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Cyclophosphamide, Fludarabine, and Total-Body Irradiation Followed By Cellular Adoptive Immunotherapy, Autologous Stem Cell Transplantation, and Interleukin-2 in Treating Patients With Metastatic Melanoma

Primary Purpose

Melanoma (Skin)

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
aldesleukin
filgrastim
therapeutic tumor infiltrating lymphocytes
cyclophosphamide
fludarabine phosphate
radiation therapy
Sponsored by
National Institutes of Health Clinical Center (CC)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Melanoma (Skin) focused on measuring stage IV melanoma, recurrent melanoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

DISEASE CHARACTERISTICS: Diagnosis of metastatic melanoma Measurable disease Resected or stable brain metastases are allowed PATIENT CHARACTERISTICS: Age 18 and over Performance status Eastern Cooperative Oncology Group (ECOG) 0-1 Life expectancy At least 3 months Hematopoietic 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 Hepatic 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 Renal Creatinine ≤ 1.6 mg/dL Cardiovascular 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 Pulmonary 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 dysfunction* No active major respiratory illness No obstructive or restrictive pulmonary disease NOTE: *For patients receiving high-dose IL-2 only Immunologic 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 Other Not pregnant or nursing Fertile patients must use effective contraception during and for 4 months after study treatment PRIOR CONCURRENT THERAPY: Biologic therapy See Disease Characteristics Chemotherapy 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 Radiotherapy Not specified Surgery See Disease Characteristics Prior minor surgery within the past 3 weeks allowed if recovered Other Recovered from all prior therapy At least 30 days since prior systemic therapy No other concurrent experimental agents

Sites / Locations

  • Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office
  • NCI - Surgery Branch

Arms of the Study

Arm 1

Arm 2

Arm Type

Other

Other

Arm Label

TBI 200cGy + TIL +HD IL-2, prior IL-2

TBI 200cGy + TIL +HD IL-2, No prior IL-2

Arm Description

Patients will receive 2Gy of total body irradiation (TBI) at a rate of 0.07 Gy/minute using a linear accelerator. Lymphocytes that that are isolated from the tumor, grown in the laboratory to high amounts and then infused into the patient.

Patients will receive 2Gy of total body irradiation (TBI) at a rate of 0.07 Gy/minute using a linear accelerator. Lymphocytes that that are isolated from the tumor, grown in the laboratory to high amounts and then infused into the patient.

Outcomes

Primary Outcome Measures

Clinical Tumor Regression
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.
Safety
Here is the number of participants with adverse events. For a detailed list of adverse events see the adverse event module.

Secondary Outcome Measures

Full Information

First Posted
November 9, 2004
Last Updated
October 6, 2015
Sponsor
National Institutes of Health Clinical Center (CC)
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00096382
Brief Title
Cyclophosphamide, Fludarabine, and Total-Body Irradiation Followed By Cellular Adoptive Immunotherapy, Autologous Stem Cell Transplantation, and Interleukin-2 in Treating Patients With Metastatic Melanoma
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
September 2015
Overall Recruitment Status
Completed
Study Start Date
September 2004 (undefined)
Primary Completion Date
January 2009 (Actual)
Study Completion Date
January 2009 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
National Institutes of Health Clinical Center (CC)
Collaborators
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
RATIONALE: Drugs used in chemotherapy, such as cyclophosphamide and fludarabine, work in different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Biological therapies, such as cellular adoptive immunotherapy, work in different ways to stimulate the immune system and stop tumor cells from growing. Autologous stem cell transplant may be able to replace immune cells that were destroyed by chemotherapy and radiation therapy. Interleukin-2 may stimulate a person's lymphocytes to kill tumor cells. Combining chemotherapy, radiation therapy, and biological therapy may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving cyclophosphamide and fludarabine together with radiation therapy followed by cellular adoptive immunotherapy, autologous stem cell transplant, and interleukin-2 works in treating patients with metastatic melanoma.
Detailed Description
OBJECTIVES: Primary 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. Secondary 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 regimen. OUTLINE: 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Melanoma (Skin)
Keywords
stage IV melanoma, recurrent melanoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
34 (Actual)

