Official Title: “A Phase II Study of GW572016 and Tamoxifen in Patients With Metastatic Breast Cancer Resistant to Single-Agent Tamoxifen”

RATIONALE: Lapatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Estrogen can cause the growth of breast cancer cells. Hormone therapy using tamoxifen may fight breast cancer by blocking the use of estrogen by the tumor cells.

Sometimes when tamoxifen is given, it does not stop the growth of tumor cells. The tumor is said to be resistant to tamoxifen. Giving lapatinib together with tamoxifen may reduce drug resistance and allow the tumor cells to be killed.

PURPOSE: This phase II trial is studying how well giving lapatinib together with tamoxifen works in treating patients with locally advanced or metastatic breast cancer that did not respond to previous tamoxifen.

Study Type: Interventional

Study Design: Treatment, Open Label

Study Primary Completion Date: December 2009

OBJECTIVES: - Determine the response rate (complete response and partial response) in patients with tamoxifen-resistant locally advanced or metastatic breast cancer treated with lapatinib and tamoxifen.

OUTLINE: This is a multicenter study.

Patients receive oral lapatinib and oral tamoxifen once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed at 1 month and then every 3 months thereafter.

PROJECTED ACCRUAL: A total of 21-41 patients will be accrued for this study within 13-21 months.

Intervention(s) in this Clinical Trial

• Drug: lapatinib ditosylate
• Drug: tamoxifen citrate

Primary Measures

• Tumor response (complete and partial) as measured by RECIST criteria
  • Safety Issue?: No

Secondary Measures

• Changes in phosphorylation in tumor tissue of epidermal growth factor receptor (EGFR), HER2, AKT kinase, MAPK, ER-Ser118, and ER-SER167
  • Safety Issue?: No

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed primary adenocarcinoma of the breast
• Locally advanced or metastatic disease not amenable to curative surgery or radiotherapy
• Tamoxifen-resistant disease, defined as 1 of the following:
• No response to initial therapy (primary resistance)
• Disease relapse or progression after showing an initial response to therapy (secondary resistance)
• Disease progression, as documented by 1 of the following:
• CT scan, MRI, or x-ray
• Increase in the number of bone lesions
• Increased pain in an area of known bony metastasis AND ≥ 2 serial tumor marker elevations
• Measurable disease, defined as ≥ 1 unidimensionally measurable target lesion ≥ 20 mm by conventional techniques OR ≥ 10 mm by MRI or spiral CT scan
• Not in a previously irradiated area
• No rapidly progressive disease in major organs (i.e., lymphangitic spread or bulky liver metastasis)
• No known brain or leptomeningeal metastases requiring active therapy
• Previously treated asymptomatic stable CNS metastases allowed provided patient does not require corticosteroids for CNS metastases
• Hormone receptor status:
• Estrogen and/or progesterone receptor positive disease

PATIENT CHARACTERISTICS:

• Age
• 18 and over
• Sex
• Male or female
• Menopausal status
• Not specified
• Performance status
• ECOG 0-2 OR
• Karnofsky 60-100%
• Life expectancy
• At least 3 months
• Hematopoietic
• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• Hemoglobin ≥ 9.0 g/dL
• Hepatic
• ALT and AST ≤ 1.5 times upper limit normal (ULN) (3 times ULN if liver metastases are present)
• Bilirubin ≤ 1.5 times ULN
• Renal
• Creatinine normal OR
• Creatinine clearance > 60 mL/min
• Cardiovascular
• Ejection fraction normal by echocardiogram or MUGA
• None of the following cardiovascular conditions within the past 6 months:
• Myocardial infarction
• Severe or unstable angina
• Symptomatic congestive heart failure
• Cerebrovascular accident or transient ischemic attack
• Deep venous thrombosis or other clinically significant thromboembolic event within the past 6 months allowed provided patient is clinically stable on anticoagulation therapy
• Pulmonary
• Pulmonary embolus within the past 6 months allowed provided patient is clinically stable on anticoagulation therapy
• Gastrointestinal
• No malabsorption syndrome
• No gastrointestinal (GI) tract disease that would preclude ability to take oral medication
• No requirement for IV alimentation
• No uncontrolled inflammatory GI disease (e.g., Crohn's disease or ulcerative colitis)
• Able to swallow and retain oral medication
• Other
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective barrier contraception during and for ≥ 2 weeks after completion of study treatment
• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
• No history of allergic reaction attributed to compounds of similar chemical or biological composition to lapatinib
• No other severe acute or chronic medical or psychiatric condition or laboratory abnormality that would preclude study participation

PRIOR CONCURRENT THERAPY:

• Biologic therapy
• Prior trastuzumab (Herceptin®) in combination with chemotherapy in the adjuvant setting only is allowed
• No prior trastuzumab in combination with hormonal therapy
• No concurrent trastuzumab
• Chemotherapy
• See Biologic therapy
• Prior cumulative doxorubicin dose ≤ 450 mg/m^2
• Endocrine therapy
• See Disease Characteristics
• See Biologic therapy
• At least 14 days since prior and no concurrent dexamethasone or dexamethasone equivalent dose > 1.5 mg/day
• Radiotherapy
• See Disease Characteristics
• More than 2 weeks since prior radiotherapy
• Surgery
• More than 4 weeks since prior surgery
• More than 6 months since prior coronary or peripheral artery bypass grafting
• No prior surgical procedure affecting absorption
• Other
• No prior epidermal growth factor receptor- or HER2/neu-targeting therapies
• At least 7 days since prior and no concurrent CYP3A4 inhibitors, including any of the following:
• Clarithromycin
• Erythromycin
• Troleandomycin
• Itraconazole
• Ketoconazole
• Voriconazole
• Fluconazole (doses ≤ 150 mg/day allowed)
• Fluvoxamine
• Nefazodone
• Verapamil
• Diltiazem
• Cimetidine
• Aprepitant
• Proton pump inhibitors
• H2 blockers
• Grapefruit or grapefruit juice
• Bitter orange
• At least 14 days since prior and no concurrent CYP3A4 inducers, including any of the following:
• Phenytoin
• Carbamazepine
• Phenobarbital
• Oxcarbazepine
• Efavirenz
• Nevirapine
• Rifampin
• Rifabutin
• Rifapentine
• Hypericum perforatum (St. John's wort)
• Modafinil
• At least 6 months since prior and no concurrent amiodarone
• No concurrent gastric pH modifiers within 1 hour before and after lapatinib administration
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No other concurrent antineoplastic agents
• No other concurrent investigational agents
• Concurrent zoledronate for bone metastases or hypercalcemia allowed
• Concurrent oral anticoagulants (e.g., warfarin) allowed provided there is increased vigilance in INR monitoring

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Barbara Ann Karmanos Cancer Institute

Overall Clinical Trial Officials and Contacts

Elaina M. Gartner, MD Study Chair Barbara Ann Karmanos Cancer Institute  

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00118157

Study ID Number: CDR0000433388

ClinicalTrials.gov Identifier: NCT00118157

Health Authority: Unspecified

Clinical trial summary from the National Cancer Institute's PDQ® database