Phase i study of capecitabine in combination with cisplatin and irinotecan in patients with advanced solid malignancies

H. Sayar, Z. Shen, S. J. Lee, M. Royce, I. Rabinowitz, F. Lee, Harriet O. Smith, S. Eberhardt, A. Maestas, H. Lu, C. Verschraegen

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Abstract

This phase I trial assessed the safety and the maximum tolerated dose of capecitabine given for 10 days prior to a combination of cisplatin and irinotecan in patients with advanced solid malignancies. It also evaluated the changes in cisplatin DNA adducts induced by capecitabine. Patients and Methods: Patients with refractory solid tumors who had not failed 5-fluorouracil (5-FU) analogs or topoisomerase I inhibitors were eligible. All cohorts of patients first received a 28-day cycle of cisplatin and irinotecan. Both drugs were given at a dose of 50 mg/m2 intravenously on day 1, followed by irinotecan on days 8 and 15 at the same dose. The first cycle served as an internal control. Starting from the second cycle, patients received increasing doses per cohort of capecitabine from day 1 to 10 of each cycle, followed by cisplatin on day 11 and irinotecan on days 11, 18 and 25, both at same doses as the first cycle. Cycles were repeated every 38 days. The starting dose of capecitabine was 500 mg/m2/day which was escalated by 250 mg/m2/day in the subsequent cohort of patients to reach the maximum tolerated dose (MTD). Later, additional patients were treated at the MTD of capecitabine to further evaluate the safety, pharmacodynamics, and tumor response. Patients blood was tested for cisplatin-DNA adducts to determine the impact of capecitabine on cisplatin-based therapy. Results: Fifteen patients received at least 2 cycles of treatment. At 1,250 mg/m2, two DLT of prolonged neutropenia of grade ≥ 3 were observed. The MTD for capecitabine was thus determined to be 1000 mg/m2/day. Fatigue and diarrhea of grade 1 or 2 were the most frequent toxicities at this dose level. No significant hematologic toxicity was observed at the MTD. Two complete and three partial remissions were observed. Four of the responders had received a platinum agent and/or 5-FU in the past. Conclusions: A sequential treatment with capecitabine followed by cisplatin and irinotecan is well tolerated and demonstrates clinical activity in patients with advanced solid malignancies. The influence of capecitabine, if any, on the efficacy of the cisplatin-irinotecan combination is not related to a variation in cisplatin-DNA adducts.

Original languageEnglish (US)
Pages (from-to)153-158
Number of pages6
JournalInvestigational New Drugs
Volume27
Issue number2
DOIs
StatePublished - Apr 2009

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irinotecan
Cisplatin
Maximum Tolerated Dose
Neoplasms
Fluorouracil
Capecitabine
Topoisomerase I Inhibitors
Safety

Keywords

  • Capecitabine
  • Cisplatin
  • DNA adducts
  • Irinotecan
  • Phase I

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Oncology

Cite this

Phase i study of capecitabine in combination with cisplatin and irinotecan in patients with advanced solid malignancies. / Sayar, H.; Shen, Z.; Lee, S. J.; Royce, M.; Rabinowitz, I.; Lee, F.; Smith, Harriet O.; Eberhardt, S.; Maestas, A.; Lu, H.; Verschraegen, C.

In: Investigational New Drugs, Vol. 27, No. 2, 04.2009, p. 153-158.

