ROCHESTER, Minnesota—The combination of irinotecan(Drug information on irinotecan) (Camptosar)and docetaxel(Drug information on docetaxel) (Taxotere) is a promising treatment for recurrent non–small-cell lung cancer (NSCLC), but the dosing schedule tested in phase I and II trials needs to be modified to reduce the potential for myelosuppression and diarrhea, cautioned Alex Adjei, MD, of the Mayo Clinic in Rochester, Minnesota.
Phase I Study
Irinotecan and docetaxel are novel cytotoxic drugs that have broad antitumor activity as single agents but different mechanisms of cytotoxicity, Dr. Adjei commented. Irinotecan inhibits DNA topoisomerase I and docetaxel interferes with microtubule disassembly.
In the phase I study, four escalating dose levels (150/50 mg/m², 160/65 mg/m², 200/65 mg/m², and 200/75 mg/m²) of irinotecan/docetaxel were tested in 18 patients with solid tumors.
Neutropenia was the most common and dose-limiting toxicity, and thrombocytopenia was rare. Diarrhea was the most common nonhematologic toxicity, although there was no grade 3 or 4 diarrhea in patients who received maximal doses of antidiarrheal agents.
Clinical activity was seen at all dose levels. Overall, there were 7 partial responses in 18 patients. Three of five patients with previously treated stage IV NSCLC had durable partial responses. There was no clinically significant pharmacokinetic interaction between the two drugs.
Phase II Study
Dr. Adjei presented toxicity data from a phase II trial in which patients received irinotecan 160 mg/m², intravenously over 90 minutes, followed by docetaxel 65 mg/m² intravenously over 60 minutes. The regimen was repeated every 3 weeks for a maximum of six cycles.
As of August 31, 2000, 25 patients had been enrolled. Fifteen were evaluable for toxicity. Response and survival data are not yet available.
Neutropenia was the predominant toxicity, with severe neutropenia occurring among 57% of the patients. Diarrhea was the most common nonhematologic toxicity. Roughly one third of patients developed severe diarrhea, about 20% reported fatigue, about 13% complained of nausea, and 13% developed severe anemia. There were no cases of severe thrombocytopenia.
“Based on our findings, we believe the dose defined in phase I studies is too toxic for community use.” Because of the toxicities encountered in the initial patients, the drug doses used in this ongoing study have been amended to irinotecan 130 mg/m², and docetaxel 50 mg/m², Dr. Adjei said.
The phase II trial included NSCLC patients who had undergone one prior chemotherapy regimen, who had stable disease for at least 4 weeks while on prior chemotherapy, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Patients who had 25% or more of their bone marrow irradiated, patients who had undergone prior treatment with either of the two study drugs, and patients who had grade 2 or worse peripheral neuropathy were excluded.
The median age of the study population was 62 years. Fourteen patients had a performance status of 0, and 11 had a performance status of 1. Thirteen patients had undergone prior treatment with paclitaxel(Drug information on paclitaxel) (Taxol), and the median duration of their prior response to chemotherapy was 7 months.
