Clinical trial NCT00939523
Conditions: Pituitary Adenomas Prolactinomas
Keywords: recurrent nonfunctioning adenoma prolactinomas resistant pituitary tumors aggressive pituitary tumors malignant pituitary adenomas
Sponsor: Cedars-Sinai Medical Center
Start date: 2009-07-01; Completion date: 2018-12-01
Enrollment: 9 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
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.

Detailed description:
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.

Arms: arm 1: All participants will be asked to take Lapatinib daily for a total of six months during the research study.
Interventions: intervention 1: Lapatinib
Intervention descriptions: intervention 1: All participants will be asked to take Lapatinib daily for six months during the research study.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
1
 
 
 
 
 
 
 
 
Title: Targeted therapy with lapatinib in patients with recurrent pituitary tumors 
resistant to standard therapy 
 
NCT numbers: NCT00939523 
 
Document date: 7/2/2015 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
2
 
 
 
Section 1.0 
 
General Information  
Treatment of recurrent pituitary tumors with lapatinib 
PI: Odelia Cooper, MD 
Co-investigators: Shlomo Melmed, MD, Jeremy Rudnick, MD, Vivien Bonert, MD, 
Barry Pressman, MD 
Study staff: Billy Gellepis, Vivian Hwe 
Version Date: 7/2/2015 (Ame16104) 
 
Section 2.0 
 
Background information 
B1. erbB receptor tyrosine kinases. 
 
The erbB receptor tyrosine kinase family consists of EGFR, erbB2, erbB3, and 
erbB4.  They comprise an extracellular ligand-binding domain, a single membrane-
spanning region and a cytoplasmic tyrosine-kinase-containing domain, and are expressed 
in epithelial, mesenchymal, and neuronal tissues.  There are three groups of ligands for 
the erbB family.  EGF, TGFα, amphiregulin, and others bind EGFR.  The second group of 
ligands includes betacellulin, heparin-binding EGF, and epiregulin which bind both EGFR 
and erbB4.  The third group comprises the neuregulins which bind erbB3 and erbB4  
(Hynes et al. 2005).  Ligand binding induces formation of receptor homo- and 
heterodimers and activation of the intrinsic kinase domain, leading to phosphorylation on 
specific tyrosine residues in the cytoplasmic tail.  Phosphorylated residues serve as 
docking sites for proteins which lead to activation of intracellular signaling pathways 
(Hynes & Lane 2005).  
erbB2 lacks a known direct ligand. erbB2 acts as a co-receptor or 
heterodimerization partner for other erbB receptors that possess stimulatory ligands.  
erbB2/erbB3 heterodimers are the most prevalent and mitogenically potent of the erbB 
receptor/ligand complexes (Roskoski 2004). Unlike other erbB receptors, erbB2 
overexpression can cause malignant transformation without expression of a growth factor.  
erbB2 has constitutive (ligand-independent) activity, and erbB2 expression above a 
specific threshold can drive tumor growth (Yarden et al. 2001).  erbB2 plays an important 
role in development in the nervous system, bone, muscle, skin, heart, and lungs, (Yarden 
& Sliwkowski 2001).   
 
erbB3 possesses a tyrosine kinase domain homologous to the other members.  
However, kinase activity of erbB3 is impaired. erbB3 forms heterodimers with the other 
three members whereby trans  phosphorylation is required for cell signaling (Roskoski 
2004).  erbB3 homodimers are mitogenically inactive (Pinkas-Kramarski et al. 1996).   
 
erbB signaling is thus an interactive system in which the ligand can lead to 
formation of different homodimers or heterodimers that interact to stimulate a variety of 
signaling pathways.  The network consist of an input layer (ligands or growth factors), 
cellular information processing layer (receptors, SH2-proteins, transcription factors), and 
an output layer (cell growth, differentiation, or migration).  Receptor dimerization allows 
the signaling network to transmit biological messages with erbB2 as the coordinator of this 
intricate network (Yarden 2001).     
 
B2. erbB receptor tyrosine kinase role in malignant transformation. 
 
EGFR regulates cell proliferation and survival.  An imbalance in this system can 
lead to increased EGFR signaling which can result in neoplastic transformation.   
The role of EGFR overexpression in tumorigenesis includes amplification of the 
EGFR gene which then increases EGFR levels (Zandi et al. 2007).  EGFR can also be 


 
 
 
3
overexpressed in the absence of gene amplification from increased activity of the EGFR 
promoter or dysregulation at translational and post-translational levels.  For instance, a 
specific region in the EGFR gene has an enhancer ability in some breast cancer lines 
overexpressing EGFR (McInerney et al. 2001).  One mechanism involved in neoplastic 
transformation is aberrant EGFR signaling due to defective receptor downregulation.  
EGFR signaling is attenuated through internalization and subsequent degradation of the 
activated receptor.  A mutant EGFR lacking part of the intracellular domain can transform 
mouse fibroblasts in a ligand dependent manner (Wells et al. 1990).  EGFR 
downregulation can be affected by overexpression of erbB2.  erbB2 is overexpressed in 
different cancers and can shift the formation of EGFR homodimers toward the formation 
of EGFR/erbB2 heterodimers.  Activated erbB2 is not downregulated and when expressed 
together with EGFR at high levels, erbB2 can inhibit downregulation of EGFR (Qian et al. 
1994).  erbB2 overexpression leads to constitutive EGFR activation independent of ligand, 
with defective downregulation of erbB2-EGFR heterodimers leading to more potent 
signaling as compared with EGFR homodimers(Worthylake et al. 1999).   
Dimerization of erbB receptors represents the fundamental mechanism that drives 
transformation.  erbB2 forms heteromeric associations with EGFR and even without 
ligand, slight overexpression of erbB2 and EGFR led to heterodimers with activated 
kinases (Wada et al. 1990).  erbB receptor dimerization triggers MAPK and PI3K-AKT 
pathways which then promote cell proliferation and survival (Zhang et al. 2007).   
 
Over expression of erbB2 in tumors is a predominant transformation-activating 
mechanism.  Over expression of erbB2 has been observed in 25-30% of breast and 
ovarian cancers, and is associated with poor prognosis (Slamon et al. 1987). This may be 
a consequence of gene amplification (Pauletti et al. 1996).  erbB2 overexpression triggers 
ligand-independent activation of the kinase domain both from spontaneous dimer 
formation and heterodimerization. erbB2 oncogenic action occurs through many pathways 
and includes a dominant role of lipid kinase Phosphatidylinositol (PI)-3K pathway (Nelson 
et al. 2001).  The ability of erbB2 to potentiate autocrine EGFR signaling may lead to 
activation of intracellular pathways, leading to increased proliferation and tumor 
development.  Loss of erbB2 function inhibits proliferation of tumor cells displaying EGFR 
autocrine activation (reviewed in (Olayioye et al. 2000).  
 
Transformation by either erbB2 or EGFR alone requires high receptor expression 
though expression of both receptors at moderate levels sufficient to cause transformation 
(Kokai et al. 1989) and depends on continuous cell surface expression of both receptors 
(Wada et al. 1990). Studies with the T757 mutant and N691stop mutant which has an 
intracellular truncation of erbB2 demonstrate that EGFR may be responsible for erbB2 
phosphorylation and that erbB2 is involved in reciprocal activation of EGFR.  Also, the 
mutations abolished transformation and tumorigenicity seen with formation of the wild type 
heterodimer (Qian et al. 1994).  Overexpression leads to spontaneous receptor 
oligomerization, as with the EGFR receptor.   
Expression of erbB3 is seen in a number of tumors which over express erbB2, 
including breast, bladder, and melanomas.  Many erbB2 overexpressing breast tumors 
have elevated levels of phosphotyrosine on erbB3 likely as a result of spontaneous 
dimerization with erbB2. erbB2 and erbB3 function together to stimulate mitogenic 
signaling networks (reviewed in (Olayioye et al. 2000). 
 
Nuclear EGFR localization has been observed in proliferating hepatocytes, 
pregnant uterus, and thyroid.  Nuclear EGFR signaling network transmits growth factor 
signals directly from the cytoplasmic membrane to transcriptional targets in the nucleus, 
bypassing traditional protein phosphorylation cascades.  The juxtamembrane region of 
EGFR harbors a putative nuclear localization sequence that mediates nuclear localization 


 
 
 
4
of EGFR (Hsu et al. 2007).  Recently, nuclear EGFR protein in oropharyngeal cancer 
tissue was shown to be associated with nuclear PCNA (Psyrri et al. 2008). 
 
B3: EGFR targeted therapy in cancer 
 
 
Knowledge of the role of the EGFR members in malignant transformation has led 
to development of a new class of therapeutics designed to interfere with this crucial 
mechanism.  Two main types of therapies are monoclonal antibodies (mAb) targeting the 
extracellular domains and tyrosine kinase inhibitors (TKIs).  mAb against EGFR inhibited 
EGF and nducted activation of EGFR tyrosine kinase activity and cell proliferation (Sato 
et al. 1983).  Cetuximab (Erbitux) is a chimeric mouse anti-EGFR mAb approved for 
treatment of refractory colorectal cancer and in advanced head and neck cancer.   
 
mAbs targeting erbB2 induce downmodulation of cell surface expression of the 
erbB2 receptor leading to reversal of the transformed phenotype of tumor cells (Drebin et 
al. 1985) as well as inhibiting growth of tumors overexpressing erbB2 implanted in athymic 
mice (Drebin et al. 1986).  Trastuzumab (Herceptin) is approved for use in combination 
with first line chemotherapy for metastatic breast cancer expressing high levels of erbB2 
(Zhang et al. 2007). 
 
A key feature of erbB receptors is the inducible kinase activity that trans-
phosphorylates tyrosine residues in the C terminal domain and leads to activation of 
downstream signaling pathways.  Reversible inhibitors of this tyrosine kinase activity 
compete with the ATP binding to the kinase.  TKIs have broad activity against multiple 
receptors in the erbB family (Zhang et al. 2007).  Reversible TKIs include gefitinib (Iressa; 
AstraZeneca) approved for chemotherapy-refractory nonsmall cell lung cancer.  It targets 
the EGFR tyrosine kinase specifically.  Lapatinib (Tykerb, Glaxo) targets both EGFR and 
erbB2, leading to apoptosis of head, neck, and breast cancer cells (Xia et al. 2002).  It is 
approved for use in combination with capecitabine for advanced erbB2-positive breast 
cancer (Cameron et al. 2008).   
 
B4. Natural history of pituitary tumors. 
 
Pituitary adenomas comprise ~15 % of intracranial neoplasms with overall 
incidence at 15 to 20 per million per year.  The prevalence of clinically significant 
adenomas is between 2 to 2.5 per 10,000 though this may be up to 9 per 10,000 in other 
series (Levy 2008).  Occult adenomas are discovered in as many as 25 % of unselected 
autopsies (Melmed 2003). Microadenomas (less than 1 cm diameter) comprise 50-60 % 
of these and tend to show no further growth.  Macroadenomas slowly expand over years.  
Pituitary carcinomas comprise less than 0.2 % of pituitary adenomas (Levy 2008).   
Pituitary tumors are generally benign but can lead to morbidity from their location near 
critical structures, increasing size, and pituitary hormone over- or under-expression.  
Patients may experience headaches, visual disorders, and cranial nerve dysfunction from 
compressive effects while changes in hormone expression may either be due to pituitary 
stalk disruption or pituitary failure from compression of normal pituitary tissue.  Pituitary 
adenomas produce clinical features based on their specific cell type.  Prolactinomas 
comprise about 30 % of pituitary adenomas with a prevalence of 60-100 per million and 
present with amenorrhea, infertility, and galactorrhea in females and impotence or 
infertility in males.  Somatotroph adenomas comprise 10 % of pituitary adenomas with 
prevalence of 40-60 per million and overexpress growth hormone leading to acromegaly 
in adults as manifested by soft tissue and bony changes and increased risk of 
hypertension, cardiac disease, and diabetes.   Another 10 % of adenomas are corticotroph 
adenomas which lead to ACTH hypersecretion and features of hypercortisolism.  
Thyrotropinomas comprise are rare (1 % of adenomas).  Approximately 30-35 % of tumors 
are 
nonfunctioning 
and 
present generally 
with 
compressive 
symptoms 
and 


 
 
 
5
hypopituitarism.  The prevalence is 70-90 per million and include the subsets of 
gonadotroph adenomas, oncocytic and non-oncocytic adenomas (Melmed 2003).   
 
