Phase 1/2 Study of Metastatic Renal Cancer Using T-Cells Transduced With a T-Cell Receptor Which Recognizes TRAIL Bound to the DR4 Receptor

Kidney Cancer Clinical Trial

Official title: Phase 1/2 Study of Metastatic Renal Cancer Using T-Cells Transduced With a T-Cell Receptor Which Recognizes TRAIL Bound to the DR4 Receptor

Status Terminated

Clinical Trial Summary

Background:

• An experimental cancer treatment procedure involves taking a patient s own tumor or blood cells, modifying them with a gene that targets proteins on the surface of tumor cells, and growing those cells in a laboratory. The modified cells are then given back to the patient by intravenous (IV) transfusion, in the hope that the new cells will attack and destroy the cancer cells without harming healthy tissue.

• This procedure has been used for melanoma patients, and researchers are now attempting to use this treatment for patients with renal (kidney) cancer. In the laboratory, this attack kills nearly all kidney cancers tested, but not normal tissues. However, the effectiveness and possible side effects of this treatment are still being studied.

Objectives:

• To find out if cells modified to target DR4 and TRAIL (two proteins found on the surface of many kidney tumors) are effective in treating kidney cancer.

• To determine the maximum tolerated dose (the highest dose that does not cause unacceptable side effects) of the modified cells.

Eligibility:

• Patients 18 years of age and older with metastatic renal cancer whose disease has not responded to standard treatment.

• Patients will be divided into two study branches: Arm A for those who will be receiving modified cells from their biopsied tumor, and Arm B for those who will be receiving their own modified white blood cells.

Design:

• Five-stage treatment process, outpatient for stages 1 and 5 and inpatient for stages 2 through 4:

• Work-up (1 to 2 weeks): Physical examination, heart and lung function tests, imaging tests, blood and/or tumor samples taken.

• IV chemotherapy (1 week): Cyclophosphamide and fludarabine to prepare for the new cell infusion.

• IV cell infusion and treatment with IL-2 to support the modified cells (4 days).

• Recovery (1 to 2 weeks): Recover from effects of chemotherapy and infusion.

• Follow-up (every 1 to 6 months): Return to clinic for physical exam, review of side effects, other tests.

• Follow-up evaluations will continue to determine the success of the treatment.

• Evaluations during the treatment period:

• Physical examination, including vital signs and body weight checks, and pregnancy test for women who can become pregnant.

• Blood and urine tests.

• Disease evaluation and monitoring on both inpatient and outpatient basis.

• Because researchers do not know the long-term side effects of gene therapy, patients will be asked to participate in long-term follow up for up to 15 years. The follow-up will involve yearly physical exams and medical history, and blood collection (3, 6 and 12 months after treatment, and every year after that).

Clinical Trial Description

Background:

• The clinical administration of tumor-reactive T-cells grown in vitro is a highly active therapy for patients with metastatic melanoma in experimental protocols when they are combined with preparative lymphodepleting chemotherapy and systemic IL-2.

• We cloned a novel T-cell from the blood of a patient with renal cell cancer (RCC), which recognizes nearly all human renal cancer lines irrespective of MHC haplotype.

• The alpha sign and beta sign chain of T-cell receptor from this clone, 2G-1, can be introduced into human lymphocytes by retroviral transduction and confers this same recognition of RCC.

• This TCR was found to recognize TNF-related apoptosis inducing ligand (TRAIL) bound to its receptor DR4.

• Both TRAIL and agonist antibodies to DR4 have tumor specificity and are in current clinical trials for cancer.

• Two amino acid modifications of the native TCR greatly augmented its recognition of RCCs without altering background reactivity.

Objectives:

• Primary:

• Determine if the administration of T-cells retrovirally transduced with the 2G-1 TCR, with preparative chemotherapy and IL-2, can cause the regression of metastatic RCC.

• To identify the maximum tolerated dose (MTD) for cells incorporating a TCR in PBL and in TIL.

• Secondary:

• Determine the toxicities of these T-cells administered in the above fashion.

• Determine TCR and vector presence in the post treatment phase.

Eligibility:

• Patients with measurable metastatic clear cell renal cancer who have previously received at least one systemic standard care regimen and have progressed or be found to be intolerant of standard therapies.

• Patients must be eligible for high-dose IL-2.

• Patients must not have active or clinically symptomatic CNS metastases within the previous 3 months.

• Patients must have acceptable hematopoietic and major organ function as determined by laboratory and/or functional testing.

Design:

• A phase I-II dose escalating protocol with 2 arms. Patients in Arm A will receive peripheral blood lymphocytes transduced with the 2G-1 TCR; patients in Arm B will receive renal TIL transduced with the 2G-1 TCR. Arm B will begin after a safe dose has been defined in Arm A.

• Once MTD has been established for each arm, up to 24 patients will be enrolled in each arm of the phase II stage.

• Patients will receive a nonmyeloablative but lymphocyte-depleting preparative regimen consisting of cyclophosphamide and fludarabine followed in one to four days by IV infusion of their transduced cells and subsequent IV aldesleukin administration.

• Up to 106 patients may be enrolled over 3-4 years. ;

Related Conditions & MeSH terms

• Carcinoma, Renal Cell
• Kidney Cancer
• Kidney Neoplasms
• Renal Cancer

• NCT number: NCT00923390
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Status: Terminated
• Phase: Phase 1
• Start date: March 2, 2009
• Completion date: August 24, 2012