Vaccine Therapy With or Without Interleukin-2 After Chemotherapy and an Autologous White Blood Cell Infusion in Treating Patients With Metastatic Melanoma

A Phase II Study Using a Peptide Vaccine With or Without Aldesleukin Following a Lymphodepleting Chemotherapy and Reinfusion of Autologous Lymphocytes Depleted of T Regulatory Lymphocytes in Metastatic Melanoma

This randomized phase II trial is studying how well giving vaccine therapy with or without interleukin-2 after chemotherapy and an autologous white blood cell infusion works in treating patients with metastatic melanoma. Vaccines made from peptides may help the body build an effective immune response to kill tumor cells. Giving vaccine therapy with interleukin-2, chemotherapy, and an autologous white blood cell infusion may be a more effective treatment for metastatic melanoma.

Study Overview

• Status: Terminated
• Conditions: Recurrent Melanoma; Stage IV Melanoma
• Intervention / Treatment: Drug: fludarabine phosphate; Drug: cyclophosphamide; Biological: filgrastim; Biological: therapeutic autologous lymphocytes; Biological: aldesleukin; Biological: incomplete Freund's adjuvant; Biological: gp100 antigen; Biological: MART-1 antigen; Procedure: in vitro-treated peripheral blood stem cell transplantation

Detailed Description

PRIMARY OBJECTIVES:

I. Determine the ability of gp100 and MART-1 peptide vaccines with or without a high-dose interleukin-2 (IL-2), when administered after a nonmyeloablative, lymphodepleting preparative regimen and reinfusion of autologous CD25+ T-regulatory-depleted lymphocytes, to mediate tumor regression in patients with metastatic melanoma.

SECONDARY OBJECTIVES:

I. Determine the generation of antitumor lymphocytes and the rate of repopulation of CD25+ T-regulatory cells in patients treated with this regimen.

II. Determine the toxicity of this treatment regimen.

OUTLINE: This is a randomized study. Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients undergo apheresis and in-vitro depletion of T-regulatory cells. Patients then receive a nonmyeloablative, lymphocyte-depleting preparative regimen comprising cyclophosphamide IV over 1 hour on days -8 and -7 and fludarabine IV over 15-30 minutes on days -6 to -2 followed by autologous T-regulatory-depleted lymphocytes IV over 20-30 minutes on day 0. Patients receive vaccination with gp100:209-217 (210M) and MART-1:27-35 peptides emulsified in Montanide ISA-51 subcutaneously (SC) on days 0-3, 20-23, 41-44, and 62-65. Patients also receive filgrastim (G-CSF) SC beginning on day 1 and continuing until blood counts recover.

ARM II: Patients receive treatment as in arm I. Patients also receive high-dose IL-2 IV over 15 minutes every 8 hours on days 0-4, beginning after the lymphocyte infusion. IL-2 treatment repeats every 3 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 1-3 months.

• Study Type: Interventional
• Enrollment (Actual): 58
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892-1201
      • National Cancer Institute Surgery Branch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of metastatic melanoma

  • No tumor reactive cells available for cell transfer therapy
• Measurable disease

• Previously treated with interleukin-2 (IL-2) and meets 1 of the following criteria:

  • No response (progressive disease)
  • Recurrent disease
• HLA*0201 positive
• ECOG performance status 0 or 1
• Absolute neutrophil count > 1,000/mm^3
• Platelet count > 100,000/mm^3
• Hemoglobin > 8.0 g/dL
• ALT and AST < 3 times upper limit of normal
• Bilirubin ≤ 2.0 mg/dL (< 3.0 mg/dL if Gilbert's disease is present)
• Creatinine ≤ 2.0 mg/dL
• Life expectancy ≥ 3 months
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for up to 4 months after receiving the preparative regimen
• No active systemic infections, coagulation disorders, or other major medical illnesses of the cardiovascular, respiratory, or immune system, as evidenced by a positive stress thallium or comparable test, myocardial infarction, cardiac arrhythmias, or obstructive or restrictive pulmonary disease
• No autoimmune disease (e.g., autoimmune colitis or Crohn's disease) or primary immunodeficiency disease
• No HIV positivity
• No hepatitis B or C virus positivity
• No Epstein-Barr virus negativity

• Eligible to receive high-dose IL-2, as evidenced by the following:

  • Patients ≥ 50 years of age must have a normal cardiac stress test (e.g., stress thallium, stress MUGA, dobutamine echocardiogram, or other stress test) AND LVEF ≥ 45%
  • Patients with a history of EKG abnormalities, symptoms of cardiac ischemia, or arrhythmias must have a normal cardiac stress test AND LVEF ≥ 45%
  • Patients with a prolonged history of cigarette smoking or symptoms of respiratory dysfunction must have a normal pulmonary function test, as evidenced by FEV 1 ≥ 60% of predicted
• At least 4 weeks since prior systemic therapy
• At least 6 weeks since prior nitrosourea therapy
• No concurrent systemic steroid therapy
• Recovered immune competence after prior chemotherapy or radiotherapy
• No prior gp100:209-217 or MART-1:27-35 peptide vaccine

