High-Dose Aldesleukin and Ipilimumab in Treating Patients With Stage III-IV Melanoma That Cannot Be Removed By Surgery

Study Overview
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Brief Summary
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This phase II trial studies how well high-dose aldesleukin and ipilimumab works in treating patients with stage III-IV melanoma that cannot be removed by surgery. Biological therapies, such as aldesleukin, may stimulate or suppress the immune system in different ways and stop tumor cells from growing. Monoclonal antibodies, such as ipilimumab, interfere with the ability of tumor cells to grow and spread. Giving high-dose aldesleukin together with ipilimumab may work better in treating patients with melanoma.

Detailed Description
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PRIMARY OBJECTIVES: I. The best overall response rate within the first 24 weeks of combination interleukin (IL)-2 (aldesleukin) and ipilimumab using the immune-related response criteria. SECONDARY OBJECTIVES: I. Best overall response (BOR). II. Progression-free survival (PFS). III. Disease control rate (DCR). IV. Overall survival. V. To collect data on the safety and feasibility of combined high-dose IL-2 and ipilimumab. VI. To evaluate the cluster of differentiation (CD)4+ and CD8+ T cell response in the tumor microenvironment and peripheral blood of patients treated on this study. OUTLINE: INDUCTION: Patients receive ipilimumab intravenously (IV) over 90 minutes on days 1, 22, 43, and 64 and high-dose aldesleukin IV on days 22-26 and 43-47. MAINTENANCE: Beginning on weeks 24, patients without disease progression or unacceptable toxicity receive ipilimumab IV over 90 minutes once every 12 weeks for up to 24 weeks in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 36 months.

Official Title
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A Phase II Single Arm Study of High-Dose IL-2 and Ipilimumab in Patients With Unresectable Stage III and Stage IV Melanoma

Conditions
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Recurrent Melanoma, Stage IIIA Melanoma, Stage IIIB Melanoma, Stage IIIC Melanoma, Stage IV Melanoma

Intervention / Treatment
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* Biological: aldesleukin
* Biological: ipilimumab
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to give written informed consent Histologic or cytologic diagnosis of cutaneous melanoma that is considered unresectable (stage III) or metastatic (stage IV); ocular and mucosal melanoma is excluded White blood cell (WBC) >= 2000/uL Absolute neutrophil count (ANC) >= 1000/uL Platelets >= 75 x 10^3/uL Hemoglobin >= 9 g/dL (>= 80 g/L; may be transfused) Creatinine =< 2.0 x upper limit of normal (ULN) Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN for patients without liver metastasis, =< 5 times for patients with liver metastases Bilirubin =< 2.0 x ULN, (except patients with Gilbert's syndrome, who must have a total bilirubin less than 3.0 mg/dL) No known active or chronic infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C; testing is not required unless clinically suspected Performance status (Eastern Cooperative Oncology Group [ECOG] 0-1) Patients must have a life expectancy of greater than three months at the start of the trial Patients must have a brain magnetic resonance imaging (MRI) that is free of active metastases; metastases that have been treated with radiation or surgical resection, are stable for at least 4 weeks and do not require steroids are eligible Patients may have received treatment of completely resected early stage melanoma, comprising interferon, radiation treatment, or experimental vaccine therapy, and in the metastatic setting patient can have had treatment such as chemotherapy, immunotherapy (except prior treatment with ipilimumab and IL-2), and other experimental agent which was completed 4 weeks prior to enrollment Normal cardiac stress test for patients over 50 years of age Forced expiratory volume in 1 second (FEV1) > 65% of prediction for those patients with extensive pulmonary metastases or chronic pulmonary disease history Forced vital capacity (FVC) > 65% of prediction for those patients with extensive pulmonary metastases or chronic pulmonary disease history Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 26 weeks after the last dose of investigational product, in such a manner that the risk of pregnancy is minimized; in general, the decision for appropriate methods to prevent pregnancy should be determined by discussions between the investigator and the study subject; WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not post-menopausal; post-menopause is defined as: Amenorrhea >= 12 consecutive months without another cause, or For women with irregular menstrual periods and taking hormone replacement therapy (HRT), a documented serum follicle stimulating hormone (FSH) level >= 35 mIU/mL Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (eg, vasectomy) should be considered to be of childbearing potential WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 72 hours before the start of ipilimumab Men of fathering potential must be using an adequate method of contraception to avoid conception throughout the study (and for up to 26 weeks after the last dose of investigational product) in such a manner that the risk of pregnancy is minimized Exclusion Criteria: Any other malignancy form which the patient has been disease-free for less than 5 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix Patients with primary ocular or mucosal melanoma are excluded Patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn's disease, are excluded from this study, as are patients with a history of symptomatic disease (eg, rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [eg, Wegener's granulomatosis]); motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre syndrome and Myasthenia Gravis) Any underlying medical or psychiatric condition, which in the opinion of the investigator will make the administration of ipilimumab hazardous or obscure the interpretation of adverse events (AEs), such as a condition associated with frequent diarrhea Patients with underlying heart conditions who are deemed ineligible for surgery by cardiology consult; patients with reversible ischemic changes on cardiac stress test Any non-oncology vaccine therapy used for prevention of infectious diseases (for up to 1 month before or after any dose of ipilimumab) A history of prior treatment with IL-2, ipilimumab or prior cytotoxic T-lymphocyte antigen 4 (CTLA4) inhibitor or agonist Concomitant therapy with any of the following: interferon, or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigation therapies; or chronic use of systemic corticosteroids Women of childbearing potential (WOCBP), who: Are unwilling or unable to use an acceptable method of contraception to avoid pregnancy for their entire study period and for at least 8 weeks after cessation of study drug, or Have a positive pregnancy test at baseline, or Are pregnant or breastfeeding Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (eg, infectious) illness

