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Phase I Study Evaluating the Combination of Lapatinib + Vinorelbine in Patients With Locally Advanced or Metastatic Breast Cancer Overexpressing HER2

Phase 1
18 Years
Open (Enrolling)
Breast Cancer

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Trial Information

Phase I Study Evaluating the Combination of Lapatinib + Vinorelbine in Patients With Locally Advanced or Metastatic Breast Cancer Overexpressing HER2



- Evaluate the tolerability and feasibility of the lapatinib ditosylate and vinorelbine
ditartrate combination by determining the maximum tolerated dose of vinorelbine
ditartrate in combination with a biologically active dose of lapatinib ditosylate.


- Determine the maximum administered dose.

- Investigate the pharmacokinetic interactions related to the combination of vinorelbine
ditartrate and lapatinib ditosylate.

- Determine the toxicity of vinorelbine ditartrate and lapatinib ditosylate.

- Determine the objective response rate in patients with measurable lesions.

- Validate the safety and efficacy of the oral vinorelbine ditartrate and lapatinib
ditosylate combination, according to the vinorelbine ditartrate oral/IV dose

OUTLINE: This is a multicenter, dose-escalation study.

Patients receive oral lapatinib ditosylate on days -7 to 21 for course 1 and on days 1-21
for all other courses. Patients also receive vinorelbine ditartrate IV over 15 minutes on
days 1 and 8. Courses repeat every 21 days for up to 12 months in the absence of disease
progression or unacceptable toxicity.

Cohorts of 3-9 patients receive escalating doses of lapatinib ditosylate and vinorelbine
ditartrate until the maximum tolerated dose (MTD) is determined. The MTD is defined as the
dose preceding that at which 2 of 9 patients experience dose-limiting toxicity during course

Once the MTD is determined for oral lapatinib ditosylate and IV vinorelbine ditartrate, an
additional cohort of 9 patients receive oral vinorelbine ditartrate with oral lapatinib
ditosylate as above.

Inclusion Criteria


- Histologically confirmed advanced breast cancer (metastatic or locally advanced)

- Tumor overexpressing HER2 (HER2 3+ by IHC OR HER2 2+ by IHC and FISH positive) in
samples from the primary and/or secondary tumor

- Measurable or evaluable disease

- Cancer is progressive after treatment with at least 1 line or, at most, 2 lines, of
chemotherapy that included trastuzumab (Herceptin®)

- Patients presenting with treated (surgical resection or radiotherapy) asymptomatic
cerebral metastases or leptomeningeal metastases may be included if they are
neurologically stable and have not received steroids or anticonvulsant treatment for
at least 4 weeks before study entry


Inclusion criteria:

- Female

- Menopausal status not specified

- Patients must have an estimated survival of at least 3 months

- WHO performance status (ECOG) 0-2

- Hemoglobin ≥ 9 g/dL

- ANC ≥ 1,500/mm³

- Platelets ≥ 100,000/mm³

- Total bilirubin ≤ 2.5 mg/dL

- ALT and AST ≤ 3 times upper limit of normal

- Serum creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 40 mL/min

- LVEF ≥ 50% (echographic or isotopic method)

- Potentially reproductive patients must agree to use an effective contraceptive method
while on study treatment

- Patients must be affiliated with a Social Security system

Exclusion criteria:

- Uncontrolled cardiac pathology, including any of the following:

- Angina pectoris

- Arrhythmia

- Cardiac insufficiency

- Dysphagia or inability to swallow the vinorelbine ditartrate soft capsules

- Malabsorption syndrome or disease significantly affecting gastrointestinal function

- Preexisting neuropathy (grade ≥ 2)

- Pregnant women, women who are likely to become pregnant, or women who are

- Any psychological, familial, sociological, or geographical condition potentially
hampering compliance with the study protocol and follow-up schedule

- Individuals deprived of liberty


Inclusion criteria:

- At least 3 weeks since prior chemotherapy or trastuzumab

- At least 4 weeks since prior radiotherapy and recovered

- More than 30 days since prior participation in another therapeutic trial using an
experimental drug

- More than 7 days since prior and no concurrent CYP3A4 inhibitors, including the

- Antibiotics: clarithromycin, erythromycin, troleandomycin

- HIV drugs: anti-retrovirals (delavirdine), protease inhibitors (ritonavir,
indinavir, saquinavir, nelfinavir, amprenavir, lopinavir)

- Antifungals: itraconazole, ketoconazole, voriconazole, fluconazole (doses less
than 150 mg/day are allowed)

- Antidepressants: nefazodone, fluvoxamine, fluoxetine

- Calcium channel blockers: verapamil, diltiazem

- Gastric pH modifiers: omeprazole, cimetidine, ranitidine (during course 1 of
study treatment)

- Gastrointestinal drugs: cimetidine, aprepitant

- Grapefruit or grapefruit juice

- More than 14 days since prior and no concurrent CYP3A4 inducers, including the

- Glucocorticoids: dexamethasone or dexamethasone equivalent dose > 1.5mg/day

- Anticonvulsive agents: phenytoin, carbamazepine, phenobarbital

- HIV drugs: efavirenz, nevirapine

- Antibiotics: rifampicin, rifabutin, rifapentine

- Miscellaneous drugs: St. John's wort, modafinil

- At least 6 months since prior and no concurrent amiodarone

Exclusion criteria:

- Prior major resection of stomach or proximal bowel that could affect absorption of
oral drugs

- Prior vinorelbine ditartrate

- Any concurrent plant-based alternative medicine

- Use of antacids (i.e., Maalox, Rennie, Smecta) is not allowed 1 hour before and 1
hour after lapatinib intake

- Concurrent yellow fever vaccine or live attenuated vaccine

- Growth factors for the prevention of neutropenia are not allowed during course 1 of
study treatment

Type of Study:


Study Design:

Primary Purpose: Treatment

Outcome Measure:

Toxicity as assessed by NCI CTCAE v3.0

Safety Issue:


Principal Investigator

Pierre Fumoleau, MD, PhD

Investigator Role:

Study Chair

Investigator Affiliation:

Centre de Lutte Contre le Cancer Georges-Francois Leclerc



Study ID:




Start Date:

June 2007

Completion Date:

Related Keywords:

  • Breast Cancer
  • recurrent breast cancer
  • stage IIIA breast cancer
  • stage IIIB breast cancer
  • stage IIIC breast cancer
  • stage IV breast cancer
  • Breast Neoplasms