Phase I Study of Two Different Schedules of Lapatinib (GW572016) in Combination With Vinorelbine in Advanced Solid Tumors
- Determine the safety and feasibility of 2 different schedules of lapatinib ditosylate
when administered with vinorelbine ditartrate in patients with advanced solid tumors.
- Determine the maximum tolerated dose (MTD) of each of these regimens in these patients.
- Determine, preliminarily, the efficacy of these regimens in these patients.
- Examine tissue and blood specimens from these patients to investigate potential
predictors of response.
- Determine the pharmacokinetics of lapatinib ditosylate and vinorelbine ditartrate in
patients treated at the MTD.
OUTLINE: This is a phase I study comprising 2 separate, sequential dose-escalation studies
of lapatinib ditosylate. Patients are assigned to 1 of 2 treatment groups.
- Group A (daily dosing): Patients receive oral lapatinib ditosylate once daily on days
1-28 and vinorelbine ditartrate IV on days 1, 8, and 15.
Cohorts of 3-6 patients receive escalating doses of lapatinib ditosylate until the maximum
tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2
of 3 or 2 of 6 patients experience dose-limiting toxicity during course 1. At least 6
patients are treated at the MTD. Once the MTD of lapatinib has been determined, patients may
be accrued to group B or to a separate pharmacokinetics cohort in group A.
- Pharmacokinetics (PK) cohort*: Patients in the PK cohort receive vinorelbine ditartrate
IV as in group A and oral lapatinib ditosylate once daily at the MTD on days 3-28
(course 1 only) and on days 1-28 in all subsequent courses. Patients undergo PK
sampling during course 1.
NOTE: *Accrual to group B and to the PK cohort of group A may occur simultaneously.
- Group B (intermittent dosing): Patients receive oral lapatinib ditosylate once daily at
the MTD on days 2-5, 9-12, and 16-25 and vinorelbine ditartrate IV, on days 1, 8, and
In both groups and in the PK cohort, treatment repeats every 28 days for 6 courses in the
absence of disease progression or unacceptable toxicity. Patients who have completed 6
courses of combined therapy may receive additional courses with lapatinib ditosylate alone.
Patients undergo blood collection and buccal brushings periodically for pharmacokinetic and
biomarker correlative studies. Archival tumor tissue is also evaluated for biomarkers,
including epidermal growth factor receptor (EGFR) and HER-2/neu expression levels, EGFR
polymorphisms and gene mutations (including RAS), levels of cellular proliferation and
apoptosis, and RAS mutations by immunohistochemistry, mutation analysis, TUNEL assay, and
polymerase chain reaction.
After completion of study treatment, patients are followed for 30 days.
PROJECTED ACCRUAL: A total of 66 patients will be accrued for this study.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Toxicity as assessed by NCI CTCAE v3.0
Completion of study
Helen K. Chew, MD
University of California, Davis
United States: Food and Drug Administration
|USC/Norris Comprehensive Cancer Center and Hospital||Los Angeles, California 90033-0804|
|University of California Davis Cancer Center||Sacramento, California 95817|
|City of Hope Comprehensive Cancer Center||Duarte, California 91010|
|Seattle Cancer Care Alliance||Seattle, Washington 98109|