A Phase I/II Trial of VUM02 Injection for Steroid-refractory Acute Graft-versus-host Disease (SR-aGvHD) Treatment

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).

Eligibility Criteria:
Inclusion Criteria:

Patients must meet all of the following criteria to be eligible for this trial:

1. Subjects aged 14-70 years (inclusive), male or female;
2. Subjects who undergone allogeneic hematopoietic stem cell transplantation as indicated for hematological malignant disease, developed with grade II to IV aGvHD and failed standard first-line steroid therapy (that is, SR-aGvHD); 1) Definition of standard first-line steroid /glucocorticoid therapy: 1 mg/kg/day or 2 mg/kg/day of Methylprednisolone, or equivalent doses of steroids; 2) According to Thomas' Hematopoietic Cell Transplantation: Stem Cell Transplantation (5th edition), subjects who meet one of the following criteria are considered to have failed the standard first-line steroid /glucocorticoid therapy:

   * 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;
3. Investigator assessment: Expected survival ≥ 3 months;
4. Clinical manifestations of aGvHD are rash and/or persistent nausea, vomiting, and/or diarrhea and/or cholestasis. For these clinical manifestations, other etiologies such as drug rash, intestinal infection, or hepatotoxicity syndrome have been ruled out;
5. Subjects will be required to receive the investigational product within 3 days of enrollment;
6. Subjects must give informed consent to the study prior to enrollment, with the subject himself/herself, or, the subject himself/herself and his/her legal guardian (only for subjects \<18 years of age), voluntarily signing a written informed consent form.

Exclusion Criteria:

Patients meeting any of the following criteria are not eligible for this trial:

1. Subjects with lung disease who, in the judgment of the investigator, are not appropriate to participate in the study;
2. 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;
3. Patients with severe hepatic veno-occlusive disease or sinus veno-occlusive syndrome;
4. Subjects who developed aGvHD after donor lymphocyte infusion therapy for recurrence of underlying hematologic malignancies;
5. Patients complicated with brain lesion or who, in the judgment of the investigator, present with mental status changes;
6. For subjects with aGvHD enrolled primarily for gastrointestinal symptoms, cytomegalovirus (CMV) enteritis, transplant-associated thrombotic microangiopathy (TA-TMA), and diarrhea due to gastrointestinal infections could not be ruled out clinically, as assessed by the investigator; pathological diagnostic criteria for CMV enteritis are: Large cells with basophilic inclusions in the intestinal mucosa; positive early/late CMV antigen by immunohistochemistry; positive CMV nucleic acid PCR in the homogenates of intestinal mucosal;
7. Patients with coagulation dysfunction requiring anticoagulant therapy or antiplatelet therapy;
8. Subject's renal function: Creatinine clearance \<30mL/min; creatinine clearance is calculated using the Cockcroft-Gault formula: Ccr(ml/min)=\[(140-age)×body weight(kg)\]/(72×blood creatinine (mg/dL), calculated results × 0.85 for females), and attention should be paid to the unit of creatinine during calculation of creatinine clearance;
9. ECOG PS score \> 3;
10. Subjects who have evidence within 6 months prior to enrollment that suggests that they have other diseases or their physiological conditions may interfere with the evaluation results of this study, or have serious life-threatening complications, including but not limited to uncontrolled infection, pulmonary hypertension, severe cardiac insufficiency (NYHA Class III and IV), unstable angina pectoris or acute myocardial infarction, refractory hypertension (defined as the simultaneous use of 3 different types of antihypertensive drugs \[one of which is the diuretic\], and blood pressure remains higher than 160/110 mmHg) (subject to the inpatient medical record diagnosis);
11. Patients with active malignant solid tumor within 5 years before the study, except radically treated cervical cancer, localized prostate cancer in situ and non-melanoma skin cancer;
12. Patients suffering from mental and neurological diseases and unable to correctly express their wishes;
13. Patients who have received ≥ 1 therapy for aGvHD other than hormonal and protocol-recommended second-line agents prior to the study (subjects who received prophylactic drugs for aGvHD prior to the study may be included in this study);
14. Patients with a known history of severe allergy to blood components or blood products, or to heterologous proteins;
15. Breastfeeding women, or female subjects who have plans to become pregnant or donate eggs from the start of the study to the follow-up period, and male subjects (or their partners) who have plans to father a child or donate sperm from the start of the study to the follow-up period and are unwilling to take contraceptive measures;
16. Patients who are not appropriate for participation in this clinical study as judged by the investigator;
17. Patients who have participated in other clinical studies within the past one month.