Phase II Study of Short-Term Cultured Anti-Tumor Autologous Lymphocytes After Lymphocyte-Depleting Chemotherapy in Metastatic Melanoma

NCT00513604 | Completed Phase 2 Results DMC

• 2 other identifiers: 07017607-C-0176
• Study Type: interventional
• Target: 158
• Locations: 1 country
• Sites: 1

Brief Summary

Background:

• Most therapeutic therapies for metastatic melanoma have focused on the ability of T-cell lymphocytes to kill cells of tumors.
• An adaptive cell transfer therapy has been pioneered, in which cells are grown for a short time in the laboratory. The way they are grown may have a better effect in a patient's body than do other cells that are cultured for a longer time. Objectives:
• To determine whether tumor-infiltrating lymphocytes (TIL) can be put in cells removed from patients' tumors or blood and then reinfused, with the purpose of shrinking tumors.
• To evaluate safety and effectiveness of the treatment. Eligibility:
• Patients 18 years of age or older with metastatic cancer melanoma (cancer that has spread beyond the original site).
• Patient's leukocyte antigen type is human leukocyte antigens (HLA-A) 0201. Design:
• Patients undergo the following procedures:
• Leukapheresis (on two occasions). This is a method of collecting large numbers of white blood cells. The cells obtained in the first leukapheresis procedure are grown in the laboratory, and the TIL cells (called young TIL cells) are inserted into the cells using an inactivated (harmless) virus in a process called retroviral transduction. Cells collected in the second leukapheresis procedure are used to evaluate the effectiveness of the study treatment.
• Chemotherapy. Patients are given chemotherapy through a vein (intravenously, IV) over 1 hour for 2 days to suppress the immune system so that the patient's immune cells do not interfere with the treatment.
• Treatment with young TIL cells. Patients receive an IV infusion of the treated cells, followed by infusions the drug aldesleukin-2 (IL-2), which helps boost the effectiveness of the treated white cells.
• Patients are given support medications to prevent complications such as infections.
• Patients may undergo a tumor biopsy (removal of a small piece of tumor tissue).
• Patients are evaluated with laboratory tests and imaging tests, such as computed tomography (CT) scans, 4 to 6 weeks after treatment and then once a month for 3 to 4 months to determine the response to treatment.
• Patients have blood tests at 3, 6, and 12 months and then annually for 5 years.

Conditions

Melanoma; Malignant Melanoma; Melanoma, Experimental; Experimental Melanomas

Keywords

Clinical Response; Immunotherapy; Cancer; Cytokines; Adoptive Cell Therapy; Melanoma; Skin Cancer; Malignant Melanoma

Outcome Measures

Primary Outcomes (2)

• Clinical Response

  Clinical response is defined as complete response (CR)- a disappearance of all target lesions, partial response (PR) - at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. Progression (PD)- at least a 20% increase in the sum of the LD of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Stable disease (SD) - neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the smallest sum LD.

  every 1-3 months until disease progression. Total length of time -8/7/2007 to 9/27/2012

• Toxicity

  Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.

  5 years

Study Arms (5)

Cohort 1 - NMA, TIL, aldesleukin

EXPERIMENTAL

Cohort 1 - Nonmyeloablative (NMA), tumor infiltrating lymphocytes (TIL), \& high dose (HD) aldesleukin: Nonmyeloablative chemotherapeutic conditioning regimen followed by bulk young tumor infiltrating lymphocytes and high dose aldesleukin. Cyclophosphamide 60 mg/kg intravenous (IV) daily x 2 days. Fludarabine 25 mg/m\^2 intravenous (IV) daily x 5 days. Bulk young TIL Aldesleukin 720,000 IU/kg intravenous (IV) (based on body weight) over 15 minutes every eight hours for up to 5 days. Cohort 1 = unselected TIL

Biological: aldesleukin; Biological: therapeutic autologous lymphocytes; Drug: Cyclophosphamide; Drug: Fludarabine phosphate

Cohort 2 - NMA, CD4+ TIL, aldesleukin

EXPERIMENTAL

Cohort 2 - Nonmyeloablative (NMA), cluster of differentiation 4 (CD4+) depleted tumor infiltrating lymphocytes (TIL), aldesleukin: Nonmyeloablative chemotherapeutic conditioning regimen followed by CD4+ depleted tumor infiltrating lymphocytes and high dose (HD) aldesleukin. Cyclophosphamide 60 mg/kg intravenous (IV) daily x 2 days. Fludarabine 25 mg/m\^2 intravenous (IV) daily x 5 days. CD4+ depleted TIL Aldesleukin 720,000 IU/kg intravenous (IV) (based on body weight) over 15 minutes every eight hours for up to 5 days. Cohort 2 = CD4+ depleted (selected) TIL

