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Conrad Notes
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P. Rougier, PhD, Ambrose Pare Hospital, Boulogne, France, obtained a 29% response rate (RR) in 5-fluorouracil (5-FU) resistant colorectal cancer (CRC) patients using CPT-11 (irinotecan) plus the De Gramont regimen. Dosing consisted of CPT-11 at 100 to 260 mg/msq and 5-FU with leucovorin (LV). The safety and efficacy data encouraged undertaking a Phase III trial as first line therapy in CRC patients. (See package insert on irinotecan for US prescribing information and related articles in ASCO'97 Report of Conrad Notes).
Rationale for study CPT-11 is a specific topoisomerase I inhibitor now indicated for 5-FU resistant advanced CRC (J Clin Oncol 1997;15:252- 260). The De Gramont regimen, used widely in France, employs LV at 200 mg/msq followed by a 400 mg/msq bolus of 5-FU and continuous intravenous 5-FU at 600 mg/msq (J Clin Oncol 1997;15: 808-815). In one randomized comparison, this method proved to be superior to the Mayo Clinic regimen. The present study sought to determine the maximally tolerated dose (MTD) of CPT-11 when used every two weeks in combination with the De Gramont regimen.
Description of study patients Thirty-two males and 14 females, ranging in age from 27 to 70 years, participated in this open study. Primary tumor sites included: colon (20/46), rectum (12/46), colorectal junction (10/46), and unspecified (4/46). The metastatic sites were: liver (34), lung (19), peritoneum (2), and lymph nodes (10). Previous chemotherapies ranged from 1 to 5 (median,2). All patients satisfied the 0 to 1 performance status of the World Health Organization.
Dose escalation with CPT-11 Two to 10 patients received CPT-11 at 100, 120, 150, 180, 200, 220 or 260 mg/msq for 3 to 11 cycles per patient totalling 327 cycles. Ten patients each had 180 or 200 mg/msq to help select the MTD for the Phase III trial.
Toxicity of combined therapy At a dose of 180 mg/msq in the first cycle, neutropenia and thrombopenia developed in one of 10 patients. At the next level (200 mg/msq), 3 of 10 patients experienced delayed diarrhea and nausea/vomiting. These adverse reactions occurred in previous studies with CPT-11 alone.

Selection of the 180 mg/msq dose of CPT-11 for combination therapy rests on the overall safety seen with 327 cycles of 100 to 269 mg/msq. CPT-11 dose lowering or delay in giving the next treatment cycle occurred because of neutropenia or thrombopenia. At 180 mg/msq, lowering of CPT-11 dose was needed in 2/80 cycles and delayed treatment in 4/80 cycles. The next dose (200 mg/msq) required lowering in 3/54 cycles and delay in an equal proportion of cycles.

Activity against CRC In this open study, an independent panel assessed the tumors every 8 weeks and the x-ray films. The 38 evaluable patients showed a RR of 29%; one patient had a complete response and 10 were partial responders.
Investigator's conclusions The MTD of CPT-11 may be higher than 260 mg/msq when given every two weeks with the De Gramont regimen. The optimal dose of CPT- 11 with the regimen in CRC patients is probably 180 mg/msq. If well-tolerated, higher doses of CPT-11 are recommended for stable CRC patients. The results of this study prompted the initiation of a Phase III trial as first-line treatment for CRC. The new CPT-11 combination treatment will be compared with the De Gramont regimen used alone.

For professional correspondence, please contact Dr. Rougier by Fax at: 33 1 4909 5327

Eugene A. Conrad

Presented at The European Cancer Conference (ECCO 9), September 14-18, 1997
Copyright © 1997 Conrad Group, Inc. All Rights Reserved
Eugene A. Conrad, PhD, MPH / ISSN 1078-2230 / November 1997
Send comments to: ConradNote@aol.com

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