Low Intensity Allogeneic Hematopoietic Stem Cell Transplantation Therapy of Metastatic Renal Cell Carcinoma Using Early and Multiple Donor Lymphocyte Infusions Consisting of Sirolimus-Generated Donor Th2 Cells
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 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 GVT effects, a G-CSF mobilized allograft
will be augmented with donor Th2.rapa cells. (3) To enhance GVT effects while limiting acute
GVHD, two additional donor lymphocyte infusions (DLI) consisting of Th2.rapa cells will be
administered at day 14 and day 45 post-transplant. (4) Finally, because mTOR inhibition can
mediate anti-tumor effects against RCC, we will utilize single-agent sirolimus drug therapy
post-transplant for GVHD prophylaxis.
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 PR/CR rate of 20% in favor of a rate of 40%.
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.
Adults (18 - 75 years) with metastatic RCC who have an eligible 6/6 HLA-matched sibling
Must have had one prior therapy with either sorafenib, sunitib, or temsirolimus.
Life expectancy greater than or equal to 3 months, Karnofsky score greater than or equal to
80, relatively normal organ function, and absence of CNS metastases.
Patients will receive a 21-day course of pentostatin (intravenous infusion on days 1, 8, and
15; 4 mg/m2 per dose) and daily oral cyclophosphamide (200 mg per day).
Patients will receive a mobilized, T cell-replete allogeneic hematopoietic stem cell graft
augmented with donor Th2.rapa cells. Patients will then receive DLI consisting of donor
Th2.rapa cells at days 14 and 45 post-transplant.
GVHD prophylaxis will consist of single-agent sirolimus through day 60 post-transplant.
If greater than or equal to 3/12 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 = 25 subjects. If greater than or equal
to 8/25 PR/CR are achieved, the therapy will be considered worthy of further investigation.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
The primary outcome will be the frequency of subjects that achieve a partial remission of tumor (PR) or complete remission of tumor (CR). Tumor response will be measured by the RECIST criteria.
Daniel H Fowler, M.D.
National Cancer Institute (NCI)
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|
|Hackensack University Medical Center||Hackensack, New Jersey 07601|