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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Steven Rosenberg, M.D., National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT00513604
First received: August 6, 2007
Last updated: May 29, 2013
Last verified: May 2013
  Purpose

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.

Condition Intervention Phase
Melanoma
Malignant Melanoma
Melanoma, Experimental
Experimental Melanomas
Biological: aldesleukin
Biological: therapeutic autologous lymphocytes
Drug: Cyclophosphamide
Drug: Fludarabine phosphate
Radiation: Total body irradiation
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Study Using Short-Term Cultured Anti-Tumor Autologous Lymphocytes Following a Lymphocyte Depleting Regimen in Metastatic Melanoma

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Clinical Response [ Time Frame: every 1-3 months until disease progression. Total length of time -8/7/2007 to 9/27/2012 ] [ Designated as safety issue: No ]
    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.

  • Toxicity [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]
    Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.


Enrollment: 158
Study Start Date: June 2007
Study Completion Date: November 2012
Primary Completion Date: November 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort 1 - NMA, TIL, aldesleukin

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
Given subcutaneously every 8 hours for up to 15 doses, day 0, 720,000 IU/kg
Other Name: IL-2
Biological: therapeutic autologous lymphocytes
Given as infusion, up to 3 x 10^11 lymphocytes (minimum of 1 x 10^9), day 0
Drug: Cyclophosphamide
Given intravenously 60 mg/kg/day, day -7 to -6
Drug: Fludarabine phosphate
Given intravenously 25 mg/m^2/day over 15-30 minutes, day -5 to -1
Other Name: Fludara
Experimental: Cohort 2 - NMA, CD4+ TIL, aldesleukin

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
Given subcutaneously every 8 hours for up to 15 doses, day 0, 720,000 IU/kg
Other Name: IL-2
Biological: therapeutic autologous lymphocytes
Given as infusion, up to 3 x 10^11 lymphocytes (minimum of 1 x 10^9), day 0
Drug: Cyclophosphamide
Given intravenously 60 mg/kg/day, day -7 to -6
Drug: Fludarabine phosphate
Given intravenously 25 mg/m^2/day over 15-30 minutes, day -5 to -1
Other Name: Fludara
Experimental: Cohort 3 - NMA, total body irradiation

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
Given subcutaneously every 8 hours for up to 15 doses, day 0, 720,000 IU/kg
Other Name: IL-2
Biological: therapeutic autologous lymphocytes
Given as infusion, up to 3 x 10^11 lymphocytes (minimum of 1 x 10^9), day 0
Drug: Cyclophosphamide
Given intravenously 60 mg/kg/day, day -7 to -6
Drug: Fludarabine phosphate
Given intravenously 25 mg/m^2/day over 15-30 minutes, day -5 to -1
Other Name: Fludara
Radiation: Total body irradiation
600 cGy
Other Name: TBI
Experimental: Cohort 4 - NMA, young TIL, aldesleukin

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
Given subcutaneously every 8 hours for up to 15 doses, day 0, 720,000 IU/kg
Other Name: IL-2
Biological: therapeutic autologous lymphocytes
Given as infusion, up to 3 x 10^11 lymphocytes (minimum of 1 x 10^9), day 0
Drug: Cyclophosphamide
Given intravenously 60 mg/kg/day, day -7 to -6
Drug: Fludarabine phosphate
Given intravenously 25 mg/m^2/day over 15-30 minutes, day -5 to -1
Other Name: Fludara
Experimental: Cohort 5 - NMA, CD4+TIL, HD aldesleukin

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
Given subcutaneously every 8 hours for up to 15 doses, day 0, 720,000 IU/kg
Other Name: IL-2
Biological: therapeutic autologous lymphocytes
Given as infusion, up to 3 x 10^11 lymphocytes (minimum of 1 x 10^9), day 0
Drug: Cyclophosphamide
Given intravenously 60 mg/kg/day, day -7 to -6
Drug: Fludarabine phosphate
Given intravenously 25 mg/m^2/day over 15-30 minutes, day -5 to -1
Other Name: Fludara

  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. Measurable metastatic melanoma with at least one lesion that is resectable for tumor infiltrating lymphocytes (TIL) generation.
  2. 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).
  3. Greater than or equal to 18 years of age .
  4. Willing to practice birth control during treatment and for four months after receiving the preparative regimen.
  5. Life expectancy of greater than three months.
  6. Willing to sign a durable power of attorney.
  7. Able to understand and sign the Informed Consent Document.
  8. Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1.
  9. 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.
  10. 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 or hepatitis C.
  11. Chemistry: . Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less than three times the upper limit of normal. Serum creatinine less than or equal to 1.6 mg/dl. Total bilirubin less than or equal to 2 mg/dl, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 3 mg/dl.
  12. 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). Patients may have undergone minor surgical procedures with the past 3 weeks, as long as all toxicities have recovered to grade 1 or less or as specified in the eligibility criteria in Section 2.1.1.
  13. Six weeks must have elapsed since prior MDX-010 (Ipilimumab) therapy to allow antibody levels to decline.
  14. Patients who have previously received any anti-CTLA4 (cytotoxic T-lymphocyte antigen 4) antibody and experienced treatment related colitis must have a normal colonoscopy with normal colonic biopsies.

EXCLUSION CRITERIA:

  1. Prior cell transfer therapy that included non-myeloablative or ablative chemotherapy (for cohorts 4 and 5).
  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. Systemic steroid therapy required.
  4. 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.
  5. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease and Acquired Immune Deficiency Syndrome (AIDS)).
  6. 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.)
  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%.
  10. 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.

  11. Documented forced expiratory volume 1 (FEV1) less than or equal to 60% predicted tested in patients with:

    • A prolonged history of cigarette smoking
    • Symptoms of respiratory dysfunction
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00513604

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
Investigators
Principal Investigator: Deborah E Citrin, M.D. National Cancer Institute (NCI)
  More Information

Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Steven Rosenberg, M.D., Dr. Steven Rosenberg, National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier: NCT00513604     History of Changes
Other Study ID Numbers: 070176, 07-C-0176
Study First Received: August 6, 2007
Results First Received: February 19, 2013
Last Updated: May 29, 2013
Health Authority: United States: Federal Government
United States: Food and Drug Administration

Keywords provided by National Institutes of Health Clinical Center (CC):
Clinical Response
Immunotherapy
Cancer
Cytokines
Adoptive Cell Therapy
Melanoma
Skin Cancer
Malignant Melanoma

Additional relevant MeSH terms:
Melanoma
Melanoma, Experimental
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Neoplasms, Experimental
Cyclophosphamide
Fludarabine monophosphate
Fludarabine
Aldesleukin
Vidarabine
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
Antiviral Agents
Anti-Infective Agents

ClinicalTrials.gov processed this record on April 17, 2014