Biological: aldesleukin; Biological: therapeutic autologous lymphocytes; Drug: Cyclophosphamide; Drug: Fludarabine phosphate

Cohort 3 - NMA, total body irradiation

EXPERIMENTAL

Cohort 3 - Nonmyeloablative (NMA), total body irradiation (TBI): Nonmyeloablative chemotherapeutic conditioning regimen and 2 gray units (Gy) of total body irradiation followed by cluster of differentiation 4 (CD4+) depleted tumor infiltrating lymphocytes and high dose (HD) aldesleukin. Cyclophosphamide 60 mg/kg intravenous (IV) daily x 2 days. Fludarabine 25 mg/m\^2 intravenous (IV) daily x 5 days. CD4+ depleted TIL 2Gy (gray units) of total body irradiation (TBI) twice on day -2 and once on day -1 (total dose 6 Gy) at a rate of 0.07 Gy/minute using a linear accelerator in Radiation Oncology Aldesleukin 720,000 IU/kg intravenous (IV) (based on body weight) over 15 minutes every eight hours for up to 5 days. Cohort 3 = CD4 + depleted (selected) TIL + 600Gy radiation

Biological: aldesleukin; Biological: therapeutic autologous lymphocytes; Drug: Cyclophosphamide; Drug: Fludarabine phosphate; Radiation: Total body irradiation

Cohort 4 - NMA, young TIL, aldesleukin

EXPERIMENTAL

Cohort 4 - Nonmyeloablative (NMA), tumor infiltrating lymphocytes (TIL), aldesleukin: Nonmyeloablative chemotherapeutic conditioning regimen followed by bulk young tumor infiltrating lymphocytes and high dose (HD) aldesleukin. Cyclophosphamide 60 mg/kg intravenous (IV) daily x 2 days. Fludarabine 25 mg/m\^2 intravenous (IV) daily x 5 days. Bulk young TIL Aldesleukin 720,000 IU/kg intravenous (IV) (based on body weight) over 15 minutes every eight hours for up to 5 days. Cohort 4 = unselected TIL - it is the SAME as cohort 1

Biological: aldesleukin; Biological: therapeutic autologous lymphocytes; Drug: Cyclophosphamide; Drug: Fludarabine phosphate

Cohort 5 - NMA, CD4+TIL, HD aldesleukin

EXPERIMENTAL

Cohort 5 - Nonmyeloablative (NMA), cluster of differentiation 4 (CD4+) tumor infiltrating lymphocytes (TIL), high dose (HD) aldesleukin: Nonmyeloablative chemotherapeutic conditioning regimen followed by CD4+ depleted tumor infiltrating lymphocytes and high dose aldesleukin. Cyclophosphamide 60 mg/kg intravenous (IV) daily x 2 days. Fludarabine 25 mg/m\^2 intravenous (IV) daily x 5 days. CD4+ depleted TIL Aldesleukin 720,000 IU/kg intravenous (IV) (based on body weight) over 15 minutes every eight hours for up to 5 days. Cohort 5 = CD4 + depleted TIL - it is the SAME as cohort 2

Biological: aldesleukin; Biological: therapeutic autologous lymphocytes; Drug: Cyclophosphamide; Drug: Fludarabine phosphate

Interventions

aldesleukin BIOLOGICAL

Given subcutaneously every 8 hours for up to 15 doses, day 0, 720,000 IU/kg

Also known as: IL-2

Cohort 1 - NMA, TIL, aldesleukin; Cohort 2 - NMA, CD4+ TIL, aldesleukin; Cohort 3 - NMA, total body irradiation; Cohort 4 - NMA, young TIL, aldesleukin; Cohort 5 - NMA, CD4+TIL, HD aldesleukin

therapeutic autologous lymphocytes BIOLOGICAL

Given as infusion, up to 3 x 10\^11 lymphocytes (minimum of 1 x 10\^9), day 0

Cohort 1 - NMA, TIL, aldesleukin; Cohort 2 - NMA, CD4+ TIL, aldesleukin; Cohort 3 - NMA, total body irradiation; Cohort 4 - NMA, young TIL, aldesleukin; Cohort 5 - NMA, CD4+TIL, HD aldesleukin

