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

May 2, 2002

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.

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 avariety of solid tumors.[1-3] It is activated by intracellular phosphorylationand has multiple mechanisms of cytotoxicity. The predominant intracellularmoiety, difluorodeoxycytidine triphosphate (dFdCTP), is incorporated as asubstrate during DNA synthesis causing inhibition of DNA elongation and chaintermination 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] Itsactive metabolite, SN-38, inhibits topoisomerase I activity by stabilizing thetopoisomerase I-DNA cleavable complex formed during enzymatic relaxation ofDNA tortional strain.[7] Irinotecan has demonstrated broad activity againsthuman tumors in vitro and in vivo.[8,9] Significant single-agent activity hasbeen reported in colorectal cancer,[10,11] small-cell lung cancer,[12] non-small-celllung cancer,[13] uterine cervix cancer,[14] and epithelial ovarian cancer.[15]

Preclinical data evaluating the combination of irinotecan and gemcitabine arelimited. Kanazawa et al,[16] evaluating the combination effects of anti-cancerdrugs, 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 above3.2 µM in the SCOG small-cell lung cancer cell line.[17] Absolute, markedsynergism was evident in the HL-60 acute myeloid leukemia cell line. Synergismat concentrations of 0.1-2 µM gemcitabine and 0.2-10 µM irinotecan, butantagonism at high concentrations (ie, concentrations > 2 µM gemcitabine and20 µM irinotecan), was seen in MCF7 breast cancer cells (unpublished data). Inaddition, preclinical data also suggest synergy with concurrent administrationof 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] andupdated here, the dose of gemcitabine was fixed at 1,000 mg/m² and irinotecandoses were escalated until a maximum tolerated dose for the combination wasdefined. Because other studies of gemcitabine combinations using a day 1, 8, and15 schedule had shown substantial day 15 marrow toxicity, we chose to administerboth 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 tostandard therapy were eligible if they had adequate organ function (granulocytecount of at least 1,500/µL, platelet count of at least 100,000/µL, serumcreatinine less than 2.1 mg/dL, and serum bilirubin less than 2.1 mg/dL), andperformance status of 0 to 2. Patients were ineligible if they had bone marrowmetastases, New York Heart Association class III or IV heart disease ormyocardial infarction within 6 months, uncontrolled infection, whole pelvicradiation, prior gemcitabine and irinotecan, or a psychiatric condition.Measurable or evaluable disease was not required. All patients gave writteninformed consent.

Treatment Plan

Gemcitabine at a fixed dose of 1,000 mg/m² was given intravenously over 30minutes on days 1 and 8 of each 3-week cycle. Irinotecan was given intravenouslyby a 90-minute intravenous infusion after gemcitabine. The dose levels ofirinotecan are shown in Table 1. Cohorts of at least three patients were treatedat each dose level. Patients were taken off protocol if they had progressivedisease, severe allergic reaction, or if the treating physician elected to stoptherapy.

Drug Administration

All patients received prophylactic antiemetic therapy with an HT3 blocker anddexamethasone. Irinotecan and gemcitabine were administered as describedpreviously. No other chemotherapy, immunotherapy, or radiation therapy waspermitted.

Dose-Escalation Rules and Maximum Tolerated Dose

The maximum tolerated dose was defined as the dose level immediately belowthe dose level at which two out of the first three patients in any cohort, or atleast two out of six patients in any expanded cohort, experienced adose-limiting toxicity. If one of three patients at any dose level experiencedDLT, three additional patients were accrued. If none of these three additionalpatients experienced DLT, then the dose was escalated in the next cohort.

Dose-Limiting Toxicity

Toxicity was graded according to the NCI Common Toxicity Criteria.Dose-limiting toxicity was defined as follows: (1) grade 4 nonhematologictoxicity (excluding nausea, vomiting, fever, anorexia) or hemorrhage orthrombocytopenia; (2) Grade 3 nonhematologic toxicity other than nausea,vomiting, fever, anorexia, stomatitis, esophagitis/dysphagia; (3) grade 3stomatitis or esophagitis/dysphagia lasting  7 days or more; (4) grade 4 neutropenialasting 4 days or longer; (5) failure to recover neutrophils (1,500/µL or more) orplatelets (100,000/µL or more) by day 28. During this phase I trial, cycle 1 day 8treatment was given at full doses if the neutrophil count was 1,500/µL or more,platelets were  75,000/µL or more, and there were no nonhematologic toxicities worsethan grade 1. Cycle 1 day 8 treatment was canceled in patients with eithercounts below this level or grade 2 or higher nonhematologic toxicity on thatday. Dose adjustments for subsequent cycles are shown in Table2.