Research output: Contribution to journalArticle

Sayar, H, Shen, Z, Lee, SJ, Royce, M, Rabinowitz, I, Lee, F, Smith, HO, Eberhardt, S, Maestas, A, Lu, H & Verschraegen, C 2009, 'Phase i study of capecitabine in combination with cisplatin and irinotecan in patients with advanced solid malignancies', Investigational New Drugs, vol. 27, no. 2, pp. 153-158. https://doi.org/10.1007/s10637-008-9172-x
Sayar, H. ; Shen, Z. ; Lee, S. J. ; Royce, M. ; Rabinowitz, I. ; Lee, F. ; Smith, Harriet O. ; Eberhardt, S. ; Maestas, A. ; Lu, H. ; Verschraegen, C. / Phase i study of capecitabine in combination with cisplatin and irinotecan in patients with advanced solid malignancies. In: Investigational New Drugs. 2009 ; Vol. 27, No. 2. pp. 153-158.
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abstract = "This phase I trial assessed the safety and the maximum tolerated dose of capecitabine given for 10 days prior to a combination of cisplatin and irinotecan in patients with advanced solid malignancies. It also evaluated the changes in cisplatin DNA adducts induced by capecitabine. Patients and Methods: Patients with refractory solid tumors who had not failed 5-fluorouracil (5-FU) analogs or topoisomerase I inhibitors were eligible. All cohorts of patients first received a 28-day cycle of cisplatin and irinotecan. Both drugs were given at a dose of 50 mg/m2 intravenously on day 1, followed by irinotecan on days 8 and 15 at the same dose. The first cycle served as an internal control. Starting from the second cycle, patients received increasing doses per cohort of capecitabine from day 1 to 10 of each cycle, followed by cisplatin on day 11 and irinotecan on days 11, 18 and 25, both at same doses as the first cycle. Cycles were repeated every 38 days. The starting dose of capecitabine was 500 mg/m2/day which was escalated by 250 mg/m2/day in the subsequent cohort of patients to reach the maximum tolerated dose (MTD). Later, additional patients were treated at the MTD of capecitabine to further evaluate the safety, pharmacodynamics, and tumor response. Patients blood was tested for cisplatin-DNA adducts to determine the impact of capecitabine on cisplatin-based therapy. Results: Fifteen patients received at least 2 cycles of treatment. At 1,250 mg/m2, two DLT of prolonged neutropenia of grade ≥ 3 were observed. The MTD for capecitabine was thus determined to be 1000 mg/m2/day. Fatigue and diarrhea of grade 1 or 2 were the most frequent toxicities at this dose level. No significant hematologic toxicity was observed at the MTD. Two complete and three partial remissions were observed. Four of the responders had received a platinum agent and/or 5-FU in the past. Conclusions: A sequential treatment with capecitabine followed by cisplatin and irinotecan is well tolerated and demonstrates clinical activity in patients with advanced solid malignancies. The influence of capecitabine, if any, on the efficacy of the cisplatin-irinotecan combination is not related to a variation in cisplatin-DNA adducts.",
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AU - Shen, Z.

AU - Lee, S. J.

AU - Royce, M.

AU - Rabinowitz, I.

AU - Lee, F.

AU - Smith, Harriet O.

AU - Eberhardt, S.

AU - Maestas, A.

AU - Lu, H.

AU - Verschraegen, C.

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N2 - This phase I trial assessed the safety and the maximum tolerated dose of capecitabine given for 10 days prior to a combination of cisplatin and irinotecan in patients with advanced solid malignancies. It also evaluated the changes in cisplatin DNA adducts induced by capecitabine. Patients and Methods: Patients with refractory solid tumors who had not failed 5-fluorouracil (5-FU) analogs or topoisomerase I inhibitors were eligible. All cohorts of patients first received a 28-day cycle of cisplatin and irinotecan. Both drugs were given at a dose of 50 mg/m2 intravenously on day 1, followed by irinotecan on days 8 and 15 at the same dose. The first cycle served as an internal control. Starting from the second cycle, patients received increasing doses per cohort of capecitabine from day 1 to 10 of each cycle, followed by cisplatin on day 11 and irinotecan on days 11, 18 and 25, both at same doses as the first cycle. Cycles were repeated every 38 days. The starting dose of capecitabine was 500 mg/m2/day which was escalated by 250 mg/m2/day in the subsequent cohort of patients to reach the maximum tolerated dose (MTD). Later, additional patients were treated at the MTD of capecitabine to further evaluate the safety, pharmacodynamics, and tumor response. Patients blood was tested for cisplatin-DNA adducts to determine the impact of capecitabine on cisplatin-based therapy. Results: Fifteen patients received at least 2 cycles of treatment. At 1,250 mg/m2, two DLT of prolonged neutropenia of grade ≥ 3 were observed. The MTD for capecitabine was thus determined to be 1000 mg/m2/day. Fatigue and diarrhea of grade 1 or 2 were the most frequent toxicities at this dose level. No significant hematologic toxicity was observed at the MTD. Two complete and three partial remissions were observed. Four of the responders had received a platinum agent and/or 5-FU in the past. Conclusions: A sequential treatment with capecitabine followed by cisplatin and irinotecan is well tolerated and demonstrates clinical activity in patients with advanced solid malignancies. The influence of capecitabine, if any, on the efficacy of the cisplatin-irinotecan combination is not related to a variation in cisplatin-DNA adducts.

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KW - Cisplatin

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