Phase II Study of Metastatic Melanoma With Lymphodepleting Conditioning and Anti-gp100:154-162 TCR Gene Engineered Lymphocytes

NCT00509496 | Terminated Phase 2 Results DMC

• 2 other identifiers: 07017407-C-0174
• Study Type: interventional
• Target: 21
• 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, human leukocyte antigen (HLA-A\*0201) derived from the gp100 protein. A retroviral vector was constructed that can deliver the TCR to cells.
• This gene-engineered cell is over 10 times more reactive with melanoma cells than is the melanoma antigen recognized by T-cells (MART-1) TCR that resulted in tumor shrinkage for two patients with metastatic melanoma. Objectives:
• To determine whether an anti-melanoma protein receptor 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-gp100 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-gp100. Patients receive an IV infusion of the treated cells containing anti-gp100 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 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

Skin Cancer; Melanoma

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Clinical Tumor Regression.

  Clinical tumor regression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) is a 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 (SD)is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the smallest sum LD.

  20 months

Secondary Outcomes (1)

• Toxicity

  6 years

Study Arms (2)

anti-gp100:154-162 TCR PBL + HD IL-2

EXPERIMENTAL

1. fludarabine phosphate-25 mg/m\^2/day intravenous piggy back over 30 minutes for 5 days 2. cyclophosphamide-60 mg/kg/day x 2 days intravenous 3. Anti-gp100:154-162 TCR-engineered peripheral blood lymphocyte (PBL) cell preparation - minimum of approximately 5 X 10\^8 cells and up to 3 x10\^11 anti-gp100:154-162 TCR engineered TIL or PBL. The cells are infused intravenously over 20-30 minutes. 4. aldesleukin-720,000 IU/kg intravenously over 15 minutes every 8 hours beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses)

Drug: fludarabine phosphate; Drug: cyclophosphamide; Biological: aldesleukin; Biological: autologous anti-gp 100:154-162 T-cell receptor gene-engineered peripheral blood lymphocytes

anti-gp100:154-162 TCR TIL + HD IL-2

EXPERIMENTAL

1. fludarabine phosphate-25 mg/m\^2/day intravenous piggy back over 30 minutes for 5 days 2. cyclophosphamide-60 mg/kg/day x 2 days intravenous 3. Anti-gp100:154-162 TCR-engineered tumor infiltrating lymphocytes (TIL) cell preparation- minimum of approximately 5 X 10\^8 cells and up to 3 x10\^11 anti-gp100:154-162 TCR engineered TIL or PBL. The cells are infused intravenously over 20-30 minutes 4. aldesleukin-720,000 IU/kg intravenously over 15 minutes every 8 hours beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses)

Drug: fludarabine phosphate; Drug: cyclophosphamide; Biological: aldesleukin; Biological: autologous anti-gp 100:154-162 T-cell receptor gene-engineered tumor infiltrating lymphocytes

Interventions

fludarabine phosphate DRUG

25 mg/m\^2/day intravenous piggy back over 30 minutes for 5 days.

Also known as: Fludara

anti-gp100:154-162 TCR PBL + HD IL-2; anti-gp100:154-162 TCR TIL + HD IL-2

cyclophosphamide DRUG

60 mg/kg/day x 2 days intravenous

Also known as: Cytoxan

anti-gp100:154-162 TCR PBL + HD IL-2; anti-gp100:154-162 TCR TIL + HD IL-2

aldesleukin BIOLOGICAL

720,000 IU/kg intravenously over 15 minutes every 8 hours beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses).

Also known as: IL-2

anti-gp100:154-162 TCR PBL + HD IL-2; anti-gp100:154-162 TCR TIL + HD IL-2

autologous anti-gp 100:154-162 T-cell receptor gene-engineered tumor infiltrating lymphocytes BIOLOGICAL

Patients will receive a minimum of approximately 5 X 10\^8 cells and up to 3 x10\^11 anti-gp100:154-162 TCR engineered TIL . The cells are infused intravenously over 20-30 minutes.

anti-gp100:154-162 TCR TIL + HD IL-2

autologous anti-gp 100:154-162 T-cell receptor gene-engineered peripheral blood lymphocytes BIOLOGICAL

Patients will receive a minimum of approximately 5 X 10\^8 cells and up to 3 x10\^11 anti-gp100:154-162 TCR engineered PBL. The cells are infused intravenously over 20-30 minutes.

anti-gp100:154-162 TCR PBL + 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 aldesleukin (IL-2) and have been either non-responders (progressive disease) or have recurred.
• Positive for gp100 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.
• h Life expectancy of greater than three months.
• i. Patients of both genders must be willing to practice birth control for four months after receiving the preparative regimen.
• j. Must be human leukocyte antigen (HLA-A 0201) positive
• k. 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 and hepatitis C antibody unless antigen negative.
• l. Hematology:
• Absolute neutrophil count greater than 1000/mm\^3.

You may not qualify if:

• Patients with reactive TIL (interferon (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.
• Documented left ventricular ejection faction (LVEF) of less than 45 percent in patients with:
• a. Clinically significant atrial and/or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, 2 degree or 3 degree heart block.
• b. Age greater than or equal to 60 years old.
• j. Documented forced expiratory volume 1 (FEV1) greater than or equal to 60 percent predicted for patients with:
• A prolonged history of cigarette smoking (greater than 20 pack/year within the past 2 years).
• Symptoms of respiratory distress.

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

• 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

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Skin Neoplasms; Melanoma

Interventions

fludarabine phosphate; Cyclophosphamide; aldesleukin; Interleukin-2

Condition Hierarchy (Ancestors)

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

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

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: PARALLEL
• 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: January 15, 2013
• Results First Posted: December 4, 2012

Record last verified: 2012-12

Locations

US (1)