Prospective Randomized Study of Cell Transfer Therapy for Metastatic Melanoma Using Tumor Infiltrating Lymphocytes Plus IL-2 Following Non-Myeloablative Lymphocyte Depleting Chemo Regimen Alone or in Conjunction With 12Gy Total Body Irradiation (TBI...

A Prospective Randomized Study of Cell Transfer Therapy for Metastatic Melanoma Using Short-Term Cultured Tumor-Infiltrating Lymphocytes Plus IL-2 Following Either a Non-Myeloablative Lymphocyte Depleting Chemotherapy Regimen Alone or in Conjunction With 12Gy Total Body Irradiation (TBI)

Background:

- An experimental treatment for metastatic melanoma involves cell therapy, in which researchers take white blood cells (lymphocytes) from the tumor tissue, grow them in the laboratory in large numbers, and then use the cells to attack the tumor tissue. Before receiving the cells, chemotherapy is needed to temporarily suppress the immune system to improve the chances that the tumor-fighting cells will be able to survive in the body. In some studies of cell therapy, individuals who have received total body irradiation (TBI) in addition to the chemotherapy (in order to increase the length of time that they do not produce white blood cells) seem to have a slightly better response to the treatment, but it is not known if adding radiation to the cell therapy will cause a better response for all individuals. Researchers are interested in comparing cell therapy given with the usual chemotherapy to cell therapy given with the usual chemotherapy and TBI.

Objectives:

- To compare the effectiveness of cell therapy given with chemotherapy to cell therapy given with chemotherapy and total body irradiation in individuals with metastatic melanoma.

Eligibility:

- Individuals at least 18 years of age who have been diagnosed with metastatic melanoma.

Design:

• Participants will be screened with a physical examination, medical history, blood tests, and tumor imaging studies.
• Participants will be divided into two groups: cell therapy with chemotherapy alone (group 1) or cell therapy with chemotherapy plus TBI (group 2).
• All participants will provide a tumor sample from either surgery or a tumor biopsy for white blood cell collection.
• Participants will have leukapheresis to collect additional white blood cells for cell growth and future testing, and TBI group participants will also provide stem cells to help them recover after radiation. (TBI participants who cannot provide enough stem cells will be moved to the non-radiation treatment group.)
• Participants will have chemotherapy with cyclophosphamide (two treatments over 2 days) and fludarabine (five treatments over 5 days) starting 7 days before the cell therapy. Participants in the TBI group will also have TBI for the 3 days immediately before the cell therapy.
• All participants will receive the white blood cells, followed by high dose aldesleukin every 8 hours for up to 5 days after the cell infusion to help keep the therapy cells alive and active. Participants will also have injections of filgrastim to stimulate blood cell production, and participants in the TBI group will also receive their stem cells.
• Participants will take an antibiotic for at least 6 months after treatment to prevent pneumonia and will be asked to return for regular monitoring and follow-up visits for at least 5 years to evaluate the tumors response to treatment.

Study Overview

• Status: Completed
• Conditions: Skin Cancer; Metastatic Melanoma
• Intervention / Treatment: Biological: Young TIL; Drug: Aldesleukin; Drug: Cyclophosphamide; Drug: Fludarabine; Radiation: Total Body Irradiation (TBI)

Detailed Description

Background:

• Adoptive cell therapy (ACT) using autologous tumor infiltrating lymphocytes can mediate the regression of bulky metastatic melanoma when administered along with high-dose aldesleukin (IL-2) following a non-myeloablative lymphodepleting chemotherapy preparative regimen consisting of cyclophosphamide and fludarabine.
• In a series of consecutive trials using this chemotherapy preparative regimen alone or with 2 Gray (Gy) or 12 Gy total body irradiation (TBI) objective response rates using Response Evaluation Criteria in Solid Tumors (RECIST) criteria were 49%, 52%, and 72%, respectively. Complete regression rates in these three consecutive trials were 12%, 20%, and 40%, respectively strongly suggesting that the addition of TBI could improve the complete regression rate. Of the 20 complete regressions seen in this trial, 19 are on-going at 37 to 82 months.
• Because of the complexity of developing selected TIL for use in adoptive transfer, we have recently developed a simplified method for producing TIL that is more applicable to use in outside institutions. Utilizing young TIL cells (sometimes with cluster of differentiation 8 (CD8) purification) in 105 patients, the objective response rate was 34% with a 6.6 % incidence of complete regressions. All patients in this trial received the cyclophosphamide fludarabine regimen alone.
• Because of the strong suggestion that the addition of TBI to the chemotherapy regimen could increase durable, complete regression rates in patients with metastatic melanoma, we are now attempting to definitively determine whether the addition of TBI to the chemotherapy preparative regimen can improve complete response rates, and overall survival in patients receiving young TIL.

