Cyclophosphamide and Fludarabine Followed By an Autologous Lymphocyte Infusion and Interleukin-2 in Treating Patients With Refractory or Recurrent Metastatic Melanoma

This study has been terminated.
National Cancer Institute (NCI)
Information provided by:
National Institutes of Health Clinical Center (CC) Identifier:
First received: August 29, 2005
Last updated: March 28, 2012
Last verified: March 2012

RATIONALE: An infusion of a patient's lymphocytes that have been treated in the laboratory to remove certain immune cells may be an effective treatment for melanoma. Drugs, such as cyclophosphamide and fludarabine, may suppress the immune system so that the patient's immune cells allow the infused lymphocytes to work. Interleukin-2 may help the lymphocytes kill more tumor cells when they are put back in the body. Giving cyclophosphamide and fludarabine followed by an autologous lymphocyte infusion and interleukin-2 may kill more tumor cells.

PURPOSE: This phase II trial is studying how well giving cyclophosphamide and fludarabine followed by an autologous lymphocyte infusion and interleukin-2 works in treating patients with refractory or recurrent melanoma.

Condition Intervention Phase
Melanoma (Skin)
Biological: aldesleukin
Biological: filgrastim
Biological: therapeutic autologous lymphocytes
Drug: cyclophosphamide
Drug: fludarabine phosphate
Phase 2

Study Type: Interventional
Study Design: Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase II Trial Using Aldesleukin (IL-2) Following a Lymphodepleting Chemotherapy and Reinfusion of Autologous Lymphocytes Depleted of T Regulatory Lymphocytes in Metastatic Melanoma

Resource links provided by NLM:

Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Tumor regression [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Rate of repopulation of CD25-positive T-regulatory cells [ Designated as safety issue: No ]
  • Toxicity [ Designated as safety issue: Yes ]

Enrollment: 6
Study Start Date: July 2005
Study Completion Date: April 2007
Detailed Description:



  • Determine tumor regression in patients with metastatic melanoma treated with nonmyeloablative lymphodepleting chemotherapy comprising cyclophosphamide and fludarabine followed by autologous CD25-positive-T-regulatory-cell-depleted lymphocyte reinfusion and high-dose interleukin-2.


  • Determine the rate of repopulation of CD25-positive T-regulatory cells in patients treated with this regimen.
  • Determine the toxicity of this regimen in these patients.


  • Apheresis and CD25-positive T-regulatory cell depletion: Patients undergo 1-2 aphereses to collect peripheral blood mononuclear cells (PBMC). CD25-positive T-regulatory cells are depleted from the collected PBMC in vitro.
  • Nonmyeloablative lymphodepleting chemotherapy: Patients receive cyclophosphamide IV over 1 hour on days -8 and -7 and fludarabine IV over 15-30 minutes on days -6 to -2.
  • Autologous CD25-positive-T-regulatory-cell-depleted lymphocyte reinfusion: Patients receive autologous lymphocytes IV over 20-30 minutes on day 0.
  • Filgrastim (G-CSF) and high-dose interleukin-2 (IL-2) therapy: Patients receive G-CSF subcutaneously (SC) daily beginning on day 0 and continuing until blood counts recover. Patients also receive high-dose IL-2 IV over 15 minutes 3 times daily on days 0-4 and 14-18. Patients are reevaluated 4-6 weeks after completion of high-dose IL-2 therapy. Patients achieving stable disease or a partial response may receive additional high-dose IL-2 as above for up to 2 retreatment courses in the absence of disease progression or unacceptable toxicity. Retreatment begins at least 6 weeks after autologous lymphocyte reinfusion.

After completion of study treatment, patients are followed at 4-6 weeks and then every 1-2 months thereafter.

PROJECTED ACCRUAL: A total of 16-29 patients will be accrued for this study within 1-1.5 years.


Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No


  • Diagnosis of melanoma

    • Metastatic disease
  • Measurable disease
  • HLA-A2 negative disease
  • Disease did not respond to OR recurred after completion of prior high-dose interleukin-2 (IL-2)
  • Eligible to receive high-dose IL-2
  • No tumor reactive cells available for cell transfer therapy



  • 18 and over

Performance status

  • ECOG 0-1

Life expectancy

  • At least 3 months


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


  • ALT and AST < 3 times upper limit of normal
  • Bilirubin ≤ 2.0 mg/dL (< 3.0 mg/dL if due to Gilbert's syndrome)
  • Hepatitis B surface antigen negative
  • Hepatitis C antigen negative


  • Creatinine ≤ 2.0 mg/dL
  • No renal failure requiring dialysis due to toxic effects of prior IL-2 administration


  • No myocardial infarction
  • No cardiac arrhythmias
  • No other major cardiovascular illness as evidenced by a positive stress thallium or comparable test
  • Normal cardiac stress test (e.g., stress thallium, stress MUGA, dobutamine echocardiogram) AND LVEF ≥ 45% (for patients ≥ 50 years of age or who have a history of EKG abnormalities, symptoms of cardiac ischemia, or arrhythmias)


  • No obstructive or restrictive pulmonary disease
  • No other major respiratory illness
  • FEV_1 ≥ 60% of predicted (for patients with a prolonged history of cigarette smoking or symptoms of respiratory dysfunction)


  • HIV negative
  • Epstein-Barr virus positive
  • No active systemic infection
  • No autoimmune disease (e.g., autoimmune colitis or Crohn's disease)
  • No immunodeficiency due to prior chemotherapy or radiotherapy

    • Recovered immune competence after prior chemotherapy or radiotherapy as evidenced by normal lymphocyte count and WBC and an absence of opportunistic infection
  • No other major immune system disease


  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception during and for 4 months after completion of study treatment
  • No other toxic effects during prior IL-2 administration that would preclude redosing with IL-2, including the following:

    • Mental status changes that would require intubation
    • Bowel perforation


Biologic therapy

  • See Disease Characteristics
  • At least 4 weeks since prior systemic therapy


  • At least 6 weeks since prior nitrosoureas
  • At least 4 weeks since prior systemic therapy

Endocrine therapy

  • No concurrent systemic steroid therapy


  • Not specified


  • Not specified
  Contacts and Locations
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Please refer to this study by its identifier: NCT00138229

United States, Maryland
Warren Grant Magnuson Clinical Center - NCI Clinical Studies Support
Bethesda, Maryland, United States, 20892-1182
NCI - Surgery Branch
Bethesda, Maryland, United States, 20892-1201
Sponsors and Collaborators
National Institutes of Health Clinical Center (CC)
National Cancer Institute (NCI)
Principal Investigator: Steven A. Rosenberg, MD, PhD NCI - Surgery Branch
  More Information Identifier: NCT00138229     History of Changes
Obsolete Identifiers: NCT00118599
Other Study ID Numbers: 050194  05-C-0194  NCI-P6573  CDR0000440165 
Study First Received: August 29, 2005
Last Updated: March 28, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by National Institutes of Health Clinical Center (CC):
recurrent melanoma
stage IV melanoma

Additional relevant MeSH terms:
Neoplasms by Histologic Type
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Neuroectodermal Tumors
Neuroendocrine Tumors
Nevi and Melanomas
Fludarabine phosphate
Alkylating Agents
Anti-HIV Agents
Anti-Infective Agents
Anti-Retroviral Agents
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Antirheumatic Agents
Antiviral Agents
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists
Physiological Effects of Drugs processed this record on May 26, 2016