Phase I trial of multiple cycles of high-dose carboplatin, paclitaxel, and topotecan with peripheral-blood stem-cell support as front-line therapy.

PURPOSE To determine the safety and feasibility of delivering multiple cycles of front-line high-dose carboplatin, paclitaxel, and topotecan with peripheral-blood stem-cell (PBSC) support. PATIENTS AND METHODS Patients were required to have a malignant solid tumor for which they had received no prior chemotherapy. Mobilization of PBSC was achieved with either filgrastim alone or in combination with cyclophosphamide and paclitaxel. Patients then received three or four cycles of high-dose carboplatin (area under the concentration-time curve [AUC] 16), paclitaxel (250 mg/m(2)), and topotecan (10-15 mg/m(2)), with the latter two agents administered as 24-hour infusions and supported with PBSC and filgrastim. Cycles were repeated every 28 days. RESULTS Twenty patients were enrolled onto the trial and were assessable for toxicity and clinical outcome. Dose-limiting toxicities were stomatitis and prolonged hematopoietic recovery. The maximum-tolerated dose of topotecan was 12.5 mg/m(2) when given with high-dose carboplatin and paclitaxel for three cycles. Four cycles were able to be given with a dose of topotecan of 10 mg/m(2). The pharmacokinetics of each compound were not affected by the other agents. Eleven (85%) of 13 patients with assessable disease responded. CONCLUSION Multiple cycles of high-dose carboplatin, paclitaxel, and topotecan can be safely administered with filgrastim and PBSC support. The recommended doses for phase II study are carboplatin AUC 16, paclitaxel 250 mg/m(2), and topotecan 10 mg/m(2). Trials are currently being conducted with this regimen as front-line treatment in patients with advanced ovarian cancer and extensive small-cell carcinoma. This approach remains experimental and should be used only in the context of a clinical trial.

[1]  M. Morgan,et al.  Lack of efficacy of 24-h infusional topotecan in platinum-refractory ovarian cancer: A Gynecologic Oncology Group trial. , 1999, Gynecologic oncology.

[2]  M. Millenson,et al.  Phase I trial of multiple cycles of high-dose chemotherapy supported by autologous peripheral-blood stem cells. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  D. Richel,et al.  Phase I and pharmacologic study of the combination of paclitaxel, cisplatin, and topotecan administered intravenously every 21 days as first-line therapy in patients with advanced ovarian cancer. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  C. Pacilio,et al.  Cisplatin-topotecan-paclitaxel weekly administration with G-CSF support for ovarian and small-cell lung cancer patients: a dose-finding study. , 1999, Annals of oncology : official journal of the European Society for Medical Oncology.

[5]  A. Lissoni,et al.  Topotecan for the treatment of advanced epithelial ovarian cancer: an open-label phase II study in patients treated after prior chemotherapy that contained cisplatin or carboplatin and paclitaxel. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  E. Eisenhauer,et al.  Randomized phase II study of two schedules of topotecan in previously treated patients with ovarian cancer: a National Cancer Institute of Canada Clinical Trials Group study. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  S Zacks,et al.  Cancer phase I clinical trials: efficient dose escalation with overdose control. , 1998, Statistics in medicine.

[8]  E. Venkatraman,et al.  Phase II study of "dose-dense" high-dose chemotherapy treatment with peripheral-blood progenitor-cell support as primary treatment for patients with advanced ovarian cancer. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  A. W. Boersma,et al.  Synergistic cytotoxicity of cisplatin and topotecan or SN-38 in a panel of eight solid-tumor cell lines in vitro , 1998, Cancer Chemotherapy and Pharmacology.

[10]  W. Mcguire CLINICAL STATUS AND OPTIMAL USE OF TOPOTECAN , 1997 .

[11]  R. Ozols,et al.  Short-course intravenous prophylaxis for paclitaxel-related hypersensitivity reactions. , 1997, Annals of oncology : official journal of the European Society for Medical Oncology.

[12]  A Gordon,et al.  Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer. , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  A. Pileri,et al.  High-dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B-cell lymphoma. , 1997, The New England journal of medicine.

