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).
The Phase I study consists of a single-dose escalation Phase 1a and a multiple-dose escalation Phase 1b. * An open-label, single-dose escalation Phase 1a study is to evaluate the safety and tolerability of a single intravenous infusion of VUM02 Injection for SR-aGvHD treatment. The study follows an accelerated titration design with 3 dose levels (1×10\^6cells/kg, 2×10\^6cells/kg, 3×10\^6cells/kg). * An open-label, multiple-dose escalation Phase 1b study follows a traditional "3 + 3" design,with 3 dose levels of VUM02 administration twice weekly for 4 consecutive weeks, to evaluate the occurrence of dose-limiting toxicity (DLT) events from the first dose to 28 days after the last dose in subjects. After the multiple-dose escalation study to assess the tolerability and safety of VUM02 is completed, the dose expansion study will be initiated. Phase II is an open-label, randomized, parallel-controlled, multiple-dose expansion study. Two dose levels will be selected to evaluate the efficacy and safety of multiple dose administration by the investigator and the sponsor according to the results of the Phase 1b study. Subjects who meet the criteria are randomly assigned in a 1:1:1 ratio to receive the corresponding treatment in 3 groups, the study group 1 (VUM02-dose 1 + best available therapy (BAT) ), study group 2 (VUM02-dose 2 + BAT), and the control group (only BAT). Subjects in the study groups will receive the corresponding dose of VUM02 Injection, twice a week for 4 consecutive weeks for a total of 8 doses, on the basis of the best available therapy. All subjects are assessed for efficacy by day 28 after the first dose. In this study, ORR at day 28 after the first dose is used as the primary endpoint to investigate the efficacy of VUM02 Injection in the treatment of SR-aGvHD. Phase II study consists of four periods, a screening period (14 days), a VUM02 treatment period (4 weeks), a follow-up period (follow-up until death, consent withdrawal, or day 180±15 after the first dose, whichever occurs first), and a long-term follow-up period (after completion of the last visit of the follow-up period, entry into the long-term follow-up period).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
149
The 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.
According to BAT scheme, the drug administration is determined by PI according to the condition of the patients.
Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
Wuhan, Hubei, China
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).
Time frame: 14 days, 28 days after the last dosing
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
Time frame: 28 days after the first dosing
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.
Time frame: 14 days, 28 days,or 180 days after the first dosing
Immunogenicity evaluation (in Phase Ib and Phase II)
Immunogenicity evaluation
Time frame: Before administration, and 8, 15, 22, 28, and 56 days after first dosing
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.
Time frame: 28 and 56 days 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.
Time frame: 28 and 56 days after the first dosing
Time to complete response (CR) and Time to partial response (PR) (in Phase II)
Time to CR /PR is defined as the time from the first dosing to time point of subjects demonstrating CR /PR, during 100 days after initiation of therapy.
Time frame: 100 days after the first dosing
Complete response rate (CRR) and partial response rate (PRR) in each involved organ (in Phase II)
Complete response rate (CRR) and partial response rate (PRR) in each involved organ at days 28, 56, and 100 after the first dosing. Complete response in each involved organ was defined as resolution of aGvHD symptoms in single involved organ. Partial response in each involved organ was defined as improvement of aGVHD in single involved organ at least 1 stage, with or without worsening of any other organ.
Time frame: 28, 56, and 100 days after the first dosing
Cumulative relapse incidence of the primary disease (in Phase II)
Defined as the cumulative incidence of relapse /progression of the primary disease (hematological malignant disease) after the day of transplantation.
Time frame: 28, 56, and 100 days after the first dosing
Overall survival (OS) and OS rate (in Phase II)
Overall survival (OS) at day 180 after the first dosing, and OS rate at days 100 and 180 after the first dosing. Overall survival is defined as the time from therapy begin to time point of death due to any cause during 180 days. OS rate is defined as the proportion of subjects who is survival at day 100 and day 180 after the first dosing.
Time frame: 100 and180 days after the first dosing
Non-relapse mortality (in Phase II)
Non-relapse mortality at days 28, 56, 100, and 180 after the first dosing. Non-relapse mortality is defined as the proportion of subjects who died not preceded by hematologic disease relapse/progression at days 28, 56, 100 and 180 after the first dosing.
Time frame: 28, 56, 100 and 180 days after the first dosing
ECOG Performance Status score (in Phase II)
The ECOG performance status, developed by the Eastern Cooperative Oncology Group (ECOG), is a scale used to assess how a patient's disease is progressing, assess how the disease affects the daily living abilities of the patient, and determine appropriate treatment and prognosis.
Time frame: 28, 56, 100 and 180 days after the first dosing
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