It is a phase I/II clinical study to evaluate the safety, tolerability and preliminary efficacy of VUM02 Injection in patients with acute graft-versus-host disease (aGvHD) who have failed systemic steroid therapy. VUM02 Injection (human umbilical cord-derived mesenchymal stromal /stem cells, hUC-MSC) is an off-the-shelf allogeneic cell therapy product comprising culture-expanded mesenchymal stromal /stem cells derived from the human umbilical cord tissue. The product is cryopreserved with the cell concentration of 5 x 10\^6 cells/mL. Patients with grade II to IV aGvHD who have failed systemic steroid therapy (i.e. patients with steroid-refractory aGvHD (SR-aGvHD)), will be recruited into this study. This study consists of two phases, a dose-escalation phase (phase I) and a dose-expansion phase (phase II).
Subjects aged 14-70 years (inclusive), male or female;
a. Steroid resistance: Progression of aGvHD at Day 3 of first-line steroid therapy, or no improvement in aGvHD at Day 7, or incomplete remission of aGvHD at Day 14;
b. Steroid dependence: failure to taper first-line steroid therapy or reactivation of aGvHD during taper;
Investigator assessment: Expected survival ≥ 3 months;
Subjects with lung disease who, in the judgment of the investigator, are not appropriate to participate in the study;
Serum virological examination shows positive results for active hepatitis B (hepatitis B core antibody positive and HBV-DNA in peripheral blood higher than the upper limit of normal), hepatitis C (hepatitis C antibody positive and HCV-RNA higher than the upper limit of normal), Treponema pallidum (TP) antibody or human immunodeficiency virus (HIV) antibody;
Patients with severe hepatic veno-occlusive disease or sinus veno-occlusive syndrome;
Subjects who developed aGvHD after donor lymphocyte infusion therapy for recurrence of underlying hematologic malignancies;
Sequential
VUM02 Injection (UC-MSCs)+BAT
DrugThe dose-escalation phase (phase I): Single dose escalation Phase 1a study: 3 dose levels of a single IV infusion; Multiple dose escalation Phase 1b study: 3 dose levels of twice weekly for 4 consecutive week. The dose-expansion phase (phase II): -Two dose groups will be selected by the investigator and the sponsor based on the results of the Phase 1b study, twice a week for 4 consecutive weeks for a total of 8 doses.
The control group with Best Available Therapy (BAT)
Other interventionAccording to BAT scheme, the drug administration is determined by PI according to the condition of the patients.
Occurrence of Dose-limiting toxicity (DLT) events (in Phase Ia and Ib )
Occurrence of Dose-limiting toxicity (DLT) events during 14 days after single administration in phase Ia, and from the first dosing to 28 days after the last dosing in phase Ib. Dose-limiting toxicity (DLT) events is defined as cell therapy-related adverse events (AEs) of grade 3 and above as assessed by CTCAE (V5.0).
Overall response rate (ORR) at day 28 post initiation of therapy (in Phase II)
ORR was defined as the percentage of participants who had achieved overall response. Overall response was defined as complete response (CR) plus partial response (PR) according to aGVHD response criteria. CR was defined as resolution of aGVHD in all involved organs. PR was defined as organ improvement of at least 1 stage without worsening of any other organ by day 28 after the first dosing in phase II
Incidence and severity of cell therapy-related adverse events (AEs) (in phase Ia, Ib and II)
Incidence and severity of cell treatment-related adverse events (AEs) as assessed by CTCAE v5.0 during 14 days after single administration in phase Ia, during 180 days after the first dosing in phase Ib and phase II.
Immunogenicity evaluation (in Phase Ib and Phase II)
Immunogenicity evaluation
Overall response rate (ORR) and Complete response rate (CRR) and Durable complete response rate (Durable-CRR) (in Phase Ib)
Overall response rate (ORR) and Complete response rate (CRR) at day 28 and day 56 after the first dosing; Durable complete response rate (Durable-CRR) from day 28 to day 56 after the first dosing. ORR was defined as the percentage of participants who had achieved overall response. Overall response was defined as complete response (CR) plus partial response (PR) according to aGVHD response criteria. CR was defined as resolution of aGVHD in all involved organs. PR was defined as organ improvement of at least 1 stage without worsening of any other organ. Durable-CRR is defined as the proportion of subjects demonstrating CR at day 28 and maintaining CR at day 56 after the first dosing.
Overall response rate (ORR), Complete response rate (CRR) and Durable complete response rate (Durable-CRR) (in Phase II)
Overall response rate (ORR) at day 56 after the first dosing; Complete response rate (CRR) at day 28 and day 56 after the first dosing; Durable complete response rate (Durable-CRR) from day 28 to day 56 after the first dosing. ORR was defined as the percentage of participants who had achieved overall response. Overall response was defined as complete response (CR) plus partial response (PR) according to aGVHD response criteria. CR was defined as resolution of aGVHD in all involved organs. PR was defined as organ improvement of at least 1 stage without worsening of any other organ. Durable-CRR is defined as the proportion of subjects demonstrating CR at day 28 and maintaining CR at day 56 after the first dosing.
Levels of TNFRI, IL-2Rα, REG3 and ST2 (Phase Ib and Phase II)
Changes from baseline in immune-related indicators of TNFRI, IL-2Rα, REG3 and ST2 levels to 15, 28, 56, and 100 days after the first dosing.
Levels of Th17 and Treg (Phase Ib and Phase II)
Changes from baseline in immune-related indicators of Th17 and Treg levels to 15, 28, 56, and 100 days after the first dosing.
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