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I; Patients undergo apheresis and in-vitro depletion of T-regulatory cells. Patients then receive a nonmyeloablative, lymphocyte-depleting preparative regimen comprising cyclophosphamide IV over 1 hour on days -8 and -7 and fludarabine IV over 15-30 minutes on days -6 to -2 followed by autologous T-regulatory-depleted lymphocytes IV over 20-30 minutes on day 0. Patients receive vaccination with gp100:209-217 (210M) and MART-1:27-35 peptides emulsified in Montanide ISA-51 subcutaneously (SC) on days 0-3, 20-23, 41-44, and 62-65. Patients also receive filgrastim (G-CSF) SC beginning on day 1 and continuing until blood counts recover.	Drug: fludarabine phosphate; Given IV; Other Names: 2-F-ara-AMP; Beneflur; Fludara; Drug: cyclophosphamide; Given IV; Other Names: Cytoxan; Endoxan; CPM; CTX; Endoxana; Biological: filgrastim; Given SC; Other Names: G-CSF; Neupogen; Biological: therapeutic autologous lymphocytes; Given IV; Other Names: AL; Autologous Lymphocytes; autologous T cells; Biological: incomplete Freund's adjuvant; Given SC; Other Names: IFA; ISA-51; Montanide ISA 51; Biological: gp100 antigen; Given SC; Other Names: gp100; Biological: MART-1 antigen; Given SC; Other Names: Antigen LB39-AA; Antigen SK29-AA; MART-1 Tumor Antigen; MART-1; Procedure: in vitro-treated peripheral blood stem cell transplantation; Undergo in vitro-treated peripheral blood stem cell transplantation; Other Names: in vitro-treated PBPC transplantation; in vitro-treated PBSC; in vitro-treated peripheral blood progenitor cell transplantation; PBPC transplantation, in vitro-treated; peripheral blood progenitor cell transplantation, in vitro-treated
Experimental: Arm II; Patients receive treatment as in arm I. Patients also receive high-dose IL-2 IV over 15 minutes every 8 hours on days 0-4, beginning after the lymphocyte infusion. IL-2 treatment repeats every 3 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity.	Drug: fludarabine phosphate; Given IV; Other Names: 2-F-ara-AMP; Beneflur; Fludara; Drug: cyclophosphamide; Given IV; Other Names: Cytoxan; Endoxan; CPM; CTX; Endoxana; Biological: filgrastim; Given SC; Other Names: G-CSF; Neupogen; Biological: therapeutic autologous lymphocytes; Given IV; Other Names: AL; Autologous Lymphocytes; autologous T cells; Biological: aldesleukin; Given IV; Other Names: Proleukin; IL-2; recombinant human interleukin-2; recombinant interleukin-2; Biological: incomplete Freund's adjuvant; Given SC; Other Names: IFA; ISA-51; Montanide ISA 51; Biological: gp100 antigen; Given SC; Other Names: gp100; Biological: MART-1 antigen; Given SC; Other Names: Antigen LB39-AA; Antigen SK29-AA; MART-1 Tumor Antigen; MART-1; Procedure: in vitro-treated peripheral blood stem cell transplantation; Undergo in vitro-treated peripheral blood stem cell transplantation; Other Names: in vitro-treated PBPC transplantation; in vitro-treated PBSC; in vitro-treated peripheral blood progenitor cell transplantation; PBPC transplantation, in vitro-treated; peripheral blood progenitor cell transplantation, in vitro-treated

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Objective clinical response (CR or PR)	Up to 2 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Presence of anti-tumor T cells	Up to 2 years
Recovery of regulatory T cells	Up to 2 years
Incidence of DLTs and SAEs graded according to CTCAE version 3.0	Up to 2 years

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Steven Rosenberg, National Cancer Institute Surgery Branch

Study record dates

Study Major Dates

• Study Start: November 1, 2005
• Primary Completion (Actual): January 1, 2007

Study Registration Dates

• First Submitted: March 15, 2006
• First Submitted That Met QC Criteria: March 15, 2006
• First Posted (Estimate): March 17, 2006

Study Record Updates

• Last Update Posted (Estimate): June 6, 2013
• Last Update Submitted That Met QC Criteria: June 5, 2013
• Last Verified: June 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Antiviral Agents; Anti-HIV Agents; Anti-Retroviral Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Adjuvants, Immunologic; Aldesleukin; Cyclophosphamide; Fludarabine; Fludarabine phosphate; Interleukin-2; Freund's Adjuvant
• Other Study ID Numbers: NCI-2012-02684; P6574; NCI-06-C-0028; CDR0000459683; NCI-7547; NCI-P6574