Cyclophosphamide and Fludarabine Followed by Vaccine Therapy, Gene-Modified White Blood Cell Infusions, and Aldesleukin in Treating Patients With Metastatic Melanoma

A Study in Metastatic Melanoma Using a Lymphodepleting Conditioning Followed by Infusion of Anti-MART-1 TCR-Gene Engineered Lymphocytes and Subsequent Peptide Immunization

RATIONALE: Inserting a laboratory-treated gene into a person's white blood cells may make the body build an immune response to kill tumor cells. Giving cyclophosphamide and fludarabine before a white blood cell infusion may suppress the immune system and allow tumor cells to be killed. Vaccines may make the body build an immune response to kill tumor cells. Aldesleukin may stimulate a person's white blood cells to kill tumor cells. Combining white blood cell infusion with vaccine therapy and aldesleukin may cause a stronger immune response and kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of gene-modified white blood cells when given together with cyclophosphamide, fludarabine, vaccine therapy, and aldesleukin and to see how well it works in treating patients with metastatic melanoma.

Study Overview

• Status: Completed
• Conditions: Melanoma (Skin)
• Intervention / Treatment: Biological: aldesleukin; Drug: cyclophosphamide; Drug: fludarabine phosphate; Procedure: in vitro-treated peripheral blood stem cell transplantation; Radiation: total-body irradiation; Biological: filgrastim; Biological: incomplete Freund's adjuvant; Procedure: autologous hematopoietic stem cell transplantation; Biological: therapeutic autologous lymphocytes; Biological: MART-1:27-35 peptide vaccine; Biological: therapeutic tumor infiltrating lymphocytes

Detailed Description

OBJECTIVES:

Primary

• Determine the safety of peripheral blood lymphocytes (PBLs) retrovirally transduced with an anti-MART-1 T-cell receptor (TCR) gene followed by high-dose aldesleukin (IL-2) and MART-1:27-35 peptide vaccine in patients with HLA-A*0201-positive metastatic melanoma receiving a myeloablative preparative regimen comprising cyclophosphamide, fludarabine phosphate, and total-body irradiation.
• Determine, preliminarily, whether antitumor antigen TCR-engineered tumor-infiltrating lymphocytes or PBLs followed by IL-2 and MART-1:26-35 after a nonmyeloablative but lymphoid-depleting preparative regimen will result in clinical tumor regression in these patients.

Secondary

• Determine the in vivo survival of TCR gene-engineered cells from these patients.
• Evaluate, preliminarily, clinical response in these patients.

OUTLINE: Patients with resectable tumor undergo tumor biopsy. Tumor-infiltrating lymphocytes (TILs) from the tumor sample are cultured in vitro and tested for reactivity to melanoma antigens. Patients who are unable to undergo biopsy or whose TILs do not grow in culture are assigned to groups I or II. Patients whose tumors yield TILs that do not exhibit melanoma reactivity are assigned to group III. Patients with TILs that exhibit melanoma reactivity are removed from the study.

• Autologous stem cell collection: Patients undergo stem cell collection on treatment protocol NCI-03-C-0277 for reinfusion after the myeloablation and cell therapy. Patients receive filgrastim (G-CSF) subcutaneously (SC) twice daily beginning on day 0 and continuing for up to 5 days. Patients then undergo stem cell collection by apheresis or bone marrow harvest beginning on day 5 and continuing for up to 3 days. Some patients may receive a second course of G-CSF and undergo additional stem cell collection by apheresis or undergo treatment as outlined in group II.
• Group I (peripheral blood lymphocytes [PBLs] with myeloablative preparative regimen): Patients receive a myeloablative preparative regimen comprising cyclophosphamide IV over 1 hour on days -7 and -6, fludarabine phosphate IV over 15-30 minutes on days -7 to -3, and total-body irradiation twice daily on days -3 to -1. Patients also receive autologous in vitro tumor-reactive, T-cell receptor (TCR) gene-transduced PBLs IV over 20-30 minutes on day 1 and aldesleukin IV over 15 minutes every 8 hours on days 1-5, and G-CSF SC daily beginning on day 1 and continuing until blood counts recover.
• Group II (PBLs with nonmyeloablative preparative regimen): Patients who do not meet the eligibility criteria for group I receive a nonmyeloablative preparative regimen comprising cyclophosphamide IV over 1 hour on days -7 and -6 and fludarabine phosphate IV over 30 minutes on days -5 to -1. Patients then receive aldesleukin, and G-CSF as in group I.
• Group III (autologous transduced TILs): Patients who have resected tumors that yield viable TILs have their TILs transduced with the anti-MART-1 TCR gene retroviral vector. Patients receive cyclophosphamide and fludarabine phosphate as in group II. Patients then receive autologous transduced TILs IV over 20-30 minutes on day 0. Patients also receive G-CSF and high-dose aldesleukin as in group I.

