Relationship between pharmacokinetics and safety of tremelimumab in patients with melanoma.
Sub-category: Other: developmental therapeutics: immunotherapy
Category: Developmental Therapeutics: Immunotherapy
Meeting: 2009 ASCO Annual Meeting
Citation: J Clin Oncol 27:15s, 2009 (suppl; abstr 3049)
Abstract No: 3049
Attend this session at the ASCO Annual Meeting!
Session: Developmental Therapeutics: Immunotherapy
Type: General Poster Session
Time: Saturday May 30, 8:00 AM to 12:00 PM
Location: Level 2, West Hall C
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Author(s): E. Wang, D. Kang, D. Wang, C. Bulanhagui, P. Hsyu; Pfizer Oncology Business Unit, San Diego, CA; Pfizer Global Research & Development, New London, CT
Abstract:
Background: Tremelimumab is a fully human anti-CTLA4 monoclonal antibody that has antitumor activity in some patients with advanced melanoma. The most common adverse event associated with tremelimumab is diarrhea/colitis. This analysis investigated the relationship between pharmacokinetics (PK) and diarrhea or colitis in 450 patients enrolled in four phase I or II clinical studies. Methods: PK parameters including AUC during the first 90 days (AUC90), Cmax, concentration at day 29 (C29), and AUC of concentration >30 µg/mL (AUCG30) of tremelimumab were determined using nonlinear mixed-effect modeling. Severity and frequency of diarrhea and colitis during the 90 days after the first dose were considered in relation to each individual PK parameter. Frequency of diarrhea was further analyzed by logistic regression analysis. Frequencies of diarrhea and colitis were combined for logistic analysis. Results: The PK/safety analysis included 450 patients (445 with advanced melanoma). In this analysis, the severity of diarrhea and colitis appeared to be independent of PK (AUC90, Cmax, C29, and AUCG30) of tremelimumab. Although frequency of diarrhea was positively related to AUC (AUC or AUCG30), Cmax, and C29, AUC appeared to be best correlated to frequency of diarrhea. Logistic regression analysis of change in AUC on probability of having diarrhea indicated that the frequency of diarrhea increased initially with increasing AUC, but reached a plateau quickly at approximately AUC value of 50,000 µg × hr/mL (20th percentile). Results of the combined diarrhea and colitis analysis were similar to those of diarrhea alone. Conclusions: Severity of diarrhea and colitis is independent of AUC in patients with melanoma treated with tremelimumab. Frequency of diarrhea and colitis initially increases with increasing AUC, but plateaus quickly. |