Though pituitary adenomas are usually benign, some exhibit aggressive growth 
patterns and may invade parasellar structures, recur and progressively grow despite 
antitumor therapy, as well as even metastasize to intracranial and other distant sites  
(Blevins et al. 1998).  There is no accepted definition of aggressive adenomas but are 
generally observed to involve massive invasion of surrounding brain and parasellar 
anatomy, rapid growth, and giant size.  They tend to recur quickly after initial treatments, 
are unresponsive to therapy, difficult to cure, and some have a fatal outcome.  Invasion 
into the cavernous sinus, skull base bone, and sphenoid sinus mucosa prevents curative 
surgery in these tumors (Buchfelder 2008).   
 
Radiologic signs of invasion include: a tumor that completely encircles or extends 
beyond the lateral limit of the cavernous carotid artery; complete erosion of the clivus; and 
the presence of tumor within the sphenoid sinuses.  Dural microinvasion occurs in 69 % 
of microadenomas and 94 % of macroadenomas(Selman et al. 1986). 
 
The pathogenesis of pituitary carcinomas is unclear. They may arise from 
preexisting adenomas as shown by the fact that many carcinomas initially present as 
macroadenomas, demonstration of a monoclonal origin, and confirmation of the 
progressive accumulation of genetic alterations in the transformation from a pituitary 
adenoma to a carcinoma.  Invasive adenomas may represent a biologically intermediate 
stage in tumor progression from benign to carcinoma (Amar et al. 1999).  According to the 
2004 WHO classification, tumors with invasive growth, elevated mitotic index, Ki-67 
labeling index > 3 %, and extensive nuclear reactivity for p53 are considered “atypical” 
adenomas warranting closer monitoring for development of early regrowth (Al-Shraim et 
al. 2006). 
 
  The standard therapy for nonfunctioning adenomas is surgical resection as there 
are no effective medical therapies to date.  Surgical success is dependent on the skill and 
experience of the neurosurgeon and on degree of invasion and size.  Tumors larger than 
2 cm can be completely removed in 20 % of cases while invasion into the cavernous sinus 
makes it difficult to resect (Chandler et al. 2008). Completeness of resection is assessed 
on the 3 month postoperative MRI scan and annual serial MRIs.  Preoperative 
hypopituitarism may resolve in 15-50 % of patients and hyperprolactinemia may improve 
in up to two-thirds of patients.  However, surgery can also lead to development of new 
onset hypopituitarism in 2-15 % of patients.  Transient diabetes insipidus (DI) may occur 
in 33 % of patients with permanent DI in 0.5-5 %.  Other complications of surgery include 
cerebrospinal fluid leak, meningitis, rebleeding, cranial nerve injury, visual field 
compromise.  Mortality is 0.3-0.5 % with higher mortality and morbidity in large tumors (> 
4 cm diameter) (Molitch 2008).  Reoperation for recurrences is often necessary in 
nonfunctioning adenomas when there is risk to the optic apparatus.  Each additional 
surgery increases the risks of bleeding and further damage to the normal pituitary and 
surrounding structures. 
 
In contrast to nonfunctioning adenomas, prolactin secreting adenomas are treated 
with primary medical therapy through use of dopamine agonists. Bromocriptine normalizes 
prolactin levels in 80-90 % of microprolactinomas and in 70 % of macroprolactinomas.  In 
20 % of cases, patients will be resistant to medications and fail to normalize prolactin 
levels and shrinkage of tumor mass on MRI.  In those cases, surgery is indicated with 75 
% cure rate in microprolactinomas and 34 % cure rate in macroprolactinomas(Mancini et 
al. 2008).   
 
 


 
 
 
6
 
B5. Pituitary tumorigenesis. 
 
Pituitary adenomas arise from clonal expansion of mutated somatic cells.  Loss of 
heterozygosity of  the chromosomal locus, 11q13, has been observed in 30 % of sporadic 
pituitary tumor, especially the invasive types (Melmed 2003).  p27 protein is absent in 
most pituitary tumors and undetectable in pituitary carcinomas (Lidhar et al. 1999).  
Disruption of p18, a cyclin inhibitor gene, and p27 lead to development of pituitary tumors 
with accelerated tumorigenesis(Franklin et al. 1998). p16 is undetectable in pituitary 
tumors and may be inactivated in adenomas (Melmed 2003).  Approximately half of 
pituitary adenomas are aneuploid(Levy et al. 2003) but the gain or loss of chromosomes 
has been inconsistent (Hui et al. 1999).  Cytologicatypia does not correlate with rapid 
tumor growth though the presence and number of mitoses may be a possible indicator 
(Kontogeorgos 2006). p53 immunoreactivity is absent in noninvasive adenomas while 
present in 15 % of invasive adenomas and in all pituitary carcinomas (Kontogeorgos 
2006).  Apoptotic reactivity has been observed in aggressive, atypical, and drug-resistant 
pituitary adenomas (Kontogeorgos et al. 2006).   
 
PTTG is over expressed in pituitary tumors and correlates with invasiveness, 
behaving as a transactivator and potent transforming gene (Pei 2000).  PTTG disruption  
in mouse models is protective for pituitary tumor development (Chesnokova et al. 2005) 
and associated with pituitary cell senescence thereby restraining development of pituitary 
tumors (Chesnokova et al. 2007).  Apoptosis and senescence control aberrant tissue 
growth and contribute to tumor suppressor activity.  Cellular senescence is characterized 
by up-regulation of cell cycle progression inhibitors, p19, p21, and p16.  PTTG may behave 
as a protooncogene depending on pituitary p21 status.  High levels of PTTG lead to 
chromosomal instability and defective metaphase-anaphase progression and promote 
pituitary tumor formation.  Activation of pituitary DNA damage pathways triggers p21, a 
barrier of tumor growth and marker of senescence, which may then restrain further growth 
and malignant transformation of pituitary tumors.  When the senescence pathway is 
bypassed, malignant transformation of pituitary adenomas may then occur.  This has been 
supported by presence of p21 expression in > 70 % of GH secreting adenomas and 
absence of p21 in GH carcinomas (Chesnokova et al. 2008).   
 
B6. erbB receptor tyrosine kinases in pituitary tumors. 
 
Crosstalk between PRL and EGF was observed in T47D cancer cells, PRL 
activated JAK2, STAT5, and ERKs and caused phosphorylation of EGFR and erbB2.  PRL 
synergized with EGF in activating ERK (Frank 2008).   
erbB receptors are over expressed in pituitary adenomas.  In 20 nonfunctioning 
adenomas, 80 % were immunopositive for EGFR and all were erbB2 positive while EGFR 
was undetectable and erbB2 weaker in functioning tumors (Chaidarun et al. 1994).  
Another study found 50 % of functioning adenomas expressed EGFR while most 
nonfunctioning adenomas and normal pituitary expressed EGFR.  EGFR mRNA 
expression was highest in somatotroph adenomas and in patients with aggressive silent 
subtype 3 adenomas and with recurrent acromegaly (LeRiche et al. 1996).  In contrast, 
others found that nonfunctioning adenomas were uniformly negative for EGFR while 50 
% of functioning tumors were positive (Kontogeorgos et al. 1996).   More recently, EGFR 
expression was shown in normal pituitaries and nonfunctioning adenomas with lowest 
expression in corticotroph adenomas.  In situ hybridization for EGFR was positive in     77 
% of null cell and 68 % of gonadotroph adenomas with variable positivity in functioning 
adenomas. Five pituitary carcinomas though were strongly positive with one tumor 
negative.  Western blot analysis confirmed expression in nonfunctioning adenomas and 
carcinomas (Onguru et al. 2004).  Furthermore, EGF binding was higher in invasive 


 
 
 
7
adenomas than in non-invasive adenomas, especially in those invading the sphenoidal 
sinus (Jaffrain-Rea et al. 1998).  However, only 3 of 40 nonfunctioning adenomas were 
immunopositive for EGFR in contrast to 33 % of prolactinomas and     25 % of somatotroph 
adenomas though 80 % of corticotroph adenomas were positive (Theodoropoulou et al. 
2004).   
 
erbB2 
is 
expressed 
in 
67 
% 
prolactinomas 
and 
in 
53 
% 
of 
somatotropinomas(Botelho et al. 2006).  erbB2 staining was observed in a pituitary 
corticotroph carcinoma but not in corticotroph adenomas (Nose-Alberti et al. 1998).  In a 
gonadotroph carcinoma, erbB2 immunoreactivity and gene amplification were manifest in 
the recurrent tumor (Roncaroli et al. 2003).  Another study did demonstrate no erbB2 
immunostaining or gene amplification of erbB2 in pituitary adenomas . 
 
 
C. Preliminary Data:  
 
C1. EGFR-mediated pituitary signaling in vitro and in vivo 
 
EGFR and erbB2 are expressed in GH3 rat lacto-somatotroph cells but not in 
AtT20 mouse corticotroph cells.  Our laboratory showed that EGF treatment enhanced 
baseline and serum-induced prolactin mRNA and gene expression in GH3 cells but did 
not change AtT20 POMC gene expression (figure 1).  Treating GH3 cells with increasing 
doses of gefitinib attenuated serum induced S phase entry and suppressed serum induced 
Pttg1 mRNA expression.  Gefitinib, an EGFR inhibitor, inhibited prolactin mRNA 
expression as well.  Doses as low as 0.1µmol/L led to a 15 % attenuation of GH3 cell 
number with a dose dependent decrease of 72 % at 10 µmol/L.  When GH3 cells were 
pretreated with gefitinib prior to induction with EGF, prolactin gene expression was 
suppressed (Vlotides et al. 2008).   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1: EGF selectively induces PRL secretion and mRNA levels. PRL and GH mRNA 
levels on Northern blot at different time points. C: control. EGF: GH3 cells treated with 5 
nmol/L. S: serum. *p < 0.05, *** p < 0.001 


 
 
 
8
(Vlotides et al. 2008) 
Induction of GH3 cells with EGF or serum induced tyrosine phosphorylation of erbB 
receptor members.  This was confirmed by immunoprecipitation with receptor-specific 
antibodies.  EGF induced tyrosine phosphorylation of EGFR which was blocked by 
gefitinib pretreatment.  GH3 cell neu tyrosine phosphorylation was seen in response to 
ligand activation.  Tyrosine phosphorylation of erbB2 was observed in response to EGF 
and heregulin, confirming that erbB2 is the preferred erbB family heterodimerization 
partner in GH3 cells.  Gefitinib treatment abrogated EGF induced erbB2 activation.  erbB3 
tyrosine phosphorylation was seen in response to heregulin but in low levels in response 
to EGF (Vlotides et al. 2008).   
 
GH3 cells were implanted into athymic mice.   In gefitinib-treated animals, tumor 
volume decreased by 50 % compared to controls.  Prolactin and IGF-1 levels as well 
decreased significantly.  Immunohistochemical analysis confirmed EGFR expression in 
tumor tissue (Vlotides et al. 2008). 
 
