Chemotherapy, Irradiation, Cell Infusions, and Interleukin-2 to Treat Metastatic Melanoma

This study has been completed.
Sponsor:
Information provided by:
National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT00314106
First received: April 11, 2006
Last updated: September 18, 2012
Last verified: September 2012
  Purpose

Background:

  • In a study in humans with melanoma, patients given total body irradiation to suppress the immune system in conjunction with chemotherapy showed a significant clinical response.
  • In previous studies, about one-half of patients given tumor-fighting cells (cells created from the patient's tumor cells and grown in the laboratory) showed some anti-tumor response.

Objective: To determine whether tumor-fighting cells taken from a melanoma tumor and grown in the lab can more effectively at fight melanoma when the patient's immune system is suppressed and cannot attack them.

Eligibility: Patients 18 years of age or older with metastatic melanoma who have tumor reactive cells available.

Design:

-Patients are assigned to one of two groups - those having received prior therapy with Interleukin-2 (IL-2) and those who have not.

After five days of injections of filgrastim, a medicine to stimulated the growth of white blood cells, patients undergo apheresis or bone marrow harvesting, or both, to collect stem cells for later re-infusion. For apheresis, whole blood is collected through a needle in an arm vein and circulated through a cell-separating machine where the stem cells are extracted. The rest of the blood is returned through the same needle or a needle in the other arm. Bone marrow harvesting is done under general anesthesia. Stem cells are collected through a large needle inserted into the hipbone.-Patients' immune system cells and bone marrow function are eliminated with chemotherapy (7 days) and total body irradiation (3 days) so the patient's immune system cells will not fight the tumor-fighting cells they are given in treatment.

  • 1 to 3 days after total body irradiation, patients receive the tumor-fighting cells by intravenous (IV) infusion. After the cells are infused, they receive interleukin-2 (IL-2) infusions every 8 hours for 5 days.
  • 2 days after infusion of the tumor-fighting cells, patients receive the stem cells collected earlier by apheresis.
  • Patients are evaluated 4 to 6 weeks after cell infusion to look for tumor response to treatment. Patients whose tumor has not grown return to the National Institutes of Health (NIH) every 1 to 3 months for blood tests, scans and x-rays.

Condition Intervention Phase
Metastatic Melanoma
Biological: Melanoma Reactive TIL
Drug: Cyclophosphamide
Biological: IL-2
Drug: Fludarabine
Radiation: 1200 total body irradiation (TBI)
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase II Study Using a Myeloablative Lymphocyte Depleting Regimen of Chemotherapy and Intensive Total Body Irradiation Followed by Infusion of Tumor Reactive Lymphocytes and Reconstitution With CD34+ Stem Cells in Metastatic Melanoma

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Complete Response [ Time Frame: 33 months ] [ Designated as safety issue: No ]

    Determine if the combination of high dose aldesleukin, reinfused cells after lymphocyte depleting chemotherapy and 1200 cGy total body irradiation (TBI) is able to be associated with a modest fraction of patients with metastatic melanoma who can experience a complete response to therapy.

    Complete response (CR) is a disappearance of all target lesions.



Secondary Outcome Measures:
  • Number of Participants With Adverse Events [ Time Frame: 33 months ] [ 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: 26
Study Start Date: April 2006
Study Completion Date: March 2009
Primary Completion Date: February 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: TBI 1200 cGy + TIL +HD IL-2, prior IL-2
Patients that received prior interleukin 2 (IL-2) therapy will receive a myeloablative lymphocyte depleting preparative regimen consisting of cyclophosphamide (60 mg/kg/day x 2 days intravenous (IV)), fludarabine (25mg/m^2/day IV X 5 days) and 1200 cGy total body irradiation (TBI). Following the lymphodepleting regimen, patient will receive intravenous adoptive transfer of tumor reactive lymphocytes (minimum 3 X 10 (9) and up to a maximum of 3 X 10(11) lymphocytes) followed by high-dose intravenous (IV) IL-2 (720,000 IU/kg/dose every 8 hours for up to 15 doses).
Biological: Melanoma Reactive TIL
Other Name: (TIL) tumor infiltrating lymphocytes
Drug: Cyclophosphamide
60 mg/kg/ day x 2 days intravenous
Other Name: Cytoxan
Biological: IL-2
720,000 IU/kg/dose every 8 hours for up to 15 doses
Other Name: Aldesleukin
Drug: Fludarabine
25 mg/m^2/day intravenous x 5 days
Other Name: Fludara
Radiation: 1200 total body irradiation (TBI)
1200 cGY total body radiation
Other Name: TBI
Experimental: TBI 1200 cGy + TIL +HD IL-2, no prior IL-2
Patients that have not received prior interleukin 2 (IL-2) therapy will receive a myeloablative lymphocyte depleting preparative regimen consisting of cyclophosphamide (60 mg/kg/day x 2 days intravenous (IV)), fludarabine (25mg/m^2/day IV X 5 days) and 1200 cGy total body irradiation (TBI). Following the lymphodepleting regimen, patient will receive intravenous adoptive transfer of tumor reactive lymphocytes (minimum 3 X 10 (9) and up to a maximum of 3 X 10(11) lymphocytes) followed by high-dose intravenous (IV) IL-2 (720,000 IU/kg/dose every 8 hours for up to 15 doses)
Biological: Melanoma Reactive TIL
Other Name: (TIL) tumor infiltrating lymphocytes
Drug: Cyclophosphamide
60 mg/kg/ day x 2 days intravenous
Other Name: Cytoxan
Biological: IL-2
720,000 IU/kg/dose every 8 hours for up to 15 doses
Other Name: Aldesleukin
Drug: Fludarabine
25 mg/m^2/day intravenous x 5 days
Other Name: Fludara
Radiation: 1200 total body irradiation (TBI)
1200 cGY total body radiation
Other Name: TBI

