A Phase II Study of Cabozantinib in Patients With KIF5B/RET Positive Advanced Non-Small Cell Lung Cancer

Inclusion Criteria:

A subject must fully meet all of the following criteria to be eligible for the study:

1. The subject has a pathologic diagnosis of non-small cell lung carcinoma that is
metastatic or unresectable.

2. Documented presence of KIF5B/RET or related variant RET fusions.

3. The subject is ≥ 18 years old on the day of consent. The subject has a Karnofsky
performance status of > 70%.

5. The subject has organ and marrow function and laboratory values as follows:

- Absolute neutrophil count (ANC) ≥ 1500/mm3 without colony stimulating factor support

- Platelets ≥ 100,000/mm3 Hemoglobin ≥ 9 g/dL

- Bilirubin ≤ 1.5 × the upper limit of normal (ULN). For subjects with known Gilbert's
disease, bilirubin ≤ 3.0 mg/dL

- Serum albumin ≥ 2.8 g/dl

- Serum creatinine ≤ 1.5 × ULN or creatinine clearance (CrCl) ≥ 50 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

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)

≤ 3.0 × ULN if no liver involvement, or ≤ 5 × ULN with liver involvement

- Lipase < 2.0 x the upper limit of normal (except for subjects with adenocarcinoma of
the pancreas)

- Urine protein/creatinine ratio (UPCR) ≤ 1

- Serum phosphorus, magnesium, and potassium ≥ LLN

- The subject is capable of understanding and complying with the protocol requirements
and has signed the informed consent document. Sexually active subjects (men and
women) must agree to use medically accepted barrier methods of contraception (eg,
male or female condom) during the course of the study and for 4 months after the last
dose of study drug(s), even if oral contraceptives are also used. All subjects of
reproductive potential must agree to use both a barrier method and a second method of
birth control. Women of childbearing potential must have a negative pregnancy test at
screening.

- Women of childbearing potential include women who have experienced menarche and who
have not undergone successful surgical sterilization (hysterectomy, bilateral tubal
ligation, or bilateral oophorectomy) or are not postmenopausal.

Postmenopause is defined as amenorrhea ≥ 12 consecutive months. Note:

women who have been amenorrheic for 12 or more months are still considered to be of
childbearing potential if the amenorrhea is possibly due to prior chemotherapy,
antiestrogens, ovarian suppression or any other reversible reason.

Exclusion Criteria:

A subject who meets any of the following criteria is ineligible for the study:

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

2. Prior treatment with cabozantinib

3. The subject has received radiation therapy:

- to the thoracic cavity or gastrointestinal tract within 3 months of the first
dose of study treatment.

- 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

4. The subject has received prior treatment with a small molecule kinase inhibitor
within 14 days or five half-lives of the compound or active metabolites, whichever is
longer, before the first dose of study treatment. Subjects on LHRH or GnRH agonists
may be maintained on these agents.

5. The subject has received any other type of investigational agent within 28 days
before the first dose of study treatment.

6. 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 active brain metastases or epidural disease (Note: Subjects with
brain metastases previously treated with whole brain radiation or radiosurgery or
subjects with epidural disease previously treated with radiation or surgery who are
asymptomatic and do not require steroid treatment for at least 2 weeks before
starting study treatment are eligible. Neurosurgical resection of brain metastases or
brain biopsy is permitted if completed at least 3 months before starting study
treatment. Baseline brain scans are not required to confirm eligibility.)

8. The subject has prothrombin time (PT)/ International Normalized Ratio (INR) or
partial thromboplastin time (PTT) test results at screening ≥ 1.3 × the laboratory
ULN.

9. The subject requires concomitant treatment, in therapeutic doses, with anticoagulants
such as warfarin or warfarin-related agents, heparin, thrombin or Factor Xa
inhibitors, or antiplatelet agents (eg, clopidogrel). Low dose aspirin (≤ 81 mg/day),
low-dose warfarin (≤ 1 mg/day), and prophylactic low molecular weight heparin (LMWH)
are permitted.

10. The subject has experienced any of the following within 3 months before the first
dose of study treatment:

- clinically-significant hematemesis or gastrointestinal bleeding

- hemoptysis of ≥ 0.5 teaspoon (2.5ml) of red blood c. any other signs indicative
of pulmonary hemorrhage

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

12. The subject has tumor in contact with, invading or encasing major blood vessels

13. The subject has any evidence of an 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 (BP must be controlled at screening)

- Any congenital history of long QT syndrome.

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

- unstable angina pectoris

- clinically-significant cardiac arrhythmias

- stroke (including TIA, or other ischemic event) myocardial infarction

- 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

- intra-abdominal tumor/metastases invading GI mucosa

- active peptic ulcer disease,

- inflammatory bowel disease (including ulcerative colitis and Crohn's
disease), diverticulitis, cholecystitis, symptomatic cholangitis or
appendicitis

- malabsorption syndrome

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

- history of abdominal fistula

- gastrointestinal perforation

- bowel obstruction or gastric outlet obstruction

- 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 that 6
months ago. GI surgery (particularly when associated with delayed or
incomplete healing) within 28 days. Note: Complete healing following
abdominal surgery must be confirmed prior to initiating treatment with
cabozantinib even if surgery occurred more that 28 days ago.

- Other disorders associated with a high risk of fistula formation including PEG
tube placement within 3 months before the first dose of study therapy or
concurrent evidence of intraluminal tumor involving the trachea and esophagus.

- Other clinically significant disorders such as:

- 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 major surgery as follows:

- major surgery within 3 months of the first dose of cabozantinib if
there were no wound healing complications or within 6 months of the
first dose of cabozantinib if there were wound healing complications

- minor surgery within 1 month of the first dose of cabozantinib if
there were no would healing complications or within 3 months of the
first dose of cabozantinib if there were wound complications

- in addition, complete wound healing from prior surgery must be
confirmed at least 28 days before the first dose of cabozantinib
irrespective of the time from surgery

15. The subject is unable to swallow tablets

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

17. The subject is pregnant or breastfeeding.

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

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

20. The subject has had evidence within 2 years of the start of study treatment of
another malignancy which required systemic treatment