GW786034 in Patients With Non Small Cell Lung Cancer 3rd Line

Better therapies for patients with NSCLC (Non Small Cell Lung Cancer) who progress after
initial chemotherapy is urgently needed.

Besides VEGF (vascular endothelial growth factor), human lung cancers are known to express
PDGFR (platelet-derived growth factor receptors). NSCLC, like most cancers, involves defects
in signal transduction pathways. Receptor tyrosine kinases (RTKs) play a pivotal role in
these signaling pathways, transmitting extracellular molecular signals into the cytoplasm
and/or nucleus of a cell. Among such RTKs are the receptors for polypeptide growth factors
such as epidermal growth factor (EGF), insulin, platelet-derived growth factor (PDGF),
neurotrophins (i.e., NGF), and fibroblast growth factor (FGF). Phosphorylation of such RTKs
activates their cytoplasmic domain kinase function, which in turns activates downstream
signaling molecules. Thus, RTKs are key mediators of cellular signaling as well as
oncogenesis resulting from over-expression and activation of such RTKs and their substrates.
Due to their pivotal role in normal and aberrant signaling, RTKs are the subject of
increasing focus as potential drug targets for the treatment of certain types of cancer. For
example, Herceptin.RTM., an inhibitor of HER2/neu, is currently an approved therapy for a
certain subset of breast cancer. Iressa.TM. (ZD1839) and Tarceva.TM. (OSI-774), both
small-molecule inhibitors of EGFR, have been approved for the treatment of NSCLC.

Platelet-derived growth factor (PDGF) and its receptors (PDGFRs) are a family of RTKs that
play an important role in the regulation of normal cell growth and differentiation. PDGFRs
are involved in a variety of pathological processes, including atherosclerosis, neoplasia,
tissue repair, and inflammation. PDGFRs, which consist of two isoforms (alpha and beta), are
membrane protein-tyrosine kinases that, upon binding to PDGF, become activated and, via
recruitment of SH domain-containing effector molecules, initiate distinct or overlapping
signaling cascades that coordinate cellular responses.

Expression of a constitutively active PDGFR leads to cellular transformation and suggests
that, in normal cells, PDGFR activity must be tightly regulated to oppose continuous
activation of its downstream effectors. PDGFR beta, for example, is known to be
over-expressed in a large number of tumors, and PDGF treatment causes transformation and
malignant tumors in a variety of experimental systems. One study reported the apparent
expression of PDGFR alpha in nearly 100% of human lung cancer tumors examined, and reported
the growth inhibition of a lung cancer cell line, A549, by Gleevec, an effect that was
surmised to be mediated via PDGFR inhibition.

Donnem et al evaluated 335 resected patients with stage I to III with NSCLC. Using IHC
(immunohistochemical staining) the expression of PDGF-A, -B, -C and -D along with PDGFR
alpha and beta. In multivariant analysis high tumor cell expression of PDGF-B and PDGF-
alpha were independent negative prognostic predictors. They suggested that PDGF inhibition
may be an option for treatment of NSCLC.

Socinski et al recently described the activity of sunitnib malate (SU11248) an oral,
multitargeted tyrosine kinase inhibitor targeting VEGFR, PDGFR, KIT, FLT3 and RET on tumor
cells, tumor neovasculature and pericytes. In an open-label, two-stage, multicenter phase II
trial evaluating the single-agent activity of sunitinib in refractory NSCLC, patients with
confirmed diagnosis of NSCLC, ECOG PS 0-1, no recent gross hemoptysis, no brain metastases,
patients (pts) previously treated with 1-2 chemotherapy regimens, and adequate end-organ
function, pts received sunitinib at 50 mg/day po for 4 weeks (wks) followed by 2 wks off
treatment (6 wks considered a cycle). A total of 64 pts were enrolled and 63 pts treated.
Six confirmed partial responses have been observed among 63 treated patients. Stable
disease has been observed in an additional 12 pts (19.0% of all treated patients). Based on
this study, Sunitinib appeared to have single-agent activity in previously treated pts with
recurrent and advanced NSCLC, with the level of activity similar to currently approved
agents. Sunitinib was well tolerated in this population. The trial was extended to explore a
continuous dosing strategy of sunitinib at 37.5 mg/day po.

