Irinotecan and Fixed-Dose-Rate Gemcitabine in Advanced Pancreatic and Biliary Cancer: Phase I Study

ABSTRACT: It is a continuing challenge for oncologists to effectively treatadvanced/metastatic pancreatic and biliary cancer. Both irinotecan(CPT-11, Camptosar) and gemcitabine (Gemzar) have shown activityagainst these diseases with different mechanisms. Preclinical andclinical data also suggest additive or synergistic effects of the combinationof these two agents with few or no overlapping toxicities. Phosphorylationof gemcitabine, a process of intracellular activation of theagent, is dose-rate dependent. It has been suggested that the fixed-doserateinfusion of gemcitabine increases the concentration of intracellulartriphosphate gemcitabine, which in turn may result in more objectiveresponses and longer median survival compared to the standard infusion.This phase I study tests the toxicity of the combination of irinotecanwith fixed-dose-rate infusion of gemcitabine, and determines thedose of the combination for phase II investigation.

Pancreatic cancer is one of theleading causes of cancer deathin the United States, with a totalof 30,700 new cases and 30,000 deathsprojected for the year 2003.[1] Mediansurvival is 6 to 10 months for patientswith locally advanced diseaseand 3 to 6 months for metastatic disease,depending on performance statusand extent of disease atdiagnosis.[2] Most patients have theirdisease diagnosed at an advanced ormetastatic stage, because of nonspecificearly symptoms of the disease.Although there have been advancesin treatment of the disease in recentyears, the effectiveness of chemotherapyis still disappointing. New strategiesboth to improve outcome and todevelop effective treatments for pancreaticcancer beyond gemcitabine(Gemzar) are desperately needed.Advanced biliary cancer is anotheraggressive gastrointestinal malignancy.The prognosis for unresectablebiliary cancer is very poor. It is projectedthat there will be 6,800 newcases and 3,500 deaths in 2003.[1]There is no standard chemotherapyregimen available, although some chemotherapeuticagents have shownsome activity for this disease. Therefore,the goal of this phase I study isto assess the maximum tolerated doseand dose-limiting toxicity of the combinationof fixed-dose-rate gemcitabineand irinotecan in advancedpancreatic and biliary cancer.Mechanisms of ActionGemcitabine (2',2'-difluorodeoxycytidine[dFdC]) is a nucleoside analogthat has a broad spectrum ofantitumor activity in solid tumors andleukemia.[3,4] A prodrug with highmembrane permeability and a highaffinity for deoxycytidine kinase,gemcitabine is converted intracellularlyto its active metabolite difluorodeoxycytidinetriphosphate (dFdCTP).dFdCTP achieves higher intracellularconcentrations and is retained significantlylonger than the triphosphate ofother pyrimidine analogs despite feedbackinhibition of cytidine deaminase,the enzyme responsible for its degradation.It competes with dCTP forincorporation into DNA, where it actsas a chain terminator.[5,6] The drugalso depletes intracellular deoxynucleosidetriphosphate pools, presumably by inhibiting ribonucleotide reductase.[7]Responses to gemcitabine as a singleagent have been reported in severalcommon solid tumors in phase IIstudies. Doses ranged from 800 to1,250 mg/m² weekly for 3 weeks every28 days, and toxicity was consideredtolerable.[8,9] Burris et alconducted a pivotal phase III trial inpatients with advanced pancreatic cancerand demonstrated that gemcitabineat 1,000 mg/m² weekly was moreeffective than fluorouracil (5-FU) inproducing clinical benefit, as measuredby a specific scale.[4] Otheroutcomes, including response rate,time to progression, and overall survival,also favored gemcitabine in thisstudy. Encouraging information forthe activity of gemcitabine in biliarycancer has also been reported fromsome small studies (combined N = 98evaluable patients), with response ratesreaching 25% to 36%.[10-12]Gemcitabine undergoes dose-rate-dependent intracellular phosphorylationto form the active di- andtriphosphates. A randomized phase IItrial suggested that a fixed-dose-rateinfusion of gemcitabine (10 mg/m²/min, 1,500 mg/m² total dose) resultedin more objective responses, longermedial survival, and higher 1-yearsurvival than the standard infusionrate.[13] Pharmacokinetic studiesshowed much higher median gemcitabinetriphosphate levels in mononuclearcells by fixed-rate infusion.Irinotecan (CPT-11, Camptosar),a camptothecin derivative, is a topoisomeraseI inhibitor that traps the topoisomeraseI-DNA cleavablecomplex following cleavage of single-strand DNA. Collision of the replicationfork converts thissingle-strand break into a doublestrandbreak, thus inducing apoptosis.The antitumor activity of irinotecanhas been well documented in colorectalcancer both as a first-line singleagent, a second-line single agent, andmost recently by Saltz and coworkersas first-line combination chemotherapywith 5-FU and leucovorin.[14] Inupper gastrointestinal malignancies,irinotecan has shown activity as a singleagent[15] and also in combinationwith 5-FU and cisplatin.[16] As a single agent, or combined with other cytotoxicagents, irinotecan possessesbroad antitumor activity against othermalignancies.[17-21] The toxicities ofirinotecan are primarily nausea, vomiting,diarrhea, and myelosuppression.The activity of irinotecan in treatmentof pancreatic cancer as a single agenthas also been demonstrated in twophase II studies with response rates ofapproximately 10%.[17,22]

The distinct mechanisms of action,different intracellular targets, and activityof both gemcitabine and irinotecanagainst various tumors providethe rationale for their combination.Theoretically, the topoisomerase I-dependent single-strand breaks stabilizedby irinotecan offer sites for theinsertion of gemcitabine triphosphateduring religation of DNA. The effectsof gemcitabine on DNA integrity inboth quiescent and cycling cells maypotentially interact with those of irinotecanon DNA repair processes inwhich topoisomerase I plays a keyrole. Preclinical data evaluating thecombination of irinotecan and gemcitabinesuggested dose-dependentsynergistic interaction in SCOG smallcelllung cancer and MCF-7 breastcancer cell lines.[23]Irinotecan andGemcitabine TrialsA combination of standard infusion(30 minutes intravenous [IV] infusion)gemcitabine with irinotecan (90 minutes IV infusion) has beenstudied in a phase I study with administrationof both agents on days 1 and8 every 3 weeks. The maximum tolerateddose was irinotecan at 100 mg/m² and gemcitabine at 1,000 mg/m².[24] A multicenter phase II trial ofirinotecan and gemcitabine in 45 chemotherapy-naive locally advanced ormetastatic pancreatic cancer patientsdemonstrated an overall objective responseof 20%.[25] One-third of thepatients had a carbohydrate antigen(CA) 19-9 decrease of more than 50%.The median survival was 5.7 monthsand the 1-year survival was 27%. Toxicitywas modest, with 2% grade 4neutropenia, 2% grade 4 vomiting,and 7% grade 3 diarrhea.A randomized multicenter phaseIII study of irinotecan and gemcitabinecompared to gemcitabine alonein patients with locally advanced ormetastatic pancreatic adenocarcinomais ongoing, with patients assigned tothe two-drug arm receiving them inthe same schedule as that used in thephase II trial. Those assigned to thegemcitabine-alone arm will receivethe agents at the U.S. Food and DrugAdministration-approved regimen (1,000 mg/m² weekly * 7) for consecutiveweeks for the first cycle followedby a days 1, 8, and 15every-28-day cycle for cycle 2 andbeyond.