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (aldesleukin, ipilimumab)<br>INDUCTION: Patients receive ipilimumab IV over 90 minutes on days 1, 22, 43, and 64 and high-dose aldesleukin IV on days 22-26 and 43-47. MAINTENANCE: Beginning on weeks 24, patients without disease progression or unacceptable toxicity receive ipilimumab IV over 90 minutes once every 12 weeks for up to 24 weeks in the absence of disease progression or unacceptable toxicity. | Biological: aldesleukin<br>* Given IV<br>* Other names: recombinant interleukin-2;Biological: ipilimumab<br>* Given IV<br>* Other names: monoclonal antibody CTLA-4;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate as Determined by mWHO Criteria | Defined as the ratio of the number of participants whose number of participants whose best response is a complete response or partial response. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR., or similar definition that is accurate and appropriate. | Up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events, Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 | The number of participants with adverse in each classification of severity and relationship to treatment will be reported. | Up to 60 weeks | 
| Overall Survival | number of until death from any cause after the start of treatment | Time from the date of registration to the date of death from any cause, assessed up to 3 years | 
| Count of Participants With Increased Effector CD8+ T Cells | Count of participants from the date of diagnosis or the start of treatment. | Time from the date of registration until the date of documented disease progression or death, assessed up to up to 104 weeks | 
| Best Overall Response, Defined as the Best Response Across All Time Points | Best overall response was defined as participants who achieved a complete or partial overall response as assessed by the Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions | After the first 24 weeks | 
| Count of Participants With Increased Effector CD8+ T Cells - Frequency of Effector CD8+ T Cells | Treatment effect for each patient will be measured as paired differences between pre and post measurements of these parameters at various times. Transformation of the data will be performed if appropriate, e.g. log transformation, and hence treatment effect will be expressed on a log scale. Data relating to immune response will be presented as descriptive summary statistics (such as mean, standard error and 90% confidence intervals [CI]). The purity of the CD8+ T cells can then be measured via flow cytometry next the cells are counted and categorized. | Up to 104 weeks | 
| Frequency of CD4+FoxP3+ Regulatory T Cells | Treatment effect for each patient will be measured as paired differences between pre and post measurements of these parameters at various times. Transformation of the data will be performed if appropriate, e.g. log transformation, and hence treatment effect will be expressed on a log scale. Data relating to immune response will be presented as descriptive summary statistics (such as mean, standard error and 90% CI).Using flow cytometry. | Up to 104 weeks |