We show immunofluorescence staining for erbB2 and erbB3 in 7 prolactinomas 
(figure 2).  mRNA expression for erbB2 and erbB3 by quantitative PCR analysis of two 
tumor specimens was elevated.  In a patient with a prolactinoma resistant to treatment 
who had multiple surgeries, higher erbB2 and erbB3 levels were seen in the recurrent 
tumor.  In rat lacto-somatotroph GH4C1 cells, immunoprecipitation and immunoblotting 
showed expression of EGFR, erbB2, and erbB3.  EGF induced EGFR and erbB2 
phosphorylation but not of erbB3.  Increasing heregulin concentrations induced PRL 
mRNA expression.  Gefitinib treatment suppressed receptor activation and signaling of 
erbB receptors and prevented heregulin-induced erbB2/erbB3 heterodimerization 
(unpublished data by Vlotides and Cooper).   
 
A. 
 
 
 
 
 
B. 
Figure 2: Immunohistochemistry of human prolactinoma A. erbB2 expression (SC-284) B: 
erbB3 (SC-284) expression 
 
C2. Lacto-somatotroph stable transfectants. 
A GH4 cell line was engineered in our laboratory to constitutively overexpress erbB2. This 
cell line increased prolactin expression 1.5 fold compared to controls.  In contrast, GH4 
cells with kinase negative erbB2 expression demonstrated lower PRL gene expression 
(figure 3-4) while GH expression was unchanged.  These stable transfectants will be used 
for in vivotumorigenesis experiments (see below). 


 
 
 
9
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1      2       3      4       5 
 
 
EV  WT   CA   KD    EGF 
Figure 3: erbB2 induced PRL expression in GH4 cells. Cells were stably transfected with 
empty vector, wild type erbB2, constitutively active erbB2 or kinase deficient erbB2. 
Lane1: empty vector. Lane 2: erbB2 wild type in GH4 cells. Lane 3: constitutively active 
erbB2 in GH4 cells. Lane 4: kinase deficient erbB2 in GH4 cells. Lane 5: EGF treated 
cells. 
 
C3. Expression of erbB receptors in invasive versus non-invasive pituitary adenomas. 
We evaluated 23 large NFAs and 13 small NFAs in a cohort analysis using 
immunohistochemistry and immunoblotting to test for EGFR, erbB2, and erbB3.  Fisher’s 
exact test was used for categorical variables, and the t-test and Mann-Whitney test used 
to compare means of continuous variables.81 % of large NFAs were males while in the 
small NFAs 20 % were males (p=0.0013).  Preoperative presentation in large NFAs 
differed in visual field loss (p = 0.0136) and secondary hypogonadism (p=0.023).  Median 
tumor MRI diameter in large NFAs was 40 ± 17 mm and 16 ± 6  mm in small NFAs 
(p=0.0002).  65 % of large NFAs had cavernous sinus invasion (p=0.0005), 96 % had optic 
chiasm compression (p=0.04), 40 % had sphenoid sinus invasion (p =0.0116), 81 % 
(p=0.03) had suprasellar tumor, 35 % had sphenoid invasion (p=0.03), and 53 % had 
extralobar spread (p=0.03).  Small NFAs underwent 1 surgery while 56 % of large NFAs 
had more than one surgery (p=0.0451). 76 % of large NFAs had residual tumor (p=0.007) 
and 56 % had recurrences (p=0.0451) compared to none in small NFAs (unpublished 
data, Cooper O).   
Positive staining for EGFR in large NFAs was 93 ± 4 % (mean) of tumor cells vs 
68 ± 11% in small NFAs (p<0.0001), and positive staining for erbB2 in large NFAs was 93 
± 4 % (mean) of tumor cells for erbB2 versus 81 ± 15 % in small NFAs (p=0.0004). Both 
large and small adenomas had nuclear localization of EGFR as opposed to membranous 
staining of erbB2.  Membranous erbB3 staining was present in 42 % of large NFAs 
compared to 33 % of small NFAs (figure 5).  Western blot confirmed expression of EGFR, 
erbB2, and erbB3 in 3 large adenomas and none in a small adenoma (figure 6).  EGFR 
staining correlated with increasing tumor diameter (p=0.0004), suprasellar spread 
(p=0.017), cavernous sinus invasion (p=0.056), extralobar spread (p=0.011), residual 
tumor after surgery (p=0.0077), and recurrences (p=0.05). erbB2 staining correlated with 
suprasellar invasion (p=0.045).  Large NFAs had 37 % higher percentage of cells 
Akt 
pAkt 
ERK 
PRL 
pERK 
GAPDH
GH 
pY 
Neu 


 
 
 
10 
expressing EGFR and 15 % higher erbB2 expression than small NFAs (unpublished data, 
Cooper O). 
 
 
 
 
 
 
 
 
 
 
 
A. 
 
 
                  B.  
 
 
 
  C. 
 
 
 
 
 
 
 
 
 
 
 
D. 
 
 
 
       E.  
 
 
 
  F. 
 
 
 
 
 
 
 
 
 
 
G.                                                  H.                                                   I. 
 
 
 
Figure 5: Immunofluorescent staining of giant nonfunctioning human pituitary adenomas 
(NFAs). A: erbB2 in breast cancer (positive control). B: Negative control for erbB2 
(corticotroph tumor) C. erbB2 in giant NFA. D: EGFR in breast cancer. E. EGFR blocking 
peptide of breast tissue. F. EGFR in giant NFA. G: erbB3 in breast cancer. H. erbB3 
blocking peptide of breast tissue.I. erbB3 in giant NFA. 
 
 
 
 
 
 
 
 


 
 
 
11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 6: erbB is overexpressed in human NFAs as assessed by Western blot. Positive 
controls for erbB2, erbB3, and EGFR: GH4 erbB2 overexpressing cells; negative controls: 
AtT20 cells; Tumors 1 and 2: small NFAs, Tumors 3 and 4: large NFAs 
 
Summary: 
We have demonstrated expression of EGFR and erbB2 in rat lacto-somatotroph cells, and 
EGF stimulation leads to increased prolactin mRNA expression. In GH4 cells which 
overexpress constitutively active erbB2, prolactin expression increased. Gefitinib 
treatment inhibits EGF induced erbB2 and EGFR in GH3 cells, and in mice implanted with 
GH3 cells, lead to decreased tumor volume and prolactin levels.  Expression of the erbB 
receptors has been shown in human prolactinomas resistant to medical therapy as well 
as in large, invasive nonfunctioning adenomas.   
 
Section 3.0 
 
Trial objectives and purpose 
Test the clinical effects of lapatinib for treatment of aggressive and recurrent 
pituitary tumors.  
Hypothesis: We hypothesize that lapatinib will inhibit tumor growth and hormonal 
secretion in patients with pituitary tumors. Gefitinib has been approved for use in non-
small-cell lung cancer but has not been proven to elicit significant tumor size reduction.  
Lapatinib, which inhibits both EGFR and erbB2 tyrosine kinases, has been proven to be 
effective in slowing disease progression in breast cancer both as monotherapy and when 
given in combination with capecitabine(Geyer et al. 2006).  In a proof of concept clinical 
trial, we plan to treat patients with aggressive pituitary tumors resistant to standard therapy 
with lapatinib for 6 months to assess for stabilization of tumor size and pituitary tumor 
secretory profiles.  In addition, we will treat subjects with malignant pituitary tumors which 
have failed to respond to other therapeutic modalities.  These subjects will be in a separate 
arm of the study for patients with malignant pituitary tumors. 
 
Section 4.0 
 
Trial Design 
Conduct a proof of concept single cohort open label study of lapatinib in patients 
with pituitary tumors. 
 
  
 
Trial design: Open label, single cohort proof of concept trial. 
An additional arm of the study will be for subjects treated with the study drug in 
malignant pituitary tumors.   
Three clinical trial sites, one at CSMC and the others at Johns Hopkins Hospital and 
Massachusetts General Hospital. 
GH4 
+erbB2 
AtT20 
    1 
  2 
  3 
  4 
GH4 
+erbB2 
AtT20 
1 
2           3 4 


 
 
 
12 
 
Study population: Patients will be recruited from the Pituitary Center at Cedars-Sinai 
Medical Center and the other two sites. 
Intervention: lapatinib 1250 mg daily for 6 months. Patients will be treated with the 
standardized dose used in breast cancer therapy for six months (Cameron & Stein 2008; 
Geyer et al. 2006).  The drug will be supplied by Novartis Oncology.   
 
a. Primary outcome variable. 
 
Primary outcome in nonfunctioning pituitary adenomas: 40% reduction in tumor 
size in any dimension. .Tumor size and volume will be calculated using Open 
Source OsiriX® Imaging Software for MacOS.  MRIs will be performed at 
baseline and at 3 and 6 months All MRIs will be centrally read by the dedicated 
pituitary radiologist at CSMC.  
 
Primary outcome in prolactinomas: 40% reduction in tumor size in any 
dimension. 
Primary outcome in malignant pituitary tumors: Progression free survival 
 
b. Secondary outcome variables. 
 
Secondary outcomes in prolactinomas:  
(a) achievement of 50% reduction of PRL levels (b) PRL normalization (c) percent 
reduction in PRL levels (d) percent reduction in tumor volume. Tumor volume will be 
calculated using Open Source OsiriX® Imaging Software for MacOS. (e) correlation of 
tumor size and PRL reduction (f) clinical predictors of TKI response, including age, gender, 
duration of disease, dose and duration of dopamine agonist therapy, baseline PRL, and 
baseline tumor size. 
 
Secondary outcomes in malignant pituitary tumors: partial response, complete 
response, mortality, 24 hour urine free cortisol levels for Cushing carcinomas, 
IGF-1 levels for acromegaly carcinomas. 
We will correlate ErbB receptor expression with the subjects' clinical response 
to the study drug.  This will be performed through immunohistochemistry 
staining of pituitary tumor slides from surgery.  
 
Section 5.0. 
 
Selection and Withdrawal of Subjects 
Inclusion criteria: Subjects with non-functioning pituitary adenomas, who have 
undergone at least one prior surgical resection and have demonstrated 
recurrence on MRI.   
Subjects with prolactinomas who are resistant to dopamine agonist therapy who 
manifest continued tumor size growth while on a dopamine agonist, unless 
intolerant of adequate doses of a dopamine agonist.  
Subjects with malignant pituitary tumors will be eligible for the malignant pituitary 
tumor arm of the study regardless of existing visual deficits.   
Exclusion criteria: Children will be excluded. If subjects have preexisting visual 
field deficits, they will be monitored on more frequent basis. Patients will also be 
excluded if they have left ventricular ejection fraction less than 50 %, moderate to 
severe hepatic impairment (see below for specifics), active hepatitis, HIV 
positivity, concurrent cancers, life expectancy less than one year, and pregnancy.  
Pregnant patients will be excluded. Childbearing age women will be require to use 


 
 
 
13 
contraception. Patients who become pregnant during the study should 
discontinue the study immediately. 
 
Withdrawal of Subjects: 
Monitoring for adverse effects: Prior to initiating therapy, patients will undergo an 
echocardiogram and ECG to evaluate the ejection fraction, and the echocardiogram will 
be repeated every 8 weeks (Visit 3, 5, and 7) and on visit 8.  Patients will also undergo  
ophthalmic testing at visits 1, 4, and 7.Patients with pre-existing stable visual field 
compromise prior to enrollment will undergo visual field testing at visits 1, 2, and 3,and if 
stable, then they will proceed with visual field testing every three months for the duration 
of the study.  Patients will be evaluated for adverse effects monthly with physical 
examinations, chemistry and hematology panels, and ECGs.  Adverse events will be 
graded by the NCI-CTC and include: anorexia, decreased ejection fraction, interstitial lung 
disease/pnemonitis, diarrhea, nausea, vomiting, hepatotoxicity, rash, and fatigue.  
Lapatinib will be discontinued in those who developed decreased ejection fraction, who 
develop pulmonary symptoms, retinal toxicity, worsening of visual fields, and those with 
toxicity greater than or equal to Grade 2 on the NCI-CTC.  Dr. Jeremy Rudnick, from 
Oncology department at Cedars-Sinai Medical Center, will assist us in monitoring patients 
for adverse events. 
If at any time a patient demonstrates compromise of his visual fields, dilated retinal exam 
or tumor growth on MRI, he will be withdrawn from the study and referred for surgery. 
 
Section   6.0  
Treatment of Subjects 
Patients with recurrent nonfunctioning pituitary tumors or prolactinomas resistant to 
medical therapy typically undergo surgical resection of the tumor once the tumor 
demonstrates radiological progression associated with clinical signs and symptoms 
and/or optic chiasm compression.  Otherwise, we observe tumor growth with serial MRIs 
as long as the chiasm is not compressed until surgery is deemed necessary for 
decompression of the optic chiasm. In our study, we are excluding any subjects who 
have compression of the optic chiasm and only will recruit those whom we would 
otherwise observe with serial MRIs to monitor the tumor growth.  After completion of 
their participation in the study, patients will then resume the standard monitoring of 
tumor growth.  However, if a given patient responds to the study drug and chooses to 
stay on the drug after cessation of the trial, clinical data will continue to be collected on 
the patient for further analysis of response to the drug.  This will continue until they 
discontinue to the drug to monitor for safety. 
 
Patients with prolactinomas who are currently being treated by dopamine agonist and 
patients with malignant tumors on dopamine agonists, somatostatin analogs, and growth 
hormone receptor antagonist medications prior to enrollment will remain on their drug 
therapy while on the study drug. 
 
Patients will have a screening visit (visit 1) to determine eligibility for the trial and to assess 
for exclusion criteria.  If the patient meets study criteria for enrollment, he will begin the 
study drug and be followed in subsequent visits.   Study staff will call patients weekly for 
the first month on the study drug and then every 2 weeks for the second month on the 
study drug. 
The following tests will be done as follows: 
 
On baseline visit 1: time 0 
History and physical exam 


 
 
 
14 
Draw screening labs: CBC with differential, BMP, LFTs (15 cc blood) 
For those with acromegaly from malignant tumors, will GH levels on 2 hour OGTT 
For those with ACTH secreting malignant tumors, will check 24 hour urinary free cortisol 
Pituitary hormone profile: PRL, TSH, thyroid panel, free T4, IGF-1, LH, FSH, 
testosterone (total and free) for males, 8 am cortisol if indicated (total of 15 cc of blood) 
Tubes of blood for lab to be frozen (to be used to measure EGFR and Her2 levels) (10 
cc) 
 ECG 
Echocardiogram 
Check Visual Fields 
Dilated retinal exam 
Visual acuity check 
Ocular pressure check 
Color vision test 
Urine Pregnancy Test 
MRI—this will be waived if subjects had an MRI performed at their outside hospital within 
3 months of the 1st study visit and if subjects provide a CD of the images for review by 
our neuroradiologist to determine if of sufficient quality for a baseline study. 
 
While on the drug, visits will occur once a month to monitor for adverse effects.  Patients’ 
visits may not deviate more than 7 days from the 30-day mark between each visit. 
 
Visit 2: time 1 month on drug 
Physical exam and history 
Will draw CBC with differential, BMP, LFTs (15 cc blood) 
For those with prolactinomas, will also check PRL. 
For those with acromegaly from malignant tumors, will GH levels on 2 hour OGTT 
For those with ACTH secreting malignant tumors, will check 24 hour urinary free cortisol 
 Do ECG 
Urine Pregnancy Test 
Those with pre-existing visual field compromise, visual field testing 
 
Visit 3: time 2 months on drug 
Physical exam and history 
Will draw CBC with differential, BMP, LFTs (15 cc blood) 
For those with prolactinomas, will also check PRL. 
For those with acromegaly from malignant tumors, will check GH levels on 2 hour OGTT 
For those with ACTH secreting malignant tumors, will check 24 hour urinary free cortisol 
Those with pre-existing visual field compromise, visual field testing 
Do ECG, echocardiogram 
Urine Pregnancy Test 
 
Visit 4: time of 3 months on drug 
Physical exam and history 
Will draw CBC with differential, BMP, LFTs (15 cc blood) 
For those with prolactinomas, will also check PRL. 
For those with acromegaly from malignant tumors, will check GH levels on 2 hour OGTT 
For those with ACTH secreting malignant tumors, will check 24 hour urinary free cortisol 
Pituitary hormones as well—TSH, thyroid panel, free T4, 8 am cortisol (if indicated), IGF-
1, LH, FSH, testosterone (15 cc blood) 
Tubes for lab for EGFR, her2 levels (10 cc blood) 


 
 
 
15 
Do ECG 
Visual field test 
Dilated retinal exam 
Color Vision test 
Do MRI of pituitary with and without IV gadolinium 
Urine Pregnancy Test 
 
Visit 5: time of 4 months on drug 
Physical exam and history 
Will draw CBC with differential, BMP, LFTs (15 cc blood) 
For those with prolactinomas, will also check PRL. 
For those with acromegaly from malignant tumors, will check GH levels on 2 hour OGTT 
For those with ACTH secreting malignant tumors, will check 24 hour urinary free cortisol 
 Do ECG, echocardiogram 
Urine Pregnancy Test 
 
Visit 6: time of 5 months on drug 
Physical exam and history 
Will draw CBC with differential, BMP, LFTs (15 cc blood) 
For those with prolactinomas, will also check PRL. 
For those with acromegaly from malignant tumors, will check GH levels on 2 hour OGTT 
For those with ACTH secreting malignant tumors, will check 24 hour urinary free cortisol 
Do ECG 
Urine Pregnancy Test 
Those with pre-existing visual field compromise, visual field testing 
 
Visit 7: time of 6 months on drug 
Physical exam and history 
Will draw CBC with differential, BMP, LFTs (15 cc blood) 
For those with acromegaly from malignant tumors, will check GH levels on 2 hour OGTT 
For those with ACTH secreting malignant tumors, will check 24 hour urinary free cortisol 
Pituitary hormones as well—PRL, TSH, thyroid panel, free T4, 8 am cortisol (if 
indicated), IGF-1, LH, FSH, total and free testosterone for males (15 cc blood) 
Tubes for lab for EGFR, her2 levels (10 cc blood) 
 Do ECG, Echocardiogram 
Check visual fields 
Dilated retinal exam 
Visual acuity check 
Ocular pressure check 
Color Vision test 
Do MRI of pituitary with and without IV gadolinium 
Urine Pregnancy Test 
 
Visit 8: time of 1 mo off drug 
Physical exam and history 
Will draw CBC with differential, BMP, LFTs (15 cc blood) 
For those with prolactinomas, will also check PRL. 
For those with acromegaly from malignant tumors, will check GH levels on 2 hour OGTT 
For those with ACTH secreting malignant tumors, will check 24 hour urinary free cortisol 
Draw tubes for EGFR, Her2 levels (10 cc blood) 
Do ECG, Echocardiogram 


 
 
 
16 
Urine Pregnancy Test 
 
Note: Study visits may be conducted over 2 days to allow for sufficient time to complete 
the procedures, scheduling availability, and patient preference. 
Study procedure flowsheet: 
 (See following page) 
 
 
 
 
Procedure 
 
Baseline 
Visit 
Visit 
#2 
(+30 
days
) 
Visit 
#3 
(+60 
days
) 
Visit 
#4 
(+90 
days
) 
Visit 
#5 
(+120 
days) 
Visit 
 #6 
(+150 
days) 
Visit 
#7 
(+180 
days) 
Visit 
#8** 
(+210 
days) 
 
 
 
 
 
 
 
 
 
Laboratory Blood Tests (may include levels of 
hormones, cholesterol, CBC, and metabolic panel) 
X 
X 
X 
X 
X 
X 
X 
X 
MRI of the Pituitary 
X^^ 
 
 
X 
 
 
X 
 
Echocardiogram 
X 
 
X 
 
X 
 
X 
X 
Electrocardiogram (ECG) 
X 
X 
X 
X 
X 
X 
X 
X 
Visual Field Test 
X 
X ^ 
X ^ 
X 
 
X ^ 
X 
 
History and Physical 
X 
X 
X 
X 
X 
X 
X 
X 
Informed Consent 
X 
 
 
 
 
 
 
 
Color Vision Test 
X 
 
 
X 
 
 
X 
 
Ocular Pressure Check 
X 
 
 
 
 
 
X 
 
Visual Acuity 
X 
 
 
 
 
 
X 
 
Dilated Retinal Exam 
X 
 
 
X 
 
 
X 
 
Hormonal profile 
X 
X 
X 
X 
X 
X 
X 
X 
Oral Glucose Tolerance Test (OGTT) (malignant 
arm) 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X* 


 
 
 
17 
24-hour Urinary Free Cortisol (malignant arm) 
X+ 
X+ 
X+ 
X+ 
X+ 
X+ 
X+ 
X+ 
Pregnancy Test for pre-menopausal women 
X 
X 
X 
X 
X 
X 
X 
X 
 
^ Only for subjects with visual field deficits 
^^ will be waived if subjects had MRI at outside hospital within 3 months of baseline 
visit 
* Only for subjects with acromegaly from malignant tumors 
+Only for subjects with ACTH secreting adenomas from malignant tumors 
**Visit 8 is only required if stopping Lapatinib at visit 7. Patients continuing on 
Lapatinib after visit 7 will be followed by their physician as clinically appropriate. 
 
Section 7.0  
 
Assessment of Efficacy 
a. Primary outcome variable. 
 
Primary outcome in nonfunctioning pituitary adenomas: 40% reduction in tumor 
size in any dimension. Tumor size and volume will be calculated using Open 
Source OsiriX® Imaging Software for MacOS.  MRIs will be performed at 
baseline and at 3 and 6 months All MRIs will be centrally read by the dedicated 
pituitary radiologist at CSMC.  
Primary outcome in prolactinomas: 40% reduction in tumor size in any 
dimension. 
Primary outcome in malignant pituitary tumors: Progression free survival 
 
b. Secondary outcome variables. 
 
Secondary outcomes in prolactinomas:  
(a) achievement of 50% reduction of PRL levels (b) PRL normalization (c) percent 
reduction in PRL levels (d) percent reduction in tumor volume. Tumor volume will be 
calculated using Open Source OsiriX® Imaging Software for MacOS. (e) correlation of 
tumor size and PRL reduction (f) clinical predictors of TKI response, including age, gender, 
duration of disease, dose and duration of dopamine agonist therapy, baseline PRL, and 
baseline tumor size. 
 
Secondary outcomes in malignant pituitary tumors: partial response, complete response, 
mortality, 24 hour urine free cortisol levels for Cushing carcinomas, IGF-1 levels for 
acromegaly carcinomas 
We will correlate ErbB receptor expression with the subjects' clinical response to the study 
drug.  This will be performed through immunohistochemistry staining of pituitary tumor 
slides from surgery.  
 
