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

Study Overview
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Brief Summary
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This randomized phase II trial studies how well cabozantinib-s-malate works compared with temozolomide or dacarbazine in treating patients with melanoma of the eye (ocular melanoma) that has spread to other parts of the body and cannot be removed by surgery. Cabozantinib-s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide and dacarbazine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether cabozantinib-s-malate works better than temozolomide or dacarbazine in treating patients with melanoma of the eye.

Detailed Description
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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.

Official Title
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Randomized Phase II Study Comparing the MET Inhibitor Cabozantinib to Temozolomide/Dacarbazine in Ocular Melanoma

Conditions
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Recurrent Uveal Melanoma, Stage III Uveal Melanoma AJCC v7, Stage IIIA Uveal Melanoma AJCC v7, Stage IIIB Uveal Melanoma AJCC v7, Stage IIIC Uveal Melanoma AJCC v7, Stage IV Uveal Melanoma AJCC v7

Intervention / Treatment
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* Drug: Cabozantinib S-malate
* Drug: Dacarbazine
* Other: Laboratory Biomarker Analysis
* Drug: Temozolomide


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (cabozantinib-s-malate)<br>Patients receive cabozantinib-s-malate PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: Cabozantinib S-malate<br>* Given PO<br>* Other names: XL184;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|
| Experimental: Arm II (temozolomide or dacarbazine)<br>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 IV over 15-60 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: Dacarbazine<br>* Given IV<br>* Other names: WR-139007;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Temozolomide<br>* Given PO<br>* Other names: TMZ;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients Without a Progression Free Survival Event at 4 Months (PFS4) | A patient will be declared a PFS4 success if they are on study and progression free for at least 4 months. Progression is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study, with an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. The success for each arm will be calculated independently as the number of successes divided by the total number of evaluable patients. A one-sided chi-squared test for a difference in PFS4 proportions will be used to test for a difference between arms. | At 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed Response Rate as Determined by the RECIST Criteria (Version 1.1) | The confirmed response rates will be estimated by dividing the number of confirmed responders by the number of evaluable patients. 95% confidence intervals will be calculated. | Up to 2 years | 
| Percentage of Patients Who Experienced Grade 3+ Adverse Events Regardless of Attribution | percentage of patients who experienced grade 3+ adverse events regardless of attribution, graded according to the National Cancer Institute CTCAE version 4.0 | Up to 2 years | 
| Overall Survival (OS) | The distribution of OS time will be estimated using the method of Kaplan Meier. | Number of days from registration until death, assessed up to 2 years | 
| PFS | The distribution of PFS time will be estimated using the method of Kaplan Meier and is defined as the number of days from registration until disease progression (or death). Progression is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study, with an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. | Number of days from registration until disease progression (or death), assessed up to 2 years |