Ongoing Phase I Trial of Sequential Administration of Docetaxel, Gemcitabine, and Irinotecan

CHARLESTON, South Carolina—A phase II trial involving the sequential administration of docetaxel (Taxotere), gemcitabine (Gemzar), and irinotecan (Camptosar) in patients with non–small-small cell lung cancer (NSCLC) is being planned. Announcement of the new trial comes in the wake of results of a phase I trial among patients with solid tumors that was reported at the 9th World Conference on Lung Cancer by Caio Max S. Rocha Lima, MD, assistant professor of medicine at the Medical University of South Carolina in Charleston.

The phase I trial identified the maximum tolerated dose (MTD) of docetaxel as 20 mg/m², on days 1 and 8, followed 24 hours later by gemcitabine, 1,000 mg/m², followed immediately by irinotecan, 100 mg/m² on days 2 and 9 in a 21-day cycle.

Synergistic Interactions

In explaining the rationale for the phase I trial, Dr. Rocha Lima pointed out that earlier research has shown that docetaxel, gemcitabine, and irinotecan are active in a variety of solid tumors. He emphasized, however, that in combination, synergism may be strictly schedule-dependent. Preclinical studies have suggested synergistic interactions when docetaxel is administered 24 hours before gemcitabine or irinotecan. In addition, concomitant exposure to gemcitabine and irinotecan led to synergistic cell destruction in lung, leukemia, and breast cancer cell lines. The schedule of chemotherapy administration in the present study complied with these preclinical data, he said.

The trial included patients who had solid tumors refractory to standard therapy or solid tumors for which there is no standard therapy. Prior chemotherapy with docetaxel, gemcitabine, or irinotecan or all three agents was allowed. Individuals who had bone marrow metastases or who had undergone prior whole pelvic irradiation were excluded.

The docetaxel dose was escalated by 5 mg/m² per cohort from an initial dose of 20 mg/m² on days 1 and 8 in arm A or 45 mg/m² on day 8 only in arm B over 1 hour. Gemcitabine and irinotecan were given on the second and ninth days in arm A and the first and ninth days in arm B at fixed doses of 1,000 mg/m² over 30 minutes and 100 mg/m² over 90 minutes.

Twenty-five patients have been enrolled in the trial thus far. The 19 patients in arm A had a median age of 61 years, and most had a Zubrod performance status of 1. The six patients in arm B had a median age of 61 years, and most also had a good performance status.

Four Dose Levels Tested

Three dose levels in arm A and one dose level in arm B have been tested. Seventeen patients were evaluable in arm A; one died of an unrelated cause in the first cycle, and another withdrew consent before starting treatment. Five of six patients were evaluable in arm B. One patient could not be evaluated for determination of the maximal tolerated dose because he inadvertently received growth factor support during the first treatment cycle. Overall, 42 cycles were delivered in arm A and 25 in arm B.

In the trial, the dose-limiting toxicity was based only on events occurring during the first treatment cycle. The MTD was defined as the dose level immediately below the dose level at which two of the first three patients in any cohort or at least two out of six patients in any expanded cohort developed a dose-limiting toxicity (DLT).

As noted, the MTD of docetaxel that could be administered on days 1 and 8 in arm A was 20 mg/m². At a docetaxel dose of 25 mg/m², there was one case of grade 3 diarrhea and one grade 3 infection.

Arm B Discontinued

Arm B was discontinued after accrual to the first dose level (docetaxel 45 mg/m²) was completed because the MTD of docetaxel to be reached by its de-escalation was felt not to be worth pursuing.

In arm A, three of three patients who had been previously treated for head and neck cancer had evidence of tumor regression. One patient who had undergone earlier treatment for small-cell lung cancer had marked tumor shrinkage after the first treatment cycle but withdrew his consent for participation in the trial. Four patients had stable disease after four or more treatment cycles.

In arm B, two patients (one who had been previously treated for liposarcoma and one who had been previously treated for NSCLC) had stable disease for at least four treatment cycles. In addition, one patient with breast cancer and a pancreatic mass had a near complete response in the breast and stable disease in the pancreas after four cycles

This nonplatinum-based triplet composed of active agents in a variety of solid tumors including NSCLC should be tested in a phase II trial, Dr. Rocha Lima said. Further escalation of docetaxel beyond 20 mg/m² on days 1 and 8 in arm A followed 24 hours later by gemcitabine at 1,000 mg/m² immediately followed by irinotecan at a reduced dose of 80 mg/m² on days 2 and 9 will be tried.