A Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase III Trial of Remestemcel-L-rknd Added to Ruxolitinib for Grade III-IV Steroid-Refractory Acute Graft-Versus-Host Disease

This study is a randomized, double-blind, placebo-controlled, multicenter Phase III trial to compare the efficacy and safety of remestemcel-L-rknd (remestemcel-L), ex-vivo cultured adult human mesenchymal stromal cells (MSC), combined with ruxolitinib vs. ruxolitinib combined with placebo as second-line therapy in adult patients with Grade III-IV steroid-refractory acute graft-versus-host disease (SR-aGVHD).

Study Overview

• Status: Not yet recruiting
• Conditions: GVHD - Graft-Versus-Host Disease
• Intervention / Treatment: Drug: Remestemcel-L-rknd; Other: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 180
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Teresa Montagut, MD; Phone Number: 19173294933; Email: Teresa.Montagut@mesoblast.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age 18 years or older at the time of enrollment.
2. Able to take oral medications

3. Have Grade III-IV SR-aGVHD at the time of enrollment, defined as aGVHD resistant to high dose corticosteroids at a dose of ≥ 1 mg/kg/day methylprednisolone (or equivalent), given alone or in combination with GVHD prophylaxis agents such as CNI, mTOR inhibitor, or MMF.

   1. The minimum time between the initiation of high-dose corticosteroids and enrollment is 3 days if aGVHD has progressed in at least one organ regardless of improvement in other organs, OR
   2. Minimum time of 5 days for aGVHD showing no improvement in GI or liver symptoms, OR
   3. Recurrence of Grade III-IV aGVHD after an initial response to steroid therapy.

4. Prior use of ruxolitinib is permissible in the following cases:

   1. If no more than 2 doses of ruxolitinib were taken for aGVHD treatment prior to enrollment.
   2. If there was prior use of ruxolitinib for GVHD prophylaxis. If aGVHD developed while on ruxolitinib for GVHD prophylaxis or within 3 days of its discontinuation, the patient is not eligible.
5. Evident myeloid and platelet engraftment. Absolute neutrophil count (ANC) > 1000/mm3 and platelets ≥ 20,000/ mm3. Use of growth factor supplementation and transfusion support is allowed.
6. Minimum Karnofsky performance score of 30 at the time of study entry.
7. Patient (or legal representative where appropriate) must be capable of providing written informed consent/assent.
8. Female patients of childbearing potential must use a medically accepted method of contraception and must agree to continue use of this method for the entire duration of study participation. Acceptable methods of contraception include abstinence, barrier method with spermicide, intrauterine device, or steroid contraceptive (oral, transdermal, implanted, and injected) in conjunction with a barrier method.
9. Male patients with partners of childbearing potential must agree to use adequate contraception (barrier method with spermicide or abstinence) for the entire duration of study participation.
10. Willing and able to comply with study requirements, remain at the clinic, and return to the clinic for the follow-up evaluation, as specified in this protocol during the study period.

Exclusion Criteria:

1. Underwent second allogeneic hematopoietic cell transplantation within six months from the first transplant.
2. Received systemic treatment for aGVHD other than corticosteroids +/- agents used for aGVHD prophylaxis (e.g., CNIs, mTOR inhibitor, and/or MMF).
3. Respiratory disease requiring continuous positive pressure ventilation or intubation. Patients who need intermittent continuous positive airway pressure (e.g., during sleep) are eligible.
4. Any underlying or current medical or psychiatric condition that, in the opinion of the investigator, would interfere with the evaluation of the patient.
5. Post-transplant morphologic relapsed malignancy [defined as > 5% blasts on bone marrow examination and/or extramedullary relapse].
6. Donor leukocyte infusion (DLI) for treatment of malignant disease relapse. Patients who received DLI for indications other than relapse, including for treatment of minimal residual disease (MRD) and mixed chimerism, are eligible.
7. Prior treatment with any mesenchymal lineage cells, including remestemcel-L.
8. Active or inadequately treated latent infection with Mycobacterium tuberculosis (i.e., tuberculosis).
9. Female patients who are pregnant, lactating, or planning a pregnancy during the expected remestemcel-L treatment period.
10. Concurrently receiving an investigational agent, device or procedure. An investigational agent, device or procedure is defined as having no known FDA-approved indications. Any prior and/or current participation in a clinical trial of an investigational medicinal product (IMP) that is registered and being used off label requires review by the study's Protocol Officer, Protocol Chairs, and Sponsor prior to enrollment.
11. Known hypersensitivity to DMSO or to porcine or bovine proteins.
12. Requiring vasopressor support.
13. Uncontrolled infections. Infections are considered controlled if appropriate therapy has been instituted and, at the time of enrollment, no signs of progression are present. Persistent fever without other signs or symptoms will not be interpreted as progressing infection. Progression of infection is defined as: hemodynamic instability attributable to sepsis OR new symptoms attributable to infection OR worsening physical signs attributable to infection OR worsening radiographic findings attributable to infection. Patients with radiographic findings attributable to infection within 4 weeks prior to enrollment must have a repeat radiographic exam within one week of enrollment that documents stable or improved findings.
14. Estimated creatinine clearance less than 15 mL/min or those requiring hemodialysis.
15. Clinically significant liver disorders or bilirubin greater than 3 mg/dl not attributable to aGVHD or Gilbert's.
16. Moderate to severe cGVHD that require systemic treatment. Chronic GVHD that is not requiring systemic therapy is allowed.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Remestemcel-L-rknd; Remestemcel-L will be administered as intravenous infusions	Drug: Remestemcel-L-rknd; Remestemcel-L is comprised of ex-vivo cultured adult human MSC
Placebo Comparator: Placebo; PTM will be administered as intravenous infusions	Other: Placebo; Placebo is infusion based to be given at the same points as remestemcel-L-rknd

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response	The primary clinical endpoint is overall response at Day 28 post-randomization. Overall response is defined as achieving a PR or CR on Day 28 post-randomization without requirement for new intervening systemic immunosuppressive therapies	28 days post randomization

Collaborators and Investigators

• Sponsor: Mesoblast, Ltd.

Study record dates

Study Major Dates

• Study Start (Estimated): August 31, 2026
• Primary Completion (Estimated): February 28, 2028
• Study Completion (Estimated): July 1, 2028

Study Registration Dates

• First Submitted: April 28, 2026
• First Submitted That Met QC Criteria: April 28, 2026
• First Posted (Actual): May 5, 2026

Study Record Updates

• Last Update Posted (Actual): May 5, 2026
• Last Update Submitted That Met QC Criteria: April 28, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Graft vs Host Disease
• Other Study ID Numbers: 2320

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No