Clinical trial NCT01236573
Conditions: Skin Cancer Metastatic Melanoma
Keywords: Gene Therapy Immunotherapy Adoptive Cell Therapy Metastatic Melanoma
Sponsor: National Institutes of Health Clinical Center (CC)
Start date: 2010-10-01; Completion date: 2015-03-01
Enrollment: 34 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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 (interleukin-12 (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.

Detailed description:
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 nuclear factor of activated T-cells (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;
* Eastern Cooperative Oncology Group (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 cluster of differentiation 8 (CD8) enrichment on a Miltenyi column and then undergo a rapid expansion by exposure to Muromoanb-CD3) 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, computed tomography (CT) of the chest, abdomen and pelvis and clinical laboratory evaluation four to six weeks after treatment. If the patient has stable disease (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 dose-limiting toxicity (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 maximum tolerated dose (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% partial response (PR) + complete response (CR) rate (p1=0.20).

Arms: arm 1: Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of interleukin-12 (IL-12) gene-transduced tumor infiltrating lymphocytes (TIL). arm 2: Phase 1. 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. arm 3: Phase 1. 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. arm 4: Phase 1. 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. arm 5: Phase 1. 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. arm 6: Phase 1. 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. arm 7: Phase 1. 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. arm 8: Phase 1. 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. arm 9: Phase 1. 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. arm 10: Phase 1. 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. arm 11: Maximum tolerated dose (MTD). 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: intervention 1: Fludarabine intervention 2: Cyclophosphamide intervention 3: IL-12 transduced TIL
Intervention descriptions: intervention 1: Fludarabine 25 mg/m\^2/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days. intervention 2: Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml dextrose 5% in water (D5W) over 1 hr. intervention 3: 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.

Protocol documents: