title: Selective kinase inhibition with daily imatinib intensifies toxicity of chemotherapy in patients with solid tumours.
abstract: The aim of this study was to determine the safety and maximum-tolerated doses of imatinib combined with cytotoxic chemotherapy (either gemcitabine or doxorubicin). Patients with advanced solid tumours were enrolled separately in two different combinations of imatinib with chemotherapy (imatinib + gemcitabine or imatinib + doxorubicin). A standard modified Fibonacci inter-cohort dose escalation was planned for each combination. Sixteen patients were accrued. Seven patients received gemcitabine and imatinib. A separate cohort of nine patients received imatinib and doxorubicin. In both groups, dose-limiting toxicity (DLT) was observed at the initial dose level requiring dose reductions for subsequent cohorts. Further DLTs were observed necessitating closure of the protocol. Daily dosing of imatinib with concurrent administration of cytotoxic chemotherapy (either gemcitabine or doxorubicin) at standard doses was associated with toxicity that was clinically unacceptable. It remains unclear whether addition of growth factors might improve tolerability for imatininb in combination with cytotoxic chemotherapy.
authors.affiliation: Dana-Farber Cancer Institute, Massachusetts General Hospital, Ludwig Center for Cancer Research at Dana-Farber/Harvard, Harvard Medical School, Boston, MA, USA. Suzanne_George@dfci.harvard.edu
authors.forename: Suzanne
authors.initials: S
authors.lastname: George
authors.forename: Jayesh
authors.initials: J
authors.lastname: Desai
authors.forename: J
authors.initials: J
authors.lastname: Paul Eder
authors.forename: Judith
authors.initials: J
authors.lastname: Manola
authors.forename: David P
authors.initials: DP
authors.lastname: Ryan
authors.forename: Leonard J
authors.initials: LJ
authors.lastname: Appleman
authors.forename: George D
authors.initials: GD
authors.lastname: Demetri
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D001549:Benzamides; D015331:Cohort Studies; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D010879:Piperazines / Q000009:adverse effects*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D011743:Pyrimidines / Q000009:adverse effects*; D000093542:Gemcitabine
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D003841:Deoxycytidine; D004317:Doxorubicin; D000068877:Imatinib Mesylate; D000093542:Gemcitabine