Section 8.0   
 
Assessment of Safety 
1. Monitoring for adverse effects (further detailed below): Data has been collected on 
over 12000 subjects on combination therapy of lapatinib and other chemotherapies, 
and over 4000 subjects have been treated with lapatinib monotherapy, with 2347 of 
those specifically in breast cancer. With monotherapy, majority of AEs were Grade 
1 or 2 in severity. The incidence of Grade 3 and Grade 4 events was 21% in those 


 
 
 
18 
who received lapatinib and 7% in those on placebo. Risks of adverse events are not 
additive or cumulative. SAEs were reported in 6% of those on lapatinib compared to 
5% on placebo. Cardiac events including left ventricular ejection fraction decreases 
were reported in approximately 1% of patients and most have partial or full recovery. 
Symptomatic decreases in ejection fraction were observed in approximately 0.3% of 
patients on lapatinib. Interstitial lung disease is observed in 0.2% of patients. 
Hepatotoxicity has been observed in <1% of patients. Grade 3 and 4 diarrhea occurs 
in <10% of patients. Nausea may be seen in 18% of patients and rash in 29% 
(Investigators’ Brochure).  
2. Prior to initiating therapy, patients will undergo an echocardiogram and ECG to 
evaluate the ejection fraction, and the echocardiogram will be repeated every 8 
weeks and on visit.  Patients will be evaluated for adverse effects monthly with 
physical examinations, chemistry and hematology panels, and ECGs.  Adverse 
events will be graded by the NCI-CTC.  Common adverse events include: hand-foot 
syndrome, rash, diarrhea, indigestion, nausea, vomiting, anorexia, anemia, low 
platelets, abnormal livers tests (ALT (SGPT) level raised, AST/SGOT level raised, 
hyperbilirubinemia, backache, pain in limb, insomnia, fatigue, and shortness of 
breath.  Rare but serious events include: heart failure (depression of left ventricular 
systolic function), abnormal heart beat (prolonged QT interval), liver damage 
(hepatotoxicity), and lung problems (interstitial lung disease/pneumonitis). Lapatinib 
will be discontinued in those who developed decreased ejection fraction, who 
develop pulmonary symptoms. Those subjects with toxicity less than or equal to 
Grade 2 on the NCI-CTC will have their dose held and resumed when the toxicity 
has resolved.  Those subjects with toxicity equal to Grade 3 on the NCI-CTC will 
have their dose held and resumed at a fifty percent dose reduction when the toxicity 
has resolved. Those subjects with toxicity equal to Grade 4 on the NCI-CTC will be 
discontinued on the study drug. Dr. Jeremy Rudnick, from Oncology department at 
Cedars-Sinai Medical Center, will assist us in monitoring patients for adverse events. 
3. If at any time a patient demonstrates a worsening of their visual fields or tumor 
growth on MRI, they will be withdrawn from the study and referred for surgery. 
4. For further safety monitoring, subjects may be asked to have additional laboratory 
testing as deemed necessary by the investigators.  This would require subjects to 
have extra blood draws which can also be done at outside laboratories.   
5. A DSMB will be set up to monitor safety of the study at all trial sites. 
 
Cardiac Events 
Addition to SAE definition: 
Cardiovascular events have been seen in 1.0% of subjects on lapatinib with or following 
anthracyclines, with symptomatic events in 0.3%. As a precaution, the following will be 
reported as an SAE: 
 
• 
Cardiac dysfunction will be reported as an SAE and will be defined as any signs or 
symptoms of deterioration in left ventricular cardiac function that are Grade 3 (NCI 
CTCAE) or a ≥20% decrease in left ventricular cardiac ejection fraction (LVEF) 
relative to baseline which is below the institution's lower limit of normal. 
Refer to NCI CTCAE grading of left ventricular cardiac function. 
 
Criteria for Evaluating Cardiac Events: 
Asymptomatic cardiac events: 


 
 
 
19 
Subjects who have a ≥20% decrease in LVEF  relative to baseline, and the ejection 
fraction is below the institution's lower limit of normal, should have a repeat evaluation of 
ejection fraction 1-2 weeks later while still receiving investigational product. 
• 
If the repeat ejection fraction evaluation confirms a ≥20% decrease in LVEF, and the 
ejection fraction is below the institution's lower limit of normal, then investigational 
product should be temporarily discontinued. 
• 
If the LVEF recovers during the next 3 weeks, after consultation and approval of the 
medical monitor, the subject may be restarted on investigational product at a 
reduced dose. For such subjects, monitoring of left ventricular ejection fraction will 
then be performed 2 weeks and 4 weeks after rechallenge, and then every 4 weeks 
thereafter. 
• 
If repeat ejection fraction evaluation still shows a decrease ≥20% in LVEF relative to 
baseline, and the value is below the institution's lower limit of normal, then the 
subject should be withdrawn from investigational product. 
 
Symptomatic cardiac events: 
Subjects with an NCI CTCAE grade 3 or 4 LVEF relative decrease must be withdrawn 
from study medication. 


 
 
 
20 
Figure 1 
Algorithm for continuation and discontinuation of GW572016 (lapatinib) 
and/or trastuzumab based on interval LVEF assessments, for patients with NYHA class I 
or II congestive heart failure 
 
LVEF drop from baseline
LVEF ≥ 50 %
LVEF < 50 % 
LVEF drop ≤20 points
LVEF drop > 20 points
LVEF drop ≤10 points
LVEF drop > 10 points
CONTINUE treatment
Continue treatment and repeat
LVEF in 3 weeks
HOLD treatment and repeat
LVEF in 3 weeks
LVEF drop CONFIRMED 
(LVEF drop >10 points
and LVEF <50 % ) 
Not confirmed
(LVEF drop ≤10 poin
Or LVEF ≥50 % )
STOP Treatment
RESUME Treatm


 
 
 
21 
Liver Chemistry Stopping Criteria 
Overall, 45% of patients experience hepatic abnormalities on lapatinib and capecitabine. 
In a phase III trial of lapatinib monotherapy (n = 1573), 8% of patients experienced 
hepatobiliary events, 3% of those were SAEs. With lapatinib monotherapy, grade 3 
hyperbilirubinemia has been reported in 2% of patients and grade 4 elevations in 
ALT/AST in 2%.   Hepatotoxicity has been observed in <1% of subjects. Liver chemistry 
stopping and follow up criteria have been designed to assure subject safety and 
evaluate liver event etiology.  All subjects who meet liver chemistry criteria requiring 
permanent discontinuation of investigational product must continue to be followed for the 
study assessments and procedures as defined in Section X and at the time points 
indicated in the Time & Events Table in Section X. 
 
If a subject experiences ALT >3 × ULN and total bilirubin >2.0 × ULN (>35% direct; 
bilirubin fractionation required*), then the following actions must be taken: 
 
immediately and permanently discontinue investigational product; 
complete the SAE data collection tool, the liver event CRF, and the liver imaging and/or 
liver biopsy CRFs, if these tests are performed; 
in addition to the liver event follow up assessments defined in Section X.X. below, the 
following are suggested:  specialist or hepatology consultation; anti-nuclear 
antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney microsomal 
antibodies; and liver imaging and/or liver biopsy to evaluate liver disease; 
promptly report the event to Novartis within 24 hours of learning its occurrence (refer to 
‘Reporting Serious Adverse Events section’ for guidance on prompt reporting to 
Novartis); 
monitor every week until liver chemistries resolve, stabilize or return to within baseline 
values; 
do not re-challenge with investigational product. 
 
*NOTE:  bilirubin fractionation should be performed if testing is available.  If testing is 
unavailable and a subject meets the criterion of total bilirubin >2.0 × ULN, then the 
aforementioned actions must still be performed. 
 
If a subject experiences: 
 
ALT >8 × ULN or 
ALT >5 × ULN persisting for ≥2 weeks : retest within 3 days from the first occurrence 
and then weekly to determine if ALT elevation persists or 
ALT >3 × ULN with signs or symptoms of hepatitis or hypersensitivity (the appearance or 
worsening of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash, or eosinophilia) 
 
then hold investigational product for 2 weeks, repeat liver chemistry testing in 2 weeks, 
and then call the Novartis Medical Monitor to discuss the possibility of re-challenging 
with investigational product. 
 
If the treatment is exhibiting efficacy and the subject wants to continue for potential 
benefit of lapatinib therapy after being informed of the results of liver chemistry testing, 


 
 
 
22 
then the investigational product may be re-started at the reduced dose agreed upon by 
the investigator and the Novartis Medical Monitor.  In such cases, Study Visit #8 will not 
take place if the decision to continue on lapatinib takes place prior to discontinuation of 
study drug on study.  Liver chemistries and aforementioned signs and symptoms should 
be monitored at a minimum of every 2 weeks until resolution, stabilization, or a return to 
baseline values, at which point monitoring should be continued per protocol. 
 
If a subject experiences ALT >3 × ULN but <5 × ULN and total bilirubin ≤2 × ULN, 
without signs or symptoms of hepatitis or hypersensitivity, and who can be monitored 
weekly, then the following actions should be taken: 
 
continue investigational product; 
monitor weekly until liver chemistries resolve, stabilize, or return to within baseline, then 
monitor liver chemistries as per protocol assessment schedule; 
if ALT >3 and < 5 × ULN for > 4 weeks , discontinue the treatment; 
if at any time this subject meets any of the aforementioned liver chemistry stopping 
criteria, then proceed as described above. 
Liver Chemistry Follow up Criteria 
For all subjects who meet any of the liver chemistry criteria described above, make 
every attempt to carry out the liver event follow up assessments described below: 
 
Viral hepatitis serology including: 
Hepatitis A IgM antibody; 
Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); 
Hepatitis C RNA; 
Cytomegalovirus IgM antibody; 
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile 
antibody or monospot testing); 
Hepatitis E IgM antibody (if subject resides or has traveled outside USA or Canada 
in past 3 months); 
Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH); 
Complete blood count with differential to assess eosinophilia; 
Record the appearance or worsening of clinical symptoms of hepatitis, or 
hypersensitivity, fatigue, decreased appetite, nausea, vomiting, abdominal pain, 
jaundice, fever, or rash as relevant on an AE report form; 
Record use of concomitant medications, acetaminophen, herbal remedies, other over 
the counter medications, or putative hepatotoxins, on the concomitant medications 
report form; 
Record alcohol use on the liver event alcohol intake case report form. 
Refer to Appendix 3 for a liver safety algorithm detailing stopping and follow up criteria. 
Safety 
Add frequency of LFTs to Safety Assessment section and Time & Events Table as 
applicable: 
 
• 
During treatment phase: every 4 - 6 weeks (to best fit protocol schedule) for 
duration of concurrent chemotherapy administration or for first 6 months, then 


 
 
 
23 
every 8 – 12 weeks (or more frequently, if clinically indicated) for remaining on 
treatment period  
• 
During post-treatment phase:  continue to monitor any liver chemistry 
abnormalities noted during treatment or within 30 days after last dose of 
investigational product until values return to normal or baseline (this language 
should be in protocols already) 
In the Safety Assessment section, make a reference to section containing the Liver 
Chemistry Stopping and Follow up Criteria. 
 
In the Laboratory Assessment section, mention that bilirubin fractionation is 
recommended if total bilirubin >2 x ULN when testing is available. 
 
Hepatobiliary events have been seen in subjects taking lapatinib and other tyrosine 
kinase inhibitors.  As a precaution, the following will be reported as an SAE: 
 
• 
ALT >3 × ULN and total bilirubin >2.0 × ULN (>35% direct; bilirubin fractionation 
required). 
NOTE:  bilirubin fractionation should be performed if testing is available.  If testing is 
unavailable and a subject meets the criterion of total bilirubin >2.0 × ULN, then the 
event should still be reported as an SAE. 
Other hepatic events should be documented as an AE or an SAE as appropriate. 
 


