Cell Therapy for Metastatic Melanoma Using CD8 Enriched Tumor Infiltrating Lymphocytes

This study has suspended participant recruitment.
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT01236573
First received: November 5, 2010
Last updated: May 15, 2014
Last verified: April 2014

November 5, 2010
May 15, 2014
October 2010
December 2017   (final data collection date for primary outcome measure)
Determine a safe dose of administration and determine if this approach will result in an objective tumor regression. [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
Not Provided
Complete list of historical versions of study NCT01236573 on ClinicalTrials.gov Archive Site
Not Provided
Not Provided
Not Provided
Not Provided
 
Cell Therapy for Metastatic Melanoma Using CD8 Enriched Tumor Infiltrating Lymphocytes
Phase I/II Study of Metastatic Melanoma Using Lymphodepleting Conditioning Followed by Infusion of Tumor Infiltrating Lymphocytes Genetically Engineered to Express IL-12

Background:

- One experimental treatment for certain types of cancer is cell therapy, which involves collecting lymphocytes (white blood cells) from a tumor, growing them in the laboratory in large numbers, and then modifying the cells with a gene (IL-12) that stimulates the immune system to attack and destroy the cancer cells. Because this treatment is experimental, researchers are interested in determining the side effects and overall effectiveness of cell therapy using white blood cells modified with IL-12 as a treatment for aggressive cancer.

Objectives:

- To determine the safety and effectiveness of cell therapy using IL-12 modified tumor white blood cells to treat metastatic melanoma.

Eligibility:

- Individuals greater than or equal to 18 years of age and less than or equal to age 66 who have been diagnosed with metastatic melanoma.

Design:

  • Participants will be screened with a medical history, physical examination, blood and urine tests, and imaging studies.
  • Cells for treatment will be collected during tumor biopsy or surgery.
  • Prior to the start of cell therapy, participants will have imaging procedures, heart and lung function tests, and blood and urine tests, as well as leukapheresis to collect additional white blood cells.
  • For 5 days before the cell infusion, participants will be admitted for inpatient chemotherapy with cyclophosphamide and fludarabine to suppress the immune system in preparation for the cell therapy.
  • Participants will receive the modified white blood cells as an infusion 1 to 4 days after the last dose of chemotherapy. The day after the infusion, participants will receive filgrastim to stimulate blood cell growth.
  • Participants will remain as inpatients for at least 5 to 10 days to recover from the treatment, and will be followed regularly after the treatment to study side effects and general effectiveness.
  • Participants who initially respond to treatment but have a relapse may have one additional treatment using the same procedure.

Background:

  • Interleukin-12 (IL-12) is an important immunostimulatory cytokine. We have constructed a retroviral vector that contains an inducible single chain IL-12 driven by an NFAT responsive promoter which can be used to mediate transfer of this gene into anti-tumor lymphocytes. This construct enables the secretion of IL-12 following stimulation of the T cell receptor.
  • Transduction of the IL-12 gene into mouse anti-tumor lymphocytes results in a profound increase in the ability of these lymphocytes to mediate tumor regression following administration to tumor bearing mice. These cells have a profound advantage in inducing anti-tumor responses because very few cells are needed and there is no requirement for the concomitant administration of interleukin-2 (IL-2) as is the case for conventional cell transfer immunotherapies.
  • Based on these murine studies we have now constructed a similar retrovirus that contains an inducible human single chain IL-12 driven by an NFAT responsive promoter. This retrovirus can be used to transduce tumor infiltrating lymphocytes (TIL) suitable for the therapy of patients with metastatic melanoma.

Objectives:

Primary objectives:

  • To evaluate the safety of the administration of IL-12 engineered TIL in patients receiving a non-myeloablative conditioning regimen.
  • Determine if the administration of IL-12 engineered TIL to patients following a non-myeloablative but lymphoid depleting preparative regimen will result in clinical tumor regression in patients with metastatic cancer.

Secondary objective:

-Determine the in vivo survival of IL-12 gene-engineered cells.

Eligibility:

Patients who are 18 years of age or older must have:

  • metastatic melanoma;
  • ECOG performance status 0 or 1;

Design:

  • TIL will be resected from metastatic deposits and grown in IL-2 using standard techniques.
  • Prior to approval of amendment A, after about 2 weeks TIL will undergo CD8 enrichment on a Miltenyi column and then undergo a rapid expansion by exposure to OKT-3 an IL-2 in the presence irradiated feeder cells. Four to five days later, transduction is initiated by addition of retroviral vector supernatant containing the IL-12 gene.

With approval of amendment A, TIL will not undergo CD8 enrichment. Starting with cohort 5, after initial growth, TIL undergo a rapid expansion by exposure to OKT-3 and IL-2 in the presence irradiated feeder cells. Four to five days later, transduction is initiated by addition of retroviral vector supernatant containing the IL-12 gene.

  • Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL. Cohorts of 3 patients each will receive increasing cell doses.
  • Patients will undergo complete evaluation of tumor with physical examination, CT of the chest, abdomen and pelvis and clinical laboratory evaluation four to six weeks after treatment. If the patient has SD or tumor shrinkage, repeat complete evaluations will be performed every 1-3 months. After the first year, patients continuing to respond will continue to be followed with this evaluation every 3-4 months until off study criteria are met.
  • The study will be conducted using a Phase I/II optimal design. The protocol will proceed in a phase 1 dose escalation design.
  • Prior to approval of amendment A, the protocol enrolled 1 patient in each of the first 3 dose cohorts. Cohort 4 proceeded in a phase 1 dose escalation design, with of n=3. Should a single patient experience a dose limiting toxicity due to the cell transfer at a particular dose level, additional patients would be treated at that dose to confirm that no greater than 1/6 patients have a DLT prior to proceeding to the next higher level. If a level with 2 or more DLTs in 3-6 patients has been identified, three additional patients will be accrued at the next- lowest dose, for a total of 6, in order to further characterize the safety of the maximum tolerated dose.
  • With approval of amendment A, no additional patients will be enrolled in cohort 4, and the protocol will enroll 1 patient in cohort 5 with a dose of 1 X 10(7) bulk young TIL cells. Cohorts 6-12 will proceeded in a phase 1 dose escalation design, with an n=3. Should a single patient experience a dose limiting toxicity due to the cell transfer at a particular dose level, additional patients would be treated at that dose to confirm that no greater than 1/6 patients have a DLT prior to proceeding to the next higher level. If a level with 2 or more DLTs in 3-6 patients has been identified, three additional patients will be accrued at the next-lowest dose, for a total of 6, in order to further characterize the safety of the maximum tolerated dose prior to starting the pahse II portion. If a dose limiting toxicity occurs in the cohort 4, that cohort will be expanded to 6 patients. If 2 DLTs are encountered in this cohort, the study will be terminated.
  • Once the MTD has been determined, the study then would proceed to the phase II portion using a phase II optimal design where initially 21 evaluable patients will be enrolled. If 0 or 1 of the 21 patients experiences a clinical response, then no further patients will be enrolled but if 2 or more of the first 21 evaluable patients enrolled have a clinical response, then accrual will continue until a total of 41 evaluable patients have been enrolled.
  • The objective will be to determine if the combination of lymphocyte depleting chemotherapy, and IL-12 gene engineered lymphocytes is associated with a clinical response rate that can rule out 5% (p0=0.05) in favor of a modest 20% PR + CR rate (p1=0.20).
Interventional
Phase 1
Phase 2
Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Skin Cancer
  • Metastatic Melanoma
  • Drug: Fludarabine
    Fludarabine 25 mg/m2/day IVPB daily over 30 minutes for 5 days.
  • Drug: Cyclophosphamide
    Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml D5W over 1 hr.
  • Biological: IL-12 transduced TIL
    On day 0 (one to four days after the last dose of fludarabine), cells will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes.
Experimental: Single Arm
Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
Interventions:
  • Drug: Fludarabine
  • Drug: Cyclophosphamide
  • Biological: IL-12 transduced TIL

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Suspended
34
December 2017
December 2017   (final data collection date for primary outcome measure)
  • INCLUSION CRITERIA:
  • Metastatic melanoma with evaluable disease.
  • Greater than or equal to 18 years of age and less than or equal to age 66.
  • Willing to sign a durable power of attorney
  • Able to understand and sign the Informed Consent Document
  • Clinical performance status of ECOG 0 or 1
  • Life expectancy of greater than three months
  • Patients of both genders must be willing to practice birth control from the time of enrollment on this study and for up to four months after the cells are no longer detected in the blood.
  • Serology:

    • Seronegative for 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 seronegative for hepatitis C antibody. If hepatitis C antibody test is positive, then patient must be tested for the presence of antigen by RT-PCR and be HCV RNA 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.
  • Hematology:

    • Absolute neutrophil count greater than 1000/mm(3) without the support of filgrastim.
    • WBC (> 3000/mm(3)).
    • Platelet count greater than 100,000/mm(3).
    • Hemoglobin greater than 8.0 g/dl.
  • Chemistry:

    • Serum ALT/AST less or equal to 2.5 times the upper limit of normal.
    • Serum creatinine less than or equal to 1.6 mg/dl.
    • 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.
  • 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).

EXCLUSION CRITERIA:

  • Previous treatment with IL-12.
  • 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).
  • Concurrent 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).
  • Concurrent systemic steroid therapy.
  • History of severe immediate hypersensitivity reaction to any of the agents used in this study.
  • In patients > 60 years old and/or history of coronary revasularization or ischemic symptoms, documented LVEF of less than or equal to 45%.
Both
18 Years to 66 Years
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT01236573
110011, 11-C-0011
Not Provided
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Steven A Rosenberg, M.D. National Cancer Institute (NCI)
National Institutes of Health Clinical Center (CC)
April 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP