Phase i dose-escalation study to determine the safety, pharmacokinetics and pharmacodynamics of brivanib alaninate in combination with full-dose cetuximab in patients with advanced gastrointestinal malignancies who have failed prior therapy

C. R. Garrett, L. L. Siu, A. El-Khoueiry, J. Buter, C. M. Rocha-Lima, J. Marshall, P. Lorusso, P. Major, J. Chemidlin, O. Mokliatchouk, L. Velasquez, W. Hayes, D. Feltquate, S. Syed, S. Ford, G. Kollia, S. Galbraith, D. S A Nuyten

Research output: Contribution to journalArticle

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Abstract

Background:The objectives of this phase I study were to determine the safety, pharmacokinetics (PK), pharmacodynamics and efficacy of brivanib combined with full-dose cetuximab in patients with advanced gastrointestinal malignancies.Methods:Patients with advanced gastrointestinal malignancies who had failed prior therapies received brivanib (320, 600 or 800 mg daily) plus cetuximab (400 mg m-2 loading dose then 250 mg m-2 weekly). Assessments included adverse events, PK, tumour response, 218Ffluoro-2-deoxyglucose positron-emitting tomography and K-Ras mutation analyses.Results:Toxicities observed were manageable; the most common treatment-related toxicities (10% of patients) were fatigue, diarrhoea, anorexia, increase in aspartate aminotransferase and alanine aminotransferase, acneiform dermatitis, headache, mucosal inflammation, nausea, dry skin, vomiting, hypertension, pruritus, proteinuria and weight loss. Of 62 patients, 6 (9.7%) had objective radiographic partial responses, with an overall response rate of 10%. Median duration of response was 9.2 months; median progression-free survival was 3.9 months.Conclusions:The acceptable toxicity profile and efficacy of brivanib observed in this study were promising. These findings are being further evaluated in a phase III study of brivanib plus cetuximab vs cetuximab alone in patients previously treated with combination chemotherapy for K-Ras wild-type advanced metastatic colorectal cancer.

Original languageEnglish
Pages (from-to)44-52
Number of pages9
JournalBritish Journal of Cancer
Volume105
Issue number1
DOIs
StatePublished - Jun 28 2011

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Pharmacokinetics
Safety
Neoplasms
Therapeutics
Deoxyglucose
Anorexia
Dermatitis
Pruritus
Aspartate Aminotransferases
Combination Drug Therapy
Alanine Transaminase
Proteinuria
Nausea
Disease-Free Survival
Vomiting
Fatigue
Headache
Weight Loss
Colorectal Neoplasms
Diarrhea

Keywords

  • antiangiogenesis
  • brivanib
  • cetuximab
  • gastrointestinal tumours

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Phase i dose-escalation study to determine the safety, pharmacokinetics and pharmacodynamics of brivanib alaninate in combination with full-dose cetuximab in patients with advanced gastrointestinal malignancies who have failed prior therapy. / Garrett, C. R.; Siu, L. L.; El-Khoueiry, A.; Buter, J.; Rocha-Lima, C. M.; Marshall, J.; Lorusso, P.; Major, P.; Chemidlin, J.; Mokliatchouk, O.; Velasquez, L.; Hayes, W.; Feltquate, D.; Syed, S.; Ford, S.; Kollia, G.; Galbraith, S.; Nuyten, D. S A.

In: British Journal of Cancer, Vol. 105, No. 1, 28.06.2011, p. 44-52.