In addition to VEGF and PDGFR, expression of c-kit has been described in NSCLC. Moreover,
it has been found to have an effect on survival. Micke et al, stained the tumor tissue of
95 consecutive patients with adenocarcinoma of the lung, using a polyclonal c-kit antibody.
c-kit expression was correlated with relevant clinical parameters obtained by chart review.
Positive c-kit expression in tumor tissue was observed in 61 of 95 patients (64%).
Univariate analysis showed a significant effect of T (p = 0.003), N (p = 0.001) and M stage
(p < 0.001) as well as of performance status (p = 0.001), surgical resection (p < 0.001),
and LDH serum levels (p = 0.016) on survival. In contrast, c-kit protein expression was non-
significant (p = 0.913). However, multivariate Cox regression with the influential
parameters revealed a significant effect of c-kit expression on survival. They concluded
that, the receptor tyrosine kinase c-kit is frequently expressed in adenocarcinomas of the
lung and has a relevant effect on patient survival. They also concluded that the results of
this study support clinical trials targeting the c-kit receptor with specific c-kit
inhibitors.

Combined blockade of VEGF, PDGFR and c-kit may result in better outcomes for patients with
Non Small Cell Lung Carcinoma.

Pazopanib is a novel, orally active small molecule inhibitor targeting multiple tyrosine
kinases including VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-alpha and - beta, and c-kit. An
antitumor effect due to inhibiting of the VEGF driven angiogenic pathway is well
established. In addition to its effects on VEGF receptors, pazopanib targets additional
tyrosine kinases including PDGF receptors and c-kit that have established roles in
tumorigenesis and oncogenic mutations in both have been described. Preliminary data from a
phase I study of pazopanib in patients with solid tumors demonstrated early evidence of
antitumor activity. Among 43 patients enrolled, a minimal response occurred in 4 patients
and stable disease >6 months, was observed in an additional 6 patients.

Pazopanib was well tolerated at doses up to 2000 mg daily. Pazopanib is a potent and
selective, orally available, small molecule inhibitor of VEGFR-1, -2, and -3, PDGF-α,
PDGF-β, and c-kit tyrosine kinases (TKs). The agent selectively inhibits proliferation of
endothelial cells stimulated with VEGF but not with basic fibroblast growth factor. In
non-clinical angiogenesis models, pazopanib inhibited VEGF-dependent angiogenesis in a
dose-dependent manner and in xenograft tumor models, twice-daily administration of pazopanib
significantly inhibited tumor growth in mice implanted with various human tumor cells. Upon
chronic oral dosing, pazopanib is expected to inhibit VEGF driven angiogenesis and as a
consequence, limit solid tumor growth. Because angiogenesis is necessary for the growth and
metastasis of solid tumors, and VEGF is believed to have a pivotal role in this process,
pazopanib treatment may have broad-spectrum clinical utility.

Based on its ability to target multiple tyrosine kinases including VEGFR-1, VEGFR-2,
VEGFR-3, PDGFR-alpha and beta and c-kit, which have been implicated in non small cancer,
investigation of Pazopanib in patients with non small cell lung cancer is warranted.

Inclusion Criteria:

Required Characteristics 3.1. Subjects must provide written informed consent prior to
performance of study-specific procedures or assessments, and must be willing to comply
with treatment and follow up. Procedures conducted as part of the subject's routine
clinical management (e.g., blood count, imaging study) and obtained prior to signing of
informed consent may be utilized for screening or baseline purposes provided these
procedures are conducted as specified in the protocol.

Note: It is not necessary that informed consent be obtained within the protocol-specified
screening window.

3.11 ≥18 years of age.

3.12 ≥2 prior systemic therapies for Non Small Cell Lung Cancer.

3.13 Histologic or cytologic diagnosis of stage IV Non Small Cell Lung cancer

. 3.14 Measurable disease. For patients having only lesions measuring ≥1 cm to ≤2 cm per
RECIST criteria must use spiral CT imaging for both pre- and post-treatment tumor
assessments.

3.15 Laboratory values obtained ≤14 days prior to registration: Hematologic Absolute
neutrophil count (ANC) 1.5 X 109/L Hemoglobin1 9 g/dL (5.6 mmol/L) Platelets 100 X
109/L Prothrombin time (PT) or international normalized ratio (INR) 1.2 X upper limit of
normal (ULN) Partial thromboplastin time (PTT) 1.2 X ULN Hepatic2 Total bilirubin 1.5 X
ULN AST and ALT 2.5 X ULN Renal Serum creatinine 1.5 mg/dL (133 µmol/L)

Or, if greater than 1.5 mg/dL:

Calculated creatinine clearance 50 mL/min

Urine Protein to Creatinine Ratio (UPC)3 < 1

1. Subjects may not have had a transfusion within 7 days of screening assessment.

2. Concomitant elevations in bilirubin and AST/ALT above 1.0 x ULN are not permitted

3. If UPC >/= 1, then a 24-hour urine protein must be assessed. Subjects must have a
24-hour urine protein value <1g to be eligible.

