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Phase I Study of Two Different Schedules of Lapatinib (GW572016) in Combination With Vinorelbine in Advanced Solid Tumors

Phase 1
18 Years
Not Enrolling
Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

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.

Inclusion Criteria:

- Cytologically or histologically proven advanced solid tumors for which there is no
known standard therapy available or are not eligible for standard therapy because of
their performance status, or have progressed after no more than 2 prior chemotherapy
regimens for metastatic disease.

- Measurable or evaluable disease. Disease in previously irradiated sites is
considered measurable if there is clear disease progression following radiation

- 18 years of age or older.

- Zubrod performance status of 0-2.

- Estimated survival of at least 3 months.

- Any prior chemotherapy must have been completed at least 4 weeks prior to start of
this protocol and all side effects (except alopecia) resolved to grade 1 or less.
Any prior radiation must have been completed at least 2 weeks prior to start of
therapy. For prior mitomycin chemotherapy a 6-week interval is required. Patients
must have completed prior trastuzumab at least 4 weeks prior to start of protocol

- Adequate renal function

- Adequate liver function

- Pretreatment granulocyte count of >1500/mm3 and platelet count of >100 000/mm3.

- Cardiac ejection fraction within the institutional range of normal as measured by 2-D
echocardiogram or MUGA scan.

- Asymptomatic treated brain metastasis may be included if they are neurologically
stable and have been off steroids and anticonvulsants for at least 4 weeks.

- All patients must give informed consent.

- Able to take and retain oral medication.

- Patients of reproductive potential must agree to use an effective contraceptive

Exclusion Criteria:

- Patients may not have previously received lapatinib, vinorelbine or any other EGFR-1
targeted agent. Prior trastuzumab is allowed.

- Females cannot be pregnant or breastfeeding

- Symptomatic brain metastasis or still requiring steroids and anticonvulsants may not

- Pre-existing neuropathy > grade 2 may not participate.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements, will be excluded.

- History of other diseases, metabolic dysfunction, physical examination finding or
clinical laboratory finding giving reasonable suspicion of a disease or condition
that contraindicates the use of an investigational drug or that might affect the
interpretation of the results of the study or render the patient at high risk from
treatment complications.

- Gastrointestinal tract disease resulting in an inability to take oral medication or a
requirement for IV alimentation, or prior surgical procedures affecting absorption.

- HIV-positive patients receiving combination anti-retroviral therapy are excluded from
the study because of possible pharmacokinetic interactions with lapatinib.

- Patients requiring oral anticoagulants are eligible provided there is appropriate
close INR monitoring is in place. If medically appropriate and treatment available,
the investigator may also consider switching these patients to LMW heparin, where an
interaction with lapatinib is not expected.

- Adherence to the requirements for concomitant medications classified as CYP3A4
inducers or inhibitors, or gastric pH modifiers

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Toxicity as assessed by NCI CTCAE v3.0

Outcome Time Frame:

Completion of study

Safety Issue:


Principal Investigator

Helen K. Chew, MD

Investigator Role:

Study Chair

Investigator Affiliation:

University of California, Davis


United States: Food and Drug Administration

Study ID:




Start Date:

December 2005

Completion Date:

December 2011

Related Keywords:

  • Unspecified Adult Solid Tumor, Protocol Specific
  • unspecified adult solid tumor, protocol specific
  • Neoplasms



USC/Norris Comprehensive Cancer Center and HospitalLos Angeles, California  90033-0804
University of California Davis Cancer CenterSacramento, California  95817
City of Hope Comprehensive Cancer CenterDuarte, California  91010
Seattle Cancer Care AllianceSeattle, Washington  98109