Phase II Study of Metastatic Melanoma With Lymphodepleting Conditioning and Infusion of Anti-MART-1 F5 TCR-Gene-Engineered Lymphocytes

NCT00509288 | Completed Phase 2 Results DMC

• 2 other identifiers: 07017507-C-0175
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

Background:

• Human peripheral blood lymphocytes have been engineered to express a T-cell receptor (TCR) that recognizes a blood type,HLA-A 0201 (human leukocyte antigen) derived from the gp100 protein. A retroviral vector was constructed that can deliver the T-cell receptor (TCR) to cells.
• Patients' cells will be converted into cells able to recognize and fight melanoma tumors. Objectives:
• To determine whether TCR-engineered lymphocytes 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 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 anti-MART-1 protein is 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 anti-melanoma antigen recognized by T-cells (MART)-1. Patients receive an intravenous (IV) infusion of the treated cells containing anti-MART-1 protein, followed by infusions of a drug called IL-2 (aldesleukin), 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 CT (computed tomography) 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; Skin Cancer

Keywords

Refractory; Gene Therapy; HLA-A2 Positive; Stage IV Melanoma; Melanoma; Skin Cancer; Malignant Melanoma

Outcome Measures

Primary Outcomes (1)

• Clinical Tumor Regression.

  Tumor regression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). 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 reference 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 recorded since the treatment started or the appearance of one or more new lesions. Stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the smallest sum LD.

  7/5/07-4/23/09

Secondary Outcomes (1)

• Toxicity

  57 months

Study Arms (2)

anti-MART-1 F5 TCR PBL + HD IL-2

EXPERIMENTAL

Patients treated with peripheral blood lymphocytes (PBL)

Biological: autologous anti-MART-1 F5 T-cell receptor; Drug: Cyclophosphamide; Drug: Fludarabine; Biological: Aldesleukin

anti-MART-1 F5 TCR TIL + HD IL-2

EXPERIMENTAL

Patients treated with TIL (tumor infiltrating lymphocytes).

Drug: Cyclophosphamide; Drug: Fludarabine; Biological: Aldesleukin; Biological: autologous anti-MART-1 F5 T-cell receptor gene-engineered tumor infiltrating lymphocytes

Interventions

autologous anti-MART-1 F5 T-cell receptor BIOLOGICAL

Autologous anti-MART-1 F5 T-cell receptor gene-engineered tumor infiltrating lymphocytes. A minimum of approximately 5 X 10\^8 cells will be given up to 3x10\^11 anti-MART-1 F5 TCR engineered TIL or PBL.

anti-MART-1 F5 TCR PBL + HD IL-2

Cyclophosphamide DRUG

Day -7 to -5: Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml D5W with mesna 15 mg/kg/day X 2 days over 1 hr

Also known as: Cytoxan

anti-MART-1 F5 TCR PBL + HD IL-2; anti-MART-1 F5 TCR TIL + HD IL-2

Fludarabine DRUG

Day -5 to 1: Fludarabine 25 mg/m\^2/day intravenous piggy back (IVPB) daily over 30 minutes for 5 days

Also known as: Fludara

anti-MART-1 F5 TCR PBL + HD IL-2; anti-MART-1 F5 TCR TIL + HD IL-2

Aldesleukin BIOLOGICAL

Day 0: Cells will be infused intravenously (i.v.). Patients will receive up to 3x10e\^11 (with a minimum of 5x10e\^8 cells) anti-MART-1 F5 TCR engineered TIL or PBL Aldesleukin (based on total body weight) 720,000 IU/kg intravenous (IV) over 15 minute every eight hours beginning within 24 hours of cell infusion

Also known as: IL-2

anti-MART-1 F5 TCR PBL + HD IL-2; anti-MART-1 F5 TCR TIL + HD IL-2

autologous anti-MART-1 F5 T-cell receptor gene-engineered tumor infiltrating lymphocytes BIOLOGICAL

anti-MART-1 F5 TCR TIL + HD IL-2

Eligibility Criteria

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

You may qualify if:

• Metastatic melanoma with measurable disease
• Previously received high dose IL-2 (aldesleukin) and have been either non-responders (progressive disease) or have recurred.
• Positive for MART-1 by immunohistochemistry (IHC)
• Greater than or equal to 18 years of age.
• 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.
• Life expectancy of greater than three months.
• Patients of both genders must be willing to practice birth control for four months after receiving the preparative regimen.
• Patients must be human leukocyte antigen (HLA-A)\*0201 positive
• Serology:
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• 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 and hepatitis C antibody unless antigen negative.
• Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the preparative chemotherapy on the fetus.

You may not qualify if:

• Patients with reactive TIL (IFN-gamma release greater than 200 pg/mL) available based on overnight co-culture assay with autologous tumor or MHC-matched tumor cells.
• 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.
• Active systemic infections, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease.
• Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
• 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).
• Systemic steroid therapy.
• 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 percent.
• Documented LVEF of less than or equal to 45 percent 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 percent predicted tested in patients with:
• A prolonged history of cigarette smoking (20 pk/yrs of smoking).
• Symptoms of respiratory dysfunction.

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 (4)

• Kawakami Y, Eliyahu S, Delgado CH, Robbins PF, Rivoltini L, Topalian SL, Miki T, Rosenberg SA. Cloning of the gene coding for a shared human melanoma antigen recognized by autologous T cells infiltrating into tumor. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3515-9. doi: 10.1073/pnas.91.9.3515.

  PMID: 8170938 BACKGROUND

• Kawakami Y, Eliyahu S, Sakaguchi K, Robbins PF, Rivoltini L, Yannelli JR, Appella E, Rosenberg SA. Identification of the immunodominant peptides of the MART-1 human melanoma antigen recognized by the majority of HLA-A2-restricted tumor infiltrating lymphocytes. J Exp Med. 1994 Jul 1;180(1):347-52. doi: 10.1084/jem.180.1.347.

  PMID: 7516411 BACKGROUND

• Kawakami Y, Eliyahu S, Delgado CH, Robbins PF, Sakaguchi K, Appella E, Yannelli JR, Adema GJ, Miki T, Rosenberg SA. Identification of a human melanoma antigen recognized by tumor-infiltrating lymphocytes associated with in vivo tumor rejection. Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6458-62. doi: 10.1073/pnas.91.14.6458.

  PMID: 8022805 BACKGROUND

• Abate-Daga D, Hanada K, Davis JL, Yang JC, Rosenberg SA, Morgan RA. Expression profiling of TCR-engineered T cells demonstrates overexpression of multiple inhibitory receptors in persisting lymphocytes. Blood. 2013 Aug 22;122(8):1399-410. doi: 10.1182/blood-2013-04-495531. Epub 2013 Jul 16.

  PMID: 23861247 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Melanoma; Skin Neoplasms

Interventions

Cyclophosphamide; fludarabine; fludarabine phosphate; aldesleukin; Interleukin-2

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)

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

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

• Steven Rosenberg, M.D.

  National Cancer Institute, National Institutes of Health

  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

Study Record Dates

• First Submitted: July 30, 2007
• First Posted: July 31, 2007
• Study Start: June 1, 2007
• Primary Completion: July 1, 2011
• Study Completion: July 1, 2012
• Last Updated: December 28, 2012
• Results First Posted: December 18, 2012

Record last verified: 2012-12

Locations

US (1)