Clinical trial NCT02062359
Conditions: Metastatic Cancer Metastatic Melanoma
Keywords: Malignant Melanoma Metastatic Cancer Gene Therapy Immunotherapy Tumor Regression
Sponsor: National Cancer Institute (NCI)
Start date: 2014-02-01; Completion date: 2016-02-01
Enrollment: 2 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

The National Cancer Institute (NCI) Surgery Branch has developed an experimental therapy for treating patients with melanoma that involves taking white blood cells from the patient, growing them in the laboratory in large numbers, genetically modifying them, and then giving the cells back to the patient. In a previous study, the NCI Surgery Branch used the anti-ESO-1 gene and a type of virus (retrovirus) to make these tumor-fighting cells (anti-ESO-1 cells). About half of the patients who received this treatment experienced shrinking of their tumors. In this study, we are using a slightly different method of producing the anti-ESO-1 cells selected for a specific cell type, which we hope, will be better in making the tumors shrink.

Objectives:

The purpose of this study is to see if these tumor fighting cells (genetically modified cells) that express the receptor for the ESO-1 molecule on their surface can cause melanoma tumors to shrink and to see if this treatment is safe.

Eligibility:

-Adults 18 and older with cancer that has the ESO-1 molecule on tumor surfaces

Design:

* Work up stage: Patients will be seen as an outpatient at the National Institutes of Health (NIH) clinical Center and undergo a history and physical examination, scans, x-rays, lab tests, and other tests as needed
* Leukapheresis: If the patients meet all of the requirements for the study they will undergo leukapheresis to obtain white blood cells to make the anti ESO-1 cells. {Leukapheresis is a common procedure, which removes only the white blood cells from the patient.}
* Treatment: Once their cells have grown, the patients will be admitted to the hospital for the conditioning chemotherapy, the anti-ESO 1 cells and aldesleukin. They will stay in the hospital for about 4 weeks for the treatment.

Follow up: Patients will return to the clinic for a physical exam, review of side effects, lab tests, and scans about every 1-3 months for the first year, and then every 6 months to 1 year as long as their tumors are shrinking. Follow up visits take up to 2 days.

Detailed description:
Background:

* A T cell receptor (TCR) that recognizes the NY-ESO-1 (ESO) tumor/testes antigen has been cloned into a retrovirus and can be used to genetically modify human peripheral blood lymphocytes (PBL) so they recognize human leukocyte antigen (HLA)-A2+, ESO+ tumors
* PBL expressing the anti-ESO TCR have been administered with aldesleukin with or without ALVAC vaccine to 21 patients with melanoma following lymphodepleting chemotherapy at the Surgery Branch, resulting in objective tumor regression (complete or partial regression) in ten patients (47%).
* In animal models using murine cells and in experiments with human T cells in vitro, T cell subsets expressing the lymphoid homing and differentiation marker cluster of differentiation 62L (CD62L), including na(SqrRoot) ve T cells (TNaive), stem cell memory T cells (TSCM), and central memory T cells (TCM), were shown to have superior attributes compared to whole PBL and CD62L- PBL for adoptive cell therapy, including superior persistence following transfer in vivo.

Objectives:

Primary objective:

\- To determine whether the administration of anti-ESO TCR engineered CD62L+-derived lymphocytes plus high-dose aldesleukin following a non-myeloablative lymphodepleting preparative regimen can result in an objective regression rate (partial response (PR) + complete response (CR)) of melanoma tumors.

Secondary objectives:

* Determine the persistence of genetically engineered, adoptively transferred CD62L+ derived lymphocytes.
* Determine the toxicity profile of this treatment regimen.

Eligibility:

Patients who are:

* Human leukocyte antigen (HLA)-A\*0201 positive
* 18 years of age or older
* Have metastatic melanoma that expresses the ESO antigen

Patients may not have:

\- Contraindications for high dose aldesleukin administration.

Design:

* Peripheral blood mononuclear cells (PBMC) will be obtained by leukapheresis and will undergo positive selection for CD62L using a CliniMACS magnetic cell separation apparatus to enrich for the less differentiated TNaive, TSCM, and TCM subsets.
* The enriched CD62L+ lymphocytes will be cultured in the presence of anti-CD3 (OKT3) and aldesleukin in order to stimulate T-cell growth, then transduced with the anti-ESO TCR.
* All patients will receive a non-myeloablative lymphocyte depleting preparative regimen of cyclophosphamide and fludarabine.
* On day 0 patients will receive anti-ESO TCR gene-transduced CD62L+ -derived lymphocytes and then begin high dose aldesleukin.
* A complete evaluation of evaluable lesions will be conducted 6 weeks (+/- 2 weeks) following the administration of the cell product.
* The primary objective will be efficacy. The study will be conducted using a phase II optimal design (Simon R, Controlled Clinical Trials 10:1-10, 1989) in order to rule out an unacceptably low 40% overall response rate (p0=0.40) in favor of an improved response rate of 65% (p1=0.65). This study will initially enroll 11 evaluable patients, and if 0 to 5 of the 11 have a response, then no further patients will be accrued. If 6 or more of the first 11 patients have a response, then accrual would continue until a total of 20 patients have been enrolled. If there were 11 or more responses in 20 patients (55%), this would be sufficiently interesting to warrant further study in later trials. To allow for a very small number of inevaluable patients, the accrual ceiling will be set at 22 patients.

Arms: arm 1: Patients will receive the standard National Cancer Institute (NCI) Surgery Branch non-myeloablative, lymphodepleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous (IV) infusion of the anti-NY ESO-1 T cell receptor (TCR) cluster of differentiation 62L (CD62L)+ engineered peripheral blood lymphocyte (PBL) and aldesleukin
Interventions: intervention 1: Anti-NY ESO-1 T cell receptor (TCR) cluster of differentiation 62L (CD62L)+ cells intervention 2: Aldesleukin intervention 3: Cyclophosphamide intervention 4: Fludarabine
Intervention descriptions: intervention 1: Patients will receive non-myeloablative lymphodepleting preparative regimen consisting of cyclophosphamide and fludarabine followed by the administration of anti-NY ESO-1 T cell receptor (TCR) CD62L+ cells and high dose aldesleukin.

On day 0, cells (1x10e9 to 2x10e11) will be infused intravenously on the Patient Care Unit over 20-30 minutes. intervention 2: Aldesleukin 720,000 IU/kg intravenous (IV) (based on total body weight) over 15 minutes approximately every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses). intervention 3: On days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml dextrose 5% in water (D5W) with Mesna 15 mg/kg/day X 2 days over 1 hr. intervention 4: On days -5 to -1: Fludarabine 25 mg/m(2)/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.

Protocol documents: