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Weekly gemcitabine in advanced or metastatic solid tumors

A clinical phase I study

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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.

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References

  1. 1.

    Data on file. Eli-Lilly Co, Indianapolis, IN

  2. 2.

    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

  3. 3.

    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

  4. 4.

    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

  5. 5.

    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

  6. 6.

    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

  7. 7.

    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

  8. 8.

    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

  9. 9.

    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

  10. 10.

    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

  11. 11.

    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

  12. 12.

    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

  13. 13.

    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

  14. 14.

    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

  15. 15.

    Hryniuk WM, Goodyear M: The calculation of received dose-intensity. J Clin Oncol 8:1935–1937, 1990

  16. 16.

    Miller AB, Hoogstraten B, Staquet B, Winkler A: Reporting results of cancer treatment. Cancer 47:207–224, 1981

  17. 17.

    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

  18. 18.

    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

  19. 19.

    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

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Correspondence to Camillo F. Pollera.

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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

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Key words

  • gemcitabine
  • phase I study
  • solid tumors