 
 
 
24 
Appendix: Liver Chemistry Stopping and Follow up Criteria 
 
a. bilirubin fractionation should be performed if testing is available.  If testing is 
unavailable and a subject meets the criterion of total bilirubin >2.0 × ULN, then the 
event should still be reported as an SAE and actions taken as described 
b. the appearance or worsening of fatigue, nausea, vomiting, right upper quadrant pain 
or tenderness, fever, rash, or eosinophilia 
c. 
once liver chemistries resolve, stabilize, or return to baseline, then continue 
monitoring per the protocol assessment schedule 
d. retest within 3 days from the first occurrence and then weekly to determine if ALT 
elevation persists 
 
Dermatologic (skin) adverse events 
Rash has been reported in 29% of patients on lapatinib monotherapy with 
significant skin adverse events (Grade 3 or more) resulting in 1-3%. 
For NCI-CTCAE v3.0 Grade 4 rash manifested as toxic epidermal necrolysis (i.e. 
Stevens-Johnson’s Syndrome etc) lapatinib must be permanently discontinued. 
Subjects with poorly tolerated skin adverse events may be successfully managed 
by providing a brief (up to 14 days) therapy interruption; the daily dose of lapatinib 
ALT >3 × ULN 
Bilirubina>2 × ULN  
(>35% direct) 
ALT >8 × ULN 
signs &symptomsb 
of hepatitis 
orhypersensitivity 
ALT >5 × ULNpersisting 
for ≥2 weeks (confirmed 
within 3daysd and then 
weekly) 
•
  immediately & permanently discontinue investigational product; 
•
  complete an SAE Form; 
•
  perform liver event follow up assessments (serologies, etc, as noted in the protocol); 
•
  report as SAE to Novartis within 24 hours  
•
  monitor weekly until liver chemistries resolve, stabilize, or return to baseline; 
•
  do NOT re-challenge with investigational product 
Yes 
Yes 
No 
No 
Yes 
Yes 
Yes 
•
hold investigational product for 2 weeks; 
•
repeat liver chemistry testing in 2 weeks; 
•
then call the Novartis Medical Monitor to discuss re-challenge (see 
protocol XXX); 
•
if re-challenged, start investigational product at agreed upon 
reduced dose; 
•
monitor at a minimum of every 2 weeks until liver chemistries 
resolve, stabilize, or return to baselinec 
No 
IF: 
No 
Continue treatment and monitor 
weekly for up to 4 weeks; if 
ALT>3 and<5 X ULN for > 4 
weeks , discontinue treatment 


 
 
 
25 
should then be reinstated. However, the rash may improve without the need for 
interrupting therapy with lapatinib. Of note in current studies, many subjects were 
able to resume lapatinib therapy at the same dose after resolution of rash, and they 
then had less extensive and/or severe rashes. A variety of agents can be used to 
manage skin rashes. These include mild-to-moderate strength steroid creams, 
topical or systemic antibiotics, topical or systemic antihistamines, and occasionally, 
retinoid creams. 
There is no standard, known, or established treatment proven effective for drug-
related skin rashes or changes due to lapatinib. If the rash is severe (1-3%) then 
most commonly, a papular/pustular rash has been observed, which frequently 
improves even though the same dose of lapatinib therapy is continued 
uninterrupted. The need for oral or topical antibiotics is a clinical decision of the 
investigator and should be preceded by a culture of affected areas and, if indicated, 
a dermatology consultation. Oral retinoids should not be given because of 
theoretical concerns about negatively affecting the lapatinib mechanism of action. 
Oral steroids are also strongly discouraged. Other options for treatment of 
significant rashes may be determined upon consultation with dermatologist. 
Gastrointestinal adverse events 
Overall 48% of patients on lapatinib monotherapy (n= 1573) experienced diarrhea, 
with grade 3 diarrhea reported in 21% of subjects and grade 4 diarrhea in 7%. If GI 
adverse events are not appropriately managed, they may be associated with the 
development of dehydration. Management of gastrointestinal adverse events is 
discussed in detail in below. 
Nausea, vomiting, or both 
Nausea was reported in 18% of patients on lapatinib monotherapy (n=1573). In 
subjects who have emesis and are unable to retain lapatinib, every attempt should 
be made to obtain control of nausea and vomiting. A dose may be repeated if 
tablets can be visually found after the vomiting episode. 
Diarrhea 
These broad general management principles are recommended to proactively try 
and avoid more serious complications by active management of diarrhea syndrome. 
Guidelines such as these should never replace sound clinical judgment. Experience 
thus far suggests that when lapatinib is used as monotherapy, uncomplicated 
Grade 1 or 2 diarrhea is most prevalent. These general management principles do 
not address comprehensive management of more serious or protracted diarrhea 
syndromes. 
Common clinical sense with the onset of uncomplicated Grade 1-2 diarrhea: stop all 
lactose containing products: drink 8-10 large glasses of clear liquids a day; eat 
frequent small meals; for Grade 2 diarrhea hold cytotoxic chemotherapy, and 
consider a dose reduction of lapatinib (discuss with medical monitor); administer 
standard doses of loperamide: initial dose 4 mg followed by 2 mg every 4 hours or 
after every unformed stool. It is suggested to continue loperamide until the subject 
is free from diarrhea for 12 hours. 
For Grade 3 or 4 diarrhea or Grade 1 or 2 with complicating features (severe 
cramping, severe nausea/vomiting, decreased performance status, fever, sepsis, 
Grade 3 or 4 neutropenia, frank bleeding, dehydration) use intravenous fluids as 


 
 
 
26 
appropriate, consider hospital administration. Use prophylactic antibiotics as 
needed (example fluoroquinolones) especially if diarrhea is persistent beyond 24 
hours or there is a fever or Grade 3-4 neutropenia, hold both cytotoxic 
chemotherapy and lapatinib and discuss with medical monitor. 
Treatment of gastrointestinal adverse events 
Diarrhea can be debilitating, and on rare occasions, it is potentially life-threatening. 
Based on experience with lapatinib alone or in combination with taxanes and/or 
trastuzumab, diarrhea should be managed proactively to avoid complications or 
worsening of the patient’s condition. Guidelines developed by an American Society 
of Clinical Oncology (ASCO) panel for treating chemotherapy-induced diarrhea are 
abstracted below. 
Pharmacological approaches include the following: 
Loperamide, administered as an initial 4-mg dose, followed by 2-mg doses every  
4 hours. This dose and regimen are moderately effective. 
Clonidine, non-steroidal anti-inflammatory drugs, and the serotonin antagonist 
cyproheptadine have been shown to be effective in controlling diarrhea associated 
with inflammation of the bowel. 
The synthetic octapeptide, octreotide, has been shown to be effective in the control 
of diarrhea induced by fluoropyrimidine-based chemotherapy regimens when 
administered as an escalating dose by continuous infusion or subcutaneous 
injection. Octreotide can be administered at doses ranging from 100 µg twice daily 
to 500 µg 3 times daily, with a maximum-tolerated dose of 2000 µg 3 times daily in 
a 5-day regimen. 
Management of interstitial lung disease 
Pulmonary events occur in approximately 0.2% of patients. If a patient develops 
symptoms suggestive of interstitial pneumonitis, adult respiratory distress syndrome 
(ARDS), or non-cardiogenic pulmonary edema, lapatinib or trastuzumab therapy 
should be interrupted and a thorough evaluation performed. If NCI-CTCAE v3.0 
Grade 3 or 4 pneumonitis/fibrosis or pulmonary infiltrate is confirmed (and the 
relationship to lapatinib and/or trastuzumab cannot be excluded), lapatinib and/or 
trastuzumab must be permanently discontinued. All incidences of interstitial lung 
disease/ interstitial pneumonitis regardless of grade must be reported as serious 
adverse events (SAEs). 
Other adverse events 
For any other NCI-CTCAE v3.0 Grade 3 or 4 adverse events or any clinically 
significant, lower-grade adverse event, treatment with lapatinib should be 
interrupted for a maximum of 14 days until the patient recovers completely or the 
adverse event reverts to NCI-CTCAE v3.0 Grade 1 or to baseline grade. 
If recurrence of adverse event after drug holiday / interruptions is observed a dose 
reduction by 250mg is recommended. Dose reduction should only be implemented 
when all supportive care measures have been exhausted without an improvement 
of patient status. Lapatinib should not be used at doses below 1000mg if given as 
monotherapy or 750mg in combination with trastuzumab. 
In all cases where the subject is withdrawn due to unusual or unusually severe 
adverse event considered related to lapatinib, the investigator must report the 
withdrawal as an SAE and on the CRFs.


 
 
 
27 
 
Table 1 
Summary of dose holding/interruptions and dose de-escalation recommendations for GW572016 (lapatinib)in case of 
lapatinib related adverse events (graded according to NCI-CTCAE v3.0) 
Adverse events 
Action 
Non-hematological, Grade 1 or 2 
Continue lapatinib therapy at full dose prescribed (see adverse 
events management instructions section Error! Reference 
source not found.. Apply maximum supportive care 
recommendations (see Error! Reference source not found.) If 
prolonged duration of Grade 2 adverse event is affecting quality of 
life a one-time decrease of dose by 250 mg is allowed. 
Non-hematological, Grade 3 or 4 
Apply maximum supportive care recommendations (see section 
Error! Reference source not found.) Hold lapatinib therapy until 
recovery to Grade ≤ 1 (up to 14 days). Refer to events 
management instructions Section Error! Reference source not 
found.. 
Grade 3 or 4 left ventricular cardiac dysfunction - please refer to 
specific section Error! Reference source not found. For NCI-
CTCAE v3.0 Grade 3 or 4 interstitial pneumonitis or Grade 4 rash 
manifested as toxic epidermal necrolysis (e.g. Stevens-Johnson 
Syndrome etc) lapatinib must be permanently discontinued 
If recurrence of adverse event after drug hold / interruptions is 
observed, and maximum supportive care measures applied, a 
dose reduction by 250mg is recommended. Lapatinib should not 
be used at doses below 1000mg if given as monotherapy or 
750mg in combination with trastuzumab. NOTE: The 750 mg 
dose should only be used after all supportive measures have 
been exhausted. (If administered in combination with paclitaxel 
refer to table 13) 
Non-hematological, Grade 3 or 4 and adverse events NOT 
resolved to Grade ≤ 2 within a maximum of 2 weeks from last 
planned administration  
Action (discontinue or resume lapatinib therapy) in individual 
cases to be decided by the Executive Committee. 
Dose reductions by 250mg (up to 2 reductions) will be considered 
after maximum supportive care recommendations (see Error! 
Reference source not found.) are introduced. 


 
 
 
28 
Cardiac* (asymptomatic drop in LVEF or symptomatic congestive 
heart failure) 
Lapatinib therapy to be discontinued permanently in case of 
symptomatic NYHA class III and IV CHF. Lapatinib therapy to be 
hold continued or resumed according to Figure 1 for patients with 
NYHA class I or II CHF. 
Hematological adverse events: 
Absolute neutrophil count (ANC) <1.0 x 109/L 
Platelets <75 x 109/L 
Hemoglobin <9.0 g/dL (after transfusion if needed) 
Hold chemotherapy if lapatinib given simultaneously; if the 
adverse event is related to chemotherapy please refer to 
appropriate label (until recovery to Grade ≤1). 
If ANC recovers to 1.5 x 109/L within 7days, then merely delaying 
dose is acceptable. If no recovery to ANC of 1.5 x 109/L within 7 
days then decrease chemotherapy dose by 20%. 
Dose modifications for thrombocytopenia, at the start of 
subsequent courses of therapy are the same as recommended for 
neutropenia above. Next cycle should not begin until the platelet 
count has recovered to 100 x 109/L or more. 
 
