CHARLESTON, South CarolinaA phase II trial involving the
sequential administration of docetaxel (Taxotere), gemcitabine
(Gemzar), and irinotecan (Camptosar) in patients with
nonsmall-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.
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
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
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
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.