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© 2002 American Society for Clinical Oncology Dose-Escalating Study of Capecitabine Plus Gemcitabine Combination Therapy in Patients With Advanced CancerByFrom the Department of Medicine, Section of Hematology-Oncology, Cancer Research Center and Committee on Clinical Pharmacology, University of Chicago, Chicago, IL. Address reprint requests to Richard L. Schilsky, MD, Biological Sciences Division, MC 1000, University of Chicago, 5841 S Maryland Ave, Chicago, IL 60637; email: rschilsk{at}medicine.bsd.uchicago.edu
PURPOSE: The goals of this phase I study were to determine the maximum-tolerated doses of capecitabine and gemcitabine in patients with advanced cancer and to describe the dose-limiting toxicities (DLT) and safety profile of this combination.
PATIENTS AND METHODS: Eligible patients had advanced solid tumors that had failed to respond to standard therapy or for which no standard therapy was available, measurable or assessable disease, Karnofsky performance status RESULTS: Forty patients were enrolled onto the study, and 33 are fully assessable for toxicity. The most common toxicities during the first cycle of chemotherapy were neutropenia and mucositis. Only one patient treated at gemcitabine and capecitabine doses of 800 and 2000 mg/m2, respectively, met protocol-specified DLT criteria; however, at these doses 65% of successive cycles required dose reduction or delay for toxicity. No episodes of DLT were observed at gemcitabine and capecitabine doses of 1,000 and 1,660 mg/m2, respectively, and 70% of cycles of therapy were delivered without dose reduction or delay. Therefore, these doses are recommended for further study. Tumor responses were observed in patients with metastatic colorectal and pancreatic cancer. CONCLUSION: Gemcitabine and capecitabine can be combined with acceptable toxicity at nearly full doses. Antitumor activity of the combination merits further investigation in phase II studies.
CAPECITABINE IS AN orally administered, tumor-selective fluoropyrimidine that is converted to fluorouracil (5-FU) in tissues by pyrimidine nucleoside phosphorylase (PyNPase).1 Its tumor selectivity seems to be derived from selective overexpression of PyNPase, a pro-angiogenic molecule, in many tumors compared with normal tissues.2-5 Capecitabine has demonstrated activity in treatment of patients with breast and colorectal cancer.6,7 Gemcitabine is a pyrimidine nucleoside antimetabolite that, once converted to difluorodeoxycytidine triphosphate, inhibits DNA synthesis by inhibition of DNA polymerase and direct incorporation into DNA leading to premature termination of DNA chain elongation.8 The diphosphate intermediate of gemcitabine also inhibits ribonucleotide reductase and thereby depletes intracellular pools of deoxyuridine monophosphate, resulting in enhanced binding of 5-fluorodeoxyuridine monophosphate, the active metabolite of 5-FU, to thymidylate synthase.9,10 This biochemical interaction may explain the supra-additive effects of combining gemcitabine and capecitabine in MAXF401 and MX-1 human breast cancer xenograft models. In MX-1 human breast cancer, treatment with gemcitabine also resulted in a dose-dependent 1.5- to 2.7-fold increase in expression of PyNPase and, presumably, an increase in intracellular release of 5-FU from capecitabine (H. Ishitsuka, personal communication, January, 2001). In vitro studies in colon cancer cells have also demonstrated synergy when exposure to 5-FU precedes exposure to gemcitabine.11 These preclinical studies provided the basis for a number of phase I clinical trials that examined combinations of 5-FU and gemcitabine administered on several doses and schedules. At the University of Chicago, we conducted a phase I trial of continuous intravenous infusion of 5-FU with weekly 30-minute intravenous infusions of gemcitabine.12 The recommended phase II doses determined in this study were 5-FU 200 mg/m2/d for 21 days with gemcitabine 450 mg/m2 weekly for 3 consecutive weeks or 5-FU 200 mg/m2/d for 14 days with gemcitabine 1,800 mg/m2 weekly for 2 consecutive weeks. Dose-limiting toxicities (DLT) were mucositis, bone marrow suppression, and diarrhea. Tumor responses were observed in several tumor types, most notably renal cell carcinoma (RCC). A subsequent phase II trial of this combination was conducted in patients with metastatic RCC most of whom had already been treated with immunotherapy or chemotherapy.13 5-FU was administered by continuous infusion at a dose of 150 mg/m2/d for 21 days with gemcitabine at 600 mg/m2 weekly for 3 weeks. Cycles were repeated every 28 days. Toxicities were primarily bone marrow suppression, mucositis, nausea, and fatigue. Partial responses were noted in 7 of 39 assessable patients (17%; 95% confidence interval, 8% to 34%). Median progression-free survival for patients in this study was 28.7 weeks, which was significantly better than that observed in similar patients with RCC treated on other phase II studies at our institution. Because daily oral capecitabine can mimic continuous infusion of 5-FU and because upregulation of PyNPase by gemcitabine can enhance the intracellular activation of capecitabine, we undertook a phase I trial of these drugs in combination with the primary objectives to determine the maximum-tolerated doses (MTD) of capecitabine and gemcitabine in patients with advanced cancer and to describe the DLT and safety profile of this combination.
