Targeted Therapy With Lapatinib in Patients With Recurrent Pituitary Tumors Resistant to Standard Therapy
Targeted Therapy With Lapatinib in Patients With Recurrent Pituitary Tumors Resistant to Standard Therapy
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.
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.
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