Document Detail


Tremelimumab in combination with exemestane in patients with advanced breast cancer and treatment-associated modulation of inducible costimulator expression on patient T cells.
MedLine Citation:
PMID:  20479064     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: Tremelimumab is a fully human monoclonal antibody specific for CTL-associated antigen 4 (CTLA4) with single-agent activity in certain tumors but has not been evaluated in patients with breast cancer.
EXPERIMENTAL DESIGN: In a phase 1 study, 26 patients with advanced, hormone-responsive breast cancer received tremelimumab (3-10 mg/kg) every 28 days or every 90 days plus exemestane 25 mg daily. The objectives were to determine safety and the maximum tolerated dose (MTD) of tremelimumab with exemestane and, secondarily, to assess tumor response, pharmacokinetics, and immune pharmacodynamics.
RESULTS: Most treatment-related adverse events were mild to moderate with the most common being diarrhea (46% of patients), pruritus (42%), constipation (23%), and fatigue (23%). Dose-limiting toxicities were transient serum transaminase elevations (one patient) and diarrhea (four patients). The MTD of tremelimumab with exemestane was 6 mg/kg every 90 days. Among 13 patients treated at the MTD, none developed grade 3 or 4 treatment-related diarrhea. No pharmacokinetic interaction was observed between tremelimumab and exemestane. The best overall response was stable disease for >or=12 weeks in 11 patients (42%). Treatment was associated in most patients with increased peripheral CD4+ and CD8+ T cells expressing inducible costimulator (ICOS) and a marked increase in the ratio of ICOS+ T cells to FoxP3+ regulatory T cells.
CONCLUSIONS: Tremelimumab plus exemestane is tolerable in patients with hormone-responsive advanced breast cancer. Treatment is associated with increased ICOS+ T cells, which likely signals immune activation secondary to CTL-associated antigen 4 blockade.
Authors:
Robert H Vonderheide; Patricia M LoRusso; Magi Khalil; Elaina M Gartner; Divis Khaira; Denis Soulieres; Prudence Dorazio; Jennifer A Trosko; Jens Rüter; Gabriella L Mariani; Tiziana Usari; Susan M Domchek
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Publication Detail:
Type:  Clinical Trial, Phase I; Journal Article; Multicenter Study; Research Support, Non-U.S. Gov't     Date:  2010-05-17
Journal Detail:
Title:  Clinical cancer research : an official journal of the American Association for Cancer Research     Volume:  16     ISSN:  1078-0432     ISO Abbreviation:  Clin. Cancer Res.     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-07-02     Completed Date:  2010-09-01     Revised Date:  2013-06-05    
Medline Journal Info:
Nlm Unique ID:  9502500     Medline TA:  Clin Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3485-94     Citation Subset:  IM    
Affiliation:
Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
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MeSH Terms
Descriptor/Qualifier:
Aged
Aged, 80 and over
Androstadienes / administration & dosage*,  adverse effects,  pharmacokinetics
Antibodies, Monoclonal / administration & dosage*,  adverse effects,  pharmacokinetics
Antigens, CD / immunology*
Antigens, Differentiation, T-Lymphocyte / metabolism*
Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
Breast Neoplasms / drug therapy*,  immunology,  metabolism
CTLA-4 Antigen
Drug Administration Schedule
Female
Humans
Inducible T-Cell Co-Stimulator Protein
Maximum Tolerated Dose
Middle Aged
Neoplasms, Hormone-Dependent / drug therapy
T-Lymphocytes / immunology
Chemical
Reg. No./Substance:
0/Androstadienes; 0/Antibodies, Monoclonal; 0/Antigens, CD; 0/Antigens, Differentiation, T-Lymphocyte; 0/CTLA-4 Antigen; 0/CTLA4 protein, human; 0/ICOS protein, human; 0/Inducible T-Cell Co-Stimulator Protein; 107868-30-4/exemestane; QEN1X95CIX/tremelimumab

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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