Trial of Cabozantinib (XL184) in Non-Small Cell Lung Cancer With Brain Metastases

This is a Phase 2, single-arm, open-label study of cabozantinib in subjects with molecularly
unselected Non-Small Cell Lung Cancer (NSCLC) with metastases to the brain and in patients
with c-MET amplified Non-Small Cell Lung Cancer (NSCLC) with metastases to the brain.

Patients will receive cabozantinib at 60 mg orally once daily and continue on treatment until
disease progression, death or unacceptable adverse events. Treatment cycles are 4 weeks in
duration.

The primary endpoint is Overall Response Rate (ORR) in both the unselected NSCLC population
and the molecularly selected patients on the basis of c-MET amplification.

Inclusion Criteria:

1. Previously treated patients with non-squamous NSCLC who have had brain metastases at
any point in their treatment history are eligible for enrollment on this clinical
trial. (Patients must have received at least one regimen for systemic disease which
may be cytotoxic or oral tyrosine kinase inhibitor therapy.)

- Patients with clinically asymptomatic untreated brain metastases will be allowed
on trial at the discretion of the treating physician

- Patients who have undergone treatment for their brain metastases with whole brain
radiotherapy, stereotactic radiosurgery, or surgical resection must be clinically
stable and recovered from all procedures at the time of study enrollment.

2. Patients must have tumor tissue available for submission that is sufficient to
complete c-MET Fluorescence in Situ Hybridization (FISH) studies as well as routine
molecular profiling at the UPMC. Patients must agree to submission of these specimens
as defined in Section 9.

- c-MET amplification will be determined by FISH ratio (c-MET/CEP7) > 2.0, based on
testing of the primary tumor and/or site of metastatic disease

- Patients' tumors must undergo testing for Epidermal Growth Factor Receptor (EGFR)
exon 19 deletion, EGFR exon 21 L858R substitution, and anaplastic lymphoma kinase
(ALK) rearrangements. If positive, patients must have been treated with an
appropriate tyrosine kinase inhibitors (TKI) prior to enrolling to the study.

3. The subject has had an assessment of all extracranial disease sites (e.g., by
computerized tomography (CT) scan, positron emission tomography-CT, and bone scan as
appropriate) within 28 days before the first dose of cabozantinib.

4. The subject must have a baseline brain MRI scan or CT scan of the head (in patients
unable to obtain an MRI) within 14 days prior to first dose of cabozantinib.

- Patients receiving glucocorticoids must be on a stable dose of glucocorticoids
during the 5 days prior to the baseline brain imaging.

5. Patients must have measurable disease as defined by Response Evaluation Criteria in
Solid Tumors (RECIST) v1.1

6. Subjects having undergone recent resection or biopsy of an intracranial tumor will be
eligible as long as all of the following conditions apply:

- First dose of cabozantinib occurs at least 28 days after surgery, and the subject
has recovered from the effects of surgery

7. Age ≥18 years

8. Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (Karnofsky ≥60%)

9. Patients must have normal organ and marrow function as defined below: (within 4 days
of beginning treatment unless noted otherwise)

- Hemoglobin ≥9 g/dL

- Absolute Neutrophil Count (ANC) ≥1,500/mm3 (no CSF support)

- Platelets ≥100,000/mm3

- Bilirubin ≤ 1.5 x upper limit of normal (ULN)

- Bilirubin (Gilbert's Disease) < 3.0 mg/dL

- Aspartate Aminotransferase (AST) (SGOT) ≤3.0 × ULN

- Alanine Aminotransferase (ALT) (SGPT) ≤3.0 × ULN

- Serum creatinine ≤ 1.5 x ULN

- Creatinine clearance (CrCl) ≥40 mL/min

- For creatinine clearance estimation, the Cockcroft and Gault equation should be
used:

- Male: CrCl (mL/min) = (140 - age) × wt (kg) / (serum creatinine × 72)

- Female: Multiply above result by 0.85 ≤ 1.5 x ULN

- Lipase (no radiologic or clinical evidence of pancreatitis) < 2.0 x ULN

- Urine protein/creatinine ratio (UPCR) ≤1

- Serum phosphorus, calcium, magnesium and potassium ≥ LLN

10. The subject is capable of understanding and complying with the protocol requirements
and has signed the informed consent document.

11. Women of childbearing potential must have a negative serum pregnancy test at
screening.

12. The effects of cabozantinib on the developing human fetus are unknown. For this reason
women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and for
4 months after the last dose of study drug, even if oral contraceptives are used.

Exclusion Criteria:

1. The subject has received cytotoxic chemotherapy (including investigational cytotoxic
chemotherapy) or biologic agents (e.g., cytokines or antibodies; including
investigational biologic agents) within 3 weeks, or nitrosoureas/ mitomycin C within 6
weeks before the first dose of study treatment.

2. The subject has received prior treatment with a small molecule kinase inhibitor or a
hormonal therapy (including investigational kinase inhibitors or hormones) within 14
days or five half-lives of the compound or active metabolites, whichever is longer,
before the first dose of study treatment.

3. Prior treatment with cabozantinib or other c-MET directed therapy.

4. The subject has received radiation therapy as follows:

- To the thoracic cavity, abdomen or pelvis within 3 months of the first dose of
study treatment or has with ongoing complications or is without complete recovery
and healing from prior radiation therapy

- To bone or brain metastasis within 14 days of the first dose of study treatment

- To any other site(s) within 28 days of the first dose of study treatment

5. The subject has received radionuclide treatment within 6 weeks of the first dose of
study treatment.

6. The subject has evidence of acute intracranial or intratumoral hemorrhage either by
MRI or computerized tomography (CT) scan. The subject has not recovered to baseline or
CTCAE ≤ Grade 1 from toxicity due to all prior therapies except alopecia and other
non-clinically significant AEs.

