Prospective Randomized Comparative Study of Cell Transfer Therapy Using CD8+-Enriched Short-Term Cultured Anti-Tumor Autologous Lymphocytes Following a Non-Myeloablative Lymphocyte Depleting Chemotherapy Regimen Compared to High-Dose Aldesleukin in M...

Phase 2

Completed

Conditions: Skin Cancer
Metastatic Melanoma
Melanoma

Interventions: Biological: CD8 enriched Young TIL
Biological: Aldesleukin

Registration Number: NCT01118091

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: Background:

- Adoptive cell therapy involves taking white blood cells called lymphocytes from patients' tumors, growing them in the laboratory in large numbers, and then giving the cells back to the patient to allow the cells to attack the tumor. Because this process is lengthy and difficult to perform, researchers have been developing improved means of performing adoptive cell therapy. Researchers are now interested in comparing adoptive cell therapy with the standard treatment for metastatic melanoma (skin cancer).

Objectives:

- To compare the effectiveness of adoptive cell therapy with standard high-dose aldesleukin as a treatment for metastatic melanoma.

Eligibility:

* Individuals 18 years of age or older who have been diagnosed with metastatic melanoma and have not previously received aldesleukin therapy or cell therapy for their disease.

* Participants must have at least one tumor that can be easily removed as part of the treatment procedure.

Design:

* Participants will be screened with a full medical history, physical examination, blood and urine tests, and imaging scans to evaluate tumor size and treatment options.

* Participants will be separated into two groups, in which one group will have adoptive cell therapy and one will have aldesleukin treatment.

* Adoptive Cell Therapy

* Participants will have a tumor sample taken in order to collect white blood cells for treatment. Participants whose tumors do not provide sufficient white blood cells may be switched to the aldesleukin-only treatment group.

* The white blood cells will be grown in the laboratory for several weeks.

* Prior to receiving cell therapy, participants will receive chemotherapy for 7 days to improve the chances of successful treatment.

* Participants will have cell therapy followed by high-dose aldesleukin treatment every 8 hours for up to 5 days. This treatment will be followed by 1 to 2 weeks of recovery time as an inpatient at the clinical center.

* Participants will be evaluated at 12 weeks following the start of the study, every 2 to 3 months for the first year, every 6 months for the next 5years, and then yearly thereafter..

* Standard Aldesleukin Treatment

* Participants will have high-dose aldesleukin treatment every 8 hours for up to 5 days (one cycle of treatment), and will have a second cycle of treatment 7 to 10 days after the first cycle.

* If tests show that the tumors have grown, participants will be offered the chance to have additional cycles of aldesleukin, or begin a cell therapy treatment.

* Participants will be evaluated at 12 weeks following the start of the study, every 2 to 3 months for the first year, every 6 months for the next 5years, and then yearly thereafter.

Detailed Description: Background:

* Tumor Infiltrating Lymphocytes (TIL) can mediate the regression of bulky metastatic melanoma when administered to the autologous patient along with high-dose aldesleukin (IL-2) following a non-myeloablative lymphodepleting chemotherapy preparative regimen.

* Although this adoptive cell therapy (ACT) has been shown capable of mediating objective clinical responses in patients with metastatic melanoma, including patients who have previously been treated with aldesleukin or chemotherapy, the treatment is only available in the Surgery Branch, National Cancer Institute (NCI) and in just one or two other institutions in the United States.

* Despite our reports of the objective regressions in patients receiving adoptive cell therapy (ACT), doubts have been raised concerning the possible influence of patient selection bias that may have accounted for the increase in survival using ACT compared to historical controls.

* ACT is a cumbersome and labor intensive procedure which has discouraged many from applying it. We have recently developed simplifications in the technique for generating TIL that are also capable of mediating objective responses.

* To evaluate the efficacy of ACT we are now proposing a prospective randomized trial to compare this form of therapy with standard available treatment for patients with metastatic melanoma.

Objectives:

* To determine, in a prospective randomized trial, the response rate and progression free survival of patients with metastatic melanoma receiving either ACT or standard high-dose aldesleukin treatment.

* Survival rate will be evaluated as a secondary endpoint.

* To determine the toxicity of these two treatment regimens.

Eligibility:

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

* Evaluable metastatic melanoma;

* No prior treatment with high-dose aldesleukin (greater than or equal to 600,000 IU IL-2 q8h or the equivalent)

* No contraindications to high-dose aldesleukin administration;

* No concurrent major medical illnesses or any form of immunodeficiency;

* Lesions of at least 2cm in diameter that can be surgically removed with minimal morbidity.

Design:

* Prior to amendment D, patients with metastatic melanoma lesions that can be resected with minimal morbidity will be prospectively randomized to receive either ACT using CD8+ young TIL (arm 2) and aldesleukin (arm 1) following a non-myeloablative chemotherapy preparative regimen, or will receive standard high-dose aldesleukin therapy.

* With the approval of amendment D, arm 1 and 2 will be closed, and two new arms will be opened. Patients with metastatic melanoma lesions that can be resected with minimal morbidity will be prospectively randomized to receive either ACT using young TIL (arm 4) and aldesleukin (arm 3) following a non-myeloablative chemotherapy preparative regimen, or will receive standard high-dose aldesleukin therapy.

* Response rate and time to progression will be evaluated for all patients on an intent-to-treat basis.

* Patients may crossover to the other treatment arm after progressive disease is documented by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, if still eligible.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 12

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Arm 2 - Adoptive cell therapy	CD8 enriched Young TIL	Adoptive Cell Therapy consisting of the lymphocyte depleting preparative regimen consisting of fludarabine and cyclophosphamide, followed by infusion of between 1x10\^9 to 2x10\^11 CD8+ enriched tumor infiltrating lymphocytes (minimum of 5 x10\^8) and the administration of high-dose aldesleukin.
Arm 1-Aldesleukin	Aldesleukin	Aldesleukin 720,000 IU/kg IV over 15 minute every eight hours and continuing for up to 5 days (maximum of 15 doses). Patients will receive one additional cycle of aldesleukin approximately 10-14 days after completion of the first cycle of aldesleukin.

Primary Outcome Measures

Name	Time	Method
Response Rate	3 years	Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Complete response (CR) is the 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 LD recorded since the treatment started or the appearance of one or more new lesions. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the smallest sum LD.
Progression Free Survival	3 years	Measured from the time of randomization to time of progression (or death).

Secondary Outcome Measures