[14]  R. Ozols,et al.  Phase I trial and pharmacologic trial of sequences of paclitaxel and topotecan in previously treated ovarian epithelial malignancies: a Gynecologic Oncology Group study. , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  L. Grochow,et al.  Sequences of topotecan and cisplatin: phase I, pharmacologic, and in vitro studies to examine sequence dependence. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  K. Hess,et al.  Phase I clinical and plasma and cellular pharmacological study of topotecan without and with granulocyte colony-stimulating factor. , 1996, Clinical cancer research : an official journal of the American Association for Cancer Research.

[17]  J. Beijnen,et al.  Clinical Pharmacokinetics of Topotecan , 1996, Clinical pharmacokinetics.

[18]  R. Ozols,et al.  Carboplatin and paclitaxel in ovarian carcinoma: a phase I study of the Gynecologic Oncology Group. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  P B Laub,et al.  NCOMP--a windows-based computer program for noncompartmental analysis of pharmacokinetic data. , 1996, Journal of pharmaceutical sciences.

[20]  L. Grochow,et al.  Phase I and pharmacologic study of high doses of the topoisomerase I inhibitor topotecan with granulocyte colony-stimulating factor in patients with solid tumors. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[21]  C. Obasaju,et al.  Evaluation of carboplatin pharmacokinetics in the absence and presence of paclitaxel. , 1996, Clinical cancer research : an official journal of the American Association for Cancer Research.

[22]  N. Saijo,et al.  Synergism between cisplatin and topoisomerase I inhibitors, NB-506 and SN-38, in human small cell lung cancer cells. , 1996, Cancer research.

[23]  E. Partridge,et al.  Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer , 1996, New England Journal of Medicine.

[24]  T. Shea,et al.  A clinical and pharmacokinetic study of high-dose carboplatin, paclitaxel, granulocyte colony-stimulating factor, and peripheral blood stem cells in patients with unresectable or metastatic cancer. , 1995, Seminars in oncology.

[25]  R. Ozols,et al.  Paclitaxel and carboplatin in combination in the treatment of advanced non-small-cell lung cancer: a phase II toxicity, response, and survival analysis. , 1995, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[26]  S. Rodenhuis,et al.  Phase I clinical and pharmacokinetic study of topotecan administered by a 24-hour continuous infusion. , 1995, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[27]  H. Rosing,et al.  High-performance liquid chromatographic determination of the novel antitumour drug topotecan and topotecan as the total of the lactone plus carboxylate forms, in human plasma. , 1995, Journal of chromatography. B, Biomedical applications.

[28]  B. Barlogie,et al.  Peripheral blood stem cell transplants for multiple myeloma: identification of favorable variables for rapid engraftment in 225 patients. , 1995, Blood.

[29]  G. Rosner,et al.  Phase I study of topotecan and cisplatin in patients with advanced solid tumors: a cancer and leukemia group B study. , 1994, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[30]  R. Motzer,et al.  Computerized quantitation of synergism and antagonism of taxol, topotecan, and cisplatin against human teratocarcinoma cell growth: a rational approach to clinical protocol design. , 1994, Journal of the National Cancer Institute.

[31]  G. Peters,et al.  Antiproliferative activity of the topoisomerase I inhibitors topotecan and camptothecin, on sub- and postconfluent tumor cell cultures. , 1994, Biochemical pharmacology.

[32]  L. Saltz,et al.  Phase I clinical and pharmacology study of topotecan given daily for 5 consecutive days to patients with advanced solid tumors, with attempt at dose intensification using recombinant granulocyte colony-stimulating factor. , 1993, Journal of the National Cancer Institute.

[33]  S. Arbuck,et al.  Taxol: the first of the taxanes, an important new class of antitumor agents. , 1992, Seminars in oncology.

[34]  E Wiltshaw,et al.  Carboplatin dosage: prospective evaluation of a simple formula based on renal function. , 1989, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[35]  D. Ettinger,et al.  Phase I and pharmacodynamic study of taxol in refractory acute leukemias. , 1989, Cancer research.

[36]  R. Lipton,et al.  Phase I trial of taxol given as a 24-hour infusion every 21 days: responses observed in metastatic melanoma. , 1987, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  E. Gluckman,et al.  PROPHYLAXIS OF HERPES INFECTIONS AFTER BONE-MARROW TRANSPLANTATION BY ORAL ACYCLOVIR , 1983, The Lancet.

[38]  Roger W. Jelliffe,et al.  Creatinine Clearance: Bedside Estimate , 1973 .