Phase I study investigating the safety and feasibility of combining imatinib mesylate (Gleevec) with sorafenib in patients with refractory castration-resistant prostate cancer.
BACKGROUND
Determining the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) of sorafenib (S) plus imatinib (IM) in castration-resistant prostate cancer (CRPC) patients.


METHODS
Refractory CRPC patients were enrolled onto this 3+3 dose escalation designed study. Imatinib pharmacokinetics (PK) were determined on day 15, 4 h post dose with a validated LC-MS assay.


RESULTS
Seventeen patients were enrolled; 10 evaluable (6 at 400 mg S qd with 300 mg IM qd (DL0) and 4 at 400 mg S bid with 300 mg IM qd (DL1)); inevaluable patients received <1 cycle. The median age was 73 (57-89); median prostatic serum antigen was 284 ng ml(-1) (11.7-9027). Median number of prior non-hormonal therapies was 3 (1-12). Dose-limiting toxicities were diarrhoea and hand-foot syndrome. Maximum tolerated dose was 400 mg S and 300 mg IM both daily. No biochemical responses were observed. Two patients had stable disease by RECIST. Median time to progression was 2 months (1-5). Median OS was 6 months (1-30+) with 3/17 patients (17%) alive at 21 months median follow-up. Ten patients had PK data suggesting that S reduced IM clearance by 55%, resulting in 77% increased exposure (P=0.005; compared with historical data).


CONCLUSIONS
This is the first report showing that S+IM can be administered in CRPC at a dose of 400 mg S and 300 mg IM, daily.
Department of Medicine, Division of Hematology and Oncology, Advocate Lutheran General Hospital, Park Ridge, IL, USA. cnabhan@oncmed.net
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Nabhan
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Villines
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Valdez
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Tolzien
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Lestingi
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Bitran
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Christner
M J
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Egorin
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Beumer
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001549:Benzamides; D001557:Benzenesulfonates / Q000008:administration & dosage*; D002369:Castration; D004334:Drug Administration Schedule; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D010879:Piperazines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011725:Pyridines / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D019233:Retreatment; D000077157:Sorafenib; D017211:Treatment Failure
D001549:Benzamides; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D010879:Piperazines; D011725:Pyridines; D011743:Pyrimidines; D009536:Niacinamide; D000068877:Imatinib Mesylate; D000077157:Sorafenib