In case of multiple short interruptions of dose due to either 
adverse events or drug supply or other reasons the sum of days 
without lapatinib treatment should not exceed 21 days in any 90 
day treatment period. 
*Severity corresponding to NYHA criteria 


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Dose Delays and Dose Reductions 
Treatment may be delayed, up to 2 weeks, to allow for resolution of toxicity except in the 
event of NCI CTCAE Grade 3 or 4 left ventricular cardiac dysfunction or NCI CTCAE 
Grade 3 or 4 interstitial pneumonitis (See Criteria for Evaluating Cardiac and Respiratory 
Events). The Investigator must consult the Novartis Medical Monitor prior to continuing 
therapy for any subject requiring a delay of more than 2 weeks for unresolved toxicity, 
but in general, such subjects should be withdrawn from the study. If treatment is delayed 
for reasons other than toxicity (i.e., unplanned travel or vacation, or lack of transportation 
to the site) and the subject has insufficient investigational product available, the subject 
should resume the usual dosing schedule once drug supply has been made available. 
However, if the subject has been off therapy for more than 2 weeks, the Investigator 
must consult the Novartis Medical Monitor prior to continuing therapy. 
 
Dose reduction for drug-related toxicity is permitted; however the Novartis Medical 
Monitor must be consulted prior to implementing any change in dosing. Only one dose 
reduction is permitted per subject and subjects should not be rechallenged to a higher 
dose level. If a NCI CTCAE Grade 3 or 4 drug-related event (other than left ventricular 
cardiac dysfunction or interstitial pneumonitis) has occurred, the investigator may 
discuss with the Novartis Medical Monitor whether a reduction of dose is appropriate. 
 
PHARMACEUTICAL INFORMATION 
 
Lapatinib (NSC #727989) 
 
Chemical Name:N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-
(methylsulfonyl)ethyl]amino}methyl)-2 furyl]-4-quinazolinamine, 
 
Other Names: None 
 
Mode of Action: Dual inhibitor of epidermal growth factor receptor (EGFR or 
ErbB1) and ErbB2 tyrosine kinases. 
 
How Supplied: lapatinib is supplied as 250 mg oval, biconvex, orange film-
coated tablets with one side plain and the opposite side debossed with FG 
HLS.  The tablets contain 410 mg of lapatinib Ditosylate Monohydrate, 
equivalent to 250 mg lapatinib free base per tablet.  The tablets are packaged 
into HDPE bottles with child-resistant closures. 
 
Excipients present in the tablet include: Microcrystalline cellulose, 
povidone, sodium starch glycolate, and magnesium stearate. 
 
The film-coat contains: Hydroxypropyl methylcellulose, titanium dioxide, 
triacetin/glycerol triacetate, and yellow iron oxide. 
 
Storage: The intact bottles should be stored at controlled room temperature 
(15°C-30°C). 
 
Stability: Shelf life surveillance studies of the intact bottle are on-going.  
Current data indicates lapatinib is stable for at least 2 years at controlled 
room temperature (15°C - 30°C). 


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Route of Administration: Oral on an empty stomach (either 1 hour before or 1 
hour after meals). 
 
Kool-Aid Flavored Suspension 
Prepare Lemonade or Tropical Punch Kool-Aid as directed on the package.  Place 2 or 4 
oz of Kool-Aid (room temperature or refrigerated) in a glass container, then add six 250 
mg lapatinib tablets to the container.  Cover the container, let it stand for 5 minutes, and 
then stir the mixture intermittently for 10-20 minutes or until the tablets are completely 
broken up.  Stir the container for 5 seconds then administer.  Rinse the container with a 
2 oz aliquot of water and administer (total of 4-6 oz of liquid is dispensed). 
Suspension in Water 
Place 4 oz of water in a glass container, then add six 250 mg lapatinib tablets to the 
container.  Cover the container, let it stand for 5 minutes, and then stir the mixture 
intermittently for 10-20 minutes or until it is fully dispersed.  Stir the container for 5 
seconds then administer.  Rinse the container with a 2 oz aliquot of water and administer 
(total of 6 oz of liquid is dispensed). 
 
Prohibited Medications 
 
Lapatinib is a substrate for CYP3A4.  Inducers and inhibitors of CYP3A4 may alter the 
metabolism of lapatinib.  The following list of CYP3A4 inducers and inhibitors are 
prohibited from screening through discontinuation from study. 
 
Drug Class 
Specific Agents 
Wash-out1 
CYP3A4 Inducers 
rifamycin antibiotics 
rifampicin, rifabutin, rifapentine 
 
 
 
 
2 weeks 
anticonvulsants 
phenytoin, carbamezepine, barbiturates 
(e.g., phenobarbital) 
antiretrovirals 
efavirenz, nevirapine, tipranivir, etravirine 
 
glucocortical steroids 
(oral only) 
cortisone (>50 mg), hydrocortisone (>40 
mg), prednisone or prednisolone (>10 
mg), methylprednisolone or 
triamcinolone (>8 mg), betamethasone or 
dexamethasone (>1.5 mg)2 
other 
St. John’s Wort, modafinil 
CYP3A4 Inhibitors 
antibiotics 
clarithromycin, erythromycin, 
troleandomycin, flucloxacillin 
 
 
 
 
1 week 
antifungals 
itraconazole, ketoconazole, fluconazole 
(>150 mg daily), voriconazole 
antiretrovirals 
delaviridine, nelfinavir, amprenavir, 
ritonavir, indinavir, saquinavir, lopinavir, 
atazanavir 
calcium channel 
blockers 
verapamil, diltiazem 
antidepressants 
nefazodone, fluvoxamine 


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gastrointestinal agents3 
cimetidine 
fruit juices 
grapefruit, star fruit, and papaw 
other 
amiodarone 
6 months 
Miscellaneous 
antacids 
Mylanta, Maalox, Tums, Rennies 
1 hour before 
and after dosing 
herbal supplements4 
ginkgo biloba, kava, grape seed, 
valerian, ginseng, echinacea, evening 
primrose oil 
2 weeks 
1. Time period between last dose of listed drug and first dose of lapatinib, required to 
avoid drug-drug interaction potential for toxicity (inhibitors) or loss of efficacy 
(inducers) that could make the patient unevaluable.  Clinically appropriate 
substitution of drugs not on the list is recommended. 
2. A standard 3-5 day course of dexamethasone at a dose following the institutions 
standard of care for the prevention and/or treatment of platinum-induced nausea 
and vomiting is allowed.  Glucocortical steroid oral dose equivalents (in 
parentheses) to dexamethasone 1.5 mg (or less) given daily are allowed.  
Intravenous dosing should be considered if clinically appropriate. 
3. Emetogenic chemotherapy may require 3-4 daily doses of aprepitant.  CYP3A4 
inhibition by oral (not IV) aprepitant may require a concurrent dose reduction of 1-2 
lapatinib tablets. 
4. This list is not all-inclusive; therefore, for herbal supplements not listed, please 
contact a Novartis Medical Monitor or Clinical Scientist. 
NOTE: If future changes are made to the list of prohibited medications, formal 
documentation will be created and stored with the study file.  Any changes will be 
communicated to the investigative sites in the form of a letter. 
 
Agent Accountability 
 
The Investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the inventory and disposition of all agents received from Novartis. 
 
REGULATORY AND REPORTING REQUIREMENTS 
 
It is the responsibility of the investigator to document all adverse events which occur 
during the investigation.  An adverse event is any untoward medical occurrence in a 
patient or clinical investigation subject, temporally associated with the use of the 
medicinal product, whether or not considered related to the medicinal product.  An AE 
can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use 
of a medicinal product.  Anticipated day-to-day fluctuations of the disease under study 
that do not represent a clinically significant exacerbation or worsening need not be 
considered an adverse event. 
 


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All adverse events occurring from the first dose of investigational product until five days 
after the last dose must be recorded REGARDLESS OF WHETHER OR NOT THEY 
ARE CONSIDERED DRUG RELATED.  In addition, any SAEs which occur as a result of 
protocol specific diagnostic procedures or interventions must also be reported. 
 
It is the responsibility of the IND holder to comply with IND safety reporting as set forth in 
the Code of Federal Regulations, Section 312.32. 
 
Assessment of Causality 
 
Every effort should be made by the investigator to explain each adverse event and 
assess its relationship, if any, to study drug treatment.  Causality should be assessed 
using the following categories: no (not related), or yes (reasonable possibility). 
 
The degree of certainty with which an adverse experience is attributed to drug treatment 
(or alternative causes, e.g. natural history of the underlying diseases, concomitant 
therapy, etc.) will be determined by how well the experience can be understood in terms 
of the following: 
 
• 
Known pharmacology of the drug 
 
• 
Reaction of similar nature being previously observed with this drug or class of 
drug 
 
• 
The event having often been reported in literature for similar drugs as drug 
related (e.g. skin rashes, blood dyscrasia) 
 
• 
The event being related by time to drug administration terminating with drug 
withdrawal (dechallenge) or reproduced on rechallenge. 
 
The investigator may change his/her opinion of causality in light of follow-up information, 
amending the SAE form.  The causality assessment is one of the criteria used when 
determining regulatory reporting requirements. 
 
Following-up of Adverse Events 
 
Investigators should follow-up subjects with adverse events until the event has subsided 
(disappeared) or until the condition has stabilized. 
 
Definition of Serious Adverse Events: 
 
A serious adverse event is an undesirable sign, symptom or medical condition which: 
• 
is fatal or life-threatening 
• 
results in persistent or significant disability/incapacity 
• 
constitutes a congenital anomaly/birth defect 
• 
requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
• 
routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes) 


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• 
elective or pre-planned treatment for a pre-existing condition that is unrelated to 
the indication under study and has not worsened since the start of study drug 
• 
treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• 
social reasons and respite care in the absence of any deterioration in the 
patient’s general condition 
• 
is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
 
Abnormal laboratory findings (e.g., clinical chemistry, hematology) or other abnormal 
assessments (e.g., x-rays, scans, vital signs, etc.) that are judged by the investigator as 
clinically significant will be recorded as AEs or SAEs if they meet the definition of an 
AE or SAE. 
 
Life threatening definition: 
 
An adverse event is life threatening if the patient was at immediate risk of death from the 
event as it occurred (i.e. it does not include a reaction that if it had occurred in a more 
serious form might have caused death).  For example, drug-induced hepatitis that 
resolved without evidence of hepatic failure would not be considered life threatening 
even though drug-induced hepatitis could be fatal. 
 
Disability/incapacitating definition: 
 
An adverse experience is incapacitating or disabling if the experience results in a 
substantial and/or permanent disruption of the patient's ability to carry out normal life 
functions. 
 
Hospitalization definition: 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
 
Additional SAE definitions 
- All Grade 4 laboratory abnormalities 
- Cardiovascular events have been seen in subjects taking other compounds that inhibit 
ErbB2 when used in combination with or following anthracyclines and interstitial 
pneumonitis has been reported in subjects taking compounds that inhibit ErbB1.  As a 
precaution, the following will be reported as a SAE: 
 
Cardiac dysfunction will be reported as an SAE and will be defined as any signs 
or symptoms of deterioration in left ventricular cardiac function that are Grade 3 (NCI 
CTCAE) or a >20% decrease in left ventricular cardiac ejection fraction relative to 
baseline, which is below the institution's lower limit of normal.  Refer to NCI CTCAE 
grading of left ventricular cardiac function. 
 
