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Ifosfamide plus paclitaxel in advanced non-small-cell lung cancer: A phase I study
Annals of Oncology 7: 314-316, 1996. O 1996 Kluwer Academic Publishers. Printed in the Netherlands.
Short report Ifosfamide plus paclitaxel in advanced non-small-cell lung cancer: A phase I study P. C. Hoffman,l G. A. Masters,' L. C . Drinkard; S. A. K r a ~ s sB. , ~L. S a m ~ e l s , ~ H. M. Golomb l & E. E. Vokes
'
From the Department o f Medicine and Cancer Research Center, The University of Chicago; *LouisA . Weiss Memorial Hospital, Chicago, l , Ridge, IL, U.S.A. IL; 3 ~ u t h e r a~ ~e n e r a~l o s ~ i t aPark
Summary
Introduction Ifosfamide has sigmficant single-agent activity in nonsmall-cell lung cancer, producing response rates in excess of 2O0lO[I-31. In combinations including cisplatin plus either rnitomycin or etoposide, response rates in the 40%-50% range have been reported [3-51. Thus, ifosfamide merits attention as one of the more active drugs in the treatment of this disease. We have conducted a phase I clinical trial using ifosfamide in combination with paclitaxel, a newer agent recently having become available with activity in non-small-cell lung cancer. We chose paclitaxel because of its reported single-agent response rate in the 20%-25% range in phase II studies [6,7]. The general goal of this study was to identlfy an active combination of drugs with less significant subjective side effects than is found with cisplatin-containing combinations. A regimen with substantial activity in patients with stage IV disease might then also be inte-
Key words: non-small-cell lung cancer, chemotherapy, ifosfamide/paclitaxel
grated into combined-modality treatment programs for patients with stage 111 disease. Because the major toxicity of ifosfamide is myelosuppression, combination with another myelosuppressive agent such as paclitaxel is feasible using granulocyte-colony-stimulating factor (G-CSF) support. Patients and methods Study design The objectives of the study were to determine the maximum tolerated dose (MTD) and dose-limiting toxicities of paclitaxel administered over 24 hours in combination with a fixed dose of ifosfamide in a phase I dose-escalation study; to establish the maximum tolerated dose of both drugs with G-CSF support; to establish the feasibility of a one-hour infusion schedule of paclitaxel at the recommended phase II dose; and secondarily to assess in a preliminary fashion prior to formal phase II testing the response rate and survival for the combination in previously untreated patients with stage IIIB or IV non-small-cell lung cancer.
Downloaded from http://annonc.oxfordjournals.org/ by guest on June 7, 2016
Background: Ifosfamide and paclitaxel are active drugs in the management of non-small-cell lung cancer. We have performed a phase I study using a fixed dose of ifosfamide with escalating doses of paclitaxel, with G-CSF support, in an effort to determine the maximum tolerated dose (MTD) of paclitaxel in this combination, and to describe the dose-limiting toxicities of the combination at the recommended phase 11 dose of paclitaxel. We also studied the feasibility of delivering the paclitaxel as a one-hour infusion at the recomrnended phase 11dose. Patients and methods: Thirty-one patients were treated, 25 with stage IV disease, and 6 with stage IIIB disease. Ifosfamide was administered at a dose of 1.6 g/m2 i.v. bolus daily x 3 days, with mesna uroprotection. Paclitaxel was administered as a 24-hour infusion at dose levels of 135, 170, 200, 250, and 300 mg/m2; six patients were treated with a onehour infusion, at a dose of 250 mg/m2. G-CSF, 5 pg/kg, was administered subcutaneously on days 4 through 10, or until the absolute neutrophil count exceeded 4000/p1. Cycles
were repeated every 21 days. Results: The dose-limiting toxicity was granulocytopenia, which increased with increasing dose levels of paclitaxel. The MTD was 300 mg/m2 of paclitaxel, and the recommended phase 11dose 250 mg/m2 administered as a 24-hour infusion. Other toxicities were generally mild, with only 5 patients demonstrating grade 3 neurotoxicity and 5 with grade 3 thrombocytopenia. Partial responses were seen in seven patients (23%), all in the 18 patients who received dose levels of 250 mg/m2or higher. Conclusions: Ifosfamide plus paclitaxel is an active treatment regimen in advanced non-small-cell lung cancer, and compares favorably with the results of cisplatin-based chemotherapy. A phase I1 study is in progress by the Cancer and Leukemia Group B, in an effort to better characterize the tolerance of the regimen, as well as its effect on tumor response and survival.
Downloaded from http://annonc.oxfordjournals.org/ by guest on June 7, 2016
Downloaded from http://annonc.oxfordjournals.org/ by guest on June 7, 2016
Short report Ifosfamide plus paclitaxel in advanced non-small-cell lung cancer: A phase I study P. C. Hoffman,l G. A. Masters,' L. C . Drinkard; S. A. K r a ~ s sB. , ~L. S a m ~ e l s , ~ H. M. Golomb l & E. E. Vokes
'
From the Department o f Medicine and Cancer Research Center, The University of Chicago; *LouisA . Weiss Memorial Hospital, Chicago, l , Ridge, IL, U.S.A. IL; 3 ~ u t h e r a~ ~e n e r a~l o s ~ i t aPark
Summary
Introduction Ifosfamide has sigmficant single-agent activity in nonsmall-cell lung cancer, producing response rates in excess of 2O0lO[I-31. In combinations including cisplatin plus either rnitomycin or etoposide, response rates in the 40%-50% range have been reported [3-51. Thus, ifosfamide merits attention as one of the more active drugs in the treatment of this disease. We have conducted a phase I clinical trial using ifosfamide in combination with paclitaxel, a newer agent recently having become available with activity in non-small-cell lung cancer. We chose paclitaxel because of its reported single-agent response rate in the 20%-25% range in phase II studies [6,7]. The general goal of this study was to identlfy an active combination of drugs with less significant subjective side effects than is found with cisplatin-containing combinations. A regimen with substantial activity in patients with stage IV disease might then also be inte-
Key words: non-small-cell lung cancer, chemotherapy, ifosfamide/paclitaxel
grated into combined-modality treatment programs for patients with stage 111 disease. Because the major toxicity of ifosfamide is myelosuppression, combination with another myelosuppressive agent such as paclitaxel is feasible using granulocyte-colony-stimulating factor (G-CSF) support. Patients and methods Study design The objectives of the study were to determine the maximum tolerated dose (MTD) and dose-limiting toxicities of paclitaxel administered over 24 hours in combination with a fixed dose of ifosfamide in a phase I dose-escalation study; to establish the maximum tolerated dose of both drugs with G-CSF support; to establish the feasibility of a one-hour infusion schedule of paclitaxel at the recommended phase II dose; and secondarily to assess in a preliminary fashion prior to formal phase II testing the response rate and survival for the combination in previously untreated patients with stage IIIB or IV non-small-cell lung cancer.
Downloaded from http://annonc.oxfordjournals.org/ by guest on June 7, 2016
Background: Ifosfamide and paclitaxel are active drugs in the management of non-small-cell lung cancer. We have performed a phase I study using a fixed dose of ifosfamide with escalating doses of paclitaxel, with G-CSF support, in an effort to determine the maximum tolerated dose (MTD) of paclitaxel in this combination, and to describe the dose-limiting toxicities of the combination at the recommended phase 11 dose of paclitaxel. We also studied the feasibility of delivering the paclitaxel as a one-hour infusion at the recomrnended phase 11dose. Patients and methods: Thirty-one patients were treated, 25 with stage IV disease, and 6 with stage IIIB disease. Ifosfamide was administered at a dose of 1.6 g/m2 i.v. bolus daily x 3 days, with mesna uroprotection. Paclitaxel was administered as a 24-hour infusion at dose levels of 135, 170, 200, 250, and 300 mg/m2; six patients were treated with a onehour infusion, at a dose of 250 mg/m2. G-CSF, 5 pg/kg, was administered subcutaneously on days 4 through 10, or until the absolute neutrophil count exceeded 4000/p1. Cycles
were repeated every 21 days. Results: The dose-limiting toxicity was granulocytopenia, which increased with increasing dose levels of paclitaxel. The MTD was 300 mg/m2 of paclitaxel, and the recommended phase 11dose 250 mg/m2 administered as a 24-hour infusion. Other toxicities were generally mild, with only 5 patients demonstrating grade 3 neurotoxicity and 5 with grade 3 thrombocytopenia. Partial responses were seen in seven patients (23%), all in the 18 patients who received dose levels of 250 mg/m2or higher. Conclusions: Ifosfamide plus paclitaxel is an active treatment regimen in advanced non-small-cell lung cancer, and compares favorably with the results of cisplatin-based chemotherapy. A phase I1 study is in progress by the Cancer and Leukemia Group B, in an effort to better characterize the tolerance of the regimen, as well as its effect on tumor response and survival.
Downloaded from http://annonc.oxfordjournals.org/ by guest on June 7, 2016
Downloaded from http://annonc.oxfordjournals.org/ by guest on June 7, 2016