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A Study in Metastatic Melanoma Using a Lymphodepleting Conditioning Followed by Infusion of Anti-MART-1 TCR-Gene Engineered Lymphocytes and Subsequent Peptide Immunization

Phase 1
18 Years
Not Enrolling
Melanoma (Skin)

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Trial Information

A Study in Metastatic Melanoma Using a Lymphodepleting Conditioning Followed by Infusion of Anti-MART-1 TCR-Gene Engineered Lymphocytes and Subsequent Peptide Immunization



- 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.


- 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

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

Inclusion Criteria


- Diagnosis of metastatic melanoma

- HLA-A*0201-positive disease

- Measurable disease

- Refractory to standard therapy, including high-dose aldesleukin therapy



- 18 and over

Performance status

- ECOG 0-1

Life expectancy

- More than 3 months


- 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


- 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)


- Creatinine ≤ 1.6 mg/dL


- 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


- 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


- 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


- 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


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,

- 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


- Recovered from prior chemotherapy

Endocrine therapy

- No concurrent systemic steroids


- Recovered from prior radiotherapy

- No prior significant mediastinal or lung radiation (for total-body irradiation


- Not specified


- More than 4 weeks since prior systemic therapy and recovered

Type of Study:


Study Design:

Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:


Safety Issue:


Principal Investigator

Steven A. Rosenberg, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

NCI - Surgery Branch


United States: Food and Drug Administration

Study ID:




Start Date:

July 2004

Completion Date:

October 2010

Related Keywords:

  • Melanoma (Skin)
  • stage IV melanoma
  • recurrent melanoma
  • Melanoma



Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office Bethesda, Maryland  20892-1182
NCI - Surgery Branch Bethesda, Maryland  20892-1201