A phase I study of bortezomib plus irinotecan in patients with advanced solid tumors

David P. Ryan, Bert H. O'Neil, Jeffrey G. Supko, Carlo M Rocha Lima, E. Claire Dees, Leonard J. Appleman, Jeffrey Clark, Phinos Fidias, Robert Z. Orlowski, Oscar Kashala, Joseph P. Eder, James C. Cusack

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Abstract

BACKGROUND. The authors conducted a Phase I dose-finding trial to study the use of combined bortezomib plus irinotecan in patients with advanced solid tumors. METHODS. Patients who had received ≥1 prior chemotherapy regimen were eligible. Patients received bortezomib (1.0 mg/m2, 1.3 mg/m 2, or 1.5 mg/m2) on Days 1, 4, 8, and 11 and received irinotecan (from 50 mg/m2 to 125 mg/m2) on Days 1 and 8 of each 21-day cycle for a maximum of 8 cycles. Bortezomib followed irinotecan on coadministration days in Cycle 1 and Cycles 3 through 8 but preceded irinotecan in Cycle 2 to assess the effect of administration sequence on bortezomib pharmacodynamics. RESULTS. Fifty-one enrolled patients with malignancies, including colorectal cancer (n = 23 patients), lung cancer (n = 6 patients), gastroesophageal cancer (n = 6 patients), and pancreatic cancer (n = 3 patients), received ≥1 dose of study drug. Nausea, vomiting, and diarrhea were the principal dose-limiting toxicities and led to the maximum tolerated doses of 1.3 mg/m2 bortezomib and 125 mg/m2 irinotecan. The most common grade ≥3 bortezomib-related nonhematologic adverse events were fatigue (n = 5 episodes), diarrhea (n = 4 episodes), and nausea (n = 4 episodes), grade ≥3 bortezomib-related hematologic adverse events included neutropenia (n = 6 episodes) and thrombocytopenia (n = 4 episodes) and rarely were dose limiting. Of 34 evaluable patients, no objective responses according to the Response Evaluation Criteria in Solid Tumors were seen; 10 patients achieved stable disease. The degree of proteasome inhibition in whole blood indicated that the biologic activity of bortezomib was unaffected by irinotecan coadministration. CONCLUSIONS. The results of this Phase I study in patients with solid tumors indicated that bortezomib at a dose of 1.3 mg/m2 on Days 1, 4, 8, and 11 plus irinotecan at a dose of 125 mg/m2 on Days 1 and 8 every 21 days were the recommended Phase II doses.

Original languageEnglish
Pages (from-to)2688-2697
Number of pages10
JournalCancer
Volume107
Issue number11
DOIs
StatePublished - Dec 1 2006

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irinotecan
Neoplasms
Nausea
Diarrhea
Bortezomib

Keywords

  • Bortezomib
  • Colorectal cancer
  • Irinotecan
  • Proteasome inhibitor
  • Solid tumors

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Ryan, D. P., O'Neil, B. H., Supko, J. G., Lima, C. M. R., Dees, E. C., Appleman, L. J., ... Cusack, J. C. (2006). A phase I study of bortezomib plus irinotecan in patients with advanced solid tumors. Cancer, 107(11), 2688-2697. https://doi.org/10.1002/cncr.22280

A phase I study of bortezomib plus irinotecan in patients with advanced solid tumors. / Ryan, David P.; O'Neil, Bert H.; Supko, Jeffrey G.; Lima, Carlo M Rocha; Dees, E. Claire; Appleman, Leonard J.; Clark, Jeffrey; Fidias, Phinos; Orlowski, Robert Z.; Kashala, Oscar; Eder, Joseph P.; Cusack, James C.

In: Cancer, Vol. 107, No. 11, 01.12.2006, p. 2688-2697.

