A Two Arm Trial of Axitinib and Carboplatin/Paclitaxel in Melanoma

This is a two arm prospective Phase II pilot trial designed to determine the optimal duration
of break between axitinib and chemotherapy with carboplatin/paclitaxel in melanoma. In this
study, 6 patients will be enrolled to Arm A, the FLT-PET (3'deoxy-3'-18F-Fluorothymidine
positron emission tomography scans)cohort. 30 patients will be enrolled to Arm B, the
treatment-only cohort. 36 total patients will be enrolled. The treatment schedule and dose
will be the same in either cohort, with the exception of the FLT PET scans. We are enrolling
only 6 patients to Arm A, the FLT-PET cohort, because of study financial considerations.

Patients will be enrolled in Arm A first, the FLT-PET cohort, to accommodate the radiological
manufacture of the FLT-PET scan dye. It is expensive to manufacture and it is not usable
forever. However if a patient is unable to participate in Arm A because of logistical issues,
i.e. not being able to travel to UCSF for FLT-PET scans we will offer them participation in
Arm B so that they can receive treatment that is not available off study.

Each treatment cycle will last for 21days. During Cycle 1, patients will be treated with:

Days 1-14: axitinib 5 mg PO twice daily Days 15-21: break from treatment

In all cycles after Cycle 1, patients will be treated with:

Day 1: paclitaxel 175 mg/m2 over 3 hours followed by carboplatin AUC 5 (AUC 5 is a term used
to describe the dosing of carboplatin based on a patient's height, weight and kidney
function) over 45 minutes Days 1-14: axitinib 5 mg PO twice daily Days 15-21: break from
treatment Arm A: FLT PET cohort subjects will have FLT PET scans up to 2 weeks prior to day 1
and on days 14, 17, and 21 of cycle 1.

Arm B: Treatment-only patients will receive administration of axitinib and
carboplatin/paclitaxel on the same schedule and dose as Arm A but will not have FLT PET
scans. Patients in Arm B will have standard tumor assessment with FDG PET-CT scans
(F18-deoxyglucose positron emission tomography scans), CT Scans, and MRI's.

Inclusion Criteria:

1. Histologically or cytologically proven melanoma with Stage IV or unresectable stage
III disease.

2. Male or female, age ≥ 18 years.

3. Resolution of all acute toxic effects of prior radiotherapy, chemotherapy or surgical
procedures to NCI CTCAE Version 4.0 grade ≤1.

4. May have ≤ 2 prior chemotherapy treatments and any prior immunotherapy treatments.
These can include dacarbazine and/or temozolomide but not carboplatin or paclitaxel.

5. At least 2 weeks since the end of prior systemic treatment (4 weeks for
bevacizumab-containing regimens), radiotherapy, or surgical procedure with resolution
of all treatment-related toxicity to NCI CTCAE Version 4.0 grade ≤ 1 or back to
baseline except for alopecia or hypothyroidism.

6. No evidence of preexisting uncontrolled hypertension. The baseline systolic blood
pressure readings must be ≤140 mm Hg, and the baseline diastolic blood pressure
readings must be ≤90 mm Hg. Patients whose hypertension is controlled by
antihypertensive therapies are eligible.

7. Adequate organ function as defined by the following criteria:

1. Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase
(SGOT)) and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase
(SGPT)) ≤ 2.5 x local laboratory upper limit of normal (ULN), or AST and ALT ≤ 5
x ULN if liver function abnormalities are due to underlying malignancy

2. Total serum bilirubin ≤ 1.5 x ULN (Grade 0-1)

3. Absolute neutrophil count (ANC) ≥ 1500 /ml

4. Platelets ≥ 100,000/mL

5. Hemoglobin ≥ 9.0 g/dL (may be transfused or erythropoietin treated)

6. Serum calcium ≥12.0 mg/dL

7. Serum creatinine ≤ 1.5 x ULN

8. Patients with CNS (central nervous system) metastasis must have had either:

1. Resected CNS metastasis without evidence of recurrence for > 12 weeks, OR

2. Brain metastasis treated by stereotactic radiosurgery without evidence of
recurrence or progression for 12 weeks, OR

3. Multiple brain lesions treated with whole brain radiation therapy with stable
disease off corticosteroids for at least 12 weeks prior to the start of therapy,
AND

4. Without any evidence of leptomeningeal disease, AND

5. Patients must be neurologically intact.

9. May have previous adjuvant therapy with interferon, vaccines, or therapy with IL-2 or
GM-CSF.

10. Measurable disease by RECIST criteria.

11. ECOG performance status 0 or 1.

Exclusion Criteria:

1. Major surgery within 4 weeks of starting the study treatment.

2. Radiation therapy within 2 weeks of starting the study treatment. Prior palliative
radiotherapy to metastatic lesion(s) is permitted, provided there is at least one
measurable lesion that has not been irradiated.

3. NCI CTCAE version 4.0 grade 2 or greater hemorrhage within 4 weeks of starting study
treatment.

4. History of hemoptysis or bleeding from GI tract.

5. History of abdominal fistulae or perforation within 6 months prior to starting study
treatment.

6. History of or known carcinomatous meningitis, or evidence of symptomatic
leptomeningeal disease on screening CT or MRI scan.

7. Any of the following within the 6 months prior to study drug administration:
myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass
graft, symptomatic congestive heart failure, cerebrovascular accident or transient
ischemic attack, or pulmonary embolism.

8. Hypertension that cannot be controlled by medications.

9. Current use or anticipated need for treatment with drugs that are known potent CYP3A
inhibitors (grapefruit juice, verapamil, ketoconazole, miconazole, itraconazole,
erythromycin, telithromycin, clarithromycin, indinavir, saquinavir, ritonavir,
nelfinavir, lopinavir, atazanavir, amprenavir, fosamprenavir and delavirdine).

10. Current use or anticipated need for treatment with drugs that are known potent CYP3A
or CYP1A2 inducers (ie, carbamazepine, dexamethasone, felbamate, omeprazole,
phenobarbital, phenytoin, amobarbital, nevirapine, primidone, rifabutin, rifampin, and
St. John's wort).

11. Requirement of anticoagulant therapy with oral vitamin K antagonists. Low-dose
anticoagulants for maintenance of patency of central venous access devise or
prevention of deep venous thrombosis is allowed. Therapeutic use of low molecular
weight heparin is allowed.

12. Active seizure disorder or evidence of brain metastases, spinal cord compression, or
carcinomatous meningitis.

13. CNS disease on stable dexamethasone

14. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome
(AIDS)-related illness or other active infection

15. Pregnancy or breastfeeding. Female subjects must be surgically sterile or be
postmenopausal, or must agree to use effective contraception during the period of
therapy. All female subjects with reproductive potential must have a negative
pregnancy test (serum or urine) prior to enrollment. Male subjects must be surgically
sterile or must agree to use effective contraception during the period of therapy. The
definition of effective contraception will be based on the judgment of the principal
investigator or a designated associate.

16. Other severe acute or chronic medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with study participation or study
drug administration, or may interfere with the interpretation of study results, and in
the judgment of the investigator would make the subject inappropriate for entry into
this study.