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

This study has been completed.
Sponsor:
Information provided by:
National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT00509288
First received: July 30, 2007
Last updated: December 27, 2012
Last verified: December 2012
  Purpose

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.

Condition Intervention Phase
Melanoma
Skin Cancer
Biological: autologous anti-MART-1 F5 T-cell receptor
Drug: Cyclophosphamide
Drug: Fludarabine
Biological: Aldesleukin
Biological: autologous anti-MART-1 F5 T-cell receptor gene-engineered tumor infiltrating lymphocytes
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase II Study of Metastatic Melanoma Using Lymphodepleting Conditioning Followed by Infusion of Anti-MART-1 F5 TCR-Gene Engineered Lymphocytes

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Clinical Tumor Regression. [ Time Frame: 7/5/07-4/23/09 ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Toxicity [ Time Frame: 57 months ] [ Designated as safety issue: Yes ]
    Here is the number of participants with adverse events. For a detailed listing of adverse events, see the adverse event module.


Enrollment: 24
Study Start Date: June 2007
Study Completion Date: July 2012
Primary Completion Date: July 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: anti-MART-1 F5 TCR PBL + HD IL-2
Patients treated with peripheral blood lymphocytes (PBL)
Biological: autologous anti-MART-1 F5 T-cell receptor

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.

Drug: Cyclophosphamide
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
Other Name: Cytoxan
Drug: Fludarabine
Day -5 to 1: Fludarabine 25 mg/m^2/day intravenous piggy back (IVPB) daily over 30 minutes for 5 days
Other Name: Fludara
Biological: Aldesleukin
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
Other Name: IL-2
Experimental: anti-MART-1 F5 TCR TIL + HD IL-2
Patients treated with TIL (tumor infiltrating lymphocytes).
Drug: Cyclophosphamide
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
Other Name: Cytoxan
Drug: Fludarabine
Day -5 to 1: Fludarabine 25 mg/m^2/day intravenous piggy back (IVPB) daily over 30 minutes for 5 days
Other Name: Fludara
Biological: Aldesleukin
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
Other Name: IL-2
Biological: autologous anti-MART-1 F5 T-cell receptor gene-engineered tumor infiltrating lymphocytes

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

    1. Metastatic melanoma with measurable disease
    2. Previously received high dose IL-2 (aldesleukin) and have been either non-responders (progressive disease) or have recurred.
    3. Positive for MART-1 by immunohistochemistry (IHC)
    4. Greater than or equal to 18 years of age.
    5. Willing to sign a durable power of attorney
    6. Able to understand and sign the Informed Consent Document
    7. Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1.
    8. Life expectancy of greater than three months.
    9. Patients of both genders must be willing to practice birth control for four months after receiving the preparative regimen.
    10. Patients must be human leukocyte antigen (HLA-A)*0201 positive
    11. Serology:
    1. 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.)
    2. Seronegative for hepatitis B antigen and hepatitis C antibody unless antigen negative.
    3. Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the preparative chemotherapy on the fetus.

    l. Hematology:

    1. Absolute neutrophil count greater than 1000/mm^3 without the support of filgrastim.
    2. White blood cell (WBC) (greater than 3000/mm^3).
    3. Platelet count greater than 100,000/ mm^3.
    4. Hemoglobin greater than 8.0 g/dl.

    m. Chemistry:

    1. Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less or equal to 2.5 times the upper limit of normal.
    2. Serum creatinine less than or equal to 1.6 mg/dl.
    3. Total bilirubin less than or equal to 1.5 mg/dl, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dl.

    n. More than four weeks must have elapsed since any prior systemic therapy at the time the patient receives the preparative regimen, and patients' toxicities must have recovered to a grade 1 or less (except for toxicities such as alopecia or vitiligo).

    o. Six weeks must have elapsed since prior anti-CTLA4 antibody therapy to allow antibody levels to decline.

    p. Patients who have previously received anti-CTLA4 antibody must have a normal colonoscopy with normal colonic biopsies.

EXCLUSION CRITERIA:

  1. 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.
  2. 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.
  3. 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.
  4. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
  5. 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).
  6. Systemic steroid therapy.
  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 an left ventricular ejection fraction (LVEF) less than or equal to 45 percent.
  10. 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.
  11. 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00509288

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
Investigators
Principal Investigator: Steven Rosenberg, M.D. National Cancer Institute, National Institutes of Health
  More Information

Additional Information:
Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Steven A. Rosenberg, M.D./National Cancer Institute, National Institutes of Health
ClinicalTrials.gov Identifier: NCT00509288     History of Changes
Other Study ID Numbers: 070175, 07-C-0175
Study First Received: July 30, 2007
Results First Received: November 14, 2012
Last Updated: December 27, 2012
Health Authority: United States: Federal Government
United States: Food and Drug Administration

Keywords provided by National Institutes of Health Clinical Center (CC):
Refractory
Gene Therapy
HLA-A2 Positive
Stage IV Melanoma
Melanoma
Skin Cancer
Malignant Melanoma

Additional relevant MeSH terms:
Skin Neoplasms
Melanoma
Neoplasms by Site
Neoplasms
Skin Diseases
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Nevi and Melanomas
Cyclophosphamide
Fludarabine monophosphate
Fludarabine
Aldesleukin
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites
Anti-HIV Agents
Anti-Retroviral Agents

ClinicalTrials.gov processed this record on July 22, 2014