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Irinotecan and Gemcitabine in Patients With Solid Tumors: Phase I Trial

Irinotecan and Gemcitabine in Patients With Solid Tumors: Phase I Trial

ABSTRACT: Using a day 1 and 8, every-3-week schedule, our purpose was to determine the maximum tolerated dose of irinotecan (CPT-11, Camptosar) that can be administered immediately after gemcitabine (Gemzar) at a dose of 1,000 mg/m² IV. In this phase I trial, the maximum tolerated dose was defined as the dose level immediately below the level in which two of the first three patients in any cohort, or at least two of six patients in any expanded cohort, experienced dose-limiting toxicity. Dose-limiting toxicity pertained only to toxicity during the first cycle of treatment. Escalation of irinotecan was planned in groups of three patients, with three additional patients added at the first indication of dose-limiting toxicity. A total of 19 patients have been enrolled. Grade 4 diarrhea was the dose-limiting toxicity at the irinotecan dose of 115 mg/m². Hematologic toxicity was not dose limiting. Three patients required canceling of the day 8 dose due to grade 3 myelosuppression. Three patients, two with pancreatic cancer and one with metastatic carcinoma of unknown primary, had a partial response. The maximum tolerated dose of irinotecan in this combination was 100 mg/m²/dose. The dose-limiting toxicity was diarrhea. The maximum tolerated dose is the recommended starting dose for phase II studies. [ONCOLOGY 16(Suppl 5):19-24, 2002]

Gemcitabine (2¢,2¢-difluorodeoxycytidine [dFdC,
Gemzar]) is a pyrimidine analog antimetabolite with single-agent activity in a
variety of solid tumors.[1-3] It is activated by intracellular phosphorylation
and has multiple mechanisms of cytotoxicity. The predominant intracellular
moiety, difluorodeoxycytidine triphosphate (dFdCTP), is incorporated as a
substrate during DNA synthesis causing inhibition of DNA elongation and chain
termination after the addition of another base or another molecule of dFdCTP.[2,4,5]

Irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino]
carbonyloxycamptothecin [CPT-11, Camptosar]) is a camptothecin analog.[6] Its
active metabolite, SN-38, inhibits topoisomerase I activity by stabilizing the
topoisomerase I-DNA cleavable complex formed during enzymatic relaxation of
DNA tortional strain.[7] Irinotecan has demonstrated broad activity against
human tumors in vitro and in vivo.[8,9] Significant single-agent activity has
been reported in colorectal cancer,[10,11] small-cell lung cancer,[12] non-small-cell
lung cancer,[13] uterine cervix cancer,[14] and epithelial ovarian cancer.[15]

Preclinical data evaluating the combination of irinotecan and gemcitabine are
limited. Kanazawa et al,[16] evaluating the combination effects of anti-cancer
drugs, suggested dose-dependent interactions between gemcitabine and irinotecan.
Moreover, our recent laboratory data suggest antagonism at low concentrations,
but synergism at concentrations of gemcitabine above 0.1 µM and irinotecan above
3.2 µM in the SCOG small-cell lung cancer cell line.[17] Absolute, marked
synergism was evident in the HL-60 acute myeloid leukemia cell line. Synergism
at concentrations of 0.1-2 µM gemcitabine and 0.2-10 µM irinotecan, but
antagonism at high concentrations (ie, concentrations > 2 µM gemcitabine and
20 µM irinotecan), was seen in MCF7 breast cancer cells (unpublished data). In
addition, preclinical data also suggest synergy with concurrent administration
of cytosine arabinoside (a gemcitabine analog) and irinotecan or SN-38.[18-20]

In this phase I trial, initially reported by our group in 1999 [21] and
updated here, the dose of gemcitabine was fixed at 1,000 mg/m² and irinotecan
doses were escalated until a maximum tolerated dose for the combination was
defined. Because other studies of gemcitabine combinations using a day 1, 8, and
15 schedule had shown substantial day 15 marrow toxicity, we chose to administer
both drugs on days 1 and 8 of a 21-day treatment cycle.

Patients and Methods

Patient Selection

Adult patients with pathologically confirmed solid tumors refractory to
standard therapy were eligible if they had adequate organ function (granulocyte
count of at least 1,500/µL, platelet count of at least 100,000/µL, serum
creatinine less than 2.1 mg/dL, and serum bilirubin less than 2.1 mg/dL), and
performance status of 0 to 2. Patients were ineligible if they had bone marrow
metastases, New York Heart Association class III or IV heart disease or
myocardial infarction within 6 months, uncontrolled infection, whole pelvic
radiation, prior gemcitabine and irinotecan, or a psychiatric condition.
Measurable or evaluable disease was not required. All patients gave written
informed consent.

Treatment Plan

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