Irinotecan/Gemcitabine Combination Chemotherapy in Pancreatic Cancer

ABSTRACT: Gemcitabine (Gemzar) and irinotecan (CPT-11, Camptosar) areactive cytotoxic drugs against pancreatic cancer. Preclinical data evaluatingthe combination of gemcitabine and irinotecan suggest dose-dependent synergisticinteractions in SCOG small-cell lung cancer and MCF-7 breast cancer cell lines.Two phase I trials of this combination have been reported to date: the day 1 and8 every-3-week schedule (IrinoGem trial), and the day 1, 8, and 15 every-4-weekschedule (MSKCC trial). Both trials aimed to determine the maximum tolerateddose of irinotecan when administered as a 90-minute IV infusion eitherimmediately after (IrinoGem) or before or immediately after (MSKCC) gemcitabineat 1,000 mg/m2 by 30-minute IV infusion in patients with solid tumors. Theachieved maximum tolerated dose of IrinoGem has a higher dose intensity ofirinotecan (100 mg/m2 on days 1 and 8, every-3-week cycle) compared with theMSKCC schedule (60 mg/m2 on days 1, 8, and 15, every-4-week trial). In IrinoGem,two of three previously untreated metastatic pancreas cancer patients haddurable radiologic partial responses. The third had stable disease with clinicalbenefit for eight cycles. In addition, a patient with metastatic adenocarcinomaof unknown primary—potentially pancreatic—has had a durable response and isalive more than 30 months after the diagnosis. Preliminary results of a45-patient multicenter phase II trial with IrinoGem in advanced and metastaticpancreas cancer were recently reported. Toxicity was modest, with no toxicdeaths or neutropenic fever. Radiologic response rate was 20% of patients (9 outof 45), and a CA 19-9 decrease of more than 50% from baseline values occurred in32.5% of patients (13 out of 40). Median survival was 6 months (range: 0.9 to12.2+ months) and median time to treatment failure was 2.9 months (range: 0.1 to11.3+ months). A pivotal international multicenter phase III trial comparingIrinoGem to single-agent gemcitabine in advanced and metastatic pancreas canceris ongoing. [ONCOLOGY 15(Suppl 5):46-51, 2001]

Introduction

Pancreatic cancer is the fourth leading cause of cancer death in malesand females in the United States.[1] Worldwide, 170,000 new cases and 168,000deaths were projected for the year 2000.[1] The anatomy of the pancreas, withits close proximity to other vital tissues, as well as the propensity ofpancreatic cancer for early spread, make the treatment of this diseasedifficult. Median survival is 6 to 10 months for patients with locally advanceddisease and 3 to 6 months for metastatic disease, depending on performancestatus and extent of disease at diagnosis.[2] Overall, only 1% to 4% of allpatients with pancreatic cancer will be alive 5 years after diagnosis.

Despite recent progress, the treatment of patients with locallyadvanced and metastatic disease continues to be palliative. Use of chemotherapyand/or radiation should not jeopardize quality of life in patients with advancedand metastatic pancreatic cancer who are candidates for treatment. Many singleagents and chemotherapy combinations have been evaluated in this disease and,with few exceptions,[3] there had been little evidence of a meaningful impact onsurvival or quality of life until the advent of gemcitabine (Gemzar).

The antimetabolite gemcitabine has been approved by the US Foodand Drug Administration (FDA) as a single agent for the treatment of advancedpancreas cancer. To better evaluate the impact of gemcitabine in this disease,an alternative methodology to measure clinical benefit—one that focuses onpatient symptoms—was developed.[4,5] Applying the clinical benefit criteria, aphase III trial in previously untreated pancreatic cancer patients was performedcomparing gemcitabine with fluorouracil (5-FU). This trial demonstrated animproved rate of clinical benefit and an overall survival advantage forgemcitabine.[6] At 12 months of follow-up, 18% of the gemcitabine-treatedpatients remained alive compared with only 2% of the 5-FU-treated patients. Inthat pivotal phase III trial, the statistically significant advantages forgemcitabine were seen despite an objective partial response rate of only5.4%.[6] This level of activity of gemcitabine was also observed in phase IItrials (Table 1).[7-9]

Gemcitabine Combinations

Improvements in the management of locally advanced andmetastatic pancreatic cancer are clearly needed. Developing gemcitabinecombinations is one strategy to achieve this goal. The experience withgemcitabine combinations in non-small-cell lung cancer suggests that thegemcitabine doublets are feasible and active. Translating the lung cancerexperience to pancreatic cancer patients might not be a simple task. Choosingthe right gemcitabine partner is very important for the success of thecombination. The agents active against non-small-cell lung cancer are notnecessarily active against pancreatic cancer.