  Show Detailed Description

  Eligibility

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

Patients must have tumor reactive cells obtained and evaluated while participating in the Surgery Branch protocol, "Cell Harvest and Preparation for Surgery Branch Adoptive Cell Therapy Protocols" or on another Institutional Review Board (IRB) approved Surgery Branch adoptive cell therapy study, i.e. 99-C-0158 or 03-C-0162.

The first ten patients enrolled must have previously received interleukin-2 (IL-2) and have been either non-responders (progressive disease) or have recurred.

Patients must be greater than or equal to 18 years of age and must have measurable metastatic melanoma.

Patients of both genders must be willing to practice birth control during treatment and for four months after receiving the preparative regimen.

Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0, 1.

Absolute neutrophil count greater than 1000/mm^3 without support of filgrastim.

Platelet count greater than 100,000/mm^3.

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.

Must be willing to sign a durable power of attorney.

Patients must be able to understand and sign the Informed Consent document.

Patients with resected or stable brain metastases will be eligible.

Left ventricular ejection fraction (LVEF) greater than or equal to 45%.

Carbon monoxide diffusing capacity (DLCO) greater than or equal to 60% predicted.

CELL INFUSION EXCLUSION CRITERIA:

Less than 30 days has elapsed since any prior systemic therapy at the time the patient receives the preparative regimen, or less than six weeks since prior nitrosurea therapy. All patients' toxicities must have recovered to a grade 1 or less or as specified in the eligibility criteria. Patients may have undergone minor surgical procedures within the past 3 weeks, as long as all toxicities have recovered to grade 1 or less or as specified in the eligibility criteria.

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.

Life expectancy of less than three months.

Systemic steroid therapy required.

Hemoglobin less than 8 g/dl unable to be corrected with transfusion.

Any 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 or secondary immunodeficiency. Must have recovered immune competence after chemotherapy or radiation therapy as evidenced by normal ANC greater than 1000/mm^3 and absence of 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.)

Seropositive 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.)

Patients with hepatitis B or hepatitis C will be excluded.

Seronegative for Epstein-Barr virus (EBV).

Patients who are not willing to complete a durable power of attorney (DPA) will be excluded.

Patients who have received prior preparative regimens with cyclophosphamide and fludarabine on prior Surgery Branch adoptive cell therapies will be excluded.

The following patients will be excluded because of inability to receive high dose IL-2:

Patients will be excluded if they have a history of electrocardiogram (EKG) abnormalities, symptoms of cardiac ischemia or arrhythmias and have a LVEF less than 45% on a cardiac stress test (stress thallium, stress multi-gated acquisition scan (MUGA), dobutamine, echocardiogram or other stress test).

Similarly, patients who are 50 years old or greater with an LVEF less than 45% will be excluded.

Patients who have a prolonged history of cigarette smoking or symptoms of respiratory dysfunction will be excluded if they have an abnormal pulmonary function test as evidenced by a forced expiratory volume 1 (FEV1) less than 60% predicted.

  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: NCT00314106

Locations
United States, Maryland
National Cancer Institute (NCI)
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
Investigators
Principal Investigator: Steven A 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: NCT00314106     History of Changes
Obsolete Identifiers: NCT00335127
Other Study ID Numbers: 060136, 06-C-0136
Study First Received: April 11, 2006
Results First Received: September 18, 2012
Last Updated: September 18, 2012
Health Authority: United States: Federal Government
United States: Food and Drug Administration

Keywords provided by National Institutes of Health Clinical Center (CC):
Clinical Response
Stage IV Melanoma
Adoptive Cell Therapy
Tumor Infiltrating Lymphocytes
Immunologic Response
Metastatic Melanoma

Additional relevant MeSH terms:
Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Cyclophosphamide
Fludarabine monophosphate
Fludarabine
Interleukin-2
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
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Central Nervous System Agents
Antimetabolites, Antineoplastic
Antimetabolites

ClinicalTrials.gov processed this record on July 22, 2014