Patient Evaluation

At enrollment, patients were evaluated with a complete history and physicalexamination and performance status assessment. Required blood counts, serumchemistries, and urinalysis were completed within 14 days of study entry. Anyx-ray, scan, CT, MRI, or ultrasound that was utilized for tumor measurement inpatients with measurable or evaluable disease had to have been performed withinthe 28 days prior to study entry. During the first cycle of chemotherapy aphysician monitored patients at least weekly. For subsequent cycles patientswere assessed at each chemotherapy visit. Complete blood count with differentialand serum chemistries were repeated on day 1 and day 8 of each chemotherapycycle. Subsequently the complete blood count with differential was repeatedevery 3 days until the end of the treatment cycle. Response criteria werestandard.


Patient Characteristics

Between July 1997 and February 1998, 19 patients were registered onto studyat the Hollings Cancer Center, Medical University of South Carolina. One patientat dose level 2 had a grade 2 allergic reaction during her second dose (cycle 1,day 8) of irinotecan. She declined further protocol therapy. All the remaining18 patients received at least two cycles. The baseline characteristics and tumortypes of the 19 patients are shown in Table 3 andTable 4, respectively.

Hematologic Toxicity

Hematologic toxicity during cycle 1 is shown in Table5. No patientexperienced hematologic dose limiting toxicity. Day 8 cycle 1 chemotherapy washeld in one patient due to thrombocytopenia (46,000 platelets), 1 forneutropenia (1,000 neutrophils), and another for both neutropenia (900/µL) andthrombocytopenia (67,000/µL). Generally, no dose response relationship forhematologic toxicity was demonstrated. Six patients had non-neutropenic fever (> 100.5°F) at some time during therapy.

Nonhematologic Toxicity

All severe or life-threatening nonhematologic toxicities occurring duringthis trial were gastrointestinal. The grade III/IV nonhematologic toxic eventsduring cycle 1 are shown Table 6.

Response Evaluation

Eighteen patients had measurable disease and were evaluated for response totreatment (Table 7). Three previously untreated patients, one in cohort 3 (100mg/m²) and two in cohort 4 (115 mg/m²), had a documented partial response. Amongthe responders, two had pancreatic cancer and one had metastases from unknownprimary.

Two additional patients, one at dose level 4 with previously untreatedpancreatic cancer and one at dose level 3 with previously treated non-small-celllung cancer, have had symptomatic benefit (increased appetite with weight gainand decrease in requirement of narcotic analgesic) and radiologic evidence of adecrease in tumor size that did not meet criteria for a partial response.

Recommended Doses for Phase II Studies

The maximum tolerated dose of irinotecan was 100 mg/m² in combination withgemcitabine (1,000 mg/m²). This dose and schedule is recommended for phase IIstudies. Escalation of irinotecan to 115 mg/m² may be considered for subsequentcycles in patients who do not experience grade 1 or higher hematologic ornonhematologic toxicity.


Both gemcitabine and irinotecan are active single agents in a number of solidtumors. Their toxicity profiles and differences in mechanism of cytotoxicitymake evaluation of a gemcitabine and irinotecan combination attractive.

Previous gemcitabine combination studies have frequently resulted in markedmyelosuppression on day 15, limiting drug administration on that day.[22-26] Theuse of the day 1 and 8 schedule was designed to avoid this problem. Otherinvestigators have used the same strategy when combining gemcitabine with othermyelosuppressive agents.[27,28] No hematologic DLT was observed in any patientin this trial during the first cycle.

The dose-limiting toxicity in this trial was diarrhea, which was notunexpected based on other experiences with irinotecan.[29-35] Delayed onsetdiarrhea occurs between the second and fourteenth day of irinotecanadministration, and lasts on average between 5 and 7 days. It is unpredictable,varying from one cycle to another, and is sometimes severe enough to requireparenteral hydration.[33,35]

Gemcitabine is approved in the United States as a single agent for managementof patients with advanced pancreatic cancer. This approval resulted from phaseIII data demonstrating an improved rate of clinical benefit and an overallsurvival advantage for gemcitabine therapy compared to treatment withfluorouracil. However, in this phase III trial the objective gemcitabine partialresponse rate was only 5.4%.[36]

Phase II data suggest that irinotecan has activity against pancreatic cancer.In previously untreated patients with advanced pancreatic cancer, Sakata etal[37] reported an 11% partial response rate (4 out of 35 patients) usingirinotecan at 100 mg/m²/wk or 150 mg/m² every other week. Wagener et al [38] saw3 partial responders out of 32 patients (9%) with pancreas cancer treated withan irinotecan dose of 350 mg/m² by 30 minute IV infusion every 3 weeks.

Three patients, two of which had pancreatic cancer, achieved a partialresponse. These observations have encouraged us to further evaluate thecombination of gemcitabine and irinotecan in patients with pancreas cancer. Amulticenter phase II trial of the combination of gemcitabine and irinotecandescribed in this article has recently been reported.[39] A phase III trial for similar patients testing gemcitabine alone vs gemcitabineplus irinotecan using this day 1 and 8 gemcitabine/irinotecan schedule hasrecently been closed to accrual after 350 patients with advanced, metastaticpancreatic cancer have been enrolled.


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