Pazopanib in Molecularly Selected Patients With Advanced NSCLC

There has been a limited benefit from anti-angiogenesis drugs in patients with NSCLC.
Bevacizumab provides a modest survival improvement when added to chemotherapy and VEGFR
tyrosine kinase inhibitors have been associated with minimal efficacy as single agents and
increased toxicity when combined with chemotherapy. We postulate that the response rates and
survival may be improved with a better selection of patients based on abnormalities of the
targets for the drugs. According to the preliminary data from the cancer genome atlas (TCGA),
the targets of pazopanib are altered in 28% of patients with adenocarcinoma and 24% of
patients with squamous cell lung cancer. Since, despite the molecular selection prior to
treatment, only a small percentage of patients will benefit from the treatment, we plan to
further investigate those patients with whole exome sequencing in both the pre-treatment
samples to identify the predictors for response and at the time of progression, with repeated
biopsy, in an attempt to identify the predictors for secondary resistance. By identifying
more reliable predictors for response to pazopanib, our study may help to establish its role
in the treatment of NSCLC.

Inclusion Criteria:

- Histologically confirmed diagnosis of advanced (metastatic or unresectable) non-small
cell lung cancer (NSCLC) with mutations, rearrangement and fusion involving RET
oncogene, or abnormalities in the pazopanib target genes defined as VEGFR1-3, PDGFRA,
PDGFRB, or TP53 with abnormalities including deletion, insertion, early stop codon,
and/or nonsynonymous mutations with functional consequences. CLIA certified lab
testing for pazopanib target genes using cell free DNA from peripheral blood and/or
assays performed on tumor tissues are acceptable.

- Evaluable disease by imaging or physical exam OR measurable disease defined as at
least one lesion that can be accurately measured in at least one dimension (longest
diameter to be recorded) as ≥ 10 mm with CT scan, as ≥ 20 mm by chest x-ray, or ≥ 10
mm with calipers by clinical exam.

- Failed at least one standard chemotherapeutic treatment for NSCLC.

- At least 18 years of age.

- ECOG performance status ≤ 2

- Normal bone marrow and organ function as defined below:

- Absolute neutrophil count ≥ 1,500/mcl

- Platelets ≥ 100,000/mcl

- Hemoglobin ≥ 9.0 g/dL

- PT or INR ≤ 1.2 x IULN

- aPTT ≤ 1.2 x IULN

- Total bilirubin ≤ 1.5 x IULN

- AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN

- Creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 30 mL/min/1.73 m2 for patients
with creatinine levels above 1.5 mg/dL

- UPC < 1 or, if UPC ≥ 1, 24-hour urine protein < 1 g; use of urine dipstick for
renal function assessment is not acceptable.

- Patients receiving anticoagulation therapy are eligible if their INR is stable and
within the recommended range for the desired level of anticoagulation.

- Ability to swallow and retain oral tablets.

- Women of childbearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control, abstinence) prior to study entry and for
the duration of study participation. Should a woman become pregnant or suspect she is
pregnant while participating in this study, she must inform her treating physician
immediately.

- Ability to understand and willingness to sign an IRB approved written informed consent
document.

Exclusion Criteria:

- 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, investigational therapy or hormonal therapy within
14 days prior to the first dose of pazopanib

- Prior treatment with any VEGFR tyrosine kinase inhibitor.

- Administration of any non-oncologic investigational drug within 30 days or 5
half-lives (whichever is longer) prior to the first dose of pazopanib.

- Use of a strong CYP3A4 inhibitor less than 14 days prior to initiation of study
treatment

- A history of other malignancy ≤ 5 years previous with the exception of basal cell or
squamous cell carcinoma of the skin which were treated with local resection only or
carcinoma in situ of the cervix.

- Symptomatic brain metastases. Patients with known brain metastases are allowed if they
are asymptomatic.

- A history of allergic reactions attributed to compounds of similar chemical or
biologic composition to pazopanib or other agents used in the study.

- Any ongoing toxicity from prior anti-cancer therapy that is > grade 1 and/or that is
progressing in severity (except alopecia). Any IO related adverse events must be ≤
grade 1 to be eligible.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, uncontrolled seizure disorder, chronic underlying liver disease unrelated
to cancer, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Corrected QT interval (QTc) > 480 msecs.

- History of any one or more of the following cardiovascular conditions within the past
6 months: cardiac angioplasty or stenting, myocardial infarction, unstable angina
pectoris, coronary artery bypass graft surgery, symptomatic peripheral vascular
disease, class III or IV congestive heart failure as defined by the New York Heart
Association (see Appendix B).

- Poorly controlled hypertension (defined as systolic blood pressure of ≥ 140 mmHg or
diastolic blood pressure of ≥ 90 mmHg). Note: initiation or adjustment of
antihypertensive medication(s) is permitted prior to study entry. Following
antihypertensive medication initiation or adjustment, blood pressure must be
reassessed three times at approximately 2-minute intervals. At least 24 hours must
have elapsed between antihypertensive medication initiation or adjustment and blood
pressure measurement. These three values should be averaged to obtain the mean
diastolic and systolic blood pressures, which must be < 140/90 mmHg in order for a
patient to be eligible for the study.

- Clinically significant gastrointestinal abnormalities that may increase the risk for
gastrointestinal bleeding, including (but not limited to) active peptic ulcer disease,
known intraluminal metastatic lesions with risk of bleeding, inflammatory bowel
disease (e.g., ulcerative colitis, Crohn's disease) or other GI conditions with
increased risk of perforation, history of abdominal fistula or intra-abdominal abscess
within 28 days prior to beginning study treatment.

- Clinically significant gastrointestinal abnormalities that may affect absorption of
pazopanib, including (but not limited to) malabsorption syndrome or major resection of
the stomach or small bowel.

- History of cerebrovascular accident including transient ischemic attack, pulmonary
embolism (including asymptomatic or previously treated PE), or untreated deep venous
thrombosis within the past 6 months. Patients with recent DVT who have been treated
with therapeutic anti-coagulating agents for at least 6 weeks are eligible.

- Major surgery or trauma within 28 days prior to first dose of pazopanib and/or
presence of any non-healing wound, fracture, or ulcer (procedures such as catheter
placement not considered to be major surgery).

- Evidence of active bleeding or bleeding diathesis.

- Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that
increase the risk of pulmonary hemorrhage. Note: lesions infiltrating major pulmonary
vessels (contiguous tumor and vessels) are excluded; however, the presence of a tumor
that is touching but not infiltrating (abutting) the vessels is acceptable (CT with
contrast is strongly recommended to evaluate such lesions). Large protruding
endobronchial lesions in the mail or lobar bronchi are excluded; however,
endobronchial lesions in the segmented bronchi are allowed. Lesions extensively
infiltrating the main or lobar bronchi are excluded; however, minor infiltrations in
the wall of thee bronchi are allowed.

- Recent hemoptysis (≥ ½ teaspoon of red blood within 8 weeks before first dose of
pazopanib).

- Pregnant and/or breastfeeding. Patient must have a negative serum pregnancy test
within 14 days of study entry.

- Known HIV-positivity. Appropriate studies will be undertaken in patients receiving
combination antiretroviral therapy when indicated.