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Phase II Study of Metastatic Melanoma Using a Chemoradiation Lymphodepleting Conditioning Regimen Followed by Infusion of Anti-Mart-1 and Anti-gp100 TCR-Gene Engineered Lymphocytes and Peptide Vaccines
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Bethesda |
| State: |
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Maryland |
| Zip Code: |
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20892 |
| Conditions: |
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Melanoma (Skin) |
| Purpose: |
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RATIONALE: Giving chemotherapy and total-body irradiation before an autologous stem cell
transplant stops the growth of tumor cells by stopping them from dividing or killing them.
Giving an infusion of the patient's lymphocytes that have been treated in the laboratory may
stimulate the immune system in different ways and stop tumor cells from growing. Aldesleukin
may stimulate lymphocytes to kill tumor cells. Vaccines made from peptides may help the body
build an effective immune response to kill tumor cells. The stem cells are then returned to
the patient to replace the blood-forming cells that were destroyed by the chemotherapy,
radiation therapy, lymphocyte therapy, and vaccine therapy.
PURPOSE: This randomized phase II trial is studying how well giving chemotherapy and
total-body irradiation together with laboratory-treated autologous lymphocytes, aldesleukin,
and vaccine therapy works in treating patients with metastatic melanoma.
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| Study Summary: |
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OBJECTIVES:
Primary
- Determine if the administration of anti-gp100:154-162 and anti-MART-1:27-35 T-cell
receptor (TCR) gene-engineered peripheral blood lymphocytes (PBL), high-dose
aldesleukin, and gp100:154-162 or MART-1:26-35(27L) peptide vaccination following a
chemoradiation lymphodepleting preparative regimen results in complete clinical tumor
regression in patients with metastatic melanoma (closed as of 09/21/09).
- Determine if the administration of anti-gp100:154-162 and anti-MART-1:27-35 TCR
gene-engineered CD8+ PBL, high-dose aldesleukin, and gp100:154-162 or MART-1:26-35(27L)
peptide vaccination following a chemoradiation lymphodepleting preparative regimen
results in complete clinical tumor regression in patients with metastatic melanoma.
- Determine whether the administration of the specific vaccine (gp100:154-162 or
MART-1:26-35[27L] peptide) can increase the persistence of the specific transferred
cells (anti-gp100:154-162, anti-gp100:154-162 TCR CD8+ PB, anti-MART-1:27-35 TCR PBL,
or anti-MART-1:27-35 TCR CD8+ PBL) in these patients.
Secondary
- Determine the toxicity profile of these treatment regimens in these patients.
OUTLINE:
- Leukapheresis and cell preparation: Patients undergo leukapheresis to obtain stem cells
(for re-infusion after peripheral blood lymphocyte [PBL] therapy) and peripheral blood
mononuclear cells (PBMCs). The PBMCs are cultured in the presence of anti-CD3 (OKT3)
and aldesleukin to stimulate T-cell growth and submitted to CliniMACS microbead for CD8
separation and purification. CD8+ PBL are then transduced by exposure to gp100:154-162
and MART-1 F5 T-cell receptor (TCR) retroviral vectors and expanded in culture.
- Lymphocyte-depleting preparative regimen: Patients receive cyclophosphamide IV over 1
hour on days -6 and -5 and fludarabine phosphate IV over 15-30 minutes on days -6 to
-2. Patients undergo total-body irradiation twice on day -2 and once on day -1.
- Gene-engineered autologous PBL infusion (closed as of 09/21/09): Patients receive
anti-MART-1:27-35 or anti-gp100:154-162 TCR gene-engineered autologous transduced PBL
IV over 20-30 minutes on day 0. Patients also receive filgrastim (G-CSF) subcutaneously
(SC) daily beginning on day 0 or 1 and continuing until blood counts recover.
