Cabozantinib-S-Malate Compared With Temozolomide or Dacarbazine in Treating Patients With Metastatic Melanoma of the Eye That Cannot Be Removed by Surgery

PRIMARY OBJECTIVES:

I. Compare the progression-free survival rate at 4 months (PFS4) of patients with ocular
melanoma treated with cabozantinib-s-malate (cabozantinib) or temozolomide (or dacarbazine).

SECONDARY OBJECTIVES:

I. Estimate the distribution of progression-free survival (PFS) times. II. Estimate the
distribution of overall survival (OS) times. III. Estimate the confirmed response rate as
determined by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria.

IV. Assess the safety of these agents by examining the toxicity profile. V. Correlate the
response of MET molecular status.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive cabozantinib-s-malate orally (PO) once daily (QD) on days 1-28.
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive temozolomide PO daily on days 1-5. Courses repeat every 28 days in
the absence of disease progression or unacceptable toxicity. If temozolomide is not
available, patients receive dacarbazine intravenously (IV) over 15-60 minutes on day 1.
Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 12 weeks for 2 years.

Inclusion Criteria:

- Histologically or cytologically confirmed uveal melanoma that is metastatic or
unresectable; if histologic or cytologic confirmation of the primary is not available,
confirmation of the primary diagnosis of uveal melanoma by the treating investigator
can be clinically obtained, as per standard practice for uveal melanoma; pathologic
confirmation of diagnosis will be performed at the participating site

- Measurable disease defined as at least one lesion that can be accurately measured in
at least one dimension (longest diameter to be recorded for non-nodal lesions and
short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm
with spiral computed tomography (CT) scan or magnetic resonance imaging (MRI)

- Prior systemic therapies allowed, except for those treatments directed toward, or with
activity against, c-Met or vascular endothelial growth factor/receptor (VEGF/R), and
the chemotherapy agents temozolomide and dacarbazine; prior treatment must have been
no earlier than 3 weeks prior to starting treatment with cabozantinib with exceptions
noted below and the following: at least 4 weeks since prior hepatic infusion or at
least 2 weeks since radiation therapy

- No cytotoxic chemotherapy including investigational cytotoxic chemotherapy or biologic
agents (e.g., cytokines or antibodies) within the last 3 weeks, or
nitrosoureas/mitomycin C within 6 weeks before the first dose of study treatment; at
least 6 weeks must have elapsed if the last regimen included an anti-cytotoxic
T-lymphocyte antigen 4 (CTLA4) antibody; patients must have experienced disease
progression on their prior therapy in the opinion of the treating investigator

- No prior radiation therapy within the last 4 weeks, except as below

- To the thoracic cavity, abdomen, or pelvis within 12 weeks before the first dose
of study treatment, or has ongoing complications, or is without complete recovery
to < grade 1 toxicity

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

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

- Prior radiation treatment may have included no more than 3000 centigray (cGy) to
fields including substantial bone marrow

- No prior radionuclide treatment within 6 weeks of the first dose of study treatment

- No prior treatment with a small molecule kinase inhibitor or a hormonal therapy within
14 days or 5 half-lives (whichever is longer)

- No concomitant anti-cancer therapy unless specified above

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

- 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 electrocardiograms (EKGs) separated by at least 3 minutes should be
performed; if the average of these three consecutive results for QTcF is =< 500 ms,
the patient meets eligibility in this regard

- Common Terminology Criteria for Adverse Events (CTCAE) recovered to baseline or CTCAE
=< grade 1 from toxicity due to all prior therapies except alopecia and other
non-clinically significant adverse events (AEs)

- No active brain metastases or epidural disease; patients with brain metastases
previously treated with whole brain radiation or radiosurgery or patients 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 12 weeks before starting study treatment; baseline brain imaging
with contrast-enhanced CT or MRI scans for patients with known brain metastases is
required to confirm eligibility

- No clinically significant gastrointestinal bleeding within 24 weeks before the first
dose of study treatment

- No hemoptysis of >= 0.5 teaspoon (2.5 mL) of red blood within 12 weeks before the
first dose of study treatment

- No signs indicative of pulmonary hemorrhage within 12 weeks before the first dose of
study treatment

- No prior radiographic evidence of cavitating pulmonary lesion(s)

- No tumor in contact with, invading or encasing any major blood vessels

- No evidence of tumor invading the gastrointestinal (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 treatment