3.16 ECOG Performance Score 0, or 1.

3.17 Negative pregnancy test done ≤ 7 days prior to registration, for women of
childbearing potential only.

A female is eligible to enter and participate in this study if she is of:
Non-childbearing potential (i.e., physiologically incapable of becoming pregnant),
including any female who has had:

- A hysterectomy

- A bilateral oophorectomy (ovariectomy)

- A bilateral tubal ligation

- Is post-menopausal

Subjects not using hormone replacement therapy (HRT) must have experienced total
cessation of menses for ≥ 1 year and be greater than 45 years in age, OR, in
questionable cases, have a follicle stimulating hormone (FSH) value >40 mIU/mL and an
estradiol value < 40pg/mL (<140 pmol/L).

Subjects using HRT must have experienced total cessation of menses for >= 1 year and
be greater than 45 years of age OR have had documented evidence of menopause based on
FSH and estradiol concentrations prior to initiation of HRT

Childbearing potential, including any female who has had a negative serum pregnancy
test within 1 week prior to the first dose of study treatment, preferably as close to
the first dose as possible, and agrees to use adequate contraception. GSK acceptable
contraceptive methods, when used consistently and in accordance with both the product
label and the instructions of the physician, are as follow:

- An intrauterine device with a documented failure rate of less than 1% per year.

- Vasectomized partner who is sterile prior to the female subject's entry and is
the sole sexual partner for that female.

- Complete abstinence from sexual intercourse for 14 days before exposure to
investigational product, through the dosing period, and for at least 21 days
after the last dose of investigational product.

- Double-barrier contraception (condom with spermicidal jelly, foam suppository,
or film; diaphragm with spermicide; or male condom and diaphragm with
spermicide).

- Oral contraceptives

- Female subjects who are lactating should discontinue nursing prior to the first
dose of study drug and should refrain from nursing throughout the treatment
period and for 14 days following the last dose of study drug

3.18 Ability and willingness to provide informed consent.

3.19 Life expectancy ≥12 weeks.

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Exclusion Criteria:

3.21 Any of the following as this regimen may be harmful to a developing fetus or
nursing child.

• Pregnant women

- Nursing women

- Men or women of childbearing potential or their sexual partners who are
unwilling to employ adequate contraception.

3.22 Any abnormal serum calcium, magnesium, and potassium levels

3.23 Clinically significant hemoptysis, cerebral hemorrhage, or gastrointestinal
hemorrhage in the past 6 months

3.24 Any patient currently on an antiarrhythmics or other medications that are know
to prolong the QT interval.

3.25 Uncontrolled infection.

3.26 Poorly controlled hypertension [defined as systolic blood pressure (SBP) of
≥140 mmHg or diastolic blood pressure (DBP) of ≥ 90mmHg].

Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior
to study entry. BP must be re-assessed on two occasions that are separated by a
minimum of 1 hour; on each of these occasions, the mean (of 3 readings) SBP / DBP
values from each BP assessment must be <140/90 mmHg in order for a subject to be
eligible for the study

3.27 Any condition (e.g., gastrointestinal tract disease resulting in an inability to
take oral medication or a requirement for IV alimentation, prior surgical procedures,
affecting absorption, or active peptic ulcer disease) that impairs their ability to
swallow and retain pazopanib tablets.

- Malabsorption syndrome

- Major resection of the stomach or small bowel. 3.28 Clinically significant
gastrointestinal abnormalities that may increase the risk for gastrointestinal
bleeding including, but not limited to:

- Active peptic ulcer disease

- Known intraluminal metastatic lesion/s with risk of bleeding

- Inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease), or other
gastrointestinal conditions with increased risk of perforation

- History of abdominal fistula, gastrointestinal perforation, or intra abdominal
abscess within 28 days prior to beginning study treatment.

3.29 Known endobronchial lesions and or lesions infiltrating major pulmonary
vessels.

3.30 Cavitary lesions deemed to be at increased risk of bleeding.

3.31 Any other severe underlying diseases that are, in the judgment of the
investigator, inappropriate for entry into this study.

