Dose escalation of CPT-11 in combination with oxaliplatin using an every two weeks schedule: a phase I study in advanced gastrointestinal cancer patients.
BACKGROUND
To determine the dose-limiting toxicity of CPT-11 in combination with oxaliplatin, and the maximal tolerated dose (MTD) and the recommended dose (RD) of CPT-11 using an every two weeks schedule.


METHODS
The study was designed to evaluate escalated doses of CPT-11 starting at 100 mg/m2 with a fixed clinically-relevant dose of 85 mg/m2 oxaliplatin given every two weeks.


RESULTS
Twenty-three patients and 186 cycles were evaluable for toxicity (median per patient: 7, range: 1-13). Grade 3 oxaliplatin-induced neurotoxicity was cumulative and limiting in 39% (9 of 23) of patients. The MTD of CPT-11 was 200 mg/m2, with incomplete neutrophil recovery at day 15 as limiting toxicity. At the RD (175 mg/m2 of CPT-11): no grade 4 neutropenia was seen in the two first cycles; 30% of patients experienced grade 3-4 diarrhea. Febrile neutropenia (3.2% of all cycles) was 3-fold more frequent in performance status (PS) 2 than in PS0-1 patients. Among eleven colorectal cancer (CRC) patients, three complete and four partial responses were documented, including in three 5-fluorouracil (5-FU) refractory patients.


CONCLUSIONS
To combine CPT-11 175 mg/m2 and oxaliplatin 85 mg/m2 every two weeks is feasible in an outpatient setting, and very active in 5-FU resistant CRC patients. A dose of 150 mg/m2 CPT-11 is recommended in PS2 patients.
Goldwasser
F
F
Service de Cancérologie, H pital Paul Brousse, Villejuif, France. F.Goldwasser@wanadoo.fr
Gross-Goupil
M
M
Tigaud
J M
JM
Di Palma
M
M
Marceau-Suissa
J
J
Wasserman
E
E
Yovine
A
A
Misset
J L
JL
Cvitkovic
E
E
D000328:Adult; D000368:Aged; D000505:Alopecia / Q000139:chemically induced; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D003967:Diarrhea / Q000139:chemically induced; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D007239:Infections / Q000139:chemically induced; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009503:Neutropenia / Q000139:chemically induced; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects; D000077150:Oxaliplatin; D016879:Salvage Therapy; D012678:Sensation Disorders / Q000139:chemically induced; D016896:Treatment Outcome
D000964:Antimetabolites, Antineoplastic; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000077146:Irinotecan; D005472:Fluorouracil; D002166:Camptothecin