Clinical trial NCT00225758: Lapatinib in Metastatic Breast Cancer Resistant to Hormone Therapy
Official title: Lapatinib in Endocrine-Resistant Metastatic Breast Cancer
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Metastatic Breast Cancer
Keywords: breast cancer
endocrine therapy
drug resistance
lapatinib
epidermal growth factor receptor
Lead sponsor: Dartmouth-Hitchcock Medical Center
Sponsor class: OTHER
Collaborators: name: University of Colorado, Denver
name: North Shore University Hospital
First posted: 2005-09-26
Enrollment: 27
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Two thirds or more of breast cancers are dependent on estrogen for growth. We use a number of estrogen-blocking medicines for treatment of metastatic breast cancer. The treatment response to these agents is unpredictable, however, and approximately one-third of patients with metastatic breast cancer with receptors for estrogen or progesterone have no benefit from hormonal therapy. Nearly all patients with metastatic breast cancer will eventually become resistant to hormonal therapy despite the fact that the hormone receptors are still present.

Some cells make a different class of growth factor receptor called the Epidermal Growth Factor Receptor. There is a growing body of experimental evidence showing that breast cancer cells that make Epidermal Growth Factor Receptors are more resistant to hormonal therapy and have a poorer prognosis. Several investigators have found that the Epidermal Growth Factor Receptor can activate the estrogen receptor, even in the presence of estrogen-blocking drugs. Growth of these cells can be slowed by blockade of both Epidermal Growth Factor Receptor signaling and estrogen-receptor signaling. Lapatinib is a small molecule which can inhibit two different forms of the Epidermal Growth Factor Receptor. It has been studied in people with a number of different cancers, including breast cancer, and a safe dose and its common side effects have been defined.

Our hypothesis is that the Epidermal Growth Factor Receptor is the dominant receptor pathway used by breast cancers in our patients with hormone-resistant tumors. Drugs like lapatinib which block several forms of the Epidermal Growth Factor Receptor would best be able to reverse resistance to hormonal agents.

Detailed description: All patients must have stopped their endocrine two to four weeks or longer prior to entry on study. Upon enrollment, patients will begin lapatinib at 1500 mg once a day orally. The original endocrine therapy will resume two weeks later. The lapatinib will be continued for a maximum of 26 weeks.

A history, physical examination, blood counts, and chemistries will be done at baseline, and at regular intervals through the course of the study. A CT scan and bone scan will be done prior to treatment and at weeks 14 and 26. Assays for plasma DNA will be performed on blood sampled at baseline and at multiple time points throughout the course of treatment. Percutaneous biopsies will be taken in selected patients with accessible disease, 72 hours or less prior to the start of lapatinib, and again 13-15 days, and 27-29 days following the start of lapatinib. The day 13-15 biopsy will be done just prior to the resumption of the patient's endocrine therapy. Assays for phospho-ERK, phospho-Akt, Cyclin D1, Ki-67, and IRS-1 will be performed by conventional immunohistochemistry on the biopsied tissue.

Eligibility criteria: Inclusion Criteria:

* Patients with histologically or cytologically proven metastatic breast cancer.
* Patients with either estrogen or progesterone receptor positivity on the most recently examined tumor biopsy.
* Patients must have most recently been using an anti-estrogen (tamoxifen, toremifene, raloxifene, or fulvestrant) or an aromatase inhibitor.
* Patients must have had either a partial response or better, or stable disease for 24 weeks or longer, followed by disease progression, on the current or most recent hormonal therapy for management of metastatic breast cancer.
* Patients must be enrolled within six weeks of defining disease progression on hormonal therapy.
* Patients must have stopped fulvestrant at least four weeks prior and other endocrine therapy at least two weeks prior to enrollment on study.
* Patients must have either measurable disease or at least one evaluable bone lesion that has not been irradiated. Measurable disease is not necessary.
* Estimated life expectancy of at least 6 months.
* ECOG performance status 0-2.
* Adequate hematologic, hepatic, and renal function.
* Patients must be post-menopausal, or they must be practicing either abstinence or an adequate method of contraception, or their sexual partner must be sterile.
* All patients must be able to swallow, retain, and absorb oral medications.
* All patients must be able to give informed consent indicating that they are aware of the investigational nature of this study.

Exclusion Criteria:

* Patients may not have received an investigational agent within the prior four weeks.
* Patients may not have received trastuzumab within three weeks of study entry.
* Patients may not have had major surgery within the prior two weeks.
* Patients may not have Class III or IV heart failure as defined by the NYHA functional classification system.
* Patients may not have a left ventricular ejection fraction \< 40% based on MUGA or echocardiogram.
* Patients may not have uncontrolled brain metastases or leptomeningeal disease.
* Patients may not have rapidly progressive visceral metastases.
* Patients may not have a serious illness or conditions including clinically significant cardiac disease, angina pectoris, serious psychiatric disorder, or an active infection.
* Patients may not be receiving concurrent medications (listed in the protocol) which may interact with lapatinib during treatment with lapatinib.

Primary outcomes:
measure: Determine the Response Rate and Progression Free Survival of Hormone Therapy-resistant Patients With Metastatic Breast Cancer Treated With the Same Continued Hormonal Agent With the Addition of Lapatinib.
timeFrame: 26 weeks
measure: Progression-free Survival
timeFrame: Up to 575 days
Secondary outcomes:
measure: Determine the Toxicities of the Combination of the Hormonal Agent and Lapatinib in Patients With Metastatic Breast Cancer
timeFrame: 26 weeks
measure: Determine Changes in Activation of Tumor Cell ERK and Akt, as Between the Hormonal Agent and Lapatinib Contributes to the Molecular Pharmacodynamic Effect Postulated Above.
timeFrame: 4 weeks
measure: Determine Whether Changes in Plasma DNA Concentrations Are Predictive Markers of an Early Response to Lapatinib
timeFrame: 14 weeks
Other outcomes:
Locations:
city: Aurora
country: United States
facility: University of Colorado Cancer Center
state: Colorado
city: Lebanon
country: United States
facility: Norris Cotton Cancer Center
state: New Hampshire
city: Lake Success
country: United States
facility: North Shore University Hospital
state: New York
Study officials:
affiliation: Norris Cotton Cancer Center
name: Gary N Schwartz, MD
role: PRINCIPAL_INVESTIGATOR
References: