A Phase I and Pharmacokinetic Study of Lapatinib in Combination with Letrozole in Patients with Advanced Cancer

• Published in: Clinical cancer research Vol. 14; no. 14; pp. 4484 - 4490
• Main Authors: Chu, Quincy S.C., Cianfrocca, Mary E., Goldstein, Lori J., Gale, Meg, Murray, Nicholas, Loftiss, Jill, Arya, Nikita, Koch, Kevin M., Pandite, Lini, Fleming, Ronald A., Paul, Elaine, Rowinsky, Eric K.
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 15.07.2008
• Subjects: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Area Under Curve; Breast Neoplasms - drug therapy; dose escalation; Female; Humans; lapatinib; letrozole; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms - drug therapy; Nitriles - administration & dosage; Nitriles - adverse effects; Nitriles - pharmacokinetics; Ovarian Neoplasms - drug therapy; pharmacokinetics; phase I; Quinazolines - administration & dosage; Quinazolines - adverse effects; Quinazolines - pharmacokinetics; Triazoles - administration & dosage; Triazoles - adverse effects; Triazoles - pharmacokinetics
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-07-4417

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.