Research output: Contribution to journalArticle

Ryan, DP, O'Neil, BH, Supko, JG, Lima, CMR, Dees, EC, Appleman, LJ, Clark, J, Fidias, P, Orlowski, RZ, Kashala, O, Eder, JP & Cusack, JC 2006, 'A phase I study of bortezomib plus irinotecan in patients with advanced solid tumors', Cancer, vol. 107, no. 11, pp. 2688-2697. https://doi.org/10.1002/cncr.22280
Ryan DP, O'Neil BH, Supko JG, Lima CMR, Dees EC, Appleman LJ et al. A phase I study of bortezomib plus irinotecan in patients with advanced solid tumors. Cancer. 2006 Dec 1;107(11):2688-2697. https://doi.org/10.1002/cncr.22280
Ryan, David P. ; O'Neil, Bert H. ; Supko, Jeffrey G. ; Lima, Carlo M Rocha ; Dees, E. Claire ; Appleman, Leonard J. ; Clark, Jeffrey ; Fidias, Phinos ; Orlowski, Robert Z. ; Kashala, Oscar ; Eder, Joseph P. ; Cusack, James C. / A phase I study of bortezomib plus irinotecan in patients with advanced solid tumors. In: Cancer. 2006 ; Vol. 107, No. 11. pp. 2688-2697.
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abstract = "BACKGROUND. The authors conducted a Phase I dose-finding trial to study the use of combined bortezomib plus irinotecan in patients with advanced solid tumors. METHODS. Patients who had received ≥1 prior chemotherapy regimen were eligible. Patients received bortezomib (1.0 mg/m2, 1.3 mg/m 2, or 1.5 mg/m2) on Days 1, 4, 8, and 11 and received irinotecan (from 50 mg/m2 to 125 mg/m2) on Days 1 and 8 of each 21-day cycle for a maximum of 8 cycles. Bortezomib followed irinotecan on coadministration days in Cycle 1 and Cycles 3 through 8 but preceded irinotecan in Cycle 2 to assess the effect of administration sequence on bortezomib pharmacodynamics. RESULTS. Fifty-one enrolled patients with malignancies, including colorectal cancer (n = 23 patients), lung cancer (n = 6 patients), gastroesophageal cancer (n = 6 patients), and pancreatic cancer (n = 3 patients), received ≥1 dose of study drug. Nausea, vomiting, and diarrhea were the principal dose-limiting toxicities and led to the maximum tolerated doses of 1.3 mg/m2 bortezomib and 125 mg/m2 irinotecan. The most common grade ≥3 bortezomib-related nonhematologic adverse events were fatigue (n = 5 episodes), diarrhea (n = 4 episodes), and nausea (n = 4 episodes), grade ≥3 bortezomib-related hematologic adverse events included neutropenia (n = 6 episodes) and thrombocytopenia (n = 4 episodes) and rarely were dose limiting. Of 34 evaluable patients, no objective responses according to the Response Evaluation Criteria in Solid Tumors were seen; 10 patients achieved stable disease. The degree of proteasome inhibition in whole blood indicated that the biologic activity of bortezomib was unaffected by irinotecan coadministration. CONCLUSIONS. The results of this Phase I study in patients with solid tumors indicated that bortezomib at a dose of 1.3 mg/m2 on Days 1, 4, 8, and 11 plus irinotecan at a dose of 125 mg/m2 on Days 1 and 8 every 21 days were the recommended Phase II doses.",
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AU - Ryan, David P.

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AU - Lima, Carlo M Rocha

AU - Dees, E. Claire

AU - Appleman, Leonard J.

AU - Clark, Jeffrey

AU - Fidias, Phinos

AU - Orlowski, Robert Z.

AU - Kashala, Oscar

AU - Eder, Joseph P.

AU - Cusack, James C.