8. Arms, Groups, and Interventions

Arm Title
TBI 200cGy + TIL +HD IL-2, prior IL-2
Arm Type
Other
Arm Description
Patients will receive 2Gy of total body irradiation (TBI) at a rate of 0.07 Gy/minute using a linear accelerator. Lymphocytes that that are isolated from the tumor, grown in the laboratory to high amounts and then infused into the patient.
Arm Title
TBI 200cGy + TIL +HD IL-2, No prior IL-2
Arm Type
Other
Arm Description
Patients will receive 2Gy of total body irradiation (TBI) at a rate of 0.07 Gy/minute using a linear accelerator. Lymphocytes that that are isolated from the tumor, grown in the laboratory to high amounts and then infused into the patient.
Intervention Type
Biological
Intervention Name(s)
aldesleukin
Other Intervention Name(s)
IL-2, Interleukin-2
Intervention Description
high dose: 720,000 IU/kg intravenously over 15 minutes every 8 hours for up to 5 days (maximum 5 doses) or low dose: 250,000 IU/kg subcutaneously daily for 5 days, after a two day rest, 125,000 IU/kg subcutaneously daily for 5 days for five weeks (2 days rest per week)
Intervention Type
Biological
Intervention Name(s)
filgrastim
Other Intervention Name(s)
GCSF
Intervention Description
10 mcg/kg/day daily subcutaneously until neutrophil count >1x10^9/1.
Intervention Type
Biological
Intervention Name(s)
therapeutic tumor infiltrating lymphocytes
Intervention Description
Lymphocytes that are isolated from the tumor, grown in the laboratory to high amounts and then infused into the patient.
Intervention Type
Drug
Intervention Name(s)
cyclophosphamide
Other Intervention Name(s)
Cytoxan
Intervention Description
60 mg/kg/day x 2 days intravenously over 1 hour
Intervention Type
Drug
Intervention Name(s)
fludarabine phosphate
Other Intervention Name(s)
Fludara
Intervention Description
25 mg/m^2/day intravenous piggyback daily over 15-20 minutes for 5 days
Intervention Type
Radiation
Intervention Name(s)
radiation therapy
Other Intervention Name(s)
total body irradiation
Intervention Description
Patients will receive 2Gy of total body irradiation (TBI) at a rate of 0.07 Gy/minute using a linear accelerator.
Primary Outcome Measure Information:
Title
Clinical Tumor Regression
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.
Time Frame
Every 4-6 weeks for up to 1 year, and then every 6 months for up to 5 years.
Title
Safety
Description
Here is the number of participants with adverse events. For a detailed list of adverse events see the adverse event module.
Time Frame
4 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
DISEASE CHARACTERISTICS: Diagnosis of metastatic melanoma Measurable disease Resected or stable brain metastases are allowed PATIENT CHARACTERISTICS: Age 18 and over Performance status Eastern Cooperative Oncology Group (ECOG) 0-1 Life expectancy At least 3 months Hematopoietic 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 Hepatic 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 Renal Creatinine ≤ 1.6 mg/dL Cardiovascular 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 Pulmonary 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 dysfunction* No active major respiratory illness No obstructive or restrictive pulmonary disease NOTE: *For patients receiving high-dose IL-2 only Immunologic 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 Other Not pregnant or nursing Fertile patients must use effective contraception during and for 4 months after study treatment PRIOR CONCURRENT THERAPY: Biologic therapy See Disease Characteristics Chemotherapy 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 Radiotherapy Not specified Surgery See Disease Characteristics Prior minor surgery within the past 3 weeks allowed if recovered Other Recovered from all prior therapy At least 30 days since prior systemic therapy No other concurrent experimental agents
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Steven A. Rosenberg, MD, PhD
Organizational Affiliation
NCI - Surgery Branch
Official's Role
Principal Investigator
Facility Information:
Facility Name
Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892-1182
Country
United States
Facility Name
NCI - Surgery Branch
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892-1201
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
22555974
Citation
Yao X, Ahmadzadeh M, Lu YC, Liewehr DJ, Dudley ME, Liu F, Schrump DS, Steinberg SM, Rosenberg SA, Robbins PF. Levels of peripheral CD4(+)FoxP3(+) regulatory T cells are negatively associated with clinical response to adoptive immunotherapy of human cancer. Blood. 2012 Jun 14;119(24):5688-96. doi: 10.1182/blood-2011-10-386482. Epub 2012 May 3.
Results Reference
derived

Learn more about this trial

Cyclophosphamide, Fludarabine, and Total-Body Irradiation Followed By Cellular Adoptive Immunotherapy, Autologous Stem Cell Transplantation, and Interleukin-2 in Treating Patients With Metastatic Melanoma

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