The topoisomerase I inhibitor irinotecan (CPT-11, Camptosar) isapproved by the FDA for the management of relapsed and metastatic colon cancerand is active in other gastrointestinal malignancies. In pancreas cancer,irinotecan was tested in two phase II trials.[10,11] The level of activity ofirinotecan is apparently similar to that of gemcitabine, with equivalent mediansurvival, as suggested by results of the European Organization for Research andTreatment of Cancer (EORTC) trial (Table 1).[10]

Gemcitabine/Irinotecan: Preclinical Data andPhase I Trials

Preclinical data for the combination of gemcitabine andirinotecan suggest antagonism at low concentrations but synergism atconcentrations of gemcitabine above 0.1 µM and irinotecan above 3.2 µM in theSCOG small-cell lung cancer cell line. Synergism at concentrations of 0.1 to 2µM for gemcitabine and 0.2 to 10 µM for irinotecan, but antagonism at highconcentrations (ie, concentrations > 2 µM for gemcitabine and 20 µM foririnotecan), was seen in MCF-7 breast cancer cells.[12]

IrinoGem Study

These preclinical observations were translated into a phase Itrial in which both agents were administered on a day 1, day 8 every-3-weekschedule (IrinoGem).[13] The gemcitabine dose was fixed at 1,000 mg/m² and theirinotecan dose was escalated from an initial dose of 50 mg/m². The maximumtolerated dose of irinotecan was 100 mg/m² given intravenously over 90 minuteson days 1 and 8 every 3 weeks immediately following gemcitabine at 1,000 mg/m²on days 1 and 8 given intravenously over 30 minutes (Figure1). Thedose-limiting toxicity was grade 3 diarrhea in two of seven patients at anirinotecan dose of 115 mg/m².

A total of 18 patients were accrued to the trial. Two of threepreviously untreated pancreas cancer patients and one patient with metastaticcarcinoma of unknown primary (possible pancreatic cancer primary) had documentedpartial responses. The third previously untreated pancreas cancer patient hadtumor reduction short of a partial response based on radiologic assessment, andclinical benefit for eight cycles of treatment (Table2).[13]

MSKCC Trial

O’Reilly et al from Memorial Sloan-Kettering Cancer Center(MSKCC) reported their phase I experience with a different schedule ofgemcitabine and irinotecan.[14] Both drugs were given on days 1, 8, and 15 on anevery-4-week cycle. As in the IrinoGem study, the gemcitabine dose was fixed at1,000 mg/m² over 30 minutes and the irinotecan dose was escalated. Thirty-fivepatients were accrued and both sequences of drug administration were tested.

Preliminary results of pharmacokinetic studies assessing levelsof gemcitabine, the uridine metabolite of gemcitabine, irinotecan, SN-38, andSN-38G did not show pharmacokinetic differences between the two administrationsequences.[14] When gemcitabine was given first immediately followed byirinotecan, diarrhea, nausea/vomiting, neutropenia, and fatigue weredose-limiting. When irinotecan was given first, immediately followed bygemcitabine, the dose-limiting toxicities were neutropenic fever and diarrhea.The maximum tolerated doses in both sequences were 1,000 mg/m² of gemcitabineand 60 mg/m² of irinotecan (Figure2).

A durable partial response was observed in one patient withgastric cancer, and five other patients had stable disease for ³ 6 months(Table 2). There was no clear evidence of a superior drug sequence, althoughpatients who achieved long-term stable disease and response had receivedgemcitabine first followed by irinotecan.

Multicenter Phase II Trials of Irinotecan/Gemcitabine

Maintaining single-agent doses of chemotherapy drugs when usedin combination regimens may be more challenging in pancreatic cancer patients,as they are generally more frail and less tolerant of toxic side effects. Astrategy one might consider to improve the dose intensity of gemcitabine andirinotecan combinations is related to the schedule of administration.

Gemcitabine regimens using the day 1 and 8 every-21-day cycleinstead of the day 1, 8, and 15 every-28-day cycle have been associated withincreased dose intensity. By avoiding the day-15 dose, when marrow suppressionfrequently prevented delivery of the gemcitabine combinations, the every-3-weekschedule has been better tolerated, requiring fewer doses to be withheld. Withsingle-agent irinotecan, a schedule of four weekly doses for an every-6-weekcycle is generally associated with more diarrhea during weeks 3 and 4.

By developing the day 1 and 8 every-3-week cycle in IrinoGem,the irinotecan-induced diarrhea and the myelosuppression of gemcitabine andirinotecan have been minimized, allowing almost single-agent doses of these twodrugs in combination. In addition, the activity in previously untreated pancreascancer patients observed in the phase I trial with IrinoGem led us to perform aphase II study of this combination in previously untreated patients with locallyadvanced or metastatic pancreatic cancer (Figure3).

The phase II trial accrued 45 chemotherapy-naive (7% had beentreated pre-viously with radiation therapy), locally advanced (unresectable), ormetastatic pancreatic cancer patients at eight US centers from July 1998 throughJune 30, 1999. Measurable disease, adequate organ function, and performancestatus of 0 to 2 were required. No previous chemotherapy except for 5-FU givenas a radiation sensitizer was allowed. The primary efficacy parameter was tumorresponse; secondary efficacy parameters were CA 19-9 response, responseduration, and overall survival. Median age was 60 years (range: 31 to 89 years),and the male/female ratio was 60%/40%. A performance status of 0/1/2 wasrecorded in 24%, 60%, and 16%, respectively. Seventy-three percent of patientshad metastatic and 27% had locally advanced disease.

