Phase I dose escalation study of the anti-insulin-like growth factor-I receptor monoclonal antibody CP-751,871in patients with refractory solid tumors

Paul Haluska, Heather M. Shaw, Gretchen N. Batzel, Donghua Yin, Julian R. Molina, L. Rhoda Molife, Timothy A. Yap, M. Luisa Roberts, Amarnath Sharma, Antonio Gualberto, Alex A. Adjei, Johann S. De Bono

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219 Scopus citations

Abstract

Purpose: This phase I study was undertaken to define the maximum tolerated dose, safety, and pharmacokinetic profile of CP-751,871. Experimental Design: Using a rapid dose escalation design, patientswith advanced nonhematologic malignancies were treated with CP-751,871 in four dose escalation cohorts. CP-751,871 was administered i.v. on day 1 of each 21-day cycle. Pharmacokinetic evaluation was done in all treatment cohorts during cycles1 and 4. Results: Twenty-four patients received 110 cycles at four dose levels. The maximum tolerated dose exceeded the maximal feasible dose of 20 mg/kg and, thus, was not identified. Treatment-related toxicities were generally mild. The most common adverse events were hyperglycemia, anorexia, nausea, elevated aspartate aminotransferase, elevated γ-glutamyltransferase, diarrhea, hyperuracemia, and fatigue. At 20 mg/kg, 10 of 15 patients experienced stability of disease. Two of these patients experienced long-term stability. There were no objective responses. Pharmacokinetic analysis revealed a dose-dependent increase in CP-751,871 exposure and ∼2-fold accumulation on repeated dosing in 21-day cycles. Plasma concentrations of CP-751,871 attained were several log-fold greater than the biologically active concentration. Treatment with CP-751,871 increased serum insulin and human growth hormone levels, with modest increases in serum glucose levels. Conclusions: CP-751,871 has a favorable safety profile and was well tolerated when given in continuous cycles. At themaximal feasible dose of 20 mg/kg, there was amoderate accumulation in plasma exposure, and most of the treated patients experienced stability of disease.

Original languageEnglish (US)
Pages (from-to)5834-5840
Number of pages7
JournalClinical Cancer Research
Volume13
Issue number19
DOIs
StatePublished - Oct 1 2007

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Haluska, P., Shaw, H. M., Batzel, G. N., Yin, D., Molina, J. R., Molife, L. R., Yap, T. A., Roberts, M. L., Sharma, A., Gualberto, A., Adjei, A. A., & De Bono, J. S. (2007). Phase I dose escalation study of the anti-insulin-like growth factor-I receptor monoclonal antibody CP-751,871in patients with refractory solid tumors. Clinical Cancer Research, 13(19), 5834-5840. https://doi.org/10.1158/1078-0432.CCR-07-1118