All patients receive peptide immunizations with MART-1:27-35 peptide vaccine emulsified in incomplete Freund's adjuvant SC on days 0-4, 11, 18, and 25.

In groups II or III, treatment may repeat once 6-8 weeks later for a total of 2 courses in the absence of disease progression or unacceptable toxicity. Treatment may consist of the first type cell infusion or patients may crossover to receive the other cell infusion (PBLs vs TILs).

After completion of study treatment, patients are followed periodically for at least 5 years.

PROJECTED ACCRUAL: A total of 136 patients will be accrued for this study.

• Study Type: Interventional
• Enrollment (Anticipated): 136
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892-1182
      • Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office
    • Bethesda, Maryland, United States, 20892-1201
      • NCI - 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

DISEASE CHARACTERISTICS:

• Diagnosis of metastatic melanoma
• HLA-A*0201-positive disease
• Measurable disease
• Refractory to standard therapy, including high-dose aldesleukin therapy

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-1

Life expectancy

• More than 3 months

Hematopoietic

• Absolute neutrophil count > 1,000/mm^3
• Platelet count > 100,000/mm^3
• Hemoglobin > 8.0 g/dL
• Lymphocyte count > 500/mm^3
• WBC > 3,000/mm^3
• No coagulation disorder

Hepatic

• ALT and AST < 3 times upper limit of normal
• Bilirubin ≤ 2.0 mg/dL (< 3.0 mg/dL for patients with Gilbert's disease)
• Hepatitis B antigen negative
• Hepatitis C antibody negative (unless antigen negative)

Renal

• Creatinine ≤ 1.6 mg/dL

Cardiovascular

• No myocardial infarction
• No cardiac arrhythmias
• No cardiac ischemia
• LVEF ≥ 45% by stress cardiac test* (for patients ≥ 50 years of age OR those with a history of EKG abnormalities)
• No other major cardiovascular illness by stress thallium or comparable test NOTE: *Stress thallium, stress MUGA, dobutamine echocardiogram, or other stress test

Pulmonary

• No major respiratory illness
• No obstructive or restrictive pulmonary disease
• FEV_1 ≥ 60% of predicted on pulmonary function test*
• DLCO ≥ 60% predicted (for total-body irradiation cohort) NOTE: *For patients with a prolonged history of cigarette smoking or symptoms of respiratory dysfunction

Immunologic

• HIV negative
• No major immune system illness
• No active systemic infection or opportunistic infection
• No primary immunodeficiency (e.g., autoimmune colitis or Crohn's disease)
• No secondary immunodeficiency (e.g., due to chemotherapy or radiotherapy)
• No history of severe immediate hypersensitivity reaction to study drugs

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 4 months after completion of study treatment
• Must sign a durable power of attorney

PRIOR CONCURRENT THERAPY:

Biologic therapy

• See Disease Characteristics
• Recovered from prior immunotherapy

• Prior immunization to melanoma antigens allowed

  • Progressive disease during prior immunization allowed
• Prior cellular therapy, including vector transduction with or without myeloablation, allowed
• More than 6 weeks since prior anticytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) monoclonal antibody (MDX-010) therapy
• No prior anti-CTLA-4 antibody unless a post anti-CTLA-4 antibody treatment colonoscopy was normal by biopsy

Chemotherapy

• Recovered from prior chemotherapy

Endocrine therapy

• No concurrent systemic steroids

Radiotherapy

• Recovered from prior radiotherapy
• No prior significant mediastinal or lung radiation (for total-body irradiation cohort)

Surgery

• Not specified

Other

• More than 4 weeks since prior systemic therapy and recovered

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Safety
Tumor regression

Secondary Outcome Measures

Outcome Measure
In vivo survival of transplanted cells
Clinical response

Collaborators and Investigators

• Sponsor: National Institutes of Health Clinical Center (CC)
• Collaborators: National Cancer Institute (NCI)

Study record dates

Study Major Dates

• Study Start: July 1, 2004
• Primary Completion (Actual): August 1, 2010
• Study Completion (Actual): October 1, 2010

Study Registration Dates

• First Submitted: September 7, 2004
• First Submitted That Met QC Criteria: September 7, 2004
• First Posted (Estimate): September 8, 2004

Study Record Updates

• Last Update Posted (Estimate): March 15, 2012
• Last Update Submitted That Met QC Criteria: March 14, 2012
• Last Verified: March 1, 2012

More Information

Terms related to this study

• Keywords: recurrent melanoma; stage IV melanoma
• 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; Antiviral Agents; Anti-HIV Agents; Anti-Retroviral Agents; 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; Freund's Adjuvant
• Other Study ID Numbers: 040251; 04-C-0251; NCI-6974; CDR0000383246