Cyclophosphamide DRUG

Given intravenously 60 mg/kg/day, day -7 to -6

Cohort 1 - NMA, TIL, aldesleukin; Cohort 2 - NMA, CD4+ TIL, aldesleukin; Cohort 3 - NMA, total body irradiation; Cohort 4 - NMA, young TIL, aldesleukin; Cohort 5 - NMA, CD4+TIL, HD aldesleukin

Fludarabine phosphate DRUG

Given intravenously 25 mg/m\^2/day over 15-30 minutes, day -5 to -1

Also known as: Fludara

Cohort 1 - NMA, TIL, aldesleukin; Cohort 2 - NMA, CD4+ TIL, aldesleukin; Cohort 3 - NMA, total body irradiation; Cohort 4 - NMA, young TIL, aldesleukin; Cohort 5 - NMA, CD4+TIL, HD aldesleukin

Total body irradiation RADIATION

600 cGy

Also known as: TBI

Cohort 3 - NMA, total body irradiation

Eligibility Criteria

• Age: 18 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.
• Patients with one to three brain metastases are eligible (lesions greater than or equal to 1 cm each, or symptomatic lesions must have been treated and stable for 3 months).
• Greater than or equal to 18 years of age .
• Willing to practice birth control during treatment and for four months after receiving the preparative regimen.
• 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 without support of filgrastim.
• Normal white blood cell (WBC) (greater than 3000/ mm\^3).
• Hemoglobin greater than 8.0 g/dl.
• Platelet count greater than 100,000/ mm\^3.
• 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.)

You may not qualify if:

• Prior cell transfer therapy that included non-myeloablative or ablative chemotherapy (for cohorts 4 and 5).
• Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant.
• Systemic steroid therapy required.
• 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 Immune Deficiency 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 an left ventricular ejection fraction (LVEF) less than or equal to 45%.
• Documented LVEF of less than or equal to 45% tested in patients with:
• \- Clinically significant atrial and/or ventricular arrhythmias including but not limited to:
• atrial fibrillation, ventricular tachycardia, second or third degree heart block.
• \- Age greater than or equal to 60 years old.
• Documented forced expiratory volume 1 (FEV1) less than or equal to 60% predicted tested in patients with:
• A prolonged history of cigarette smoking

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (5)

• Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am. 2000 Feb;6 Suppl 1:S11-4.

  PMID: 10685652 BACKGROUND

• Gogas HJ, Kirkwood JM, Sondak VK. Chemotherapy for metastatic melanoma: time for a change? Cancer. 2007 Feb 1;109(3):455-64. doi: 10.1002/cncr.22427.

  PMID: 17200963 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

• Dudley ME, Gross CA, Somerville RP, Hong Y, Schaub NP, Rosati SF, White DE, Nathan D, Restifo NP, Steinberg SM, Wunderlich JR, Kammula US, Sherry RM, Yang JC, Phan GQ, Hughes MS, Laurencot CM, Rosenberg SA. Randomized selection design trial evaluating CD8+-enriched versus unselected tumor-infiltrating lymphocytes for adoptive cell therapy for patients with melanoma. J Clin Oncol. 2013 Jun 10;31(17):2152-9. doi: 10.1200/JCO.2012.46.6441. Epub 2013 May 6.

  PMID: 23650429 DERIVED

• 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.

  PMID: 22555974 DERIVED

MeSH Terms

Conditions

Melanoma; Melanoma, Experimental; Neoplasms; Skin Neoplasms

Interventions

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

Condition Hierarchy (Ancestors)

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

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

Results Point of Contact

• Title: Dr. Steven Rosenberg
• Organization: National Cancer Institute, National Institutes of Health

sar@mail.nih.gov

301-496-4164

Study Officials

• Deborah E Citrin, 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: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Dr. Steven Rosenberg

Study Record Dates

• First Submitted: August 6, 2007
• First Posted: August 8, 2007
• Study Start: June 1, 2007
• Primary Completion: November 1, 2012
• Study Completion: November 1, 2012
• Last Updated: June 3, 2013
• Results First Posted: May 27, 2013

Record last verified: 2013-05

Locations

US (1)