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...

NCT01319565 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: 11012311-C-0123
• Study Type: interventional
• Target: 102
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Metastatic Melanoma; Skin Cancer

Keywords

Young TIL; Metastatic Melanoma; Immunotherapy; Adoptive Cell Therapy; Skin Cancer

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (3)

• Progression-free Survival (PFS)

  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

  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

  30 days after end of treatment, up to 6 years

Other Outcomes (1)

• Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v3.0)

  Participants will be followed for adverse events from registration through 30 days after the last treatment, up to 6 years

Study Arms (2)

Arm 1/Adoptive Cell Therapy (ACT)

EXPERIMENTAL

Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + young tumor infiltrating lymphocytes (TIL) + high dose aldesleukin

Drug: Aldesleukin; Drug: Cyclophosphamide; Drug: Fludarabine; Biological: Young TIL

Arm 2/Adoptive Cell Therapy (ACT) + Total Body Irradiation (TBI)

EXPERIMENTAL

Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + young tumor infiltrating lymphocytes (TIL) + high dose aldesleukin + total body irradiation (TBI)

Drug: Aldesleukin; Drug: Cyclophosphamide; Drug: Fludarabine; Biological: Young TIL; Radiation: Total Body Irradiation (TBI)

Interventions

Aldesleukin DRUG

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).

Also known as: Interleukin-2

Arm 1/Adoptive Cell Therapy (ACT); Arm 2/Adoptive Cell Therapy (ACT) + Total Body Irradiation (TBI)

Cyclophosphamide DRUG

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.

Also known as: Cytoxan

Arm 1/Adoptive Cell Therapy (ACT); Arm 2/Adoptive Cell Therapy (ACT) + Total Body Irradiation (TBI)

Fludarabine DRUG

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.

Also known as: Fludara

Arm 1/Adoptive Cell Therapy (ACT); Arm 2/Adoptive Cell Therapy (ACT) + Total Body Irradiation (TBI)

Young TIL BIOLOGICAL

Arm 1 and Arm 2 - Day 0: Cells will be infused intravenously (IV) on the Patient Care Unit over 20-30 minutes.

Also known as: Young tumor infiltrating lymphocytes

Arm 1/Adoptive Cell Therapy (ACT); Arm 2/Adoptive Cell Therapy (ACT) + Total Body Irradiation (TBI)

Total Body Irradiation (TBI) RADIATION

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.

Also known as: TBI

Arm 2/Adoptive Cell Therapy (ACT) + Total Body Irradiation (TBI)

Eligibility Criteria

• Age: 18 Years - 66 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).
• 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.
• Greater than or equal to 18 years of age and less than or equal to 66 years of age.
• Willing to practice birth control during treatment and for four months after receiving all protocol related therapy.
• Life expectancy of greater than three months
• Willing to sign a durable power of attorney.
• Able to understand and sign the Informed Consent Document
• Clinical performance status of eastern Cooperative Oncology Group (ECOG) 0 or 1.
• 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.

You may not qualify if:

• Prior cell transfer therapy which included a non-myeloablative or myeloablative chemotherapy regimen.
• 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.
• Systemic steroid therapy requirement.
• 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.
• Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease and acquired immunodeficiency syndrome (AIDS).
• 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.)
• History of severe immediate hypersensitivity reaction to any of the agents used in this study.
• History of coronary revascularization or ischemic symptoms.
• Any patient known to have a left ventricular ejection fraction (LVEF) less than or equal to 45%.
• In patients \> 60 years old, documented LVEF of less than or equal to 45%.
• 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
• Prior radiation therapy that, in the judgment of the radiation oncologist, precludes the administration of total body irradiation.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (6)

• 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.

  PMID: 18809613 BACKGROUND

• 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.

  PMID: 10561265 BACKGROUND

• 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.

  PMID: 8028037 BACKGROUND

• 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.

  PMID: 27217459 BACKGROUND

• 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.

  PMID: 34413159 BACKGROUND

• 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.

  PMID: 25432172 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Melanoma; Skin Neoplasms

Interventions

aldesleukin; Interleukin-2; Cyclophosphamide; fludarabine; fludarabine phosphate; Whole-Body Irradiation

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Interleukins; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Lymphokines; Proteins; Biological Factors; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Radiotherapy; Therapeutics; Investigative Techniques

Limitations and Caveats

Grade 1/2 adverse events were only captured in conjunction with serious adverse events or when attributed to TIL.

Results Point of Contact

• Title: Dr. Steven A. Rosenberg
• Organization: National Cancer Institute

sar@mail.nih.gov

240-858-3080

Study Officials

• Steven A Rosenberg, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: March 18, 2011
• First Posted: March 21, 2011
• Study Start: March 24, 2011
• Primary Completion: September 10, 2024
• Study Completion: September 10, 2024
• Last Updated: December 19, 2025
• Results First Posted: December 19, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data available during the study and indefinitely.
• 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).

Locations

US (1)