Clinical trial NCT00923845
Conditions: Renal Cell Carcinoma Graft-Versus-Host Disease Engraftment Syndrome
Keywords: Metastatic Renal Cell Carcinoma Allogeneic Hematopoietic Stem Cell Transplant Th2 Cells Sirolimus Pentostatin Kidney Cancer Renal Cell Carcinoma Metastatic Renal Cell Cancer
Sponsor: National Cancer Institute (NCI)
Start date: 2008-03-01; Completion date: 2017-06-22
Enrollment: 25 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
Background:

Low-dose chemotherapy is easier for the body to tolerate than typical high-dose chemotherapy and involves a shorter period of complete immune suppression.

Donor immune cells called lymphocytes, or T cells, fight residual tumor cells that might have remained in the recipients body after stem cell transplant, in what is called a graft-versus-tumor (GVT) effect.

The immune-suppressing drug sirolimus appears to help prevent graft-versus-host disease (GVHD), a side effect of stem cell transplant in which donated T cells sometimes attack healthy tissues, damaging organs such as the liver, intestines and skin.

Th2 cells are cells collected from the transplant donor and grown in a high concentration of sirolimus.

Objectives:

To determine whether stem cell transplantation using low-dose chemotherapy and sirolimus-generated Th2 cells can cause a remission of advanced kidney cancer.

Eligibility:

Patients between 18 and 75 years of age who have kidney cancer that has spread beyond the kidney and who have a tissue-matched sibling stem cell donor.

Design:

Patients undergo stem cell transplantation as follows:

* Low-intensity chemotherapy with pentostatin and cyclophosphamide over a 21-day period to reduce the level of the immune system to prepare for the transplant. Pentostatin is given through a vein (intravenous (IV)) on days 1, 8 and 15; cyclophosphamide tablets are taken by mouth for 21 consecutive days.
* Sirolimus tablets, taken by mouth, starting 2 days before the transplant and continuing until 60 days after the transplant.
* IV infusions of stem cells and Th2 cells.

Following the transplant, patients have the following procedures:

* Additional Th2 cell infusions on days 14 and 45 after the transplant.
* Follow-up visits at the National Institutes of Health (NIH) Clinical Center twice a week for the first 6 months after the transplant and then less frequently for at least 5 years to evaluate response to treatment and treatment side effects. Evaluations include a bone marrow aspirate and biopsy 1 month after transplant and periodic blood tests and imaging procedures (e.g., computed tomography (CT) or magnetic resonance imaging (MRI) scans).

Detailed description:
Background:

Allogeneic hematopoietic stem cell transplantation (HSCT) represents a potentially effective treatment option for patients with metastatic renal cell carcinoma (RCC).

In a pilot clinical trial in refractory hematologic malignancy subjects, we have found that augmentation of a T cell-replete allograft with donor Th2 cells generated ex vivo in sirolimus (rapamycin; Th2.rapa cells) allows prompt donor engraftment after outpatient-intensity chemotherapy. This transplant approach has been associated with a low incidence of acute graft versus host disease (GVHD).

Based on these data, we seek to safely achieve objective clinical regression of metastatic RCC by the following new transplant approach. (1) The allograft will be administered after a low intensity, outpatient induction chemotherapy regimen consisting of pentostatin and cyclophosphamide. This regimen is intended to provide sufficient host immune T cell depletion, and as such, a conventional preparative regimen will not be administered. (2) To avoid mixed chimerism for rapid potentiation of graft-versus-tumor (GVT) effects, a growth colony stimulating factor (G-CSF) mobilized allograft will be augmented with donor lymphocyte infusion at day 14 post-transplant consisting of Th2.rapa cells.

Objectives:

Primary objective: (1) Determine whether this new, low-intensity transplant approach can yield objective partial or complete remission of metastatic RCC, with the goal of ruling out a partial response (PR)/complete response (CR) rate of 20% in favor of a rate of 60%.

Secondary objectives: (1) Evaluate the safety and immune-depleting properties of the pentostatin/cyclophosphamide regimen; (2) Characterize the engraftment kinetics and GVHD profile of this new transplant approach; and (3) Characterize post-transplant immunity in study subjects, including cytokine phenotype, immune reconstitution, and potential anti-tumor effector mechanisms.

Eligibility:

Adults (18 - 75 years) with metastatic RCC who have an eligible 6/6 human leukocyte antigen (HLA)-matched sibling donor.

Must have had one prior therapy with either sorafenib, sunitinib, or temsirolimus or any other Food and Drug Administration (FDA)-approved agent for therapy of metastatic renal cell carcinoma..

Life expectancy greater than or equal to 3 months, Karnofsky score greater than or equal to 80, relatively normal organ function, and absence of central nervous system (CNS) metastases.

Design:

Patients will receive a 21-day course of pentostatin (intravenous infusion on days 1, 8, and 15; 4 mg/m\^2 per dose) and daily oral cyclophosphamide (200 mg per day).

Patients will receive a mobilized, T cell-replete allogeneic hematopoietic stem cell graft followed by a pre-emptive donor lymphocyte infusion with donor Th2 cells at day 14 post-transplant. GVHD prophylaxis will consist of a short-course of sirolimus plus maintenance therapy with cyclosporine A.

If greater than or equal to 2/5 partial or complete responses are observed within 6 months post-transplant, the therapy will be considered potentially promising, and will be expanded in a Simon two-stage design to evaluate a total of n = 14 subjects. If greater than or equal to 5/14 PR/CR are achieved, the therapy will be considered worthy of further investigation.

Arms: arm 1: A sibling who is 6/6 HLA --matched with the recipient. Donors undergo donor lymphocyte harvest and stem cell mobilization and harvest. arm 2: Recipients undergo induction therapy, allogeneic stem cell therapy and GVHD prophylaxis.
Interventions: intervention 1: Pentostatin intervention 2: Sirolimus intervention 3: Cyclophosphamide intervention 4: Allogeneic Hematopoietic Stem Cell Transplant (HSCT) intervention 5: Th2 rapa cells intervention 6: Donor Lymphocyte Harvest intervention 7: Induction Therapy intervention 8: GVHD prophylaxis intervention 9: Donor Hematopoietic Stem Cell Harvest
Intervention descriptions: intervention 1: Pentostatin: 2- 4mg/m\^2(CrCL based dosing) intravenous (IV) on days 1, 8, and 15 intervention 2: Sirolimus: 4 mg by mouth (PO) on days -3 to +7 post-transplant (No Sirolimus administered after day 7 post-stem cell transplant (SCT)) intervention 3: Cyclosporine: 2 mg/kg every 12 hours PO or IV starting on day -4 of hematopoietic stem cell transplant (HSCT) intervention 4: Allogeneic Hematopoietic Stem Cell Transplant intervention 5: Th2 rapa cell Transplantation intervention 6: Apheresis intervention 7: Pentostatin and cyclophosphamide (PC) conditioning regimen. intervention 8: Short course of sirolimus plus maintenance therapy with sirolimus A. intervention 9: Following lymphocyte harvest, donors for recipients will undergo stem cell mobilization and harvest.

Protocol documents: