Summary
Gemcitabine (GEM) is a novel deoxycytidine analogue which has shown promising antitumor activity in solid tumor models and a broad range of schedule-dependent MTDs (12-4560 mg/m2) in preliminary clinical studies. The present phase I trial evaluated escalating doses of weekly GEM using a 30-min infusion at a starting dose-level of 300 mg/m2/wk x 3 every 28 days.
At least 3 patients entered each dose-level step and 3 more cases were treated when significant toxicity was seen. A total of 39 patients with various advanced solid tumors and prior chemotherapy entered this study.
Six escalation steps (102 courses) were tested to define the MTD at 1,370 mg/m2/wk. No definite dose-effect relationships were observed for myelosuppression up to 1,095 mg/m2/wk. However, increased severity of leucopenia (dose-limiting) and greater non-hematologic toxicity as well as a higher number of toxic treatment delays, requiring subsequent dose attenuation in 6 out of 12 patients, were observed at 1,370 mg/ m2/wk. In all, 6 out of 11 patients experiencing WHO grade≥ 3 toxicity (11/21 events recorded in 11/18 courses) were treated at the MTD. Clinically significant toxicity included (patients with WHO grade 2–3): leucopenia (44%), thrombocytopenia (26%), anemia (23%), fever (69%), emesis (38%) and AST/ALT rise (26%). Mild proteinuria, ankle edema, skin rash, hair loss and mucositis were seen in ≤ 5%.
The good tolerability and the evidence of antitumor activity of GEM at doses ≥ 875 mg/m2/wk (1 CR and 3 PRs in 15 bladder cancer patients) encourage further phase II studies at much higher dose-levels (1,370 mg/m2) than previously suggested.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Data on file. Eli-Lilly Co, Indianapolis, IN
Hertel LW, Boder GB, Kroin JS, Rinzel SM, Poore GA, Todd GC, Grindey GBI: Evaluation of the antitumor activity of gemcitabine (difluor-2′-deoxy-cytidine). Cancer Res 50:4417–4422, 1990
Heinemann V, Hertel LW, Grindey GB, Plunkett W: Comparison of the cellular pharmacokinetics and toxicity of 2′2′-difluoro-deoxycytidine and 1B D-Arabinofurosylcytosine. Cancer Res 48:4024–4031, 1988
Huang P, Chubb S, Hertel LW, Grindey GB, Plunkett W: Action of 2′2′-difluoro-deoxycytidine on DNA synthesis. Cancer Res 51:6110–6117, 1991
Grunewald R, Kantarjian H, Keating MJ, Abbruzzese J, Tarasoff P, Plunkett W: Pharmacologically directed design of the dose rate and schedule of 2′2′-difluorodeoxy-cytidine (gemcitabine) administration in leukemia. Cancer Res 50:6823–6826, 1990
Abbruzzese JL, Grunewald R, Weeks EA, Gravel D, Adams T, Nowak B, Mineishi S, Tarasoff P, Satterlee W, Raber MN, Plunkett W: A phase I clinical, plasma and cellular pharmacology study of gemcitabine. J Clin Oncol 9:491–498, 1991
O'Rourke T, Brown T, Havlin K, Kuhn J, Craig J, Boldt D, Burris H, Hamilton M, Satterlee W, Tarasoff P, Von Hoff D: Phase I trial and immunologie assessment of difluorodeoxycytidine. Proc Am Soc Clin Oncol 8:82, 1989
Poplin E, Corbett T, Flaherty L, Tarasoff P, Redman BG, Valdivieso M, Baker L: Difluorodeoxycytidine (dFdC)-gemcitabine: A phase I study. Investigational New Drugs 10:165–170, 1992
Tanis B, Clavel M, Guastalla J, Osborne D, Quik R, McDaniel C, Pinedo H, Vermorken J: Phase I study of gemcitabine (difluorodeoxycytidine, dFdC (LY188011)) administered in a two-weekly schedule. Proc Am Ass Ca Res 31:207, 1990
Abratt R, Bezwoda W, Falkson G, Goedhals L, Hacking D, Rugg T: Efficacy and safety of gemcitabine in non-small cell lung cancer. Phase II study results. Proc Am Soc Clin Oncol 12:338, 1993
Lund B, Hansen OP, Theilade K, Hansen M, Neijt JP: Phase II study of gemcitabine in previously platinum treated ovarian cancer patients. An update. Proc A Soc Clin Oncol 12:262, 1993
Charmichael J, Possinger K, Philip P, Beykrich M, Kerr H, Walling J, Harris AL: Difluorodeoxy-cytidine (gemcitabine): A phase II study in patients with advanced breast cancer. Proc Am Soc Clin Oncol 12:64, 1993
Cormier Y, Eisenhauer E, Gregg R, Ayoub J, Goss G, Stewart D, Muldal A, Tarasoff P: Gemcitabine: an active new agent in patients with previously untreated small cell lung cancer. A phase II trial of the NCI Canada Clinical Trials Group. Proc Am Soc Clin Oncol 12:330, 1993
Pollera CF, Ceribelli A, Crecco M, Moreschi M, Voi M, Calabresi F: Weekly gemcitabine (2′2′-difluorodeoxy-cytidine, LY188011): A priliminary report of a phase I study. Ann Oncol l(suppl l):40(abs. P5:28), 1990
Hryniuk WM, Goodyear M: The calculation of received dose-intensity. J Clin Oncol 8:1935–1937, 1990
Miller AB, Hoogstraten B, Staquet B, Winkler A: Reporting results of cancer treatment. Cancer 47:207–224, 1981
Hanauske AR, Degen D, Marshall MH, Hilsenbeck SG, Grindey GB, Von Hoff DD: Activity of 2′2′-difluoroxycytidine (gemcitabine) against human tumor colony forming units. Anti Cancer Drugs 3:143–146, 1992
Grunewald R, Kantarjian H, Du M, Faucher K, Tarasoff P, Plunkett W: Gemcitabine in leukemia: a phase I clinical, plasma and cellular pharmacology study. J Clin Oncol 10:406–413, 1992
Pollera CF, Ceribelli A, Crecco M, Sabino F, Calabresi F: Weekly gemcitabine: a phase I study with short and prolonged infusion schedules. Proc Am Soc Clin Oncol 11:127, 1992
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Pollera, C.F., Ceribelli, A., Creccon, M. et al. Weekly gemcitabine in advanced or metastatic solid tumors. Invest New Drugs 12, 111–119 (1994). https://doi.org/10.1007/BF00874440
Issue Date:
DOI: https://doi.org/10.1007/BF00874440