The DMC has recommended the FREEDOM-1 trial to continue without restrictions as the patient was treated before protocols were amended to mitigate GvHD risk.
A patient that received a living donor kidney transplant and was treated with FCR001 as part of the phase 3 FREEDOM-1 trial (NCT03995901) has died after being hospitalized with grade 4 graft-vs-host disease (GvHD) complicated by serious infections leading to respiratory and renal failure.1
While the death triggered a pre-specified stop and review by a Data Monitoring Committee (DMC), the committee decided that the trial may continue with dosing and enrollment as the patient was treated prior to a June 2022 protocol amendment meant to mitigate GvHD rates. Talaris has reported the death and the DMC recommendation to the FDA.
“We are exceptionally saddened by this news, and patient safety remains our top priority. Kidney disease and its related effects are why we are conducting FREEDOM-1, with the goal of improving the lives of patients undergoing kidney transplantation,” Scott Requadt, chief executive officer, Talaris, said in a statement.1
The patient was originally diagnosed with grade 2 acute GvHD along with 3 other study participants in June 2022 and had also been diagnosed with chronic, moderate GvHD that was responding to treatment.2 The grade 2 GvHD completely resolved in the other 2 participants affected although 1 patient had additional flares that responded to treatment.1
With the June 2022 update, Talaris announced protocol amendments to the trial that included the discontinuation of plerixafor as a donor mobilizing agent and the addition of a second dose of cyclophosphamide after transplant.2 Plerixafor was noted to significantly increase CD34+ and total nucleated cell counts with FCR001 which was correlated with an increased incidence of GvHD. Cyclophosphamide has been demonstrated to reduce risk of severe GvHD in allogeneic, haplo-identical hematopoietic stem cell transplant.
The deceased patient had received a transplant from a related, same-sex donor with ahuman leukocyte antigen mismatch of 2/6. Plerixafor was not used to mobilize the donor but the starting FCR001 product had a high number of CD34+ cells and total nucleated cells and the patient did not receive a second dose of cyclophosphamide after transplant as implemented in the amendment.
“Today, organ transplant recipients must take lifelong immunosuppression to avoid rejecting their transplanted organ. These immunosuppressive regimens have significant morbidities, risks and quality of life challenges,” Requadt said in a statement at that time.2 “A treatment alternative for these patients is greatly needed.”
The open-label, randomized, controlled, phase 3 registration FREEDOM-1 study has enrolled 120 adult patients receiving living donor kidney transplant in the US. The trial is primarily assessing the proportion of chronic immunosuppression-free participants who have no biopsy-proven acute rejection at 24 months after FCR001 treatment. Secondary outcome measures include other biomarkers of assimilation, including renal and allograft function, glomerular filtration rate, time to rejection events or death, acute rejection, de novo donor-specific antibody incidence, renal replacement therapy, adverse events, infection, quality of life, hospitalization, survival, engraftment, donor chimerism, and GvHD.
FCR001 is a single dose, cryopreserved, allogeneic stem cell therapy derived from mobilized peripheral blood of the kidney donor administered with a non- myeloablative conditioning regimen. It contains the donor's CD34+ cells, facilitating cells, and αβ T cells.