A phase I and pharmacokinetic study of lapatinib in combination with letrozole in patients with advanced cancer

被引:54
作者
Chu, Quincy S. C. [1 ]
Cianfrocca, Mary E. [2 ]
Goldstein, Lori J. [2 ]
Gale, Meg [3 ]
Murray, Nicholas [3 ]
Loftiss, Jill [4 ]
Arya, Nikita [4 ]
Koch, Kevin M. [4 ]
Pandite, Lini [4 ]
Fleming, Ronald A. [4 ]
Paul, Elaine [4 ]
Rowinsky, Eric K. [1 ]
机构
[1] Inst Drug Dev, Canc Therapy & Res Ctr, San Antonio, TX USA
[2] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA
[3] Univ Southampton, Ctr Canc, Southampton, Hants, England
[4] GlaxoSmithKline, Res Triangle Pk, NC USA
关键词
D O I
10.1158/1078-0432.CCR-07-4417
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: The main objectives of this phase I and pharmacokinetic, open-label study were to determine the optimally tolerated regimen (OTR), safety, pharmacokinetics, and clinical activity of lapatinib in combination with letrozole in patients with advanced solid malignancies. Experimental Design: Patients with advanced breast cancer with immunohistochemically detectable estrogen or progesterone receptors or other cancers were eligible. Doses of lapatinib were escalated in cohorts of three subjects from 1,250 to a maximum of 1,500 mg/d based on dose-limiting toxicities in the first treatment cycle. The letrozole dose was fixed at 2.5 mg/d. Additional patients were enrolled at the OTR dose level to further evaluate safety and for pharmacokinetic analyses. Results: Thirty-nine patients were enrolled in the study: 12 in the dose-escalation group, 7 in the OTR safety group, and 20 in the pharmacokinetic group. The OTR dose level was identified as 1,500 mg/d lapatinib and 2.5 mg/d letrozole. The most common (>25% of patients) drug-related adverse events were diarrhea (77%), rash (62%), nausea (46%), and fatigue (26%). No significant differences were observed in the pharmacokinetic variables (C-max and AUC) of lapatinib and letrozole when coadministered compared with single-agent administration. One patient with endometrial cancer had a confirmed partial response. Conclusions: Clinically relevant doses of lapatinib in combination with letrozole were well tolerated and did not result in a pharmacokinetic interaction, and clinical antitumor activity was observed.
引用
收藏
页码:4484 / 4490
页数:7
相关论文
共 50 条
[1]  
Baselga J, 2001, EUR J CANCER, V37, pS16
[2]   Phase II study of efficacy, safety, and pharmacokinetics of trastuzumab monotherapy administered on a 3-weekly schedule [J].
Baselga, J ;
Carbonell, X ;
Castañeda-Soto, NJ ;
Clemens, M ;
Green, M ;
Harvey, V ;
Morales, S ;
Barton, C ;
Ghahramani, P .
JOURNAL OF CLINICAL ONCOLOGY, 2005, 23 (10) :2162-2171
[3]   Clinical trial with escalating doses of the antiepidermal growth factor receptor humanized monoclonal antibody EMD 72 000 in patients with advanced squamous cell carcinoma of the larynx and hypopharynx [J].
Bier, H ;
Hoffmann, T ;
Hauser, U ;
Wink, M ;
Öchler, M ;
Kovar, A ;
Müser, M ;
Knecht, R .
CANCER CHEMOTHERAPY AND PHARMACOLOGY, 2001, 47 (06) :519-524
[4]  
BLACKWELL KL, 2004, J CLIN ONCOL, V22, P3006
[5]   Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas [J].
Burris, HA ;
Hurwitz, HI ;
Dees, EC ;
Dowlati, A ;
Blackwell, KL ;
O'Neil, B ;
Marcom, PK ;
Ellis, MJ ;
Overmoyer, B ;
Jones, SF ;
Harris, JL ;
Smith, DA ;
Koch, KM ;
Stead, A ;
Mangum, S ;
Spector, NL .
JOURNAL OF CLINICAL ONCOLOGY, 2005, 23 (23) :5305-5313
[6]   Dual kinase inhibition in the treatment of breast cancer: Initial experience with the EGFR/ErbB-2 inhibitor lapatinib [J].
Burris, HA .
ONCOLOGIST, 2004, 9 :10-15
[7]   RECEPTORS FOR EPIDERMAL GROWTH-FACTOR AND OTHER POLYPEPTIDE MITOGENS [J].
CARPENTER, G .
ANNUAL REVIEW OF BIOCHEMISTRY, 1987, 56 :881-914
[8]  
Chavey WE, 2001, AM FAM PHYSICIAN, V64, P769
[9]  
Chow LWC, 2006, BREAST CANCER RES TR, V100, pS286
[10]   Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease [J].
Cobleigh, MA ;
Vogel, CL ;
Tripathy, D ;
Robert, NJ ;
Scholl, S ;
Fehrenbacher, L ;
Wolter, JM ;
Paton, V ;
Shak, S ;
Lieberman, G ;
Slamon, DJ .
JOURNAL OF CLINICAL ONCOLOGY, 1999, 17 (09) :2639-2648