Summary
Background: Gemcitabine is a pro-drug that has to be phosphorylated to gemcitabine-triphosphate in order to exhibit its antineoplastic activity. This reaction involves the enzyme deoxycytidine kinase which is saturated at plasma concentrations following standard 30-min infusions. Pharmacological studies indicate that prolonged administration of gemcitabine might result in higher intracellular concentrations of active metabolites. This phase I trial was therefore initiated to determine the optimal dose of gemcitabine administered over 4h in patients with advanced solid tumors. Patients and Methods: Patients were treated with gemcitabine as 4h-infusion on day 1, 8 and 15 in 4 week intervals. The starting dose was 350 mg/m2. Doses were escalated in 50 mg/m2 increments.
Results: Twenty-one patients were treated at doses ranging from 350 to 450 mg/m2. The maximum tolerated dose was 400 mg/m2 with neutropenia, thrombocytopenia, stomatitis and elevation of liver enzymes being dose limiting toxicities (DLTs). Hematologic and nonhematological toxicities were generally mild to moderate. Most common side effects were myelosuppression, nausea, elevation of liver enzymes and asthenia. Objective responses were noted in patients with hepatocellular carcinoma and cholangio-carcinoma.
Conclusion: In this phase I study of gemcitabine as 4h-infusion, DLTs were neutropenia, thrombocytopenia, stomatitis and elevation of liver enzymes. The recommended dose for phase II studies is 400 mg/m2.
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References
Kaye SB: Gemcitabine: Current status of phase I and II trials. J Clin Oncol 12(8): 1527–1531, 1994
Heinemann V, Schukz L, Issels RD, Plunkett W: Gemcitabine: A modulator of intracellular nucleotide and deoxynucleotide metabolism. Semin Oncol 22(suppl 11): 11–18, 1995
Plunkett W, Huang P, Xu YZ, Heinemann V, Grunewald R, Gandhi V: Gemcitabine: Metabolism, mechanisms of action, and self-potentiation. Semin Oncol 22(suppl 11): 3–10, 1995
Huang P, Plunkett W: Induction of apoptosis by gemcitabine. Semin Oncol 22(suppl 11): 19–25, 1995
Grunewald R, Abbruzzese JL, Tarassoff P, Plunkett W: Saturation of 2′,2′-difluorodeoxycytidine 5′-triphosphate accumulation by mononuclear cells during a phase I trial of gemcitabine. Cancer Chemother Pharmacol 27(4): 258–262, 1991
Abbruzzese JL, Grunewald R, Weeks EA, Gravel D, Adams T, Nowak B, Mineishi S, Tarassoff P, Satterlee W, Raber MN: A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J Clin Oncol 9(3): 491–498, 1991
Bouffard DY, Laliberte J, Momparler RL: Kinetic studies on 2′2′-difluorodeoxycitidin with purfied human deoxycitidine kinase and cytidine deaminase. Biochem Pharmac 45: 1875–1861, 1993
Grunewald R, Kantarjian H, Keating M, Abbruzzese J, Tarassoff P, Plunkett W: Pharmacologically directed design of the dose rate and schedule of 2′2′-difluorodeoxycitidin (gemcitabine) administration in leukemia. Cancer Res 50: 6823–6826, 1990
Veerman G, Ruiz van Haperen VW, Vermorken JB: Antitumor activity of prolonged as compared with bolus administration of 2′,2′-difluorodeoxycytidine in vivo against murine colon tumors. Cancer Chemother Pharmacol 38(4): 335–342, 1996
Pollera CF, Ceribelli A, Crecco M, Oliva C, Calabresi F: Prolonged infusion of gemcitabine: A clinical phase I study at low- (300mg/m2) and high- (875mg/m2) levels. Invest New Drugs 15(2): 115–121, 1997
Akrivakis K, Schmid P, Flath B, Schweigert M, Mergenthaler HG, Possinger K: Prolonged infusion of gemcitabine in stage IV breast cancer: A phase-I-study. Anticancer Drugs 10(6): 525–531, 1999
Schmid P, Akrivakis K, Flath B, Grosse Y, Sezer O, Possinger K: A phase II trial of gemcitabine as prolonged infusion in metastatic breast cancer. Anticancer Drugs 10(7): 625–31, 1999
Publication in preparation (Flath B, Possinger K)
Tonato M, Mosconi AM, Martin C: Safety profile of gemcitabine. Anticancer Drugs 6(suppl 6): 27–32, 1995
Maurel J, Zorrilla M, Puertolas T, Anton A, Herrero A, Artal A, Alonso V, Martinez-Trufero J, Puertas MM: Phase I trial of weekly gemcitabine at 3-h infusion in refractory, heavily pretreated advanced solid tumors. Anticancer Drugs 12(9): 713–717, 2001
Brand R, Capadano M, Tempero M: A phase I trial of weekly gemcitabine administered as a prolonged infusion in patients with pancreatic cancer and other solid tumors. Invest New Drugs 15(4): 331–341, 1997
Touroutoglou N, Gravel D, Raber MN, Plunkett W, Abbruzzese JL: Clinical results of a pharmacodynamically-based strategy for higher dosing of gemcitabine in patients with solid tumors. Ann Oncol 9: 1003–1008, 1998
Mani S, Kugler JW, Knost JA, Sciortino DF, Gibbons J, Garcia JC, Ansari RH, Schilsky RL, Vokes EE: Phase II trial of 150-minute weekly infusion of gemcitabine in advanced colorectal cancer: Minimal activity in colorectal cancer. Invest New Drugs 16: 275–278, 1999
Cascinu S, Frontini L, Labianca R, Catalano V, Barni S, Graiff C, Picone G, Farinati E, Zonato S, Pessi MA, Curti C, Catalano G: A combination of a fixed dose rate infusion of gemcitabine associated to a bolus-5-fluorouracil in advanced pancreatic cancer: A report from the Italian Group for the Study of Digestive Tract. Ann Oncol 11: 1309–1311, 2000
Poplin E, Benson A, Musanti R, Rubin E, Mulcahy M: Pilot study of gemcitabine (10 mg/m2 per min) and cisplatin. Cancer Chemother Pharmacol 50(1): 80–83, 2002
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Schmid, P., Schweigert, M., Beinert, T. et al. Prolonged infusion of gemcitabine in advanced solid tumors: A phase-I-study. Invest New Drugs 23, 139–146 (2005). https://doi.org/10.1007/s10637-005-5859-4
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DOI: https://doi.org/10.1007/s10637-005-5859-4