Cyclophosphamide and Fludarabine Followed by Vaccine Therapy, Gene-Modified White Blood Cell Infusions, and Aldesleukin in Treating Patients With Metastatic Melanoma

National Institutes of Health Clinical Center (CC)

Status and phase

Completed

Phase 1

Conditions

Melanoma (Skin)

Treatments

Procedure: autologous hematopoietic stem cell transplantation

Biological: aldesleukin

Biological: therapeutic tumor infiltrating lymphocytes

Biological: therapeutic autologous lymphocytes

Radiation: total-body irradiation

Biological: filgrastim

Biological: MART-1:27-35 peptide vaccine

Drug: cyclophosphamide

Biological: incomplete Freund's adjuvant

Drug: fludarabine phosphate

Procedure: in vitro-treated peripheral blood stem cell transplantation

Study type

Interventional

Funder types

NIH

Identifiers

NCT00091104

04-C-0251

040251

CDR0000383246

NCI-6974

Details and patient eligibility

About

RATIONALE: Inserting a laboratory-treated gene into a person's white blood cells may make the body build an immune response to kill tumor cells. Giving cyclophosphamide and fludarabine before a white blood cell infusion may suppress the immune system and allow tumor cells to be killed. Vaccines may make the body build an immune response to kill tumor cells. Aldesleukin may stimulate a person's white blood cells to kill tumor cells. Combining white blood cell infusion with vaccine therapy and aldesleukin may cause a stronger immune response and kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of gene-modified white blood cells when given together with cyclophosphamide, fludarabine, vaccine therapy, and aldesleukin and to see how well it works in treating patients with metastatic melanoma.

Full description

OBJECTIVES:

Primary

Determine the safety of peripheral blood lymphocytes (PBLs) retrovirally transduced with an anti-MART-1 T-cell receptor (TCR) gene followed by high-dose aldesleukin (IL-2) and MART-1:27-35 peptide vaccine in patients with HLA-A*0201-positive metastatic melanoma receiving a myeloablative preparative regimen comprising cyclophosphamide, fludarabine phosphate, and total-body irradiation.
Determine, preliminarily, whether antitumor antigen TCR-engineered tumor-infiltrating lymphocytes or PBLs followed by IL-2 and MART-1:26-35 after a nonmyeloablative but lymphoid-depleting preparative regimen will result in clinical tumor regression in these patients.

Secondary

Determine the in vivo survival of TCR gene-engineered cells from these patients.
Evaluate, preliminarily, clinical response in these patients.

OUTLINE: Patients with resectable tumor undergo tumor biopsy. Tumor-infiltrating lymphocytes (TILs) from the tumor sample are cultured in vitro and tested for reactivity to melanoma antigens. Patients who are unable to undergo biopsy or whose TILs do not grow in culture are assigned to groups I or II. Patients whose tumors yield TILs that do not exhibit melanoma reactivity are assigned to group III. Patients with TILs that exhibit melanoma reactivity are removed from the study.

Autologous stem cell collection: Patients undergo stem cell collection on treatment protocol NCI-03-C-0277 for reinfusion after the myeloablation and cell therapy. Patients receive filgrastim (G-CSF) subcutaneously (SC) twice daily beginning on day 0 and continuing for up to 5 days. Patients then undergo stem cell collection by apheresis or bone marrow harvest beginning on day 5 and continuing for up to 3 days. Some patients may receive a second course of G-CSF and undergo additional stem cell collection by apheresis or undergo treatment as outlined in group II.
Group I (peripheral blood lymphocytes [PBLs] with myeloablative preparative regimen): Patients receive a myeloablative preparative regimen comprising cyclophosphamide IV over 1 hour on days -7 and -6, fludarabine phosphate IV over 15-30 minutes on days -7 to -3, and total-body irradiation twice daily on days -3 to -1. Patients also receive autologous in vitro tumor-reactive, T-cell receptor (TCR) gene-transduced PBLs IV over 20-30 minutes on day 1 and aldesleukin IV over 15 minutes every 8 hours on days 1-5, and G-CSF SC daily beginning on day 1 and continuing until blood counts recover.
Group II (PBLs with nonmyeloablative preparative regimen): Patients who do not meet the eligibility criteria for group I receive a nonmyeloablative preparative regimen comprising cyclophosphamide IV over 1 hour on days -7 and -6 and fludarabine phosphate IV over 30 minutes on days -5 to -1. Patients then receive aldesleukin, and G-CSF as in group I.
Group III (autologous transduced TILs): Patients who have resected tumors that yield viable TILs have their TILs transduced with the anti-MART-1 TCR gene retroviral vector. Patients receive cyclophosphamide and fludarabine phosphate as in group II. Patients then receive autologous transduced TILs IV over 20-30 minutes on day 0. Patients also receive G-CSF and high-dose aldesleukin as in group I.