Patient Selection Patients with histologically confirmed advanced solid tumors that had failed to respond to standard therapy or for which no standard therapy was available were eligible to participate in this study. Other eligibility criteria included measurable or assessable disease by computed tomography, magnetic resonance imaging, radiograph, or physical examination; age at least 18 years; Karnofsky performance status of at least 70% (ambulatory and capable of self-care); life expectancy of at least 3 months; and adequate organ function defined as absolute neutrophil count of at least 1,500/µL, platelet count of at least 100,000/µL, hemoglobin at least 9.0 g/dL, serum creatinine level < 1.6 mg/dL, total bilirubin < 2.0 mg/dL, serum albumin > 2.5 g/dL, prothrombin time < 1.5 times control level, AST and ALT levels < 2.5 times the upper limit of normal or < five times the upper limit of normal if liver metastases were present, and serum alkaline phosphatase < 2.5 times the upper limit of normal or < five times the upper limit of normal if liver metastases were present or < 10 times the upper limit of normal if bone metastases were present. Patients must have been off previous anticancer therapy, including radiation therapy, for at least 4 weeks (6 weeks if the previous therapy included a nitrosourea or mitomycin) and must have recovered from the toxic effects of any previous therapy. Patients were excluded from the study if they had any unstable, pre-existing medical condition, prior unanticipated severe reaction to fluoropyrimidine therapy, organ allograft, evidence of CNS metastases, or history of significant gastric or small bowel resection, malabsorption syndrome, or other lack of integrity of the upper gastrointestinal tract that might compromise absorption of capecitabine. Pregnant and lactating women were also excluded from participation, and all patients with reproductive potential were required to use an effective contraceptive method if they were sexually active. All patients gave written informed consent according to federal and institutional guidelines.
Study Design
Dose-Escalation and Definition of Study End Points Capecitabine was supplied by Roche Pharmaceuticals (Nutley, NJ) as Xeloda tablets in two dosage strengths, 150-mg and 500-mg tablets. The total daily dose was taken as two divided doses approximately 12 hours apart within 30 minutes after the ingestion of food. The two doses were divided so as to allow the administration of whole tablets. Gemcitabine was commercially available as Gemzar (Eli Lilly, Indianapolis, IN) in 20-mg/mL vials, 10- and 50-mL sizes. The drug was prepared for administration according to directions in the package labeling.
For purposes of determining the MTD, only DLTs occurring during the first cycle of therapy were considered. DLTs were defined as any of the following: grade 4 neutropenia lasting at least 3 days or grade 3 or 4 neutropenia associated with fever
Pretreatment and Follow-Up Studies
Dose Modifications
The characteristics of the 40 patients enrolled onto this study are listed in Table 2. The median age was 65 years (range, 41 to 83 years) and the median Karnofsky performance status was 80% (range, 70% to 100%). All but two patients had previously received chemotherapy.
Seven patients did not complete the first cycle of therapy and are, therefore, not assessable for toxicity. Three patients were noncompliant with the treatment protocol; one patient had rapid tumor progression and was withdrawn from the study, one patient developed sepsis from a pre-existing indwelling central venous catheter shortly after beginning treatment, one patient developed arm pain within 2 days of initiating chemotherapy and withdrew from the study to undergo a cardiac evaluation, and one patient was determined to be ineligible because of a prior bone marrow transplant. The dose levels evaluated in the 33 fully assessable patients are listed in Table 3.
