Targeted Therapy With Lapatinib in Patients With Recurrent Pituitary Tumors Resistant to Standard Therapy
| Status: | Completed |
|---|---|
| Conditions: | Cancer, Brain Cancer, Lymphoma, Endocrine |
| Therapuetic Areas: | Endocrinology, Oncology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 2/2/2019 |
| Start Date: | July 2009 |
| End Date: | December 2018 |
This study focuses on new therapies for a challenging disease in pituitary medicine, that of
aggressive pituitary tumors which have limited therapeutic options beyond standard surgical,
radiotherapy, and select medical therapies, each incurring significant morbidity and
mortality, and each not optimally effective. To improve this gap in knowledge, we seek to
translate findings from the laboratory into clinical practice and hone in on therapies
directed at pituitary molecular targets, namely ErbB receptors. We have shown that human
prolactinomas express nuclear EGFR and membranous ErbB2, ErbB3 and ErbB4, and expression
correlates with tumor invasion. Pituitary tumor cell lines transfected with EGFR and ErbB2
translated to downstream effects on prolactin (PRL) gene expression and secretion,as well as
cell proliferation. Animal models implanted with these cell lines developed larger tumors and
PRL elevations. Treatment with ErbB tyrosine kinase inhibitors (TKIs) led to regression of
tumors xenografted into these animals and attenuated PRL secretion. Primary culture of human
prolactinomas confirmed expression of ErbB receptors and inhibitory effects of TKIs on PRL
secretion and cell proliferation. Based on these exciting preliminary data, the objective of
this new proposal is to conduct a Phase IIa clinical trial as a trenchant test of our
translational hypothesis that tyrosine kinase inhibition constitutes highly effective
targeted biologic therapy for these hitherto refractory pituitary adenomas. Specifically, our
aims are to test the: 1) efficacy of TKI therapy with a clinical trial; 2) threshold level of
tumor receptor expression to achieve TKI clinical response. Nineteen subjects will be treated
with lapatinib for 6 months in combination with their current dopamine agonist therapy, with
monthly measurements of PRL levels and MRI imaging every 3 months to evaluate the primary
endpoints of achieving 40% reduction in tumor size and 50% reduction in PRL and secondary
endpoints of radiologic stabilization and/or reduction and PRL normalization. Mean ErbB
receptor protein expression will be compared between responders to lapatinib and
non-responders by immunohistochemistry in pituitary tumor samples of these subjects collected
from prior surgeries.
aggressive pituitary tumors which have limited therapeutic options beyond standard surgical,
radiotherapy, and select medical therapies, each incurring significant morbidity and
mortality, and each not optimally effective. To improve this gap in knowledge, we seek to
translate findings from the laboratory into clinical practice and hone in on therapies
directed at pituitary molecular targets, namely ErbB receptors. We have shown that human
prolactinomas express nuclear EGFR and membranous ErbB2, ErbB3 and ErbB4, and expression
correlates with tumor invasion. Pituitary tumor cell lines transfected with EGFR and ErbB2
translated to downstream effects on prolactin (PRL) gene expression and secretion,as well as
cell proliferation. Animal models implanted with these cell lines developed larger tumors and
PRL elevations. Treatment with ErbB tyrosine kinase inhibitors (TKIs) led to regression of
tumors xenografted into these animals and attenuated PRL secretion. Primary culture of human
prolactinomas confirmed expression of ErbB receptors and inhibitory effects of TKIs on PRL
secretion and cell proliferation. Based on these exciting preliminary data, the objective of
this new proposal is to conduct a Phase IIa clinical trial as a trenchant test of our
translational hypothesis that tyrosine kinase inhibition constitutes highly effective
targeted biologic therapy for these hitherto refractory pituitary adenomas. Specifically, our
aims are to test the: 1) efficacy of TKI therapy with a clinical trial; 2) threshold level of
tumor receptor expression to achieve TKI clinical response. Nineteen subjects will be treated
with lapatinib for 6 months in combination with their current dopamine agonist therapy, with
monthly measurements of PRL levels and MRI imaging every 3 months to evaluate the primary
endpoints of achieving 40% reduction in tumor size and 50% reduction in PRL and secondary
endpoints of radiologic stabilization and/or reduction and PRL normalization. Mean ErbB
receptor protein expression will be compared between responders to lapatinib and
non-responders by immunohistochemistry in pituitary tumor samples of these subjects collected
from prior surgeries.
