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

Sponsor

National Institutes of Health Clinical Center (CC) (NIH)

Overall Status

Completed

CT.gov ID

NCT00062036

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Locations

Duration (Months)

16.5

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy such as cyclophosphamide and fludarabine use different ways to stop tumor cells from dividing so they stop growing or die. Inserting the gene for interleukin-2 into a person's tumor infiltrating lymphocytes may make the body build an immune response to kill tumor cells. Combining cyclophosphamide and fludarabine with gene-modified tumor cells may kill more cancer cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of gene-modified tumor infiltrating lymphocytes when given together with cyclophosphamide and fludarabine and to see how well they work in patients with metastatic melanoma (phase I is closed to accrual 3/29/06).

Condition or Disease	Intervention/Treatment	Phase
Melanoma (Skin)	Biological: aldesleukin Biological: filgrastim Biological: incomplete Freund's adjuvant Biological: interleukin-2 gene Biological: therapeutic tumor infiltrating lymphocytes Drug: cyclophosphamide Drug: fludarabine phosphate	Phase 1/Phase 2

Detailed Description

OBJECTIVES:

Primary

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

Secondary

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

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.

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

Study Design

Study Type:

Interventional

Anticipated Enrollment :

33 participants

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Study Start Date :

Jun 1, 2003

Actual Primary Completion Date :

Feb 1, 2007

Actual Study Completion Date :

Sep 1, 2008

Outcome Measures

Primary Outcome Measures

Survival []

Secondary Outcome Measures

Clinical tumor regression []
Toxicity profile []

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 120 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

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/mm^3
WBC greater than 3,000/mm^3
Lymphocyte count greater than 500/mm^3
Platelet count greater than 100,000/mm^3
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
FEV_1 > 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

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office	Bethesda	Maryland	United States	20892-1182
2	NCI - Center for Cancer Research	Bethesda	Maryland	United States	20892