The most common toxicities observed during the first cycle of chemotherapy are listed in Tables 4 and5. The severity of neutropenia and mucositis increased with increasing doses of chemotherapy, although only one patient, treated at gemcitabine/capecitabine doses of 800/2,000 mg/m2, respectively, met protocol-specified criteria for DLT (grade 3 mucositis). Although no episodes of DLT were observed at gemcitabine/capecitabine doses of 1,000/1,660 mg/m2, respectively, further escalation of the gemcitabine dose above the standard dose of 1,000 mg/m2 was prohibited by the protocol. Furthermore, our ability to administer successive cycles of chemotherapy without dose modification necessitated by toxicity became increasingly difficult at higher dosage levels. Table 6 lists the number of cycles of chemotherapy at each dosage level requiring protocol-specified dose reduction or delay because of severe or unresolved toxicity. At the gemcitabine/capecitabine dose level of 800/2,000 mg/m2, respectively, 15 (65%) of 23 cycles of therapy (cycle 2 or higher) required dose reduction or delay for toxicity. In 10 of the 15 dose-modified cycles, dose reduction or delay was required because of grade 2 to 3 neutropenia or thrombocytopenia that had occurred during the prior cycle of therapy. Despite the 3-week duration of dosing, few patients experienced clinically significant hand-foot syndrome (grade 2 or higher), and no patients experienced febrile neutropenia or required platelet transfusion. Based on the absence of DLT in cycle 1 and the ability to deliver 70% of successive cycles without dose modification or delay, we recommend doses of gemcitabine and capecitabine of 1,000 mg/m2 and 1,660 mg/m2, respectively, for further evaluation in phase II studies.
Although assessment of tumor response was not a primary objective of this study, patients were evaluated for tumor response after every two cycles of treatment. Partial or significant minor responses occurred in four patients whose characteristics are listed in Table 7. The time to progression for these patients ranged from 24 to 32 weeks. The responses in the colon cancer patients are of particular note in that all had previously received fluoropyrimidine-based therapy. The median time to progression for all 33 assessable patients was 12 weeks ranging from 4 to 32 weeks and 16 patients had a time to progression of 16 weeks or longer.
A number of phase I and II trials have now been completed that evaluated various ways of combining 5-FU and gemcitabine.12-19 In most studies, DLTs of the combination have included mucositis, fatigue, thrombocytopenia, and neutropenia. 5-FU has often been administered as a continuous intravenous infusion for 14 to 21 days, requiring that patients have central venous catheters and infusion pumps. Activity of the combination has been reported in patients with pancreatic cancer and RCC.13,16,19 At the University of Chicago, we have conducted phase I and II trials of infusional 5-FU and gemcitabine. In patients with RCC, partial responses were observed in seven of 39 assessable patients (17%, 95% confidence interval, 8% to 34%). Toxicities were primarily neutropenia, mucositis, and fatigue, and infectious complications included an episode of Staphylococcus aureus endocarditis and a central line infection.13 Therefore, we sought to develop a combination of gemcitabine with capecitabine that would mimic the continuous intravenous infusion of 5-FU used in our prior studies without the complications related to indwelling venous catheters. Indeed, the 21-day regimen described here allows administration of gemcitabine at standard doses (1,000 mg/m2/wk) with capecitabine at doses that provide similar dose-intensity to the standard dose and schedule for this agent and the same total dose per cycle, ie, 1,660 mg/m2/d for 21 days is equivalent to 2,500 mg/m2/d for 14 days. This regimen is generally well tolerated, with the major toxicity being neutropenia and anemia at the recommended phase II dose. Remarkably, little clinically significant hand-foot syndrome was observed despite the 21-day schedule of capecitabine administration. Repetitive cycles could be administered without dose reduction or delay in 70% of cycles, and dose delays, when necessary, rarely required interruption of therapy for longer than 1 week. Indeed, 15 of the 33 fully assessable patients received four or more cycles of therapy, with two patients receiving eight cycles. At the recommended gemcitabine and capecitabine doses of 1,000 mg/m2 and 1,660 mg/m2, respectively, seven