3.32 Second primary malignancy except for carcinoma in situ of the cervix or
nonmelanomatous skin cancer, unless that prior malignancy was diagnosed and
definitively treated ≥5 years previously with no subsequent evidence of recurrence.
Patients with a history of low-grade (Gleason score ≤6) localized prostate cancer
will be eligible even if diagnosed <5 years prior to registration.

3.33 Any ancillary therapy considered investigational (utilized for a non-FDA
approved indication and in the context of a research investigation) ≤4 weeks prior to
registration.

3.34 Other concurrent chemotherapy, immunotherapy, radiotherapy.

3.35a. History of allergic reactions attributed to compounds of similar chemical
or biologic composition to pazopanib or other agents used in the study.

b. Medications that act through the CYP450 system. Some medications that act through
the cytochrome P450 system are specifically prohibited in patients receiving
pazopanib. Certain other agents should be used with caution. (A list of medications
that are specifically prohibited or that should be used with caution during this
trial of pazopanib will be provided with the full study protocol as Appendix 1. A
list of selected agents that could affect pazopanib will be listed in Appendix I. )
c. Any of the following concurrent severe and/or uncontrolled medical conditions:

• Serious or non-healing wound, ulcer, or bone fracture

• History of abdominal fistula, diverticulosis, gastrointestinal perforation, or
intra-abdominal abscess ≤28 days prior to registration

- Any history of cerebrovascular accident (CVA) ≤6 months prior to registration

- History of any one or more of the following cardiovascular conditions within the
past 6 months:

- Cardiac angioplasty or stenting

- Myocardial infarction

- Unstable angina

- Coronary artery bypass graft surgery

- Symptomatic peripheral vascular disease

- Class III or IV congestive heart failure, as defined by the New York Heart
Association (NYHA)

- History of venous thrombosis ≤12 weeks prior to registration.

- Class III or IV heart failure as defined by the NYHA functional classification
system .History of Class II heart failure and is asymptomatic on treatment may
be considered eligible.

- Poorly controlled diabetes.

- Interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the
lung.

- QTc prolongation (defined as a QTc interval ) > 480 msecs using Bazett's
formula) or other significant ECG abnormalities d. Symptomatic, untreated, or
uncontrolled CNS metastases or seizure disorder. Patients with CNS metastases
treated with whole brain radiation (WBRT)or gamma knife may be enrolled after
completion of WBRT or gamma knife. Patients may begin chemotherapy as early as
the next day after completion of WBRT or gamma knife.

e. Uncontrolled intercurrent illness including, but not limited to, ongoing or
active infection or psychiatric illness/social situations that would limit
compliance with study requirements.

f. HIV-positive patients on combination antiretroviral therapy because of the
potential for pharmacokinetic interactions with pazopanib. In addition, these
patients are at increased risk of lethal infections when treated with marrow
suppressive therapy

g. Any of the following prior therapies:

- Major surgery (i.e., laparotomy), open biopsy, or significant traumatic injury
≤4 weeks prior to registration. Minor surgery ≤4 weeks prior to registration.
Insertion of a vascular access device is not considered major or minor surgery
in this regard.

- Treatment with any of the following anti-cancer therapies:

- radiation therapy, surgery or tumor embolization within 14 days prior to the
first dose of Pazopanib OR

- chemotherapy, immunotherapy, biologic therapy, investigational therapy or
hormonal therapy within 14 days or five half-lives of a drug (whichever is
longer) prior to the first dose of pazopanib

Patients with progressive disease inside of the radiation field are not eligible.

3.36 History of cerebrovascular accident including transient ischemic attack (TIA),
pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6
months.

Note: Subjects with recent DVT who have been treated with therapeutic
anti-coagulating agents for at least 6 weeks are eligible

3.37 Evidence of active bleeding or bleeding diathesis.

3.38 Hemoptysis within 6 weeks of first dose of study drug.

3.39 Unable or unwilling to discontinue use of prohibited medications for at least
14 days or five half-lives of a drug (whichever is longer) prior to the first dose of
study drug and for the duration of the study.

3.40 Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 and/or that
is progressing in severity, except alopecia.

3.41 Other Eligibility Criteria Considerations To assess any potential impact on
subject eligibility with regard to safety, the investigator must refer to the
following document(s) for detailed information regarding warnings, precautions,
contraindications, adverse events, and other significant data pertaining to the
investigational product(s) being used in this study: Clinical Investigator's Brochure
for pazopanib.[Investigator Brochure]

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