Phase I Dose Escalation Trial of Weekly Docetaxel Plus Irinotecan in Patients with Advanced Cancer

Abstract

Background. Docetaxel and irinotecan have additive or synergistic activity in vitro and in vivo as well as differing toxicities and unique mechanisms of action. We conducted a phase I trial to determine the maximum-tolerated dose of docetaxel and irinotecan given on a weekly schedule.Methods. Eligible patients had advanced, incurable, solid tumors. Docetaxel was administered as a 1-hour infusion and escalated over four dose levels (25,30, 35, and 40 mg/m 2 ) followed by irinotecan administered over 30 minutes at a fixed dose of 50 mg/m 2 . Treatment was administered weekly for four weeks followed by two weeks of rest. To improve tolerability, the schedule was modified to weekly administration for two weeks with one week of rest, and irinotecan was escalated over 3 dose levels (55, 60, and 65 mg/m 2 ) with docetaxel fixed at 35 mg/m 2 .Results. Forty-four patients were treated and the most common dose-limiting toxicity was diarrhea observed in 11% of patients. Severe neutropenia was rare (grade 4: 2%, grade 3: 23%). Other nonhematologic toxicities included nausea/vomiting, dehydration and fatigue. Partial responses occurred in two patients with pancreatic cancer, and one patient each with non-small cell lung and esophageal cancer.Conclusions. Weekly docetaxel and irinotecan is a promising non-cisplatin doublet with preliminary evidence of activity in advanced solid tumors. Diarrhea is the predominant dose-limiting toxicity but unlike the every 3 weeks schedule myelosuppression is modest. The recommended phase II doses are docetaxel 35 mg/m 2 and irinotecan 60 mg/m 2 on days 1 and 8 of a 21-day schedule. Phase II trials of this regimen are ongoing or planned in lung, head and neck, stomach, esophageal, and pancreatic cancers.

Phase I and pharmacokinetic study of docetaxel, irinotecan, and celecoxib in patients with advanced non-small cell lung cancer

“…Diarrhea was the predominant toxicity, whereas the hematologic toxicity profile was, in general, mild or moderate. However, the toxicities we observed when irinotecan and docetaxel were used in combination with celecoxib appear more pronounced than the ones reported for comparable doses/schedules of irinotecan and docetaxel given alone in the study by Bleickardt et al [13] The decrease in the AUC of SN-38 in Cycle 2 and the concomitant administration of irinotecan and celecoxib in that same cycle would have led to the expectation of an amelioration of diarrhea in the present study [26]. Nevertheless, diarrhea was commonly seen and was often severe in our patients.…”

“…The combination of irinotecan and docetaxel has been tested in a number of phase I clinical trials [13,[33][34][35] as well as in a phase II randomized study in NSCLC conducted in Japan [14] and other phase II trials in NSCLC [36,37] and other solid tumors [38]. The design of our study was based on the observations by Bleickardt et al [13] who recommended for phase II study docetaxel 35 mg/m 2 and irinotecan 60 mg/m 2 on days 1 and 8 of a 21-day schedule.…”

“…The design of our study was based on the observations by Bleickardt et al [13] who recommended for phase II study docetaxel 35 mg/m 2 and irinotecan 60 mg/m 2 on days 1 and 8 of a 21-day schedule. In the present study, we were able to add celecoxib 400 mg twice daily without the development of prohibitive toxicity.…”

“…Their combination is supported by preclinical data that have demonstrated an additive or synergistic effect between the camptothecins and the taxanes, which may be schedule-dependent [11,12]. A phase I trial by Bleickardt et al investigated the administration of both drugs on a weekly schedule [13]. Diarrhea was the predominant dose-limiting toxicity but, unlike the every 3 weeks schedule, neutropenia was modest.…”

Clinical applications of nucleic acid aptamers in cancer

“…The anti-PSMA A10 aptamer, or its truncated version A10-3, was used to target NPs, demonstrating that the A10-3 aptamer may be used to target poly(lactic acid)-block PEG copolymer NPs to PSMA-positive prostate cancer cells (69). Furthermore, the A10-3 aptamer was modified by poly(D,L-lactic-co-glycolic acid; PLGA) NPs to deliver docetaxel (Dtxl); an antimitotic chemotherapy drug (70) to prostate tumors in vivo. When compared with non-targeted NPs that lacked the anti-PSMA aptamer, the Dtxl-NP-Apt conjugates mediated targeted uptake and controlled release of drugs, resulting in potent efficacy and reduced toxicity after intratumoral injection (71).…”