of 12 patients received four or more cycles of treatment, with four of these seven patients receiving all cycles of chemotherapy without dose reduction or delay. We were encouraged to observe significant antitumor activity in this heavily pretreated patient population. Four patients had minor or partial responses with progression-free survival of 24 to 32 weeks. Disease stabilization was also observed in 12 patients who, therefore, received multiple cycles of treatment. Phase II studies are now being planned for patients with pancreatic cancer and RCC to further define the antitumor activity and tolerability of this regimen. Pharmacologic studies were not performed as part of this clinical trial, but it is unlikely that such studies would have contributed much information at this point in the development of this regimen. Gemcitabine is metabolized by deoxycytidine kinase to inactive compounds that are then eliminated primarily by renal excretion. Capecitabine undergoes a complex metabolic activation, but the final cytotoxic derivative, 5-FU, is then rapidly degraded by dihydropyrimidine dehydrogenase to biologically inactive compounds.1 Given the substrate specificity of these metabolic pathways, it is unlikely that a pharmacokinetic interaction would occur between gemcitabine and capecitabine. Overexpression of PyNPase in tumor cells may be an important, although not the sole determinant of tumor response to fluoropyrimidines, particularly capecitabine. Cellular levels of thymidylate synthase and dihydropyrimidine dehydrogenase are likely to be important determinants of outcome as well.20 Because tumor response was not a primary end point of our study, we did not evaluate tumor blocks for expression of these enzymes. Such studies are likely to be more informative if performed in the context of phase II and III clinical trials where a more homogeneous population of patients is treated with uniform doses of chemotherapy with the goal of assessing antitumor activity and determining the characteristics of those tumors most likely to respond to therapy with this regimen.
Supported in part by grant no. CA 14599 and by a grant from Hoffman-LaRoche, Inc, Nutley, NJ.
Presented at the Thirty-Seventh Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12-15, 2001.
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Huang P, Chubb S, Hertel LW, et al: Action of 2,2-difluoro 2-deoxycytidine on DNA synthesis. Cancer Res 51: 6110–6117, 1991 9. Heineman V, Xu YZ, Chubb S, et al: Inhibition of ribonulceotide reduction in CCRF-CLM cells by 2, 2-difluoro-2-deoxycytidine. Mol Pharmacol 38: 567–572, 1990[Abstract] 10. Ren Q, Kao V, Grem JL: Cytotoxicity and DNA fragmentation associated with sequential gemcitabine and 5-fluoro 2-deoxyuridine in HT-29 colon cancer cells. Clin. Cancer Res 4: 2811–2818, 1998 11. Schulz L, Schalhorn A, Wilmanns W, et al: Synergistic interactions of gemcitabine and 5-FU in colon cancer cells. Proc Am Soc Clin Oncol 17: 251a, 1998 (abstr 965) 12. Mani S, Vogelzang NJ, Bertucci D, et al: Phase I study to evaluate multiple regimens of intravenous 5-fluorouracil administered in combination with weekly gemcitabine in patients with advanced solid tumors: A potentially broadly active regimen for advanced solid tumor malignancies. Cancer 92: 1567–1576, 2001[CrossRef][Medline]
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Oettle H, Arning M, Pelzer U, et al: A phase II trial of gemcitabine in combination with 5-fluorouracil and folinic acid in patients with chemonaive advanced pancreatic cancer. Ann Oncol 11: 1267–1272, 2000 19. Shulman KL, Kindler HL, Lad TE, et al: Phase II study of gemcitabine and continuous intravenous infusion of 5-fluorouracil in advanced pancreatic cancer: A University of Chicago phase II consortium study. Proc Am Soc Clin Oncol 19: 288a, 2000 (abstr 1126)
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Salonga D, Danenberg K, Johnson M, et al: Colorectal tumors responding to 5-fluorouracil have low gene expression levels of dihydropyrimidine dehydrogenase, thymidylate synthase and thymidine phosphorylase. Clin Cancer Res 6: 1322–1327, 2000 Submitted April 5, 2001; accepted May 21, 2001. This article has been cited by other articles:
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
70%, and acceptable organ function. Capecitabine was administered twice daily by mouth each day for 21 consecutive days followed by a 1-week break. Gemcitabine was administered as a 30-minute intravenous infusion weekly for 3 weeks followed by a 1-week break. 