Since the additive or synergisticeffects of the combination of irinotecanand gemcitabine have been suggestedin the treatment of pancreaticadenocarcinoma with modest toxicity,the fixed-dose-rate infusion ofgemcitabine may be superior to standardinfusion. Based on this rationale,a combination of irinotecan and gemcitabinewith fixed-dose-rate infusionwarrants investigation.Phase I Study DesignThis study is designed as an openlabelphase I dose-escalating trial toevaluate the safety of a combinationof gemcitabine with fixed-dose-rateinfusion and irinotecan for treatingadvanced/metastatic pancreatic andbiliary cancer. The primary end pointsare to find the dose for a phase IIstudy, the dose-limiting toxicity, andthe maximum tolerated dose. The responseto the combination will alsobe determined for those patients withmeasurable or evaluable disease.Gemcitabine is infused intravenouslywith a fixed dose rate of 10mg/m²/min; the infusion time will bebased on the dose level. Irinotecan isadministered IV over 60 minutes aftergemcitabine. Both gemcitabine andirinotecan are given on days 1 and 8of a 21-day cycle (Figure 1).Patients with histologicallyconfirmed and clinical advanced/metastatic pancreatic or biliary adenocarcinomaare eligible for the study. Theyshould be older than 18 years withrelatively good overall performancestatus and reasonable liver and kidneyfunction. Since the study is designedto test the hypothesis that thefixed-dose-rate infusion may be moreeffective than standard infusion gemcitabine,and to assess the combinationof irinotecan and gemcitabine,patients who previously had eitherdrug are eligible to be enrolled on thestudy. Patients who were previouslytreated with both drugs would notqualify for the trial.The dose-escalating schedule of thestudy is listed in Table 1. Based onpublished data and clinical experience,the recommended doses for the followingphase II study would be approximately100 mg/m² for irinotecan,the commonly accepted "standard"weekly dose, and fixed-dose-rate infusionof gemcitabine at about 70%to 80% of the single-agent dose. Thedose-limiting toxicities attributed tothe study are defined as toxicities relatedto the treatment requiring discontinuationor significant dosereduction in study drugs. Toxicitiesare to be assessed according to theNational Cancer Institute CommonToxicity Criteria scale. The maximumtolerated dose is defined as one doselevel below the dose that induced doselimitingtoxicity in greater than onethirdof patients in a given cohort.The dose modification is designedbased on the type (hematologic vsnonhematologic) and grade of toxicitiesa patient may have.Preliminary ResultsThe trial is still in its early stages.At present, five patients have beenenrolled (three patients at level 1, twoat level 2). Four of them have pancreaticcancer and one has metastatic biliarycancer. The preliminary resultsof the study are encouraging. Therehave been no dose-limiting toxicitiesrecorded. Grade 2 hematologic toxicity(neutropenia) has been observedin one patient at dose level 1 whopreviously had a Whipple procedureand adjuvant chemoradiation with epirubicin(Ellence), cisplatin, and 5-FU.Grade 1 nonhematologic toxicities(alopecia and nausea/vomiting) havealso been recorded in two patients.Although response is not the primarystudy end point, all three evaluablepancreatic cancer patients had stabledisease and a more than 60% decreaseof their CA 19-9 level. All patientshave tolerated the treatment well sofar. Enrollment of the study is continuing.ConclusionIrinotecan and gemcitabine possesssignificant activity against various tumors,including pancreatic and biliarycarcinoma. Data also suggest thatthese two agents may be additive orsynergistic with few or no overlappingtoxicities. Compared to the standardinfusion of gemcitabine, afixed-dose-rate infusion increases theconcentration of intracellular triphosphategemcitabine, which may resultin increased response rates and mediansurvival. Thus, our ongoing phaseI study is investigating the toxicity ofirinotecan combined with a fixeddose-rate infusion of gemcitabine, anddetermining the dose for phase IIstudy. Preliminary results are encouraging,and accrual of patientscontinues.

Disclosures:

The author(s) have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1.

Jemal A, Murray T, Samuels A, et al:Cancer Statistics, 2003. CA Cancer J Clin 53:5-26, 2002.

2.

Evans DB, Abbruzzese JL, Willett CG:Cancer of the pancreas, in DeVita VT Jr, HellmanS, Rosenberg SA (eds): Cancer: Principlesand Practice of Oncology, 5th ed, pp 1126-1161. Philadelphia, Lippincott, 2001.

3.

Hertel LW, Boder GB, Kroin JS, et al:Evaluation of the antitumor activity of gemcitabine(2′,2′-difluoro-2′-deoxycytidine). CancerRes 50:4417-4422, 1990.

4.

Burris III HA 3rd, Moore MJ, Andersen J,et al: Improvements in survival and clinicalbenefit with gemcitabine as first-line therapyfor patients with advanced pancreas cancer: Arandomized trial. J Clin Oncol 15:2403-2413,1997.

5.

Heinemann V, Hertel L, Grindey GB, etal: Comparison of the cellular pharmacokineticsand toxicity of 2′, 2′-difluorodeoxycytidineand 1-β-D-arabinofluranosyl cytosine. CancerRes 48:4024-4031, 1988.

6.

Huang P, Chubb S, Hertel LW, et al:Action of 2', 2'-difluorodeoxycytidine on DNAsynthesis. Cancer Res 51:6110-6117, 1991.

7.