- The patient may not have 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 blood pressure
(BP) > 140 mmHg systolic, or > 90 mmHg 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 24 weeks before the first dose of study
treatment:

- Unstable angina pectoris

- Clinically-significant cardiac arrhythmias

- Stroke (including transient ischemic attack [TIA], or other ischemic
event)

- Myocardial infarction

- Thromboembolic event requiring therapeutic anticoagulation (Note:
patients 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 24 weeks before the first dose of study
treatment:

- Abdominal fistula

- Gastrointestinal perforation

- 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 24 weeks
before the first dose of study treatment

- Bowel obstruction or gastric outlet obstruction

- Other clinically significant disorders such as:

- 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 in past 8 weeks of the first dose of cabozantinib if
there were no wound healing complications or within 24 weeks of the
first dose of cabozantinib if there were wound complications

- Minor surgery within 4 weeks of the first dose of cabozantinib if there
were no wound healing complications or within 12 weeks 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

- Active infection requiring systemic treatment within 28 days before the
first dose of study treatment

- No concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin
or warfarin-related agents, heparin, thrombin or factor Xa inhibitors, or antiplatelet
agents (e.g., clopidogrel); low dose aspirin (=< 81 mg/day), low-dose warfarin (=< 1
mg/day), and prophylactic low molecular weight heparin (LMWH) are permitted; please
note that drugs that strongly induce or inhibit cytochrome P450 family 3, subfamily A,
polypeptide 4 (CYP3A4) or are associated with a risk of Torsades are not allowed;
chronic concomitant treatment of CYP3A4 inducers is not allowed (e.g., dexamethasone,
phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St.
John's wort); as part of the enrollment/informed consent procedures, the patient will
be counseled on the risk of interactions with other agents, and what to do if new
medications need to be prescribed or if the patient is considering a new
over-the-counter medicine or herbal product; the following drugs are strong inhibitors
of CYP3A4 and are not allowed during the treatment with cabozantinib:

- Boceprevir

- Indinavir

- Nelfinavir

- Lopinavir/ritonavir

- Saquinavir

- Telaprevir

- Ritonavir

- Clarithromycin

- Conivaptan

- Itraconazole

- Ketoconazole

- Mibefradil

- Nefazodone

- Posaconazole

- Voriconazole

- Telithromycin

- Drugs with possible or conditional risk of torsades should be used with caution
knowing that cabozantinib could prolong the QT interval

- Patients who are pregnant or nursing are not eligible; women of child bearing
potential must have a negative serum or urine pregnancy test within 16 days prior to
registration; women of child-bearing potential include:

- Any female who has experienced menarche and who has not undergone surgical
sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy)
or is not postmenopausal (defined as amenorrhea >= 12 consecutive months)

- Women on hormone replacement therapy (HRT) with documented serum follicle
stimulating hormone (FSH) level > 35m IU/mL

- Women who are using oral, implanted or injectable contraceptive hormones or
mechanical products such as an intrauterine device or barrier methods (diaphragm,
condoms, spermicides) to prevent pregnancy or practicing abstinence or where
partner is sterile (e.g., vasectomy)

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to cabozantinib, temozolomide and dacarbazine

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Total bilirubin =< 1.5 × upper limit of normal (ULN)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 5.0 × institutional upper limit of normal (for patients with metastases); AST
(SGOT)/ALT (SGPT) =< 2.5 × institutional upper limit of normal (for patients without
metastases)

- Serum creatinine =< 1.5 × ULN, OR calculated creatinine clearance >= 30 mL/minute
(modified Cockcroft and Gault formula)

- Hemoglobin >= 9 g/dL

- Serum albumin >= 2.8 g/dL

- Urine protein/creatinine ratio (UPCR) =< 1; if urine/protein creatinine (UPC) >= 1,
then a 24-hour urine protein must be assessed; eligible patients must have a 24-hour
urine protein value < 1 g/L

- Thyroid-stimulating hormone (TSH) within normal limits (WNL); supplementation is
acceptable to achieve a TSH WNL; in patients with abnormal TSH however free T4 and
free thyroxine index (FTI) are normal and patient is clinically euthyroid, patient is
eligible

- Prothrombin time (PT)/international normalized ratio (INR) must be =< 1.2 x the
laboratory ULN

- No clinical or radiographic evidence of pancreatitis