Lapatinib in Metastatic Breast Cancer Resistant to Hormone Therapy
| Status: | Terminated |
|---|---|
| Conditions: | Breast Cancer, Cancer |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 7/29/2018 |
| Start Date: | January 2006 |
| End Date: | October 2011 |
Lapatinib in Endocrine-Resistant Metastatic Breast Cancer
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.
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.
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.
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.
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.
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