Objectives:

-To determine, in a prospective randomized trial, the complete response rate and survival of patients with metastatic melanoma receiving adoptive cell transfer (ACT) using young TIL plus aldesleukin treatment following either a chemotherapy preparative regimen alone, or the same chemotherapy preparative regimen plus TBI.

Eligibility:

-Patients who are 18 years or older must have:

• Evaluable metastatic melanoma;
• Metastatic melanoma lesion suitable for surgical resection for the preparation of TIL;
• No contraindications to high dose aldesleukin administration or total body irradiation;
• No concurrent major medical illnesses or any form of immunodeficiency

Design:

-Patients with metastatic melanoma will have lesions resected and after TIL growth is established patients with will be prospectively randomized to receive ACT with young TIL plus aldesleukin following either a non-myeloablative chemotherapy preparative regimen or this same regimen plus TBI.

• Study Type: Interventional
• Enrollment (Actual): 102
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 66 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

• INCLUSION CRITERIA:

  1. Measurable metastatic melanoma with at least one lesion that is resectable for tumor infiltrating lymphocytes (TIL) generation. The lesion must be of at least 1cm in diameter that can be surgically removed with minimal morbidity (defined as any operation for which expected hospitalization less than or equal to 7 days).
  2. Patients with 3 or less brain metastases are eligible. Note: If lesions are symptomatic or greater than or equal to 1 cm each, these lesions must have been treated and stable for 3 months for the patient to be eligible.
  3. Greater than or equal to 18 years of age and less than or equal to 66 years of age.
  4. Willing to practice birth control during treatment and for four months after receiving all protocol related therapy.
  5. Life expectancy of greater than three months
  6. Willing to sign a durable power of attorney.
  7. Able to understand and sign the Informed Consent Document
  8. Clinical performance status of eastern Cooperative Oncology Group (ECOG) 0 or 1.
  9. Hematology:
• Absolute neutrophil count greater than 1000/mm(3)
• Hemoglobin greater than 8.0 g/dl

• Platelet count greater than 100,000/mm(3)

  j. Serology:

• Seronegative for human immunodeficiency virus (HIV) antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immune competence and thus be less responsive to the experimental treatment and more susceptible to its toxicities.)

• Seronegative for hepatitis B antigen, or hepatitis C antibody or antigen.

  k. Chemistry:

• Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less than three times the upper limit of normal.
• Calculated creatinine clearance (eGFR) > 50 ml/min.
• Total bilirubin less than or equal to 2 mg/dl, except in patients with

Gilbert's Syndrome who must have a total bilirubin less than 3 mg/dl.

l. More than four weeks must have elapsed since any prior systemic therapy at the time of randomization, and patient's toxicities must have recovered to a grade 1 or less (except for alopecia or vitiligo). Patients must have stable or progressing disease after prior treatment.

Note: Patients may have undergone minor surgical procedures within the past 3 weeks, as long as all toxicities have recovered to grade 1 or less or as specified in the inclusion criteria.

m. Six weeks must have elapsed since any prior anti-cytotoxic T-lymphocyte associated protein 4 (CTLA4) antibody therapy to allow antibody levels to decline.

Note: Patients who have previously received ipilimumab or tremelimumab, anti-programmed cell death protein 1 (PD1) or anti-programmed cell death ligand 1 (PD-L1) antibodies and have documented gastrointestinal (GI) toxicity must have a normal colonoscopy with normal colonic biopsies.

EXCLUSION CRITERIA:

1. Prior cell transfer therapy which included a non-myeloablative or myeloablative chemotherapy regimen.
2. Women of child-bearing potential who are pregnant or breastfeeding because 10 of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant.
3. Systemic steroid therapy requirement.
4. Active systemic infections, coagulation disorders or other active major medical illnesses of the cardiovascular, respiratory or immune system, as evidenced by a positive stress thallium or comparable test, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease.
5. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease and acquired immunodeficiency syndrome (AIDS).
6. Opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities.)
7. History of severe immediate hypersensitivity reaction to any of the agents used in this study.
8. History of coronary revascularization or ischemic symptoms.
9. Any patient known to have a left ventricular ejection fraction (LVEF) less than or equal to 45%.
10. In patients > 60 years old, documented LVEF of less than or equal to 45%.

