Phase I and pharmacokinetic study of imatinib mesylate (Gleevec) and gemcitabine in patients with refractory solid tumors.
OBJECTIVE
Preclinical data shows improvements in response for the combination of imatinib mesylate (IM, Gleevec) and gemcitabine (GEM) therapy compared with GEM alone. Our goals were to determine the maximum tolerated dose of GEM and IM in combination, the pharmacokinetics of GEM in the absence and in the presence of IM, and IM pharmacokinetics in this combination.


METHODS
Patients with refractory malignancy, intact intestinal absorption, measurable/evaluable disease, adequate organ function, Eastern Cooperative Oncology Group PS 0-2, and signed informed consent were eligible. Initially, treatment consisted of 600 mg/m2 of GEM (10 mg/m2/min) on days 1, 8, and 15, and 300 mg of IM daily every 28 days. Due to excessive toxicity, the schedule was altered to IM on days 1 to 5 and 8 to 12, and GEM on days 3 and 10 every 21 days. Two final cohorts received IM on days 1 to 5, 8 to 12, and 15 to 19.


RESULTS
Fifty-four patients were treated. IM and GEM given daily at 500 to 600 mg/m2 on days 1, 8, and 15 produced frequent dose-limiting toxicities. With the modified scheduling, GEM given at 1,500 mg/m2/150 min was deliverable, along with 400 mg of IM, without dose-limiting toxicities. Three partial (laryngeal, renal, and mesothelioma) and two minor (renal and pancreatic) responses were noted at GEM doses of 450 to 1,500 mg/m2. Stable disease >24 weeks was seen in 17 patients. CA19-9 in 7 of 10 patients with pancreatic cancer was reduced by approximately 90%. IM did not significantly alter GEM pharmacokinetics.


CONCLUSIONS
The addition of intermittently dosed IM to GEM at low to full dose was associated with broad antitumor activity and little increase in toxicity.
Ali
Yaqoob
Y
The Cancer Institute of New Jersey, University of Medicine & Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, New Jersey 08903, USA.
Lin
Yong
Y
Gharibo
Mecide M
MM
Gounder
Murugesan K
MK
Stein
Mark N
MN
Lagattuta
Theodore F
TF
Egorin
Merrill J
MJ
Rubin
Eric H
EH
Poplin
Elizabeth A
EA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001549:Benzamides; D015331:Cohort Studies; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D010879:Piperazines / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D016896:Treatment Outcome; D000093542:Gemcitabine
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D003841:Deoxycytidine; D000068877:Imatinib Mesylate; D000093542:Gemcitabine