Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Related Information
Registry 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	Completed	18 and over	NCI	NCI-03-C-0162 NCI-5855, 5855, NCT00062036

Special Category: NCI Web site featured trial

Objectives

Primary

1. Determine the survival of patients with metastatic melanoma administered interleukin-2 gene-modified tumor infiltrating lymphocytes after cyclophosphamide and fludarabine.
2. Compare survival results with prior Surgery Branch studies using adoptive cell therapy without the interleukin-2 retroviral vector (SBIL-2) gene.

Secondary

1. Determine clinical tumor regression in patients administered interleukin-2 gene-modified TIL after cyclophosphamide and fludarabine followed by interleukin-2.
2. Determine the toxicity profile of this regimen in these patients.

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 or cellular therapy, with or without myeloablation, allowed



• Symptomatic CNS lesions allowed provided immediate active treatment for symptomatic lesions has been completed

Prior/Concurrent Therapy:

Biologic therapy

• See Disease Characteristics
• No prior anti-cytotoxic T-lymphocyte antibody-4 antibody (CTLA-4) allowed unless post-MDX010 treatment and colonoscopy with colonic biopsies are normal

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
• WBC greater than 3,000/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 myocardial infarction
• No cardiac arrhythmias
• No abnormal stress thallium or comparable test
• LVEF > 45% and normal stress cardiac test in patients with the following criteria:
  • 50 years old or greater
  • History of EKG abnormalities, symptoms of cardiac ischemia or arrhythmias
• No major cardiovascular illness

Pulmonary

• No obstructive or restrictive pulmonary disease
• No major respiratory illness
• FEV₁ > 60% predicted in patients with prolonged history of cigarette smoking or symptoms of respiratory dysfunction

Immunologic

• HIV negative
• 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
• Must sign a durable power of attorney

Expected Enrollment

A total of 33 patients will be accrued for this study.

Outcomes

Survival

Clinical tumor regression
Toxicity profile

Outline

• Phase I (closed to accrual as of 3/29/06):
  • Harvest: TIL are harvested, transduced with IL-2 gene, and expanded in vitro over a period of approximately 4 weeks.
  
  
  
  • 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. They also receive high-dose IL-2 IV over 15 minutes every 8 hours on days 0 -5 (maximum 15 doses). Beginning 1-2 days after lymphocyte administration, patients receive filgrastim (G-CSF) subcutaneously (SC) daily, , until blood counts recover.
  
  
  
  • 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 are followed or removed from the study.
    • Partial response: Patients with a partial or minor response after the initial treatment may receive retreatment, approximately 2-4 weeks later, with chemotherapy, IL-2 gene-transduced TIL, immunization, and high-dose IL-2 as above, every 4-6 weeks for up to 2 courses provided at least a partial response is documented after each regimen.
    • 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 every 3-6 weeks in the absence disease progression.

Trial Contact Information

Trial Lead Organizations

NCI - Center for Cancer Research

Steven Rosenberg, MD, PhD, Principal investigator		Ph: 866-820-4505 Email: sar@nih.gov

Related Information

Featured trial article

Registry Information
Official Title		Tumor Infiltrating Lymphocytes (TIL cells) Transduced With An Interleukin-2 (SBIL-2) Gene Following The Administration Of A Nonmyeloablative But Lymphocyte Depleting Regimen in Metastatic Melanoma
Trial Start Date		2003-06-03
Trial Completion Date		2008-09-17
Registered in ClinicalTrials.gov		NCT00062036
Date Submitted to PDQ		2003-04-22
Information Last Verified		2007-02-06