Therapeutic Autologous Lymphocytes, Aldesleukin, and Denileukin Diftitox in Treating Patients With Stage III-IV Melanoma

Study Overview
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Brief Summary
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RATIONALE: White blood cells that have been treated in a laboratory may be able to kill tumor cells in patients with melanoma. Aldesleukin and denileukin diftitox may stimulate the white blood cells to kill melanoma cells. Giving therapeutic autologous lymphocyte therapy together with aldesleukin and denileukin diftitox may kill more tumor cells. PURPOSE: This phase I/II trial is studying the side effects of giving therapeutic autologous lymphocytes together with aldesleukin and denileukin diftitox and to see how well it works in treating patients with stage III-IV melanoma

Detailed Description
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PRIMARY OBJECTIVES: I. Assess the safety of cellular adoptive immunotherapy in melanoma patients using autologous CD8+ antigen-specific T-cell clones following CD25 lymphodepletion. II. Determine the influence of CD25 lymphodepletion on the duration of in vivo persistence of adoptively transferred CD8+ antigen-specific cytotoxic T-cell (CTL) clones. SECONDARY OBJECTIVES: I. Assess the anti-tumor efficacy of cellular adoptive immunotherapy in melanoma patients using autologous CD8+ antigen-specific T cell clones following CD25 lymphodepletion. II. Evaluate the induction of T cells to non-targeted tumor-associated antigens (antigen-spreading) following adoptive transfer of CD8+ antigen-specific CTL and CD25 lymphodepletion. OUTLINE: This is a phase I study followed by a phase II study. Patients receive autologous T-cell intravenously (IV) over 30-60 minutes on days 0 and 28 and low-dose aldesleukin subcutaneously (SC) twice daily on days 0 to 13 and 28 to 41. Beginning 4-6 days before second T- cell infusion, patients receive denileukin diftitox IV over 30 minutes on days 1-3. Treatment continues in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 4 weeks, 8 weeks, and then every 3 months thereafter.

Official Title
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Phase I/II Study To Evaluate The Safety Of Cellular Adoptive Immunotherapy Using Autologous CD8+ Antigen-Specific T Cell Clones Following CD25 Lymphodepletion For Patients With Metastatic Melanoma

Conditions
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Recurrent Melanoma, Stage III Melanoma, Stage IV Melanoma

Intervention / Treatment
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* Biological: therapeutic autologous lymphocytes
* Biological: aldesleukin
* Biological: denileukin diftitox
* Procedure: biopsy
* Other: immunohistochemistry staining method
* Other: laboratory biomarker analysis
* Genetic: polymerase chain reaction


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histopathological documentation of melanoma Expression of human leukocyte antigen (HLA)-A2 or B44 as determined by HLA typing lab Patients whose tumor expresses targeted antigen and restricting allele against which CD8 T cell clones can be generated Karnofsky Performance status of at least 80% and an expected survival of greater than 6 months Bi-dimensionally measurable disease by palpation on clinical exam, or radiographic imaging (X-ray, computed tomography [CT] scan) Normal cardiac stress test (treadmill, echocardiogram, or myocardial perfusion scan) within 182 days prior to enrollment is required of patients with a history of cardiac disease Pulse > 45 or < 120 Weight >= 45 kg Temperature =< 38C (< 100.4 F) White blood cells (WBC) >= 3,000 Hematocrit (HCT) >= 30% Platelets >= 100,000 Patients must be willing and able to discontinue the use of all antihypertensive medications 24 hours prior to and during IL2 therapy Exclusion Criteria: Pregnant women, nursing mothers, or women of reproductive ability who are unwilling to use effective contraception or abstinence Serum creatinine > 1.6mg/dL Creatinine clearance < 75 ml/min Aspartate aminotransferase (AST) > 2.5 x upper limit of normal Alanine aminotransferase (ALT) > 2.5 x upper limit of normal Bilirubin > 1.6 or international normalized ratio (INR) > 1.5 due to hepatic dysfunction Albumin < 3.0g/dL Clinically significant pulmonary dysfunction, as determined by medical history and physical exam; patients so identified will undergo pulmonary functions testing and those with Forced expiratory volume in one second (FEV1) < 80% predicted or diffusing capacity of the lung for carbon monoxide (DLco) (corr for hemoglobin [Hgb]) < 75% will be excluded Significant cardiovascular abnormalities as defined by any one of the following: congestive heart failure, symptoms of coronary artery disease Symptomatic central nervous system (CNS) metastases greater than 1 cm at time of therapy; patients with 1-2 asymptomatic, less than 1cm brain/CNS metastases without significant edema may be considered for treatment Patients with active infections or oral temperature > 38.2 C within 48 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) Concurrent treatment with steroids Patients must not be receiving any other experimental drugs within 3 weeks of the initiation of the protocol and must have recovered from all side effects of such therapy The following agents are not allowed while on study: systemic corticosteroids (except as outlined for management of toxicity of nontransduced CTL), immunotherapy (for example, interleukins, interferons, melanoma vaccines, intravenous immunoglobulin, expanded polyclonal TIL or LAK therapy), pentoxifylline, or other investigational agents

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 (cellular adoptive immunotherapy)<br>Patients receive autologous T-cell IV over 30-60 minutes on days 0 and 28 and low-dose aldesleukin SC twice daily on days 0 to 13 and 28 to 41. Beginning 4-6 days before second T-cell infusion, patients receive denileukin diftitox IV over 30 minutes on days 1-3. | Biological: therapeutic autologous lymphocytes<br>* Given IV<br>* Other names: autologous T cells;Biological: aldesleukin<br>* Given SC<br>* Other names: recombinant interleukin-2;Biological: denileukin diftitox<br>* Given IV<br>* Other names: DABIL2;Procedure: biopsy<br>* Optional correlative studies<br>* Other names: biopsies;Other: immunohistochemistry staining method<br>* Correlative studies<br>* Other names: immunohistochemistry;Other: laboratory biomarker analysis<br>* Correlative studies<br>Genetic: polymerase chain reaction<br>* Correlative studies<br>* Other names: PCR;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| In vivo survival of CD8+ transferred T-clones | The design of this trial using the first infusion of CD8 T cells administered alone as a baseline for each patient permits intra-patient analysis using paired samples with increased statistical power. | Days +0, 1, 3, 7, 14, 22, 28, 29, 31, 35, 42, 49, 56, 63, 70, 77, 84 |