1522-8517
Publisher: Oxford University Press  
Date Published: 2015-07-01
Start Page: 992
End Page: 998
Language: English
DOI: 10.1093/neuonc/nov011
PROVIDER: scopus
PUBMED: 25758746
PMCID: PMC5762006
Notes: Export Date: 3 August 2015 -- Source: Scopus
Citation Impact
MSK Authors
  1. Andrew Lassman
    111 Lassman