- Gene-engineered autologous CD8+ peripheral blood lymphocyte infusion: Patients receive
anti-MART-1:27-35 and anti-gp100:154-162 TCR gene-engineered autologous transduced CD8+
PBL IV over 20-30 minutes on day 0. Patients also receive filgrastim (G-CSF)
subcutaneously (SC) daily beginning on day 0 or 1 and continuing until blood counts
recover.
- High-dose aldesleukin: Patients receive high-dose aldesleukin IV over 15 minutes every
8 hours on days 0-4 (maximum of 15 doses).
- Peptide vaccination:Patients are randomized to 1 of 2 peptide vaccination arms.
- Arm I: Patients receive gp100:154-162 peptide vaccine emulsified in incomplete
Freund's adjuvant (IFA) SC on days 0, 7, and 14.
- Arm II: Patients receive MART-1:26-35(27L) peptide vaccine emulsified in IFA SC on
days 0, 7, and 14.
- Autologous stem cell infusion: Patients receive autologous CD34+ selected stem cells IV
on day 1.
Blood samples are collected periodically for immunological monitoring. Samples are analyzed
by PCR, FACS analysis using tetramer staining, immunological assays, and RT-PCR.
After completion of study therapy, patients are followed periodically for up to 15 years.
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| Criteria: |
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DISEASE CHARACTERISTICS:
- Diagnosis of metastatic melanoma
- Measurable disease
- Progressive or recurrent disease after prior aldesleukin
- HLA-A*0201 positive
- gp100 and MART-1 positive (≥ 1+ and > 5%) as assessed by IHC
PATIENT CHARACTERISTICS:
- ECOG performance status 0-1
- Life expectancy > 3 months
- Absolute neutrophil count > 1,000/mm³
- WBC > 3,000/mm³
- Platelet count > 100,000/mm³
- Hemoglobin > 8.0 g/dL
- ALT and AST ≤ 2.5 times upper limit of normal
- Total bilirubin ≤ 1.5 mg/dL (< 3.0 g/dL in patients with Gilbert syndrome)
- Serum creatinine ≤ 1.6 mg/dL
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception during and for up to 4 months after
receiving the preparative regimen
- LVEF ≥ 45% in patients ≥ 60 years of age or with clinically significant atrial and/or
ventricular arrhythmias including, but not limited to, any of the following:
- Atrial fibrillation
- Ventricular tachycardia
- Second or third degree heart block
- FEV_1 > 60% predicted in patients with a prolonged history of cigarette smoking
(i.e., > 20 pack/year within the past 2 years) or symptoms of respiratory distress
- HIV antibody negative
- Hepatitis B antigen negative
- Hepatitis C antibody negative (unless antigen negative)
- Normal colonoscopy with normal colonic biopsies (for patients previously treated with
anti-CTLA4 antibody therapy)
- No coagulation disorders
- No myocardial infarction or cardiac arrhythmias
- No history of coronary revascularization
- No obstructive or restrictive pulmonary disease
- No active systemic infections
- No primary immunodeficiency (e.g., severe combined immunodeficiency disease)
- No other major medical illnesses of the cardiovascular, respiratory, or immune system
- No history of severe immediate hypersensitivity reaction to any of the agents used in
this study
- No contraindications for high-dose aldesleukin administration
PRIOR CONCURRENT THERAPY:
- See Disease Characteristics
- More than 4 weeks since prior systemic therapy and recovered (alopecia or vitiligo
allowed)
- At least 6 weeks since prior anti-CTLA4 antibody therapy
- No concurrent systemic steroid therapy
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| NCT ID: |
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NCT00814684 |
| Primary Contact: |
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Principal Investigator
Steven A. Rosenberg, MD, PhD
NCI - Surgery Branch
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| Backup Contact: |
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N/A |
| Location Contact: |
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Bethesda, Maryland 20892
United States
Clinical Trials Office - Warren Grant Magnusen Clinical Center
Phone: 888-NCI-1937
Site Status: Recruiting |
| Data Source: |
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ClinicalTrials.gov |
| Date Processed: |
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May 22, 2013 |
| Modifications to this listing: |
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