Vaccine Therapy Following Therapeutic Autologous Lymphocytes and Cyclophosphamide in Treating Patients With Metastatic Melanoma

Study Overview
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Brief Summary
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This phase I trial studies the side effects and best dose of autologous T-antigen-presenting cells (T-APC) vaccine following therapeutic autologous lymphocytes (CTL) and cyclophosphamide in treating patients with metastatic melanoma. Aldesleukin may stimulate lymphocytes, such as CTL, to kill melanoma cells. Treating lymphocytes with aldesleukin in the laboratory may help the lymphocytes kill more tumor cells when they are put back in the body. Vaccines made from melanoma antigen may help the body build an effective immune response to kill tumor cells and may boost the effect of the CTL. 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 T-APC vaccine after CTL and cyclophosphamide may be an effective treatment for melanoma

Detailed Description
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PRIMARY OBJECTIVES: I. Assess the safety and toxicity of T-APC vaccination following adoptive T cell therapy. II. Evaluate the functional and numeric in vivo persistence of adoptively transferred cytotoxic t lymphocytes (CTL) followed by T-APC vaccination. SECONDARY OBJECTIVES: I. Evaluate the antitumor effect of adoptive T cell therapy followed by T-APC vaccination. OUTLINE : This is a dose-escalation study of T-APC vaccine. INFUSION I: Patients receive high-dose cyclophosphamide intravenously (IV) on days -4 and -3 and low-dose aldesleukin (IL-2) subcutaneously (SC) twice daily (BID) on days 0-14. Patients also receive CTL IV on day 0. INFUSION II: Beginning 6-48 hours later, patients receive high-dose cyclophosphamide, low-dose IL-2, and CTL as in Infusion I. Patients also receive T-APC vaccine IV within 18-36 hours following CTL infusion and in week 4, and IL-2 SC BID on days 0-14 following second T-APC vaccination. After completion of study treatment, patients are followed up for 8 weeks.

Official Title
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Phase I Study To Evaluate The Use Of Autologous T- Antigen-Presenting Cells (T-APC) To Enhance The Persistence Of Adoptively Transferred CD8+ Antigen-Specific T Cells (CTL) Following Cyclophosphamide Conditioning For Patients With Metastatic Melanoma

Conditions
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Recurrent Melanoma, Stage IV Melanoma

Intervention / Treatment
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* Drug: cyclophosphamide
* Biological: aldesleukin
* Biological: autologous tumor cell vaccine
* Other: laboratory biomarker analysis
* Other: immunologic technique
* Other: immunohistochemistry staining method
* Genetic: polymerase chain reaction
* Biological: therapeutic autologous lymphocytes


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histopathological documentation of melanoma concurrent with the diagnosis of metastatic disease Tumor expression of melanocyte differentiation antigen (MDA: MART-1 = 2+ staining or > 25%) by immunohistochemistry (IHC) Expression of human leukocyte antigen (HLA)-A201 Zubrod performance status of '0-1' at the time of treatment Bi-dimensionally measurable disease by palpation on clinical exam, or radiographic imaging (X-ray, computed tomography [CT] scan) Normal cardiac stress test will be required for all patients with any history of cardiac disease 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 < 75 ml/min Serum glutamic oxaloacetic transaminase (SGOT) > 150 IU or > 3x upper limit of normal Bilirubin > 1.6 mg/dL Prothrombin time > 1.5 x control 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) < 2.0 L or carbon monoxide diffusing capacity (DLco) (corr for hemoglobin [Hgb]) < 75% will be excluded Congestive heart failure Clinically significant hypotension Symptoms of coronary artery disease Presence of cardiac arrhythmias on electrocardiograph (EKG) requiring drug therapy Ejection fraction < 50 % (echocardiogram or multi gated acquisition scan [MUGA]) Symptomatic central nervous system metastases greater than 1 cm at time of therapy; patients with 1-2 asymptomatic, less than 1 cm brain/central nervous system (CNS) metastases without significant edema may be considered for treatment 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 immune deficiency syndrome (AIDS) or human immunodeficiency virus (HIV)-1 associated complex or known to HIV antibody seropositive or known to be recently polymerase chain reaction (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 Chemotherapeutic agents (standard or experimental), radiation therapy, or other immunosuppressive therapies less than 3 weeks prior to T cell therapy Current 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 Patients for whom we are unable to generate MART-1 specific T cells

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 (dose-escalation, T-APC boost, CTL)<br>INFUSION I: Patients receive high-dose cyclophosphamide IV on day days -4 and -3 and low-dose IL-2 SC BID on days 0-14. Patients also receive CTL IV on day 0. INFUSION II: Beginning 6-48 hours later, patients receive high-dose cyclophosphamide, low-dose IL-2, and CTL as in Infusion I. Patients also receive T-APC vaccine IV within 18-36 hours following CTL infusion and in week 4, and IL-2 SC BID on days 0-14 following second T-APC vaccination. | Drug: cyclophosphamide<br>* Given IV<br>* Other names: Endoxana;Biological: aldesleukin<br>* Given SC<br>* Other names: recombinant interleukin-2;Biological: autologous tumor cell vaccine<br>* Receive T-APC via IV<br>* Other names: Autologous Cell Vaccine;Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: immunologic technique<br>* Correlative studies<br>* Other names: laboratory methods, immunological;Other: immunohistochemistry staining method<br>* Correlative studies<br>* Other names: immunohistochemistry;Genetic: polymerase chain reaction<br>* Correlative studies<br>* Other names: PCR;Biological: therapeutic autologous lymphocytes<br>* Receive adoptively transferred CD8+ antigen-specific T cell clones via IV<br>* Other names: autologous T cells;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment-related dose limiting toxicity (DLT) as defined by Grade 3 or greater unexpected toxicity by the NCI Common Toxicity Criteria (CTC) v4.0 | Assessed at the maximum tolerated dose (MTD) or dose level immediately below the dose level for which the incidence of DLT was less than 35%. | Up to 8 weeks after the T cell infusion | 
| In vivo persistence of adoptively transferred T cells | Assessed by intrapatient comparison between the first (without T-APC) and second (with T-APC) CTL infusion. Descriptive statistics will be applied and t-tests of intrapatient in vivo T cell persistence between the two Infusions will be determined. | At 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical response |  | Up to 8 weeks after second dose |