Therapeutic Autologous Lymphocytes, Cyclophosphamide, and Aldesleukin in Treating Patients With Metastatic Melanoma

Study Overview
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Brief Summary
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RATIONALE: Aldesleukin may stimulate lymphocytes to kill melanoma cells. Treating lymphocytes with interleukin-21 in the laboratory may help the lymphocytes kill more tumor cells when they are put back in the body. Giving therapeutic autologous lymphocytes together with cyclophosphamide and aldesleukin may kill more tumor cells. PURPOSE: This phase I trial is studying the side effects and best dose of giving therapeutic autologous lymphocytes together with cyclophosphamide and aldesleukin in treating patients with metastatic melanoma

Detailed Description
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PRIMARY OBJECTIVES: I. Assess the safety and toxicity of adoptively transferred interleukin (IL)-21 modulated cytotoxic T-lymphocyte (CTL) targeting a melanoma associated antigen in patients following cyclophosphamide conditioning. II. Evaluate the functional and numeric in vivo persistence of adoptively transferred IL-21 modulated CTL and factors contributing to immunopotentiation in patients receiving IL-21 modulated CTL following cyclophosphamide conditioning. SECONDARY OBJECTIVES: I. Evaluate the antitumor effect of adoptively transferred IL-21 modulated CD8+ antigen-specific CTL following cyclophosphamide conditioning and post-infusion IL-2. OUTLINE: Patients receive cyclophosphamide intravenously (IV) on days -3 and -2 followed by an infusion of IL-21 modulated, melanoma antigen recognized by T cell (MART)-1 specific CD8+ cytotoxic T lymphocytes over 30-60 minutes on day 0. Beginning within 24 hours of T-cell infusion, patients receive low-dose aldesleukin subcutaneously (SC) twice daily (BID) for 14 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed for 8-10 weeks.

Official Title
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Phase I Study To Evaluate Cellular Adoptive Immunotherapy Using Autologous IL-21 Modulated CD8+ Antigen-Specific T Cells For Patients With Metastatic Melanoma

Conditions
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Stage IV Melanoma

Intervention / Treatment
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* Biological: therapeutic autologous lymphocytes
* Biological: aldesleukin
* Drug: cyclophosphamide
* Procedure: biopsy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: FOR LEUKAPHERESIS: Pulse > 45 or < 120 Weight >= 45 kg Temperature =< 38 Celsius (C) (=< 100.4 Fahrenheit [F]) White blood cells (WBC) >= 3000 Hematocrit (HCT) >= 30% Platelets >= 100,000 FOR T CELL INFUSION: Histopathological documentation of melanoma concurrent with the diagnosis of metastatic disease Tumor expression of MART-1 (2+ staining or > 25%) by immunohistochemistry (IHC) Able to tolerate high-dose cyclophosphamide Expression of human leukocyte antigen (HLA)-A2 Zubrod performance status of 0-1 Bi-dimensionally measurable disease by palpation on clinical exam, or radiographic imaging (X-ray, computed tomography [CT] scan) Normal cardiac stress test within 182 days prior to enrollment is required of all patients over 50 years old or those with an abnormal electrocardiogram (ECG), any history of cardiac disease, a family history of cardiac disease or hypertension Exclusion Criteria: Pregnant women, nursing mothers, men or women of reproductive ability who are unwilling to use effective contraception or abstinence; women of childbearing potential must have a negative pregnancy test within two weeks prior to entry Serum creatinine > 1.6 mg/dL or creatinine clearance (CrCl) < 75 ml/min (calculated: Cockcroft and Gault equation: CrCl = (140 - age) x ideal body weight (IBW)/(serum creatinine [Scr] x 72) (x 0.85 for females) Serum glutamic oxaloacetic transaminase (SGOT) > 150 IU or > 3 x upper limit of normal Direct bilirubin > 1.0 mg/dL Prothrombin time > 1.5 x control (in the absence of systemic anticoagulation) Clinically significant pulmonary dysfunction, as determined by medical history and physical exam; patients so identified will undergo pulmonary functions testing at the discretion of their primary physician Significant cardiovascular abnormalities as defined by any one of the following: Congestive heart failure, Clinically significant hypotension, Symptoms of coronary artery disease, Presence of cardiac arrhythmias on electrocardiogram (EKG) requiring drug therapy Symptomatic central nervous system metastases greater than 1 cm at time of therapy; patients with 1-2 asymptomatic, less than 1cm brain/central nervous system (CNS) metastases without significant edema may be considered for treatment; if sub-centimeter CNS lesions are noted at study entry, then a repeat imaging will be performed if more than 3 weeks have elapsed from the last scan; patients will not be treated if CNS lesions are > 1 cm or if patient is symptomatic from brain metastasis Patients with active infections or oral temperature > 38.2 C within 72 hours of study entry or systemic infection requiring chronic maintenance or suppressive therapy Chemotherapeutic agents (standard or experimental), radiation therapy, or other immunosuppressive therapies less than 3 weeks prior to T cell therapy; (patients with bulky disease may undergo cytoreductive chemotherapy but treatment will be discontinued at least 3 weeks prior to T cell therapy) Clinically significant autoimmune disorders or conditions of immunosuppression; patients with acquired immunodeficiency syndrome (AIDS) or human immunodeficiency virus (HIV)-1 associated complex or known to HIV antibody seropositive or known to be recently polymerase chain reaction positive (PCR+) for hepatitis are not eligible for this study; virology testing will be done within 6 months of T cell infusion; the severely depressed immune system found in these infected patients and the possibility of premature death would compromise study objectives Patients who, in the opinion of their physician, are not clinically suited for high-dose cytoxan

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (immunostimulant, autologous lymphocytes, and chemo)<br>Patients receive cyclophosphamide IV on days -3 and -2 followed by an infusion of IL-21 modulated, MART-1 specific CD8+ cytotoxic T lymphocytes over 30-60 minutes on day 0. Beginning within 24 hours of T cell infusion, patients receive low-dose aldesleukin SC BID for 14 days in the absence of disease progression or unacceptable toxicity. | Biological: therapeutic autologous lymphocytes<br>* Given IV<br>* Other names: autologous T cells;Biological: aldesleukin<br>* Given SC<br>* Other names: recombinant interleukin-2;Drug: cyclophosphamide<br>* Given IV<br>* Other names: Endoxana;Procedure: biopsy<br>* Optional correlative studies<br>* Other names: biopsies;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and toxicity as assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 3.0 |  | 10 weeks post infusion | 
| Functional and numeric in vivo persistence of adoptively transferred IL-21 modulated CTL and factors contributing to immunopotentiation in patients receiving IL-21 modulated CTL following cyclophosphamide conditioning | Descriptive statistics (average, median standard deviation and student's t test) will be used to determine if an increase in the duration of in vivo persistence is observed using IL-21 modulated T cells when retrospectively compared with T cells generated under standard culture conditions (no IL-21 exposure in vitro). | 10 weeks post infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| In vivo persistence and anti-tumor effect of the infused IL-21 modulated CTL |  | 10 weeks post infusion |