Intraocular Melanoma, Malignant Conjunctival Neoplasm
Conditions
Keywords
recurrent intraocular melanoma, metastatic intraocular melanoma, ciliary body and choroid melanoma, medium/large size, extraocular extension melanoma, iris melanoma, conjunctival melanoma
Brief summary
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
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.
Interventions
DRUGcyclophosphamide
25-50 mg by mouth once daily on days 1-28.
DRUGlenalidomide
10 mg by mouth once daily on days 1-28.
DRUGsunitinib malate
12.5 - 25 mg by mouth once daily on days 1-28.
Sponsors
National Cancer Institute (NCI)
National Institutes of Health Clinical Center (CC)
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate (Complete and Partial Response) | 2 years | 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. |
| Toxicity | 16 months | Here is the number of participants with adverse events. For a detailed list of adverse events see the adverse event module. |
| Overall Survival | up to 16 months | Time from date of on study to the date of death from any cause or last follow up |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | up to 16 months | Proportion of patients who progress or die after the start of treatment |
| Changes in Gene Expression, Methylation and Protein Modification | Baseline and end of treatment course 1 and 2, approximately 42 days | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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). | 3 |
| 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). | 9 |
| Total | 12 |
Baseline characteristics
| Characteristic | Cohort 1-lenalidomide & Cyclophosphamide | Cohort 2-sunitinib & Cyclophosphamide | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 1 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 8 Participants | 10 Participants |
| Age, Continuous | 64.4 years STANDARD_DEVIATION 15.52 | 54.89 years STANDARD_DEVIATION 6.44 | 57.27 years STANDARD_DEVIATION 9.61 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 9 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 8 Participants | 11 Participants |
| Region of Enrollment United States | 3 Participants | 9 Participants | 12 Participants |
| Sex: Female, Male Female | 3 Participants | 6 Participants | 9 Participants |
| Sex: Female, Male Male | 0 Participants | 3 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 8 / 9 |
| serious Total, serious adverse events | 0 / 3 | 2 / 9 |
Outcome results
Primary
Overall Survival
Time from date of on study to the date of death from any cause or last follow up
Time frame: up to 16 months
Population: Overall survival is not the same as response, to obtain overall survival the investigator would have to follow patients until death, which the original investigator left the institution well before this outcome could be accomplished.
Primary
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.
Time frame: 2 years
Population: Cohort 2 = 9 patients. Two patients received Dose B-QD in cycle 1 as outlined in participant flow. Seven patients received Dose D-QD in cycle 1 as outlined in participant flow.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1-lenalidomide & Cyclophosphamide | Response Rate (Complete and Partial Response) | Complete Response | 0 Participants |
| Cohort 1-lenalidomide & Cyclophosphamide | Response Rate (Complete and Partial Response) | Partial Response | 0 Participants |
| Cohort 2-sunitinib & Cyclophosphamide | Response Rate (Complete and Partial Response) | Complete Response | 0 Participants |
| Cohort 2-sunitinib & Cyclophosphamide | Response Rate (Complete and Partial Response) | Partial Response | 0 Participants |
Primary
Toxicity
Here is the number of participants with adverse events. For a detailed list of adverse events see the adverse event module.
Time frame: 16 months
Population: Cohort 2 = 9 patients. Two patients received Dose B-QD in cycle 1 as outlined in participant flow. Seven patients received Dose D-QD in cycle 1 as outlined in participant flow.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1-lenalidomide & Cyclophosphamide | Toxicity | 3 Participants |
| Cohort 2-sunitinib & Cyclophosphamide | Toxicity | 8 Participants |
Secondary
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.
Time frame: Baseline and end of treatment course 1 and 2, approximately 42 days
Population: Overall survival is not the same as response, to obtain overall survival the investigator would have to follow patients until death, which the original investigator left the institution well before this outcome could be accomplished
Secondary
Progression Free Survival
Proportion of patients who progress or die after the start of treatment
Time frame: up to 16 months
Population: Overall survival is not the same as response, to obtain overall survival the investigator would have to follow patients until death, which the original investigator left the institution well before this outcome could be accomplished