PURPOSE
The drug Lapatinib has been shown to inhibit both epidermal growth factor receptor (EGFR) and
erbB2 tyrosine kinases resulting in an effective slowing of disease progression in breast
cancer. It has also been demonstrated that erbB is overexpressed in human pituitary adenomas.
The investigators are therefore assessing tumor size stabilization and pituitary tumor
secretory profiles during the course of a six month therapy of lapatinib. The purpose of this
trial will be to estimate the activity of lapatinib in slowing the growth rate of pituitary
tumors. Lapatinib is an FDA approved drug used to treat breast cancer. However, in this
study, the drug will be used to treat pituitary cancer.
STUDY POPULATION
This study will recruit patients from the Pituitary Center at CSMC who are over the age of 18
that have a recurrent nonfunctioning adenoma after at least one surgical resection as well as
patients with prolactinomas who are resistant to dopamine agonist therapy and patients with
recurrent Cushing's disease.
PARTICIPANT'S JOURNEY THROUGH THE RESEARCH
The principal investigator (PI) or co-investigator will determine patients' potential
eligibility for the study based on inclusion and exclusion criteria.
The PI or the co-investigator will then approach subjects with recurrent nonfunctioning
adenomas or prolactinomas resistant to dopamine agonist therapy or recurrent Cushing's
disease during a visit in the clinic office and ask if these subjects would be interested in
participating in this study. If the subjects express interest, they will be given the consent
form to review. They will be encouraged to review it with family, friends, and/or other
physicians. The PI, co-investigators, or research nurse will be available for any questions
the subjects might have. If the subjects are still interested, they will be asked to sign and
return the consent form to the office and a study visit will be scheduled.
The PI, co-investigator, or member of study staff may also attempt to contact current
patients by phone to assess interest in participating in the study. The purpose and overall
structure of the study will be discussed with the possible participant. They will be reminded
that the study is strictly voluntary and that their involvement or disinterest in the study
will not affect their ongoing care. If the patient is interested they will be mailed a
consent to review and will be asked to call the center to schedule an appointment to further
discuss the study if they decide they are interested.
Each participant will undergo 8 visits of the course of the study. Each participant will have
a baseline visit where a medical history will be taken, a physical, visual field test,
electrocardiogram (ECG), echocardiogram (ECHO), and blood draw will be performed. At this
point lapatinib therapy will begin and the patients will be asked to take the drug daily for
the next six months. Patients will take Lapatinib 1250 mg daily (orally), which is the
standardized dose used to treat breast cancer patients. Visit 2 will be 1 month after the
participant has started lapatinib. At visit 2 all participants will receive a physical exam,
a history will be taken, an ECG will be performed, and a blood draw will occur. Visit 3 will
be 2 months after starting lapatinib. A physical exam and history will be performed along
with an ECG and echocardiogram and blood draw. Visit 4 will be 3 months after starting
lapatinib. A physical, history, blood draw, ECG, visual field test, and a magnetic resonance
imaging (MRI) of the pituitary will be performed. Visit 5 will occur 4 months after starting
lapatinib. A physical exam and history along with a blood draw and ECG and echocardiogram
will occur. Visit 6 will be 5 months after starting lapatinib. A physical exam, history, ECG,
and a blood draw will occur. Visit 7 will occur 6 months after the start of lapatinib. A
physical exam, history, blood draw, visual field test, ECG, echocardiogram and MRI of the
pituitary will occur. At this point lapatinib will be discontinued. Visit 8 will occur 1
month after visit 7 and a physical exam, history, blood draw, and ECG and and echocardiogram
will occur.
The drug Lapatinib has been shown to inhibit both epidermal growth factor receptor (EGFR) and
erbB2 tyrosine kinases resulting in an effective slowing of disease progression in breast
cancer. It has also been demonstrated that erbB is overexpressed in human pituitary adenomas.
The investigators are therefore assessing tumor size stabilization and pituitary tumor
secretory profiles during the course of a six month therapy of lapatinib. The purpose of this
trial will be to estimate the activity of lapatinib in slowing the growth rate of pituitary
tumors. Lapatinib is an FDA approved drug used to treat breast cancer. However, in this
study, the drug will be used to treat pituitary cancer.
STUDY POPULATION
This study will recruit patients from the Pituitary Center at CSMC who are over the age of 18
that have a recurrent nonfunctioning adenoma after at least one surgical resection as well as
patients with prolactinomas who are resistant to dopamine agonist therapy and patients with
recurrent Cushing's disease.
