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Treatment of Patients With Metastatic Melanoma Using a Transplant of Autologous Lymphocytes Reactive With Tumor Following a Myeloablative Lymphocyte Depleting Regimen of Chemotherapy, Total Body Irradiation and Reconstitution With CD34+ Cells

Phase 2
18 Years
Not Enrolling
Melanoma (Skin)

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Trial Information

Treatment of Patients With Metastatic Melanoma Using a Transplant of Autologous Lymphocytes Reactive With Tumor Following a Myeloablative Lymphocyte Depleting Regimen of Chemotherapy, Total Body Irradiation and Reconstitution With CD34+ Cells



- Determine complete clinical tumor regression in patients with metastatic melanoma
treated with a myeloablative lymphoid-depleting preparative regimen comprising
cyclophosphamide, fludarabine, and total body irradiation followed by autologous
tumor-reactive tumor-infiltrating lymphocyte infusion, autologous CD34+ stem cell
transplantation, and low-dose or high-dose interleukin-2.

- Evaluate the safety of this regimen in these patients.


- Determine the survival of the infused lymphocytes by analyzing the sequence of the
variable region of the T-cell receptor or flow cytometry in patients treated with this


- Autologous stem cell collection: Patients receive filgrastim (G-CSF) subcutaneously
(SC) twice daily for 8 days. Beginning on day 5 of G-CSF, patients undergo apheresis
daily for up to 3 days. Patients may receive 1 additional course of G-CSF and apheresis
or use stem cells stored from a prior stem cell harvest in order to obtain an adequate
number of cells.

- Lymphocyte-depleting myeloablative preparative regimen: Patients receive
cyclophosphamide intravenous (IV) over 1 hour on days -5 and -6 and fludarabine IV over
15-30 minutes on days -6 to -2. Patients also undergo total body irradiation on day -1.

- Autologous lymphocyte infusion: Patients receive autologous tumor-reactive
tumor-infiltrating lymphocytes IV over 20-30 minutes on day 0* followed by G-CSF SC
once daily until blood counts recover.

- Autologous stem cell transplantation: Patients receive autologous CD34+ stem cells IV
on day 2.

- Interleukin therapy: Patients are assigned to 1 of 2 cohorts, depending on whether they
have received prior high-dose interleukin-2 (IL-2).

- Cohort 1 (patients who received prior high-dose IL-2): Beginning on day 0*,
patients receive high-dose IL-2 IV over 15 minutes 3 times daily for up to 5 days
(maximum of 15 doses).

- Cohort 3 (patients who have not received prior high-dose IL-2): Patients receive
treatment as in cohort 1.

NOTE: *Day 0 is 1-4 days after the last dose of fludarabine.

Patients are evaluated at 4-6 weeks.

PROJECTED ACCRUAL: A total of 116 patients will be accrued for this study.

Inclusion Criteria


- Diagnosis of metastatic melanoma

- Measurable disease

- Resected or stable brain metastases are allowed



- 18 and over

Performance status

- Eastern Cooperative Oncology Group (ECOG) 0-1

Life expectancy

- At least 3 months


- See Immunologic

- Absolute neutrophil count > 1,000/mm^3 (without support of filgrastim [G-CSF])

- Platelet count > 100,000/mm^3

- Hemoglobin ≥ 8 g/dL (transfusion allowed)

- No coagulation disorders


- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3 times upper
limit of normal

- Bilirubin ≤ 2 mg/dL (< 3 mg/dL in patients with Gilbert's syndrome)

- No hepatitis B or C


- Creatinine ≤ 1.6 mg/dL


- Left ventricular ejection fraction (LVEF) ≥ 45% by cardiac stress test*

- No active major cardiovascular illness as evidenced by stress thallium or other
comparable test

- No myocardial infarction

- No cardiac arrhythmias NOTE: *For patients ≥ 50 years of age receiving high-dose
interleukin-2 (IL-2) OR patients with a history of electrocardiogram (EKG)
abnormalities, symptoms of cardiac ischemia, or arrhythmias


- Forced expiratory volume 1 (FEV_1) ≥ 60% of predicted by pulmonary function test in
patients with prolonged history of cigarette smoking or symptoms of respiratory

- No active major respiratory illness

- No obstructive or restrictive pulmonary disease NOTE: *For patients receiving
high-dose IL-2 only


- No active major immunologic illness

- No active systemic infections

- No primary or secondary immunodeficiency

- Fully recovered immune competence after prior chemotherapy or radiotherapy as
evidenced by both of the following:

- Absolute neutrophil count > 1,000/mm^3

- No opportunistic infections

- Human Immunodeficiency virus (HIV) negative

- Epstein-Barr virus positive


- Not pregnant or nursing

- Fertile patients must use effective contraception during and for 4 months after study


Biologic therapy

- See Disease Characteristics


- At least 6 weeks since prior nitrosourea therapy

- No prior cyclophosphamide and fludarabine as part of a preparative regimen on
National Cancer Institute (NCI) Surgery Branch adoptive cell therapy studies unless
sufficient numbers of CD34+ stem cells (more than 2 x10^6/kg patient weight) have
been obtained prior to the administration of chemotherapy

Endocrine therapy

- No concurrent systemic steroid therapy


- Not specified


- See Disease Characteristics

- Prior minor surgery within the past 3 weeks allowed if recovered


- Recovered from all prior therapy

- At least 30 days since prior systemic therapy

- No other concurrent experimental agents

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Clinical Tumor Regression

Outcome Description:

Tumor regression is defined as a complete response (CR) or partial response (PR) and was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response is the disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD.

Outcome Time Frame:

Every 4-6 weeks for up to 1 year, and then every 6 months for up to 5 years.

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:

September 2004

Completion Date:

January 2009

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