Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Projected Accrual
Outline
Trial Contact Information

Alternate Title

Cyclophosphamide and Fludarabine Followed By Interleukin-2 Gene-Modified Tumor Infiltrating Lymphocytes in Treating Patients With Metastatic Melanoma

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase II, Phase I Treatment Active 18 and over NCI NCI-03-C-0162 NCI-5855

Special Category: NIH Clinical Center trial

Objectives

1. Determine the maximum tolerated dose of interleukin-2 gene-modified tumor infiltrating lymphocytes after cyclophosphamide and fludarabine in patients with metastatic melanoma.
2. Determine the safety and toxicity profile of this regimen in these patients.
3. Determine clinical tumor regression in patients treated with this regimen.
4. Determine the survival of patients treated with this regimen.

Entry Criteria

Disease Characteristics:

• Diagnosis of melanoma
  • Metastatic disease
  • Refractory to standard therapy including high-dose interleukin-2 (IL-2) therapy



• Evaluable disease



• Patients may enroll at the cell infusion stage provided they have tumor available for biopsy OR expandable SBIL-2-transduced tumor infiltrating lymphocytes available



• Progressive disease during prior immunization to melanoma antigens allowed



• No brain metastases

Prior/Concurrent Therapy:

Biologic therapy

• See Disease Characteristics
• Prior anti-cytotoxic T-lymphocyte antibody-4 antibody or prior cellular therapy allowed if all toxic effects are resolved (except vitiligo)

Chemotherapy

• Recovered from prior chemotherapy

Endocrine therapy

• No concurrent steroids

Radiotherapy

• Recovered from prior radiotherapy

Surgery

• Not specified

Other

• More than 4 weeks since prior systemic therapy

Patient Characteristics:

Age

• 18 and over

Performance status

• ECOG 0-1

Life expectancy

• More than 3 months

Hematopoietic

• Absolute neutrophil count greater than 1,000/mm³
• Lymphocyte count greater than 500/mm³
• Platelet count greater than 100,000/mm³
• Hemoglobin greater than 8.0 g/dL
• No coagulation disorder

Hepatic

• Bilirubin no greater than 2.0 mg/dL (less than 3.0 mg/dL in patients with Gilbert's syndrome)
• AST/ALT less than 3 times upper limit of normal
• Hepatitis B surface antigen negative
• Hepatitis C virus negative

Renal

• Creatinine no greater than 1.6 mg/dL

Cardiovascular

• No abnormal stress thallium or comparable test
• No myocardial infarction
• No cardiac arrhythmias
• No major cardiovascular illness

Pulmonary

• No obstructive or restrictive pulmonary disease
• No major respiratory illness

Immunologic

• HIV negative
• Negative for Epstein-Barr virus
• No prior severe immediate hypersensitivity reaction
• No primary or secondary immunodeficiency
• No active systemic infection
• No concurrent opportunistic infection
• No major immune system illness

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 4 months after study therapy

Projected Accrual

A total of 132 patients will be accrued for this study within approximately 3-6 years.

Outline

• Phase I: This is a dose-escalation study of interleukin-2 (IL-2) gene-transduced tumor infiltrating lymphocytes (TIL).
  • Harvest: TIL are harvested, transduced with IL-2 gene, and expanded in vitro over a period of approximately 4 weeks. Patients receive filgrastim (G-CSF) subcutaneously (SC) daily for 5 days followed by apheresis to harvest autologous peripheral blood stem cells which are stored in case rescue is needed after chemotherapy.
  
  
  
  • Nonmyeloablative preparative regimen (chemotherapy): Patients receive cyclophosphamide IV over 1 hour on days -7 and -6 and fludarabine IV over 30 minutes on days -5 to –1.
  
  
  
  • Lymphocyte administration: Patients receive IL-2 gene-transduced TIL IV over 20-30 minutes on day 0.

    Cohorts of 3-6 patients receive escalating doses of IL-2 gene-transduced TIL until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 1 of 3 or 2 of 6 patients experience dose-limiting toxicity.

  
  
  
  • Immunization: Patients are immunized with a peptide emulsified in incomplete Freund’s adjuvant SC once daily on days 0, 2, and 4, depending on lymphocyte reactivity.
    • Patients receiving gp100-reactive cells receive the gp100 peptide.
    • Patients receiving MART-1-reactive cells receive the MART-1 peptide.
    • Patients receiving gp100- and MART-1-reactive cells receive both peptides.
    • Patients receiving cells that are not reactive to either peptide are not immunized.
  
  
  
  • Retreatment: Patients are re-evaluated every 4-6 weeks. Retreatment depends on disease status after each regimen. Patients with dose-limiting toxicity do not receive further treatment.
    • No response: Patients with stable disease or disease progression after the initial treatment may receive retreatment, approximately 2-4 weeks later, with chemotherapy, IL-2 gene-transduced TIL, and immunization as above. Patients also receive high-dose IL-2 IV over 15 minutes every 8 hours on days 0-5.

      Patients with a partial, minor, or mixed response after this treatment may receive 1 additional regimen comprising chemotherapy, IL-2 gene-transduced TIL, immunization, and high-dose IL-2 in 4-6 weeks.

    • Partial response: Patients with a partial, minor, or mixed response after the initial treatment may receive retreatment, approximately 2-4 weeks later, with IL-2 gene-transduced TIL and immunization as above, but without the chemotherapy, every 4-6 weeks for up to 3 courses provided at least a partial response is documented after each regimen.

      Patients with no response to this treatment may receive retreatment comprising chemotherapy, IL-2 gene-transduced TIL, immunization, and high-dose IL-2 as above

    • Complete response: Patients with a complete response receive no further treatment.
  
  
  



• Phase II: Patients receive treatment and retreatment as in phase I with the MTD of IL-2 gene-transduced TIL.

Patients are followed at 3, 6, and 12 months after cell infusion and then annually thereafter.

Disclaimer

The purpose of most clinical trials listed in this database is to test new cancer treatments, or new methods of diagnosing, screening, or preventing cancer. Because all potentially harmful side effects are not known before a trial is conducted, dose and schedule modifications may be required for participants if they develop side effects from the treatment or test. The therapy or test described in this clinical trial is intended for use by clinical oncologists in carefully structured settings, and may not prove to be more effective than standard treatment. A responsible investigator associated with this clinical trial should be consulted before using this protocol.

Trial Contact Information

Trial Lead Organizations

NCI - Center for Cancer Research

Richard Morgan, Protocol chair		Ph: 301-594-9629
Steven Rosenberg, MD, PhD, Principal investigator		Ph: 866-820-4505 Email: sar@nih.gov

U.S.A.
Maryland
	Bethesda
	Warren Grant Magnuson Clinical Center - NCI Clinical Studies Support
		Patient Recruitment	Ph:  888-NCI-1937

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