PARTICIPANT'S JOURNEY THROUGH THE RESEARCH
The principal investigator (PI) or co-investigator will determine patients' potential
eligibility for the study based on inclusion and exclusion criteria.
The PI or the co-investigator will then approach subjects with recurrent nonfunctioning
adenomas or prolactinomas resistant to dopamine agonist therapy or recurrent Cushing's
disease during a visit in the clinic office and ask if these subjects would be interested in
participating in this study. If the subjects express interest, they will be given the consent
form to review. They will be encouraged to review it with family, friends, and/or other
physicians. The PI, co-investigators, or research nurse will be available for any questions
the subjects might have. If the subjects are still interested, they will be asked to sign and
return the consent form to the office and a study visit will be scheduled.
The PI, co-investigator, or member of study staff may also attempt to contact current
patients by phone to assess interest in participating in the study. The purpose and overall
structure of the study will be discussed with the possible participant. They will be reminded
that the study is strictly voluntary and that their involvement or disinterest in the study
will not affect their ongoing care. If the patient is interested they will be mailed a
consent to review and will be asked to call the center to schedule an appointment to further
discuss the study if they decide they are interested.
Each participant will undergo 8 visits of the course of the study. Each participant will have
a baseline visit where a medical history will be taken, a physical, visual field test,
electrocardiogram (ECG), echocardiogram (ECHO), and blood draw will be performed. At this
point lapatinib therapy will begin and the patients will be asked to take the drug daily for
the next six months. Patients will take Lapatinib 1250 mg daily (orally), which is the
standardized dose used to treat breast cancer patients. Visit 2 will be 1 month after the
participant has started lapatinib. At visit 2 all participants will receive a physical exam,
a history will be taken, an ECG will be performed, and a blood draw will occur. Visit 3 will
be 2 months after starting lapatinib. A physical exam and history will be performed along
with an ECG and echocardiogram and blood draw. Visit 4 will be 3 months after starting
lapatinib. A physical, history, blood draw, ECG, visual field test, and a magnetic resonance
imaging (MRI) of the pituitary will be performed. Visit 5 will occur 4 months after starting
lapatinib. A physical exam and history along with a blood draw and ECG and echocardiogram
will occur. Visit 6 will be 5 months after starting lapatinib. A physical exam, history, ECG,
and a blood draw will occur. Visit 7 will occur 6 months after the start of lapatinib. A
physical exam, history, blood draw, visual field test, ECG, echocardiogram and MRI of the
pituitary will occur. At this point lapatinib will be discontinued. Visit 8 will occur 1
month after visit 7 and a physical exam, history, blood draw, and ECG and and echocardiogram
will occur.
Inclusion Criteria:
- Patients with nonfunctioning adenomas who have undergone at least one prior surgical
resection and have demonstrated recurrence on MRI
- Patients with prolactinomas who are resistant to dopamine agonist therapy
- Patients with malignant pituitary tumors
- Patients with visual field deficits and/or compression of the optic chiasm must be
stable for at least 6 months
Exclusion Criteria:
- Patients with compromised visual fields and/or compression of the optic chiasm on MRI
that has not been stable for last 6 months.
- Patients that have reduced left ventricular ejection fraction less than 50%
- Patients with moderate to severe hepatic impairment
- Patients that are pregnant or lactating
- Patients under the age of 18
- Active hepatitis
- Known previous HIV Positive
- Concurrent cancers
- Life expectancy less than one year
We found this trial at
3
sites
8700 Beverly Blvd # 8211
Los Angeles, California 90048
Los Angeles, California 90048
(1-800-233-2771)
Principal Investigator: Odelia Cooper, MD
Phone: 424-315-4489
Cedars Sinai Med Ctr Cedars-Sinai is known for providing the highest quality patient care. Our...
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3400 N Charles St
Baltimore, Maryland 21205
Baltimore, Maryland 21205
410-516-8000
Principal Investigator: Roberto Salvatori, MD
Phone: 410-955-3921
Johns Hopkins University The Johns Hopkins University opened in 1876, with the inauguration of its...
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185 Cambridge Street
Boston, Massachusetts 02114
Boston, Massachusetts 02114
617-724-5200
Principal Investigator: Janet Lo, MD
Phone: 617-726-7473
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