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

Sponsor:	National Cancer Institute (NCI)
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00062036

Purpose

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	Intervention	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 I Phase II

Study Type:	Interventional
Study Design:	Masking: 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

Resource links provided by NLM:

Genetics Home Reference related topics: Help Me Understand Genetics

MedlinePlus related topics: Cancer Melanoma

Drug Information available for: Cyclophosphamide Fludarabine Fludarabine monophosphate Interleukin-2 Aldesleukin Filgrastim Lenograstim Granulocyte colony-stimulating factor Freund's adjuvant

U.S. FDA Resources

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:

Survival [ Designated as safety issue: No ]

Secondary Outcome Measures:

Clinical tumor regression [ Designated as safety issue: No ]
Toxicity profile [ Designated as safety issue: Yes ]

Estimated Enrollment:	33
Study Start Date:	June 2003
Primary Completion Date:	September 2008 (Final data collection date for primary outcome measure)

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.

Eligibility

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

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

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

Please refer to this study by its ClinicalTrials.gov identifier: NCT00062036

Locations

United States, Maryland
NCI - Center for Cancer Research
Bethesda, Maryland, United States, 20892
Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office
Bethesda, Maryland, United States, 20892-1182

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

Principal Investigator:

Steven A. Rosenberg, MD, PhD

NCI - Surgery Branch

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

Featured trial article This link exits the ClinicalTrials.gov site

No publications provided

ClinicalTrials.gov Identifier:	NCT00062036 History of Changes
Obsolete Identifiers:	NCT00059163
Other Study ID Numbers:	CDR0000304438, NCI-03-C-0162, NCI-5855
Study First Received:	June 5, 2003
Last Updated:	February 6, 2009
Health Authority:	United States: Food and Drug Administration

Keywords provided by National Cancer Institute (NCI):

stage IV melanoma
recurrent melanoma

Additional relevant MeSH terms:

Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Cyclophosphamide
Fludarabine monophosphate
Fludarabine
Aldesleukin
Interleukin-2
Freund's Adjuvant
Lenograstim

Vidarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Adjuvants, Immunologic
Analgesics, Non-Narcotic
Analgesics

ClinicalTrials.gov processed this record on February 12, 2012