11. Documented forced expiratory volume in one second (FEV1) less than or equal to 60% predicted tested in patients with:

    • A prolonged history of cigarette smoking (20 pk/year of smoking within the past 2 years)
    • Symptoms of respiratory dysfunction
12. Prior radiation therapy that, in the judgment of the radiation oncologist, precludes the administration of total body irradiation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1/Adoptive Cell Therapy (ACT); Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + young tumor infiltrating lymphocytes (TIL) + high dose aldesleukin	Biological: Young TIL; Arm 1 and Arm 2 - Day 0: Cells will be infused intravenously (IV) on the Patient Care Unit over 20-30 minutes.; Other Names: Young tumor infiltrating lymphocytes; Drug: Aldesleukin; Arm 1 and Arm 2 - Days 1 to 4: Aldesleukin 720,000 IU/kg intravenous (IV) (based on total body weight) over 15 minutes every eight hours (+/- 1 hour) for up to 5 days (maximum 15 doses).; Other Names: Interleukin-2; Drug: Cyclophosphamide; Arm 1 and Arm 2 - Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 mL dextrose 5% in water (D5W) with Mesna 15 mg/kg/day X 2 days over 1 hr.; Other Names: Cytoxan; Drug: Fludarabine; Arm 1 and Arm 2 - Days -7 to -3: Fludarabine 25 mg/m^2/day intravenous piggyback (IVPB) daily over 15-30 minutes for 5 days.; Other Names: Fludara
Experimental: Arm 2/Adoptive Cell Therapy (ACT) + Total Body Irradiation (TBI); Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + young tumor infiltrating lymphocytes (TIL) + high dose aldesleukin + total body irradiation (TBI)	Biological: Young TIL; Arm 1 and Arm 2 - Day 0: Cells will be infused intravenously (IV) on the Patient Care Unit over 20-30 minutes.; Other Names: Young tumor infiltrating lymphocytes; Drug: Aldesleukin; Arm 1 and Arm 2 - Days 1 to 4: Aldesleukin 720,000 IU/kg intravenous (IV) (based on total body weight) over 15 minutes every eight hours (+/- 1 hour) for up to 5 days (maximum 15 doses).; Other Names: Interleukin-2; Drug: Cyclophosphamide; Arm 1 and Arm 2 - Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 mL dextrose 5% in water (D5W) with Mesna 15 mg/kg/day X 2 days over 1 hr.; Other Names: Cytoxan; Drug: Fludarabine; Arm 1 and Arm 2 - Days -7 to -3: Fludarabine 25 mg/m^2/day intravenous piggyback (IVPB) daily over 15-30 minutes for 5 days.; Other Names: Fludara; Radiation: Total Body Irradiation (TBI); Arm 2 - Days -3 to -1: Ondansetron 0.15 mg/kg intravenous (IV) x 1 dose pre-total body irradiation (TBI). Patients will then receive 2 Gray (Gy) TBI twice a day for 3 days (total dose 12 Gy using a linear accelerator in Radiation Oncology.; Other Names: TBI

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Have a Clinical Response to Treatment (Objective Tumor Regression)	Percentage of participants who have a clinical response to treatment (objective tumor regression) was measured by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Complete Response (CR) is disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as refence the baseline sum LD. Progressive Disease (PD) is at least a 20% increase in the sum of LD of target lesions taking as reference the smallest sum LD. The appearance of one or more new lesions is also considered progressions. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum LD.	Participants were followed from treatment to progression of disease or until principal investigator (PI) discretion (average 91.8 months).
Overall Survival (OS)	OS is defined as the time to death following the start of treatment.	Participants were followed from treatment until death (median 14 months) or until principal investigator (PI) discretion (median 99.0 months) for participants alive at study closure.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival (PFS)	PFS is defined as time to disease progression following the start of treatment. Disease progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v3.0. Progressive Disease is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD. The appearance of one or more new lesions is also considered progression.	Participants were followed from treatment until death or until principal investigator (PI) discretion. A median of 91.8 months.
Number of Grades 1, 2, 3, 4, and/or 5 Serious Adverse Events Possibly and/or Probably Related to Treatment	Here is the number of Grades 2, 3, 4, and/or 5 serious adverse events possibly and/or probably related to treatment. Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v3.0). Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe. Grade 4 is life-threatening. Grade 5 is death related to adverse event.	Time of registration through 6 years after the last treatment.
Number of Grades 1, 2, 3, 4, and/or 5 Non-serious Adverse Events Possibly and/or Probably Related to Treatment	Here is the number of Grades 1, 2, 3, 4, and/or 5 non-serious adverse events possibly and/or probably related to treatment. Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v3.0). Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe. Grade 4 is life-threatening. Grade 5 is death related to adverse event.	30 days after end of treatment, up to 6 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v3.0)	Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v3.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.	Participants will be followed for adverse events from registration through 30 days after the last treatment, up to 6 years

