Dasatinib With Ifosfamide, Carboplatin, Etoposide: A Pediatric Phase I/II Trial
OBJECTIVES:
Primary
- To determine the maximum tolerated dose (MTD) of dasatinib when given immediately
following ifosfamide, carboplatin, and etoposide phosphate (D-ICE) as a re-induction
regimen in young patients with metastatic or recurrent malignant solid tumors. (Phase
I)
- To describe and define the toxicities of D-ICE in these patients. (Phase I)
- To determine the safety and feasibility of prolonged administration of single-agent
dasatinib following completion of 2-6 courses of D-ICE in these patients. (Phase I)
- To estimate the overall survival, progression-free survival, and time to progression in
patients treated with D-ICE at the MTD followed by single-agent dasatinib. (Phase II)
- To estimate the response rate to two courses of D-ICE when given at the MTD in these
patients. (Phase II)
Secondary
- To determine the phosphotyrosine state of SRC family kinases and related signaling
pathways, including FAK, STAT3, VEGFR, AKT, EGFR, KIT, EPHA2, and PDGFR, in
paraffin-embedded tumor samples as measured by immunohistochemistry prior to and during
treatment with dasatinib.
- To assess gene expression profiling in fresh frozen tissue samples as measured by
microarray analysis (Affymetrix GeneChips) at baseline to identify molecular signatures
that may predict response to dasatinib.
- To correlate biomarkers and molecular signatures with dasatinib dosage, toxicity, and
antitumor activity.
- To evaluate the effect of dasatinib on phosphorylation of SRC family kinases in
peripheral blood mononuclear cell samples as a surrogate marker of response prior to
treatment with dasatinib, at days 14-21 or when WBC ≥ 500/μL, during each treatment
course, at the time of local control, and at the time of progression.
OUTLINE: This is a multicenter, phase I, dose-escalation study of dasatinib followed by a
phase II study. Patients enrolled in phase II are stratified according to disease.
Patients receive D-ICE comprising oral dasatinib twice daily on days 5-21, ifosfamide IV
over 1 hour and etoposide phosphate IV over 1 hour on days 1-5, and carboplatin IV over 1
hour on days 1 and 2. Treatment repeats every 28 days for up to 6 courses in the absence of
disease progression or unacceptable toxicity. Patients then undergo radiotherapy and/or
surgery (consolidation therapy) after 2, 4, or 6 courses of D-ICE. After completion of
consolidation therapy, patients receive oral dasatinib twice daily for up to 6 months in the
absence of disease progression or unacceptable toxicity.
Tumor tissue and peripheral blood mononuclear cell (PBMC) samples are collected periodically
for correlative laboratory studies. PBMCs are analyzed by western blotting for total and
phospho-SRC, phospho-FAK, and other relevant biomarkers. Tumor tissue samples are analyzed
by IHC for total and phospho-SRC, phospho-FAK, phospho-STAT3, phospho-KIT, and
phospho-PDGFR, EPHA2, and VEGF. Tumor tissue samples are also analyzed by microarray gene
expression profiling to define a potential molecular signature or gene expression pattern
that may predict response to dasatinib.
After completion of study treatment, patients are followed periodically.
Interventional
Primary Purpose: Treatment
Maximum tolerated dose of dasatinib (Phase I)
Yes
Judith K. Sato, MD
Principal Investigator
Beckman Research Institute
United States: Food and Drug Administration
07053
NCT00788125
September 2008
Name | Location |
---|---|
City of Hope Comprehensive Cancer Center | Duarte, California 91010 |