Hepatobiliary events have been seen in subjects taking lapatinib and other tyrosine 
kinase inhibitors.  As a precaution, the following will be reported as an SAE: 
 
• 
 ALT >3 × ULN and total bilirubin >2.0 × ULN (>35% direct; bilirubin fractionation 
required). 


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NOTE:  bilirubin fractionation should be performed if testing is available.  If testing is 
unavailable and a subject meets the criterion of total bilirubin >2.0 × ULN, then the 
event should still be reported as an SAE. 
Other hepatic events should be documented as an AE or an SAE as appropriate. 
 
SAEs, pregnancies, and liver function abnormalities meeting pre-defined stopping 
criteria will be reported promptly to Novartis as described in the following table once the 
investigator determines that the event meets the protocol definition for that event. 
 
 
Initial Reports 
Follow-up Information on a 
Previous Report 
Type of Event 
Time Frame Documents 
Time Frame 
Documents 
All SAEs 
24 hours 
“SAE” data 
collection tool 
24 hours 
Updated “SAE” 
data collection 
tool  
Pregnancy 
2 Weeks 
Pregnancy 
Notification Form 
2 Weeks 
Pregnancy 
Follow up Form 
Liver chemistry 
abnormalities: 
 
 
 
 
ALT >3 × ULN and 
bilirubina>2 × ULN 
(35% direct) 
24 hours 
CRF 
24 hours 
CRF 
a. bilirubin fractionation should be performed if testing is available.  If testing is 
unavailable and a subject meets the criterion of total bilirubin >2.0 × ULN, then the 
event should still be promptly reported as defined. 
 
 
Reporting Serious Adverse Events 
 
Any serious adverse events which occur during the clinical study or within 30 days of 
receiving the last dose of study medication, whether or not related to the study drug, 
must be reported by the investigator.  In addition, any SAEs which occur as a result of 
protocol specific diagnostic procedures or interventions must also be reported. 
 
 
The principal investigator has the obligation to report all serious adverse events to the 
FDA, IRB, and Novartis Pharmaceuticals Drug Safety and Epidemiology Department 
(DS&E) (For patients taking Lapatinib / Novartis drugs). 
All events reported to the FDA by the investigator are to be filed utilizing the Form FDA 
3500A (MedWatch Form).  
To ensure patient safety, every SAE, regardless of suspected causality, occurring 
• 
after the patient has provided informed consent and until atleast 30 days after the 
patient has stopped study treatment/participation 
• 
after protocol-specified procedures begin (e.g., placebo run-in, washout period, 
double-blind treatment, etc.) and 30 days after the patient has stopped study 
treatment 


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• 
after the start of any period in which the study protocol interferes with the standard 
medical treatment given to a patient (e.g., treatment withdrawal during washout 
period, change in treatment to a fixed dose of concomitant medication) and until 30 
days after the patient has stopped study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence  Information 
about all SAEs is collected and recorded on a Serious Adverse Event Report Form; all 
applicable sections of the form must be completed in order to provide a clinically thorough 
report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE 
Report Form in English, and send the completed, signed form by fax to (fax: 877-778-
9739) within 24 hours to the oncology Novartis DS&E department with the provided 
FAX cover sheets. 
. This includes serious, related, labeled (expected) and serious, related, unlabeled 
(unexpected) adverse experiences. All deaths during treatment or within 30 days following 
completion of active protocol therapy must be reported within 5 working days. 
Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study drug. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the 
original episode within 24 hours of the investigator receiving the follow-up information. A 
SAE occurring at a different time interval or otherwise considered completely unrelated to 
a previously reported one should be reported separately as a new event.  The end date of 
the first event must be provided. 
The original copy of the SAE Report and the fax confirmation sheet must be kept within 
the Trial Master File at the study site. 
Follow-up information is sent to the same fax number as the original SAE Report Form 
was sent, using a new fax cover sheet, stating that this is a follow-up to the previously 
reported SAE, and giving the date of the original report. Each re-occurrence, complication, 
or progression of the original event should be reported as a follow-up to that event 
regardless of when it occurs. The follow-up information should describe whether the event 
has resolved or continues, if and how it was treated, whether the blind was broken or not 
(if applicable), and whether the patient continued or withdrew from study participation. 
If the SAE is not previously documented in the Lapatinib Investigator Brochure or Package 
Insert (new occurrence) and is thought to be related to the Novartis study drug, a DS&E 
associate may urgently require further information from the investigator for Health 
Authority reporting. Novartis may need to issue an Investigator Notification (IN), to inform 
all investigators involved in any study with the same drug that this SAE has been reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and 
reported to the competent authorities and relevant ethics committees in accordance with 
Directive 2001/20/EC or as per national regulatory requirements in participating countries. 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. 
 
 
Lack of Efficacy 
 


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“Lack of efficacy” per se will not be reported as an AE.  The signs and symptoms or 
clinical sequelae resulting from lack of efficacy will be reported if they fulfill the AE or 
SAE definition (including clarifications). 
 
All serious adverse events, in addition to being reported to the FDA by the 
investigator, must be reported by facsimile within 24 hours to Novartis Oncology. 
 
The SAE report should comprise a full written summary, detailing relevant aspects of the 
adverse events in question.  Where applicable, information from relevant hospital case 
records and autopsy reports should be included.  Follow-up information should be 
forwarded to Novartis within 24 hours. 
 
SAEs brought to the attention of the investigator at any time after cessation of 
lapatinib and considered by the investigator to be related or possibly related 
to lapatinib must be reported to Novartis if and when they occur. Additionally, 
in order to fulfill international reporting obligations, SAEs that are related to study 
participation (e.g., procedures, invasive tests, change from existing therapy) or are 
related 
to a concurrent medication will be collected and recorded from the time the subject 
consents to participate in the study until he/she is discharged. 
 
Pregnancy 
 
Patients who become pregnant during the study should discontinue the study 
immediately. 
 
Patients should be instructed to notify the investigator if it is determined after completion 
of the study that they become pregnant either during the treatment phase of the study or 
within five days after the treatment period. 
 
Whenever possible a pregnancy should be followed to term, any premature termination 
reported, and the status of the mother and child should be reported to GlaxoSmithKline 
after delivery. 
 
 
Section 9.0. 
 
Statistics 
 
Sample size calculation for prolactinomas: Sample size was computed using proportions 
as standard deviation for tumor reduction on the study drug was unknown. While for the 
data analysis we will use quantitative analysis using the Hotelling’s T2, using binary data 
for power calculations would be inefficient as this would require a larger sample size. We 
could not use the quantitative analysis for power calculations, however, as we do not 
know the variance. 
The primary outcome is a reduction in maximal size of resistant tumors.  Stabilization is 
defined as <20% reduction in any dimension on MRI by RECIST criteria.  MRIs will be 
performed at baseline and at 3 and 6 months. 
The null hypothesis is H0: no reduction P<0.20 vs. the alternative hypothesis Ha: P>0.40. 
This will give an effect size of 0.20 to detect. Exact confidence interval and significance 
test is obtained from the binomial distribution.  The reduction is for resistant 
prolactinomas (Di Sarno, 2001; Delgrange, 2009).  Power is >80%, using one tailed 


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hypothesis, alpha of 0.10.  This gives a target sample size of 24 subjects to achieve this 
power.  
 
Sample size: use one-sided exact test. H0: p = p0; HA: p > p0.  
 
Power 
alpha 
P0: null proportion 
P1: true proportion  
N  
80% 
0.05 
20% 
30% 
116 
80% 
0.10 
20% 
30% 
88 
80% 
0.05 
20% 
35% 
56 
80% 
0.10 
20% 
35% 
44 
80% 
0.05 
20% 
40% 
35 
80% 
0.10 
20% 
40% 
24 
 
 
Secondary MRI studies will deal with various aspects and location by MRI of these 
tumors. Secondary PRL statistical studies will also be carried out under secondary 
outcomes.  
 
Tumor maximal size will be obtained at baseline, 3 months, 6 months after initiation of 
treatment.  The primary hypothesis is the change from baseline to 6 months.  The 
analysis using maximal resistant tumor size will be carried out for the specified times 
given above.  Initially this will be by descriptive analytic and then by inferential analysis 
using the test for change between baseline and 6 months and change between baseline 
and 3 months using rank test.  We will also use Hotelling's T2 to combine both pre-post 
changes.   
 
This study is in the clinical trials paradigm essentially a Phase IIa trial and thus use of 
alpha type 1 error is at 10%. This is sanctioned by the biostatistics section of NCI.40  We 
will also analyze the secondary endpoints of Aim 1 according to the above models. 
Concepts behind analysis for quantitative and binary are the same though the methods 
are different. 
 
Our overall target sample size is 30 subjects which includes nonfunctioning adenomas 
and prolactinomas, 15 to be recruited from Cedars Sinai Medical Center and 15 from 
Johns Hopkins Hospital and Massachusetts General Hospital.  We aim to recruit 24 
subjects with prolactinomas and 6 nonfunctioning adenomas.  
            Due to the rarity of pituitary tumors in the general population and even more rare 
are aggressive pituitary tumors such as we propose to study, it is difficult to do a 
randomized placebo controlled trial with sufficient sample size numbers to achieve 
adequate power.  By using the subjects as their own controls, we alleviate the issues 
with recruitment.  This is a safety and activity trial to look for a sufficient effect of the drug 
on tumor growth before proceeding to a larger, randomized placebo controlled trial. 
 
 
Section 10.0. 
 
Quality Control and Quality Assurance 
 
Only samples and data collected with appropriate consent will be used for the 
proposed analysis.  Specimens and data collected under the proof of concept clinical 
trial of lapatinib will be coded in such a way so that other members of the research 
team will be unable to ascertain the identity of specific patients.  All of our data will be 


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maintained confidentially.  Data will be kept in locked file cabinets and in password 
protected files on computer systems. 
 
Section 11.0    
 
Ethical considerations relating to the trial 
 
Subjects will be recruited from the Pituitary Center.  They will be patients followed  
clinically.  Patients will be approached regarding participation in the study and given  
consent forms to review at home.  They will be reassured that their clinical care will not 
be affected if they choose not to participate.  Patients will be given opportunities to ask 
questions and review the consent process.  Once they consent and enroll in the study, 
their data will be deidentified for the duration of the study.  All patients entering the trial 
will be given the study drug.  There is no placebo arm.  The risks of the study are related 
to the side effects of the study drug and patients will be monitored for this and informed 
on the effects.  The benefits of the study are stabilization of tumor growth.   
There are potential conflicts of interest between the patient’s need for surgical referral  
and participation in the research study.  However, by excluding patients who would meet  
definite criteria for surgery, we will minimize the conflict of interest. 
 
 
Section 12.0.  
 
Data Handling and Recordkeeping 
Data will be maintained in separate research charts in a locked cabinet in a locked 
office.   
The data will be entered as well into an electronic database on a password protected   
computer.  Only study staff and the investigators will have access to these records. 
 
 
Section 13.0.  
 
Financing and Insurance 
Funding for this study will be through institutional funds.  Patients will only be charged 
for the initial MRI and visual field test, as well as hormonal tests during the study period. 
 
 
 
Section 14.0.  
 
Publication Policy 
We intend to submit our research findings to relevant peer-reviewed journals for 
publication.  We will submit data for presentation at international meetings.  We will 
adhere to the NIH Grants Policy Statement on Sharing of Biomedical Research 
Resources, including the “Principles and Guidelines for Recipients of NIH Research 
Grants and Contracts on Obtaining and Disseminating Biomedical Research Resources: 
Final Notice” (64FR 72090, December 23, 1999; and described at 
http://ott.od.nih.gov/NewPages/RTguide/final.html.