Lapatinib and Vinorelbine in Treating Patients With Advanced Solid Tumors

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
University of California, Davis
ClinicalTrials.gov Identifier:
NCT00389922
First received: October 18, 2006
Last updated: April 17, 2012
Last verified: April 2012
  Purpose

RATIONALE: Lapatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as vinorelbine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving lapatinib together with vinorelbine may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of lapatinib when given together with vinorelbine in treating patients with advanced solid tumors.


Condition Intervention Phase
Unspecified Adult Solid Tumor, Protocol Specific
Drug: lapatinib ditosylate
Drug: vinorelbine ditartrate
Genetic: comparative genomic hybridization
Genetic: cytogenetic analysis
Genetic: gene expression analysis
Genetic: mutation analysis
Genetic: polymerase chain reaction
Genetic: polymorphism analysis
Genetic: proteomic profiling
Genetic: reverse transcriptase-polymerase chain reaction
Other: immunohistochemistry staining method
Other: laboratory biomarker analysis
Drug: Vinorelbine ditartrate
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Study of Two Different Schedules of Lapatinib (GW572016) in Combination With Vinorelbine in Advanced Solid Tumors

Resource links provided by NLM:


Further study details as provided by University of California, Davis:

Primary Outcome Measures:
  • Toxicity as assessed by NCI CTCAE v3.0 [ Time Frame: Completion of study ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Maximum tolerated dose of lapatinib ditosylate when administered with vinorelbine ditartrate as assessed by NCI CTCAE v3.0 [ Time Frame: Completion of study ] [ Designated as safety issue: Yes ]
  • Response rate (complete response, partial response, progressive disease, and stable disease) assessed at baseline and prior to courses 3 and 5 [ Time Frame: Completion of study ] [ Designated as safety issue: No ]
  • Best response [ Time Frame: Completion of study ] [ Designated as safety issue: No ]
  • Survival [ Time Frame: Completion of study ] [ Designated as safety issue: No ]
  • Progression-free survival [ Time Frame: Completion of study ] [ Designated as safety issue: No ]
  • Biological markers as predictors of response [ Time Frame: Completion of study ] [ Designated as safety issue: No ]

Enrollment: 22
Study Start Date: December 2005
Study Completion Date: December 2011
Primary Completion Date: April 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: A (Daily Dosing)

Oral lapatinib given daily for 28 days plus IV vinorelbine given weekly (3 out of 4 weeks)

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.

Drug: lapatinib ditosylate
Given orally for 28 days per dose level (Dose level 1: 250mg; Dose level 2: 500mg; Dose level 3: 1000mg; Dose level 4: 1250mg; Dose level 5: 1500mg; Dose level 6: 1500mg)
Other Name: Tykerb
Drug: vinorelbine ditartrate
Given IV Days 1, 8 and 15 per dose level (Dose level 1: 20mg/m2; Dose level 2: 20mg/m2; Dose level 3: 20mg/m2; Dose level 4: 20mg/m2; Dose level 5: 20mg/m2; Dose level 6: 25mg/m2)
Other Name: Navelbine
Genetic: comparative genomic hybridization
Molecular correlative study
Genetic: cytogenetic analysis
Molecular correlative study
Genetic: gene expression analysis
Molecular correlative study
Genetic: mutation analysis
Molecular correlative study
Genetic: polymerase chain reaction
Molecular correlative study
Genetic: polymorphism analysis
Molecular correlative study
Genetic: proteomic profiling
Molecular correlative study
Genetic: reverse transcriptase-polymerase chain reaction
Molecular correlative study
Other: immunohistochemistry staining method
Molecular correlative study
Other: laboratory biomarker analysis
Molecular correlative study
Experimental: B (Intermittent Dosing)

Oral lapatinib given days 2-5, 9-12 and 16-25 plus IV vinorelbine given weekly (3 out of 4 weeks)

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.

Drug: lapatinib ditosylate
Given orally on Days 2-5, 9-12 and 16-25 per dose level (Dose level 1: 1250mg; Dose level 2: 1500mg; Dose level 3: 1500mg; Dose level 4: 1700mg)
Other Name: Tykerb
Drug: Vinorelbine ditartrate
Given IV Days 1, 8 and 15 per dose level (Dose level 1: 20mg/m2; Dose level 2: 20mg/m2; Dose level 3: 25mg/m2; Dose level 4: 25mg/m2)
Other Name: Navelbine

Detailed Description:

OBJECTIVES:

Primary

  • Determine the safety and feasibility of 2 different schedules of lapatinib ditosylate when administered with vinorelbine ditartrate in patients with advanced solid tumors.

Secondary

  • 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 15.

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 therapy.
  • 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 therapy.
  • 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 method

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 participate.
  • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00389922

Locations
United States, California
City of Hope Comprehensive Cancer Center
Duarte, California, United States, 91010-3000
USC/Norris Comprehensive Cancer Center and Hospital
Los Angeles, California, United States, 90089-9181
University of California Davis Cancer Center
Sacramento, California, United States, 95817
United States, Washington
Seattle Cancer Care Alliance
Seattle, Washington, United States, 98109-1023
Sponsors and Collaborators
University of California, Davis
Investigators
Study Chair: Helen K. Chew, MD University of California, Davis
  More Information

Additional Information:
No publications provided

Responsible Party: University of California, Davis
ClinicalTrials.gov Identifier: NCT00389922     History of Changes
Other Study ID Numbers: CDR0000505878, P30CA093373, UCDCC-171, UCDCC-200513681-1, GSK-104241
Study First Received: October 18, 2006
Last Updated: April 17, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by University of California, Davis:
unspecified adult solid tumor, protocol specific

Additional relevant MeSH terms:
Neoplasms
Lapatinib
Vinorelbine
Vinblastine
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Phytogenic
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators

ClinicalTrials.gov processed this record on September 30, 2014