A phase I dose escalation study of a pharmacobiologically based scheduling of capecitabine and mitomycin C in patients with gastrointestinal malignancies.
BACKGROUND
Mitomycin C (MMC) produces significant upregulation of thymidine phosphorylase, a principal determinant of the therapeutic index of capecitabine-based treatment, starting 4-6 days after treatment. On the basis of the time-dependency of this upregulation, we performed a phase I dose escalation study of capecitabine and MMC in patients with gastrointestinal malignancies.


METHODS
A total of 29 patients with advanced gastrointestinal malignancies received MMC at 6 mg/m2 on day 1 and capecitabine escalated in four successive patient cohorts of doses 500-1,000 mg/m2/day twice daily on days 8-21, every 28 days. MMC was capped at 36 mg/m2.


RESULTS
A total of 29 patients were enrolled and 90% had at least one prior treatment in the metastatic setting. There was one DLT, grade 3 hand and foot syndrome, at dose level four. The most common toxicity was fatigue (61%). No patients experienced grade 4 toxicities. Nine patients experienced prolonged stability of disease.


CONCLUSIONS
Capecitabine in combination with MMC in the proposed schedule is well-tolerated with evidence of preliminary activity. The recommended dose for phase II studies are MMC at 6 mg/m2 on day 1 of a 28-day cycle with the dose capped at 36 mg/m2, in combination with capecitabine at 1,000 mg/m2 twice daily on days 8-21.
Bekaii-Saab
Tanios
T
The Ohio State University Comprehensive Cancer Center, B407 Starling Loving Hall, 320 West 10th Avenue, Columbus, OH 43210, USA. Tanios.Bekaii-Saab@osumc.edu
Hill
Marisa
M
Campbell
Angela
A
Kosuri
Kavitha
K
Thomas
James
J
Villalona-Calero
Miguel
M
D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D000069287:Capecitabine; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016685:Mitomycin / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use
D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D016685:Mitomycin; D000069287:Capecitabine; D005472:Fluorouracil