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N2 - BACKGROUND. The authors conducted a Phase I dose-finding trial to study the use of combined bortezomib plus irinotecan in patients with advanced solid tumors. METHODS. Patients who had received ≥1 prior chemotherapy regimen were eligible. Patients received bortezomib (1.0 mg/m2, 1.3 mg/m 2, or 1.5 mg/m2) on Days 1, 4, 8, and 11 and received irinotecan (from 50 mg/m2 to 125 mg/m2) on Days 1 and 8 of each 21-day cycle for a maximum of 8 cycles. Bortezomib followed irinotecan on coadministration days in Cycle 1 and Cycles 3 through 8 but preceded irinotecan in Cycle 2 to assess the effect of administration sequence on bortezomib pharmacodynamics. RESULTS. Fifty-one enrolled patients with malignancies, including colorectal cancer (n = 23 patients), lung cancer (n = 6 patients), gastroesophageal cancer (n = 6 patients), and pancreatic cancer (n = 3 patients), received ≥1 dose of study drug. Nausea, vomiting, and diarrhea were the principal dose-limiting toxicities and led to the maximum tolerated doses of 1.3 mg/m2 bortezomib and 125 mg/m2 irinotecan. The most common grade ≥3 bortezomib-related nonhematologic adverse events were fatigue (n = 5 episodes), diarrhea (n = 4 episodes), and nausea (n = 4 episodes), grade ≥3 bortezomib-related hematologic adverse events included neutropenia (n = 6 episodes) and thrombocytopenia (n = 4 episodes) and rarely were dose limiting. Of 34 evaluable patients, no objective responses according to the Response Evaluation Criteria in Solid Tumors were seen; 10 patients achieved stable disease. The degree of proteasome inhibition in whole blood indicated that the biologic activity of bortezomib was unaffected by irinotecan coadministration. CONCLUSIONS. The results of this Phase I study in patients with solid tumors indicated that bortezomib at a dose of 1.3 mg/m2 on Days 1, 4, 8, and 11 plus irinotecan at a dose of 125 mg/m2 on Days 1 and 8 every 21 days were the recommended Phase II doses.

AB - BACKGROUND. The authors conducted a Phase I dose-finding trial to study the use of combined bortezomib plus irinotecan in patients with advanced solid tumors. METHODS. Patients who had received ≥1 prior chemotherapy regimen were eligible. Patients received bortezomib (1.0 mg/m2, 1.3 mg/m 2, or 1.5 mg/m2) on Days 1, 4, 8, and 11 and received irinotecan (from 50 mg/m2 to 125 mg/m2) on Days 1 and 8 of each 21-day cycle for a maximum of 8 cycles. Bortezomib followed irinotecan on coadministration days in Cycle 1 and Cycles 3 through 8 but preceded irinotecan in Cycle 2 to assess the effect of administration sequence on bortezomib pharmacodynamics. RESULTS. Fifty-one enrolled patients with malignancies, including colorectal cancer (n = 23 patients), lung cancer (n = 6 patients), gastroesophageal cancer (n = 6 patients), and pancreatic cancer (n = 3 patients), received ≥1 dose of study drug. Nausea, vomiting, and diarrhea were the principal dose-limiting toxicities and led to the maximum tolerated doses of 1.3 mg/m2 bortezomib and 125 mg/m2 irinotecan. The most common grade ≥3 bortezomib-related nonhematologic adverse events were fatigue (n = 5 episodes), diarrhea (n = 4 episodes), and nausea (n = 4 episodes), grade ≥3 bortezomib-related hematologic adverse events included neutropenia (n = 6 episodes) and thrombocytopenia (n = 4 episodes) and rarely were dose limiting. Of 34 evaluable patients, no objective responses according to the Response Evaluation Criteria in Solid Tumors were seen; 10 patients achieved stable disease. The degree of proteasome inhibition in whole blood indicated that the biologic activity of bortezomib was unaffected by irinotecan coadministration. CONCLUSIONS. The results of this Phase I study in patients with solid tumors indicated that bortezomib at a dose of 1.3 mg/m2 on Days 1, 4, 8, and 11 plus irinotecan at a dose of 125 mg/m2 on Days 1 and 8 every 21 days were the recommended Phase II doses.

KW - Bortezomib

KW - Colorectal cancer

KW - Irinotecan

KW - Proteasome inhibitor

KW - Solid tumors

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