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Tumor Treating Field Therapy in Combination with Bevacizumab for the Treatment of Recurrent Glioblastoma
Published on: October 27, 2014
Phase 2 trial of dasatinib in target-selected patients with recurrent glioblastoma (RTOG 0627)
Andrew B Lassman1, Stephanie L Pugh1, Mark R Gilbert1
1Department of Neurology and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York (A.B.L. current); Memorial Sloan Kettering Cancer Center, New York, New York (A.B.L. during accrual, L.M.D.); NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania (S.L.P., S.G., M.W); The University of Texas MD Anderson Cancer Center, Houston, Texas (M.R.G., K.D.A. during accrual; R.K.); Neuro-Oncology Branch, National Cancer Institute/National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (M.R.G. current); University of Toronto and Princess Margaret Cancer Centre, Toronto, Canada (K.D.A. current); Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (J.H.B., S.M.C.); Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy Pittsburgh, Pennsylvania (J.H.B.); NCI Community Oncology Research Program - Kansas City, Prairie Village, Kansas (R.G.); Arizona Oncology Services Foundation, Tucson, Arizona (E.Y.); Penn State University and The Milton S. Hershey Medical Center, Hershey, Pennsylvania (H.W.); University of Maryland Medical Systems, Baltimore, Maryland (M.P.M.).
Background:
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).
Insights
Dasatinib, a tyrosine kinase inhibitor, showed no efficacy in recurrent glioblastoma (GBM) patients. Dose escalation was feasible but did not improve outcomes in this phase II trial.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Phase II trial investigating dasatinib, a multitargeted tyrosine kinase inhibitor.
- Focus on adult patients with recurrent glioblastoma (GBM).
Purpose of the Study:
- Evaluate the efficacy of dasatinib in recurrent GBM.
- Assess the feasibility of intrapatient dose escalation.
Main Methods:
- Eligibility criteria included specific performance status and prior treatments.
- Targeted activation or overexpression of SRC, c-KIT, EPHA2, and PDGFR.
- Two-stage design with initial enrollment and potential expansion.
Main Results:
- High ineligibility rate (27%) impacted initial efficacy assessment.
- Intrapatient dose escalation was tolerable in 59% of participants.
- No radiographic responses observed; median overall survival 7.9 months; median PFS 1.7 months; 6-month PFS rate 6%.
Conclusions:
- Dasatinib demonstrated ineffectiveness in recurrent GBM.
- Intraparticipant dose escalation was feasible but did not translate to clinical benefit.
- Trial closed without proceeding to stage 2 due to insufficient efficacy.
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