Preliminary results were reported at the American Society ofClinical Oncology (ASCO) 2000 meeting, and suggest that the combination isactive and well tolerated in patients with locally advanced and metastaticpancreatic cancer.[15] Of 351 total doses delivered (day 1 or 8), full doses ofirinotecan and gemcitabine were given for 91% and 88%, respectively. Toxicityhas been modest, with no reports of toxic deaths or neutropenic fever thus far (Table3). Preliminary radiologic response rate is 20% (9 out of 45), and therate of CA 19-9 decrease of more than 50% from baseline value is 32.5% (13 outof 40). Median survival is 6 months (range: 0.9 to 12.2+ months) and median timeto treatment failure is 2.9 months (range: 0.1 to 11.3+ months) (Table4).

Follow-Up Studies With IrinoGem

Multicenter Phase III Trial

Based on the phase I and II experience with IrinoGem in locallyadvanced and metastatic pancreas cancer, an international phase III trialcomparing gemcitabine alone to gemcitabine plus irinotecan has been initiated. Atotal of 75 participating centers from the United States, Canada, South America,Japan, and Australia will have the study activated.

The patients accrued for this trial will be randomly assigned toreceive day 1 and 8 IrinoGem as used in the phase II study or gemcitabine at1,000 mg/m²/wk for 7 consecutive weeks for the first cycle followed by a day 1,8, and 15 every-28-day cycle for cycle 2 and beyond (Figure4). This gemcitabineadministration schedule is the same as that used in the pivotal phase III trialthat supported FDA approval of gemcitabine therapy for pancreas cancer.[6]Patient eligibility criteria are consistent with those used in the phase I andII evaluations of IrinoGem.[13,15]

The primary end point of the trial is overall survival;secondary end points will be antitumor activity including objective response anda CA 19-9 decline of ³ 50 % when elevated at baseline, time to treatmentfailure, safety, clinical benefit (measured by time to performance statusdecline, time to weight loss, and time to albumin level decrease), andquality-of-life analyses (as assessed by FACT-Hep, the Functional Assessment ofCancer Therapy-Hepatobiliary).[16]

The trial is powered to detect a 40% improvement in mediansurvival (from 4.8 to 6.8 months) and 1-year survival (from 18% to 29%) forpatients receiving IrinoGem. A total of 306 deaths are required at asignificance level of 0.05 and a power of 0.85. The target accrual is 175patients per treatment arm with the expectation that approximately 5% ofpatients will be lost to follow-up. If the planned monthly accrual of 20patients per month is reached, the accrual period will be approximately 18months. A minimum additional follow-up period of 12 months will be necessarybefore the statistical analyses.

Randomized Phase II Trial

Drs. Matthew Kulke and Margaret Tempero of Cancer and LeukemiaGroup B (CALGB) will chair a four-arm randomized phase II trial that willinclude the IrinoGem regimen (personal communication, M. Kulke, July 2000). Twoother gemcitabine doublets with promising activity and median survivals in phaseII trials involving pancreas cancer patients—gemcitabine/cisplatin(Platinol)[17-19] and gemcitabine/docetaxel (Taxotere)[20,21]—and fixed-rateinfusion 1,500 mg/m² of gemcitabine at 10 mg/m²/min[22] will also be studied(Figure 5). Patients with measurable metastatic disease, performance status of 0to 2, and chemotherapy-naive status (except for previous treatment with 5-FU)will be eligible.

Conclusions

The combination of gemcitabine and irinotecan as administered inthe IrinoGem study has proved to be safe, active, and well tolerated in pancreascancer patients. The ongoing international phase III trial comparing gemcitabinealone to IrinoGem has been initiated. By assessing survival, quality of life,and clinical benefit as end points in the randomized phase III trial, the roleof this new combination in advanced and metastatic pancreas cancer patients willbe more comprehensively defined. If the results establish the superiority ofIrinoGem over single-agent gemcitabine, other opportunities for testing thisdoublet in earlier stages of the disease as neoadjuvant and adjuvant therapywill be considered. Both gemcitabine and irinotecan are potent radiationsensitizers, and the combination should be studied with radiation therapy inpatients with pancreas cancer and other malignancies.

The easy tolerability, modest toxicity, and the percentage ofdrug delivered (approximately 90% of full doses of irinotecan and gemcitabine)in the phase II trial of IrinoGem in advanced and metastatic pancreas cancermake this combination attractive for the addition of a third drug. Phase Itrials with DIG (IrinoGem plus docetaxel) and PIG (IrinoGem plus cisplatin[Platinol]) are currently accruing patients.

In addition, the single-agent activities of gemcitabine andirinotecan in a variety of solid tumors led us and other investigators to studyIrinoGem in other cancer types. Several ongoing phase II trials will help definethe activity of this two-drug combination in first-line therapy for non-small-celllung cancer and colon and biliary cancers, as first- and second-line therapy insmall-cell lung cancer, and in taxane- and antracycline-resistant breast cancerpatients (Table 5).

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