Phase I dose escalation and pharmacokinetic study of lapatinib in combination with trastuzumab in patients with advanced ErbB2-positive breast cancer.

Full Abstract

PURPOSE:
The combination of lapatinib and trastuzumab has been observed to have a synergistic, antiproliferative effect against ErbB2-positive breast cancer cells in vitro. This phase I study assessed the safety, clinical feasibility, optimally tolerated regimen (OTR), pharmacokinetics (PK), and preliminary clinical activity of this combination in patients with ErbB2-positive advanced breast cancer.

PATIENTS AND METHODS:
Cohorts of three patients with ErbB2-positive advanced breast cancer were treated with escalating doses of lapatinib (750 to 1,500 mg) administered once daily (continuous) in combination with trastuzumab (4 mg/kg loading dose then 2 mg/kg weekly) to determine the OTR. Once the OTR was determined, additional patients were enrolled to provide the PK profile of both agents alone and in combination.

RESULTS:
A total of 54 patients were treated:
27 in the dose-escalation group and 27 in the PK group. Overall, adverse events were mild to moderate in severity, with no drug-related grade 4 events. The most frequent drug-related grade 3 events included diarrhea (17%), fatigue (11%), and rash (6%). The OTR was 1,000 mg lapatinib with standard weekly trastuzumab. One patient had a complete response and seven patients had partial responses. The PK parameters (maximum concentration in plasma and area under the curve) of lapatinib and trastuzumab in combination were not significantly different than when either was administered alone.

CONCLUSION:
The OTR of the lapatinib/trastuzumab combination was lapatinib 1,000 mg per day with standard weekly trastuzumab. At these doses, the regimen was well tolerated and clinically active in this heavily pretreated ErbB2-positive breast cancer population.

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Author information

Author/s: Storniolo, Anna Maria (AM); Pegram, Mark D (MD); Overmoyer, Beth (B); Silverman, Paula (P); Peacock, Nancy W (NW); Jones, Suzanne F (SF); Loftiss, Jill (J); Arya, Nikita (N); Koch, Kevin M (KM); Paul, Elaine (E); Pandite, Lini (L); Fleming, Ronald A (RA); Lebowitz, Peter F (PF); Ho, Peter T C (PT); Burris, Howard A (HA);

Affiliation: Indiana University Melvin and Bren Simon Cancer Center, 535 Barnhill Dr, Room 473, Indianapolis, IN 46202, USA. astornio(-atsign-)iupui.edu

Journal and publication information

Publication Type: Clinical Trial, Phase I; Journal Article; Research Support, Non-U.S. Gov't

Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol), published in United States. (Language: eng)

Reference: 2008-Jul; vol 26 (issue 20) : pp 3317-23

Dates: Created 2008/07/09; Completed 2008/08/13;

PMID: 18490651, status: MEDLINE (last retrieval date: 11/6/2008)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

Comments and Corrections

CommentIn: J Clin Oncol. 2008 Jul 10;26(20):3301-2. (PMID: 18490647)

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Adult
Aged
Aged, 80 and over
Antibodies, Monoclonal - administration & dosage; pharmacokinetics
Antineoplastic Combined Chemotherapy Protocols - administration & dosage; pharmacokinetics
Breast Neoplasms - drug therapy; genetics; mortality; pathology
Dose-Response Relationship, Drug
Drug Administration Schedule
Female
Follow-Up Studies

Humans
Infusions, Intravenous
Maximum Tolerated Dose
Middle Aged
Neoplasm Invasiveness - pathology
Quinazolines - administration & dosage; pharmacokinetics
Receptor, erbB-2 - metabolism
Risk Assessment
Survival Analysis
Treatment Outcome

Associated Chemicals: Antibodies, Monoclonal (0) ; Quinazolines (0) ; lapatinib (0) ; trastuzumab (0) ; Receptor, erbB-2 (EC 2.7.1.112)

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