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

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

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.

Study Overview

• Status: Terminated
• Conditions: Intraocular Melanoma; Malignant Conjunctival Neoplasm
• Intervention / Treatment: Drug: cyclophosphamide; Drug: lenalidomide; Drug: sunitinib malate

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892-1182
      • Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Cohort 1-lenalidomide & cyclophosphamide; 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; 25-50 mg by mouth once daily on days 1-28.; Other Names: cytoxan; Drug: lenalidomide; 10 mg by mouth once daily on days 1-28.; Other Names: revlimid
EXPERIMENTAL: Cohort 2-sunitinib & cyclophosphamide; 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; 25-50 mg by mouth once daily on days 1-28.; Other Names: cytoxan; Drug: sunitinib malate; 12.5 - 25 mg by mouth once daily on days 1-28.; Other Names: sutent

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National Institutes of Health Clinical Center (CC)
• Collaborators: National Cancer Institute (NCI)

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 1, 2007
• Primary Completion (ACTUAL): April 1, 2009
• Study Completion (ACTUAL): April 1, 2009

Study Registration Dates

• First Submitted: June 4, 2007
• First Submitted That Met QC Criteria: June 4, 2007
• First Posted (ESTIMATE): June 5, 2007

Study Record Updates

• Last Update Posted (ACTUAL): March 27, 2017
• Last Update Submitted That Met QC Criteria: February 6, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Keywords: ciliary body and choroid melanoma, medium/large size; extraocular extension melanoma; iris melanoma; recurrent intraocular melanoma; metastatic intraocular melanoma; conjunctival melanoma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Eye Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Conjunctival Diseases; Neuroendocrine Tumors; Nevi and Melanomas; Eye Neoplasms; Melanoma; Conjunctival Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Protein Kinase Inhibitors; Cyclophosphamide; Sunitinib; Lenalidomide
• Other Study ID Numbers: 070134; NCI-07-C-0134

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No