7. The subject has prothrombin time (PT)/ International Normalized Ratio (INR) or partial
thromboplastin time (PTT) test ≥ 1.3 x the laboratory ULN within 7 days before the
first dose of study treatment.

8. The subject is receiving concomitant treatment with warfarin, warfarin-related agents,
or low molecular weight heparin (LMWH) at the time of study entry at therapeutic
doses. Low-dose warfarin (≤ 1 mg/day) or LMWH at prophylactic doses are permitted.

9. The subject has received enzyme-inducing anti-epileptic agents within 2 weeks before
the first dose of cabozantinib (e.g., carbamazepine, phenytoin, phenobarbital,
primidone). Other enzyme inducing agents prohibited within 2 weeks before the first
dose of cabozantinib include rifampin, rifabutin, rifapentin, and St. John's Wort.

10. The subject has experienced any of the following:

- Clinically-significant gastrointestinal bleeding within 6 months before the first
dose of study treatment b.Hemoptysis of ≥ 0.5 teaspoon (2.5ml) of red blood
within 3 months before the first dose of study treatment

- Any other signs indicative of pulmonary hemorrhage within 3 months before the
first dose of study treatment

11. The subject has radiographic evidence of cavitating pulmonary lesion(s)

12. The subject has tumor abutting, invading or encasing any major blood vessels.

13. The subject has evidence of tumor invading the Gastro Intestinal (GI) tract
(esophagus, stomach, small or large bowel, rectum or anus), or any evidence of
endotracheal or endobronchial tumor within 28 days before the first dose of
cabozantinib.

14. The subject has uncontrolled, significant intercurrent or recent illness including,
but not limited to, the following conditions:

- Cardiovascular disorders including:

- Congestive heart failure (CHF): New York Heart Association (NYHA) Class III
(moderate) or Class IV (severe) at the time of screening

- Concurrent uncontrolled hypertension defined as sustained BP > 140 mm Hg
systolic, or > 90 mm Hg diastolic despite optimal antihypertensive treatment
within 7 days of the first dose of study treatment

- Any history of congenital long QT syndrome

- Any of the following within 6 months before the first dose of study
treatment:

1.unstable angina pectoris 2.clinically-significant cardiac arrhythmias 3.stroke (including
Transient Ischemic Attack (TIA), or other ischemic event) 4.myocardial infarction (MI)
5.thromboembolic event requiring therapeutic anticoagulation (Note: subjects with a venous
filter (e.g. vena cava filter) are not eligible for this study)

- Gastrointestinal disorders particularly those associated with a high risk of
perforation or fistula formation including:

- Any of the following within 28 days before the first dose of study treatment

1. Intra-abdominal tumor/metastases invading GI mucosa

2. Active peptic ulcer disease,

3. Inflammatory bowel disease (including ulcerative colitis and Crohn's disease),
diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis

4. Malabsorption syndrome

- Any of the following within 6 months before the first dose of study treatment:

1. Abdominal fistula

2. Gastrointestinal perforation

3. Bowel obstruction or gastric outlet obstruction

4. Intra-abdominal abscess. Note: Complete resolution of an intra-abdominal abscess
must be confirmed prior to initiating treatment with cabozantinib even if the
abscess occurred more than 6 months before the first dose of study treatment.

- Other disorders associated with a high risk of fistula formation including
Percutaneous Endoscopic Gastrostomy (PEG) tube placement within 3 months before the
first dose of study therapy.

- Other clinically significant disorders such as:

- Serious active infection requiring systemic treatment within 28 days before the
first dose of study treatment.

- Serious non-healing wound/ulcer/bone fracture within 28 days before the first
dose of study treatment.

- History of organ transplant

- Concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days
before the first dose of study treatment.

- History of surgery as follows:

1. Subjects having undergone recent resection or biopsy of an intracranial tumor
will be eligible as long as all of the following conditions apply: First dose of
cabozantinib occurs at least 28 days after surgery, and the subject has recovered
from the effects of surgery.

2. Other minor surgery within 28 days of the first dose of cabozantinib if there
were no wound healing complications. If there is evidence of wound dehiscence,
subjects will be eligible for trial after a minimum of 3 months after surgery to
the first dose of cabozantinib, provided complete wound healing is confirmed at
least 28 days before the first dose of cabozantinib.

3. Other major surgery within 2 months of the first dose of cabozantinib if there
were no wound healing complications. If there is evidence of wound dehiscence,
subjects will be eligible for trial after a minimum of 6 months after surgery to
the first dose of cabozantinib, provided complete wound healing in confirmed at
least 28 days before the first dose of cabozantinib.

4. The subject is unable to swallow tablets.

5. The subject has a corrected QT interval calculated by the Fridericia formula
(QTcF) >500 ms within 28 days before randomization. Note: if initial QTcF is
found to be > 500 ms, two additional EKGs separated by at least 3 minutes should
be performed. If the average of these three consecutive results for QTcF is ≤ 500
ms, the subject meets eligibility in this regard.

6. The subject is pregnant or breastfeeding.

7. The subject has a previously identified allergy or hypersensitivity to components
of the study treatment formulation.

8. The subject is unable or unwilling to abide by the study protocol or cooperate
fully with the investigator or designee.

9. The subject has had evidence within 2 years of the start of study treatment of
another malignancy which required systemic treatment. Note: Subjects with a
history of early stage or locally advanced non-metastatic prostate cancer within
2 years of the start of study treatment may be included in the study.