All patients receive peptide immunizations with MART-1:27-35 peptide vaccine emulsified in incomplete Freund's adjuvant SC on days 0-4, 11, 18, and 25.

In groups II or III, treatment may repeat once 6-8 weeks later for a total of 2 courses in the absence of disease progression or unacceptable toxicity. Treatment may consist of the first type cell infusion or patients may crossover to receive the other cell infusion (PBLs vs TILs).

After completion of study treatment, patients are followed periodically for at least 5 years.

PROJECTED ACCRUAL: A total of 136 patients will be accrued for this study.

Enrollment

136 estimated patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

DISEASE CHARACTERISTICS:

Diagnosis of metastatic melanoma
HLA-A*0201-positive disease
Measurable disease
Refractory to standard therapy, including high-dose aldesleukin therapy

PATIENT CHARACTERISTICS:

Age

18 and over

Performance status

ECOG 0-1

Life expectancy

More than 3 months

Hematopoietic

Absolute neutrophil count > 1,000/mm^3
Platelet count > 100,000/mm^3
Hemoglobin > 8.0 g/dL
Lymphocyte count > 500/mm^3
WBC > 3,000/mm^3
No coagulation disorder

Hepatic

ALT and AST < 3 times upper limit of normal
Bilirubin ≤ 2.0 mg/dL (< 3.0 mg/dL for patients with Gilbert's disease)
Hepatitis B antigen negative
Hepatitis C antibody negative (unless antigen negative)

Renal

Creatinine ≤ 1.6 mg/dL

Cardiovascular

No myocardial infarction
No cardiac arrhythmias
No cardiac ischemia
LVEF ≥ 45% by stress cardiac test* (for patients ≥ 50 years of age OR those with a history of EKG abnormalities)
No other major cardiovascular illness by stress thallium or comparable test NOTE: *Stress thallium, stress MUGA, dobutamine echocardiogram, or other stress test

Pulmonary

No major respiratory illness
No obstructive or restrictive pulmonary disease
FEV_1 ≥ 60% of predicted on pulmonary function test*
DLCO ≥ 60% predicted (for total-body irradiation cohort) NOTE: *For patients with a prolonged history of cigarette smoking or symptoms of respiratory dysfunction

Immunologic

HIV negative
No major immune system illness
No active systemic infection or opportunistic infection
No primary immunodeficiency (e.g., autoimmune colitis or Crohn's disease)
No secondary immunodeficiency (e.g., due to chemotherapy or radiotherapy)
No history of severe immediate hypersensitivity reaction to study drugs

Other

Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception during and for 4 months after completion of study treatment
Must sign a durable power of attorney

PRIOR CONCURRENT THERAPY:

Biologic therapy

See Disease Characteristics
Recovered from prior immunotherapy
Prior immunization to melanoma antigens allowed
- Progressive disease during prior immunization allowed
Prior cellular therapy, including vector transduction with or without myeloablation, allowed
More than 6 weeks since prior anticytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) monoclonal antibody (MDX-010) therapy
No prior anti-CTLA-4 antibody unless a post anti-CTLA-4 antibody treatment colonoscopy was normal by biopsy