Chemotherapy Followed by Infusion of DMF5 Cells to Treat Metastatic Melanoma

Background:

In previous trials in the Surgery Branch, a 51 percent objective response rate has been observed in heavily pre-treated patients with metastatic melanoma undergoing adoptive cell transfer therapy utilizing a non-myeloablative preparative regimen followed by administration of autologous tumor-reactive lymphocytes and subsequent treatment with high-dose aldesleukin.

However, in patients with metastatic melanoma undergoing metastasectomy, recovery of adequate numbers of tumor specific T lymphocytes from surgical specimens is possible in approximately half of all patients, thus limiting the application of adoptive cell transfer therapy.

Murine models performed in the Surgery Branch have demonstrated solid tumor regression in mice treated with allogeneic tumor specific T cells combined with a preinfusion lymphodepleting regimen.

We have identified a tumor specific lymphocyte cell line (DMF5) used previously in an autologous adoptive cell transfer protocol that was associated with an objective clinical response in that patient.

In subsequent preclinical testing of this lymphocyte population, we have demonstrated high specificity against HLA-A 0201 positive melanoma cell lines as well as the common shared melanocyte differentiation antigen MART-1:27-35. We have expanded this lymphocyte population to provide up to 30 individual allogeneic cell transfers to HLAA 0201 positive patients with metastatic melanoma.

In this trial we want to test our hypothesis that objective tumor regression can be achieved with the DMF5 allogeneic T-cell product using a non-myeloablative regimen followed by cell transfer and high-dose aldesleukin.

It should be emphasized that this protocol is designed to test whether highly melanoma reactive allogeneic lymphocytes can mediate cancer regression. The DMF5 cell line is a limited reagent only available for the treatment of up to 30 patients. However, if this treatment results in cancer regression, it will represent an important step in our development of an allogeneic T-cell receptor engineered universal effector cell line for the treatment of patients with cancer.

Objectives:

To evaluate the safety of the administration of the DMF5 allogeneic T-cell product in patients receiving the non- myeloablative conditioning regimen, and aldesleukin.

To determine whether this allogeneic tumor-specific lymphocyte cell line, hereafter referred to as DMF5, infused in conjunction with the administration of high-dose aldesleukin may result in objective clinical tumor regression in eligible HLA-A 0201 positive patients with metastatic melanoma receiving a non-myeloablative lymphoid depleting preparative regimen.

To determine the in vivo survival of the infused cells following the non-myeloablative regimen, via analysis of the sequence of the variable region of the T cell receptor or flow cytometry (FACS).

Eligibility:

Patients with metastatic melanoma who are greater than or equal to 18 years of age, HLA-A 0201 positive, do not have suitable autologous tumor reactive TIL cells available, and are able to tolerate high-dose aldesleukin.

Design:

Patients will receive a non-myeloablative lymphocyte depleting preparative regiment consisting of cyclophosphamide (60 mg/kg/day times 2 days intravenous (IV)) and fludarabine (25 mg/m2/day IV times 5 days).

Patients will receive intravenous adoptive transfer of the tumor reactive lymphocyte cell line DMF5 (after its expansion in interleukin-2 and OKT3) followed by high-dose intravenous (IV) aldesleukin (720,000 IU/kg/dose every 8 hours for up to 15 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 and then monthly for approximately 3 to 4 months or 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, with three cohorts. Should a single patient experience a dose limiting toxicity at a particular dose level, three more 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 phase II portion. If a dose limiting toxicity occurs in the first cohort, 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, and initially, 9 total patients will be administered the therapy at the maximum tolerated dose. The plan will utilize a Simon two-stage optimal phase II design. If 0 of the 9 patients experiences a clinical response, then no further patients will be enrolled but if 1 or more of the first 9 evaluable patients enrolled have a clinical response, then accrual will continue until a total of 30 evaluable patients have been enrolled.

This design has the ability to distinguish a 5% response rate (p0=0.05) from a 25% response rate (p1=0.25), with 10% probability of falsely "accepting" the DMF5 cell therapy approach (alpha=0.10), and 10% probability of incorrectly discarding this strategy as if it were unacceptably poor (beta=0.10). This design also has 63% probability of stopping early (at 9 patients) if the true response rate is 5%.