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Steven A Rosenberg, M.D., National Cancer Institute (NCI)

Publications and helpful links

General Publications

• Rosenberg SA, Yannelli JR, Yang JC, Topalian SL, Schwartzentruber DJ, Weber JS, Parkinson DR, Seipp CA, Einhorn JH, White DE. Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2. J Natl Cancer Inst. 1994 Aug 3;86(15):1159-66. doi: 10.1093/jnci/86.15.1159.
• Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M, Paradise C, Kunkel L, Rosenberg SA. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999 Jul;17(7):2105-16. doi: 10.1200/JCO.1999.17.7.2105.
• Dudley ME, Yang JC, Sherry R, Hughes MS, Royal R, Kammula U, Robbins PF, Huang J, Citrin DE, Leitman SF, Wunderlich J, Restifo NP, Thomasian A, Downey SG, Smith FO, Klapper J, Morton K, Laurencot C, White DE, Rosenberg SA. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol. 2008 Nov 10;26(32):5233-9. doi: 10.1200/JCO.2008.16.5449. Epub 2008 Sep 22.
• Crompton JG, Sukumar M, Roychoudhuri R, Clever D, Gros A, Eil RL, Tran E, Hanada K, Yu Z, Palmer DC, Kerkar SP, Michalek RD, Upham T, Leonardi A, Acquavella N, Wang E, Marincola FM, Gattinoni L, Muranski P, Sundrud MS, Klebanoff CA, Rosenberg SA, Fearon DT, Restifo NP. Akt inhibition enhances expansion of potent tumor-specific lymphocytes with memory cell characteristics. Cancer Res. 2015 Jan 15;75(2):296-305. doi: 10.1158/0008-5472.CAN-14-2277. Epub 2014 Nov 28.
• Goff SL, Dudley ME, Citrin DE, Somerville RP, Wunderlich JR, Danforth DN, Zlott DA, Yang JC, Sherry RM, Kammula US, Klebanoff CA, Hughes MS, Restifo NP, Langhan MM, Shelton TE, Lu L, Kwong ML, Ilyas S, Klemen ND, Payabyab EC, Morton KE, Toomey MA, Steinberg SM, White DE, Rosenberg SA. Randomized, Prospective Evaluation Comparing Intensity of Lymphodepletion Before Adoptive Transfer of Tumor-Infiltrating Lymphocytes for Patients With Metastatic Melanoma. J Clin Oncol. 2016 Jul 10;34(20):2389-97. doi: 10.1200/JCO.2016.66.7220. Epub 2016 May 23.
• Seitter SJ, Sherry RM, Yang JC, Robbins PF, Shindorf ML, Copeland AR, McGowan CT, Epstein M, Shelton TE, Langhan MM, Franco Z, Danforth DN, White DE, Rosenberg SA, Goff SL. Impact of Prior Treatment on the Efficacy of Adoptive Transfer of Tumor-Infiltrating Lymphocytes in Patients with Metastatic Melanoma. Clin Cancer Res. 2021 Oct 1;27(19):5289-5298. doi: 10.1158/1078-0432.CCR-21-1171.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): March 24, 2011
• Primary Completion (Actual): September 10, 2024
• Study Completion (Actual): September 10, 2024

Study Registration Dates

• First Submitted: March 18, 2011
• First Submitted That Met QC Criteria: March 18, 2011
• First Posted (Estimated): March 21, 2011

Study Record Updates

• Last Update Posted (Estimated): December 19, 2025
• Last Update Submitted That Met QC Criteria: December 4, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Immunotherapy; Skin Cancer; Adoptive Cell Therapy; Metastatic Melanoma; Young TIL
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Skin Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin and Connective Tissue Diseases; Melanoma; Skin Neoplasms; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Investigative Techniques; Therapeutics; Hydrocarbons; Biological Factors; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Intercellular Signaling Peptides and Proteins; Radiotherapy; Cytokines; Interleukins; Lymphokines; Cyclophosphamide; Interleukin-2; fludarabine; aldesleukin; fludarabine phosphate; Whole-Body Irradiation
• Other Study ID Numbers: 110123; 11-C-0123

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request.
• IPD Sharing Time Frame: Clinical data available during the study and indefinitely.
• IPD Sharing Access Criteria: Clinical data will be made available via subscription to Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI).
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No