Research output: Contribution to journalArticle

Garrett, CR, Siu, LL, El-Khoueiry, A, Buter, J, Rocha-Lima, CM, Marshall, J, Lorusso, P, Major, P, Chemidlin, J, Mokliatchouk, O, Velasquez, L, Hayes, W, Feltquate, D, Syed, S, Ford, S, Kollia, G, Galbraith, S & Nuyten, DSA 2011, 'Phase i dose-escalation study to determine the safety, pharmacokinetics and pharmacodynamics of brivanib alaninate in combination with full-dose cetuximab in patients with advanced gastrointestinal malignancies who have failed prior therapy', British Journal of Cancer, vol. 105, no. 1, pp. 44-52. https://doi.org/10.1038/bjc.2011.182
Garrett, C. R. ; Siu, L. L. ; El-Khoueiry, A. ; Buter, J. ; Rocha-Lima, C. M. ; Marshall, J. ; Lorusso, P. ; Major, P. ; Chemidlin, J. ; Mokliatchouk, O. ; Velasquez, L. ; Hayes, W. ; Feltquate, D. ; Syed, S. ; Ford, S. ; Kollia, G. ; Galbraith, S. ; Nuyten, D. S A. / Phase i dose-escalation study to determine the safety, pharmacokinetics and pharmacodynamics of brivanib alaninate in combination with full-dose cetuximab in patients with advanced gastrointestinal malignancies who have failed prior therapy. In: British Journal of Cancer. 2011 ; Vol. 105, No. 1. pp. 44-52.
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abstract = "Background:The objectives of this phase I study were to determine the safety, pharmacokinetics (PK), pharmacodynamics and efficacy of brivanib combined with full-dose cetuximab in patients with advanced gastrointestinal malignancies.Methods:Patients with advanced gastrointestinal malignancies who had failed prior therapies received brivanib (320, 600 or 800 mg daily) plus cetuximab (400 mg m-2 loading dose then 250 mg m-2 weekly). Assessments included adverse events, PK, tumour response, 218Ffluoro-2-deoxyglucose positron-emitting tomography and K-Ras mutation analyses.Results:Toxicities observed were manageable; the most common treatment-related toxicities (10{\%} of patients) were fatigue, diarrhoea, anorexia, increase in aspartate aminotransferase and alanine aminotransferase, acneiform dermatitis, headache, mucosal inflammation, nausea, dry skin, vomiting, hypertension, pruritus, proteinuria and weight loss. Of 62 patients, 6 (9.7{\%}) had objective radiographic partial responses, with an overall response rate of 10{\%}. Median duration of response was 9.2 months; median progression-free survival was 3.9 months.Conclusions:The acceptable toxicity profile and efficacy of brivanib observed in this study were promising. These findings are being further evaluated in a phase III study of brivanib plus cetuximab vs cetuximab alone in patients previously treated with combination chemotherapy for K-Ras wild-type advanced metastatic colorectal cancer.",
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T1 - Phase i dose-escalation study to determine the safety, pharmacokinetics and pharmacodynamics of brivanib alaninate in combination with full-dose cetuximab in patients with advanced gastrointestinal malignancies who have failed prior therapy

AU - Garrett, C. R.

AU - Siu, L. L.

AU - El-Khoueiry, A.

AU - Buter, J.

AU - Rocha-Lima, C. M.

AU - Marshall, J.

AU - Lorusso, P.

AU - Major, P.

AU - Chemidlin, J.

AU - Mokliatchouk, O.

AU - Velasquez, L.

AU - Hayes, W.

AU - Feltquate, D.

AU - Syed, S.

AU - Ford, S.

AU - Kollia, G.

AU - Galbraith, S.

AU - Nuyten, D. S A

PY - 2011/6/28

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N2 - Background:The objectives of this phase I study were to determine the safety, pharmacokinetics (PK), pharmacodynamics and efficacy of brivanib combined with full-dose cetuximab in patients with advanced gastrointestinal malignancies.Methods:Patients with advanced gastrointestinal malignancies who had failed prior therapies received brivanib (320, 600 or 800 mg daily) plus cetuximab (400 mg m-2 loading dose then 250 mg m-2 weekly). Assessments included adverse events, PK, tumour response, 218Ffluoro-2-deoxyglucose positron-emitting tomography and K-Ras mutation analyses.Results:Toxicities observed were manageable; the most common treatment-related toxicities (10% of patients) were fatigue, diarrhoea, anorexia, increase in aspartate aminotransferase and alanine aminotransferase, acneiform dermatitis, headache, mucosal inflammation, nausea, dry skin, vomiting, hypertension, pruritus, proteinuria and weight loss. Of 62 patients, 6 (9.7%) had objective radiographic partial responses, with an overall response rate of 10%. Median duration of response was 9.2 months; median progression-free survival was 3.9 months.Conclusions:The acceptable toxicity profile and efficacy of brivanib observed in this study were promising. These findings are being further evaluated in a phase III study of brivanib plus cetuximab vs cetuximab alone in patients previously treated with combination chemotherapy for K-Ras wild-type advanced metastatic colorectal cancer.

AB - Background:The objectives of this phase I study were to determine the safety, pharmacokinetics (PK), pharmacodynamics and efficacy of brivanib combined with full-dose cetuximab in patients with advanced gastrointestinal malignancies.Methods:Patients with advanced gastrointestinal malignancies who had failed prior therapies received brivanib (320, 600 or 800 mg daily) plus cetuximab (400 mg m-2 loading dose then 250 mg m-2 weekly). Assessments included adverse events, PK, tumour response, 218Ffluoro-2-deoxyglucose positron-emitting tomography and K-Ras mutation analyses.Results:Toxicities observed were manageable; the most common treatment-related toxicities (10% of patients) were fatigue, diarrhoea, anorexia, increase in aspartate aminotransferase and alanine aminotransferase, acneiform dermatitis, headache, mucosal inflammation, nausea, dry skin, vomiting, hypertension, pruritus, proteinuria and weight loss. Of 62 patients, 6 (9.7%) had objective radiographic partial responses, with an overall response rate of 10%. Median duration of response was 9.2 months; median progression-free survival was 3.9 months.Conclusions:The acceptable toxicity profile and efficacy of brivanib observed in this study were promising. These findings are being further evaluated in a phase III study of brivanib plus cetuximab vs cetuximab alone in patients previously treated with combination chemotherapy for K-Ras wild-type advanced metastatic colorectal cancer.

KW - antiangiogenesis

KW - brivanib

KW - cetuximab

KW - gastrointestinal tumours

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