Lenalidomide, Sunitinib, and Cyclophosphamide in Treating Patients With Stage IV Eye Melanoma

Study Overview
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Brief Summary
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RATIONALE: Lenalidomide may stop the growth of tumor cells by blocking blood flow to the tumor. Sunitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving lenalidomide together with sunitinib and low doses of cyclophosphamide once a day may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving lenalidomide together with sunitinib and cyclophosphamide works in treating patients with stage IV eye melanoma.

Detailed Description
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OBJECTIVES: Primary Determine the response rate in patients with stage IV ocular melanoma treated with lenalidomide, sunitinib malate, and low-dose metronomic cyclophosphamide. Secondary Determine the toxicity of this regimen in these patients. Determine the progression-free survival of patients treated with this regimen. Obtain blood, urine, and tissue samples from these patients, when easily accessible, to determine the effects of this regimen on pathways thought to have been modulated by this regimen in pre-clinical studies. OUTLINE: This is nonrandomized, uncontrolled, open-label study. Patients receive oral lenalidomide, oral sunitinib malate*, and oral low-dose cyclophosphamide once daily on days 1-28. Treatment repeats every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. NOTE: *Some patients will not receive sunitinib malate during course 1. After completion of study treatment, patients are followed every 3 months for 2 years, every 4 months for 3 years and then annually thereafter.

Official Title
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A Phase II Study of Combination Oral CC-5013 Lenalidomide (Revlimid™), Oral Sunitinib (Sutent™) and Low Dose Oral Metronomic Cyclophosphamide for the Treatment of Stage IV Ocular Melanoma

Conditions
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Intraocular Melanoma, Malignant Conjunctival Neoplasm

Intervention / Treatment
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* Drug: cyclophosphamide
* Drug: lenalidomide
* Drug: sunitinib malate


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed ocular melanoma Stage IV disease Measurable disease No active brain metastases Patients with brain metastases must have had a complete excision or radiotherapy and remain asymptomatic with stable disease by magnetic resonance imaging (MRI) or computed tomography (CT) scan for ≥ 6 months PATIENT CHARACTERISTICS: Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Life expectancy > 3 months Granulocyte count > 1,500/mm^3 Platelet count > 100,000/mm^3 Creatinine ≤ 1.5 mg/dL OR creatinine clearance > 60 mL/min Bilirubin ≤ 2.0 mg/dL Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 10 times upper limit of normal (ULN) Prothrombin time (PT)/partial thromboplastin time (PTT)/International Normalized Ratio (INR) normal Not pregnant or nursing Negative pregnancy test Fertile patients must use one highly effective method of contraception (with an additional method) or barrier methods of contraception for ≥ 4 weeks before, during, and for ≥ 4 weeks after completion of study therapy Ejection fraction normal by echocardiogram No acute, critical illness, including serious untreated infection No history of any of the following: Unstable or newly diagnosed angina pectoris Myocardial infarction within the past 6 months New York Heart Association class II-IV heart disease Congestive heart failure Chronic obstructive lung disease requiring oxygen therapy Chronic uncontrollable hypertension Uncontrolled seizure activity No known human immunodeficiency virus (HIV) positivity No known hypersensitivity reaction to thalidomide, lenalidomide, sunitinib malate, or cyclophosphamide PRIOR CONCURRENT THERAPY: See Disease Characteristics Recovered from all prior therapy At least 4 weeks since prior surgery, chemotherapy (6 weeks for mitomycin C, nitrosoureas, or carboplatin), hormonal therapy, radiotherapy, or biological therapy No concurrent grapefruit or grapefruit juice No other concurrent antitumor therapy

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1-lenalidomide & cyclophosphamide<br>Participants first started on 2 Interventions (Dose A-QD) in Cycle 1, with 10 mg Lenalidomide (Len) once daily and 50 mg Cyclophosphamide (Cyc) once daily; 25 mg Sunitinib (Sun) was added once daily as a 3rd Intervention (Dose B-QD) from Cycle 2 onwards. Doses were adjusted in subsequent cycles depending on toxicity, including incremental step downs to 5/25/12.5 mg Len/Cyc/Sun once daily (Dose C-QD) or once every other day (Dose C-QOD). | Drug: cyclophosphamide<br>* 25-50 mg by mouth once daily on days 1-28.<br>* Other names: cytoxan;Drug: lenalidomide<br>* 10 mg by mouth once daily on days 1-28.<br>* Other names: revlimid;|
| Experimental: Cohort 2-sunitinib & cyclophosphamide<br>2 participants started Cycle 1 with Dose B as described above and had adjusted-dosing as described for Cohort 1. The remaining 7 participants began Cycle 1 with 10 mg Len, 25 mg Cyc and 12.5 mg Sun once daily (Dose D-QD). Doses were adjusted in subsequent cycles depending on toxicity, including step up to 10/50/12.5 mg Len/Cyc/Sun once daily (Dose E-QD) and step down to Dose D once every other day (Dose D-QOD). | Drug: cyclophosphamide<br>* 25-50 mg by mouth once daily on days 1-28.<br>* Other names: cytoxan;Drug: sunitinib malate<br>* 12.5 - 25 mg by mouth once daily on days 1-28.<br>* Other names: sutent;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate (Complete and Partial Response) | Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response is the disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. | 2 years | 
| Toxicity | Here is the number of participants with adverse events. For a detailed list of adverse events see the adverse event module. | 16 months | 
| Overall Survival | Time from date of on study to the date of death from any cause or last follow up | up to 16 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | Proportion of patients who progress or die after the start of treatment | up to 16 months | 
| Changes in Gene Expression, Methylation and Protein Modification | Ribonucleic acid (RNA), deoxyribonucleic acid (DNA) and protein obtained from blood, urine and/or tissue was to be evaluated for changes in gene expression, methylation and/or protein modification. | Baseline and end of treatment course 1 and 2, approximately 42 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent intraocular melanoma, metastatic intraocular melanoma, ciliary body and choroid melanoma, medium/large size, extraocular extension melanoma, iris melanoma, conjunctival melanoma