Ghandi V, Plunket W: Modulatory activityof 2', 2'-defluorodeoxycytidine on the phosphorylationand cytotoxicity of arabinosylnucleosides. Cancer Res 50:3675-3680, 1990.

8.

Casper ES, Green MR, Kelsen DP, et al:Phase II trial of gemcitabine (2′, 2′-difluorodeoxycytidine)in patients with adenocarcinomaof the pancreas. Invest New Drugs 12:29-34,1994.

9.

Gatzemeier U, Shepherd FA, Le ChevalierT, et al: Activity of gemcitabine in patientswith non-small cell lung cancer: A multicentre,extended phase II study. Eur J Cancer 32A:243-248, 1996.

10.

Gallardo JO, Rubio B, Fodor M, et al: Aphase II study of gemcitabine in gallbladdercarcinoma. Ann Oncol 12:1403-1406, 2001.

11.

Penz M, Kornek GV, Raderer M, et al:Phase II trial of two-weekly gemcitabine inpatients with advanced biliary tract cancer. AnnOncol 12:183-186, 2001.

12.

Raderer M, Hejna MH, Valencak JB, etal: Two consecutive phase II studies of 5-fluorouracil/leucovorin/mitomycin C and of gemcitabinein patients with advanced biliary cancer.Oncology (Basel) 56:177-180, 1999.

13.

Tempero M, Plunkett W, van HaperenVR, et al: Randomized phase II trial of doseintense gemcitabine by standard infusion vs.fixed dose rate in metastatic pancreatic adenocarcinoma(abstract 1048). Proc Am Soc ClinOncol 18:273a, 1999.

14.

Saltz LB, Cox JV, Blanke C, et al: Irinotecanplus fluorouracil and leucovorin for metastaticcolorectal cancer. Irinotecan StudyGroup. New Engl J Med 343:905-914, 2000.

15.

Bleiberg H: CPT-11 in gastrointestinalcancer. Eur J Cancer 35:371-379, 1999.

16.

Blanke CD, Haller DG, Benson AB, etal: A multicenter phase II study of CPT-11, 5-fluorouracil, and leucovorin (LCV) in patients(Pts) with previously untreated adenocarcinomaof the stomach or GE junction (abstract1141). Proc Am Soc Clin Oncol 19:292a, 2000.

17.

Wagener DJ, Verdonk HE, Dirix LY, etal: Phase II trial of CPT-11 in patients withadvanced pancreatic cancer: An EORTC earlyclinical trials group study. Ann Oncol 6:129-132, 1995.

18.

Rosen LS: Irinotecan in lymphoma, leukemia,and breast, pancreatic, ovarian, andsmall-cell lung cancers. Oncology 12(8 suppl6):103-109, 1998.

19.

Ilson DH, Saltz L, Enzinger P, et al:Phase II trial of weekly irinotecan plus cisplatinin advanced esophageal cancer. J Clin Oncol17:3270-3275, 1999.

20.

Ueoka H, Tanimoto M, Kiura K, et al:Fractionated administration of irinotecan andcisplatin for treatment of non-small-cell lungcancer: A phase II study of Okayama LungCancer Study Group. Br J Cancer 85:9-13,2001.

21.

Choy H, MacRae R: Irinotecan in combined-modality therapy for locally advancednon-small-cell lung cancer. Oncology 15(1 suppl1):31-36, 2001.

22.

Sakata Y, Shimada Y, Yoshno M, et al:A late phase II study of CPT-11, irinotecanhydrochloride, in patients with advanced pancreaticcancer. CPT-11 Study Group on GastrointestinalCancer. Jpn J Cancer Chemother21:1039-1046, 1994.

23.

Bahadori HR, Lima CM, Green MR, etal: Synergistic effect of gemcitabine and irinotecan(CPT-11) on breast and small cell lungcancer cell lines. Anticancer Res 19:5423-5428,1999.

24.

Rocha Lima CS, Leong SS, ShermanCA, et al: Phase I study of CPT-11 and gemcitabinein patients with solid tumors. CancerTherapeut 2:58-66, 1999.

25.

Rocha Lima CM, Savarese D, BrucknerH, et al: Irinotecan plus gemcitabine inducesboth radiographic and CA 19-9 tumor markerresponses in patients with previously untreatedadvanced pancreatic cancer. J Clin Oncol20:1182-1191, 2002.