A Multicenter, Randomized, Double-blind, Placebo-Controlled Phase II Study to Investigate the Efficacy and Safety of CYP-001 in Combination with Corticosteroids vs Corticosteroids Alone for the Treatment of High-Risk Acute Graft Versus Host Disease

Trial ID: 2022-502673-41-01
Protocol: CYP-GVHD-P2-01
Sponsor: Cynata Therapeutics Limited

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Diseases & Conditions

Acute graft versus host disease

Objectives

The primary objective of this study is to evaluate the **efficacy** of CYP-001 in combination with corticosteroids compared to placebo and corticosteroids in adults with high-risk acute graft versus host disease (HR-aGvHD). This is assessed based on the Overall Response Rate at Day 28. The clinical relevance of this objective lies in determining the potential of CYP-001 to improve treatment outcomes in HR-aGvHD, a condition associated with significant morbidity and mortality following allogeneic hematopoietic stem cell transplantation.

Secondary objectives include:

Assessing additional responses and long-term efficacy outcomes.
Evaluating Overall Survival (OS).
Assessing Event-Free Survival (EFS).
Evaluating Non-Relapse Mortality (NRM).
Assessing Failure Free Survival (FFS).
Evaluating the incidence of relapse/progression of the underlying hematologic disease for which allogeneic HSCT was performed.
Measuring the incidence of chronic Graft versus Host Disease (GvHD).
Assessing the cumulative steroid dose until Day 100.
Evaluating changes in Subject Reported Outcomes.
Evaluating the safety and tolerability of CYP-001 in subjects with acute GvHD.

Participants

The clinical trial involves a total of **22 participants** diagnosed with **High-Risk Acute Graft Versus Host Disease** (HR-aGvHD). The study population comprises both male and female subjects who are **18 years of age or older**. Participants have undergone a first allogeneic hematopoietic stem cell transplant to treat a hematologic disease, either malignant or non-malignant, and have been clinically diagnosed with acute GvHD requiring systemic therapy. The trial does not include a vulnerable population. Participants are expected to have a life expectancy of at least one month, as assessed by the investigator. The selection criteria ensure that participants have evidence of myeloid engraftment post-transplant, defined as three consecutive days of achieving sustained ANC >500 x 10^6/L. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The sponsor has not provided additional information regarding the general health status or specific lifestyle habits of the participants.

Plans and Procedures

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** Phase II study to evaluate the efficacy and safety of CYP-001 in combination with corticosteroids compared to corticosteroids alone in adults with high-risk acute graft versus host disease (**HR-aGvHD**). The trial aims to assess the overall response rate at Day 28, defined as the proportion of participants achieving a complete or partial response without the need for additional systemic therapies. The study is expected to commence recruitment on January 31, 2024, and conclude by December 31, 2025.

Participants will be involved in the study for a maximum treatment period of four weeks, with the investigational product administered via **intravenous infusion**. The trial includes several key visits: an initial screening visit to confirm eligibility, followed by regular follow-up visits to monitor response and safety, and an end-of-study visit to assess final outcomes. The primary endpoint is the overall response rate at Day 28, while secondary endpoints include durable overall response at Days 60 and 100, overall survival, event-free survival, and failure-free survival, among others.

Inclusion criteria require participants to be 18 years or older, have undergone a first allogeneic hematopoietic stem cell transplant, and have a clinical diagnosis of acute GvHD requiring systemic therapy. Participants must also demonstrate evidence of myeloid engraftment and have a life expectancy of at least one month. Conditions for early termination from the study include the need for additional systemic therapies due to progression or lack of response, or any adverse events that compromise participant safety.

Treatment

The clinical trial involves the administration of **allogeneic mesenchymoangioblast-derived mesenchymal stem cells** (CYP-001) as the experimental medication. This investigational product is provided in the form of an **infusion** and is administered via **intravenous infusion**. The maximum daily dose is set at 200 million cells, with a total maximum dose of 400 million cells over the treatment period. The treatment is scheduled to be administered over a maximum period of 4 weeks. The active substance is a structurally diverse cell therapy product, developed by Cynata Therapeutics Limited, and is not formulated for pediatric use. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol.

The study also includes a **placebo** as a comparator treatment. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo does not contain any active substance and is not associated with any specific pharmaceutical form or route of administration. It serves as a control to evaluate the efficacy and safety of the experimental treatment in combination with corticosteroids, compared to corticosteroids alone.

Efficacy

The efficacy of the investigational product, **CYP-001**, in combination with corticosteroids, will be assessed in a Phase II clinical trial for the treatment of high-risk acute Graft Versus Host Disease (HR-aGvHD). The primary endpoint for evaluating efficacy is the Overall Response Rate (ORR) at Day 28. This is defined as the proportion of participants in each treatment arm who demonstrate a complete response (CR), characterized by the resolution of aGvHD signs and symptoms, or a partial response (PR), indicated by an improvement in the severity of GvHD by at least one grade compared to baseline, without the need for additional systemic therapies due to earlier progression, mixed response, or lack of response.

Secondary endpoints include the proportion of subjects with durable overall response at Day 60 and Day 100, overall survival (OS), event-free survival (EFS), time to non-relapse mortality (NRM), and failure-free survival (FFS). Additional assessments will include the incidence and severity of chronic GvHD (cGvHD), weekly cumulative steroid dose up to Day 100 or end of treatment, changes in patient-reported outcomes (PRO), and the incidence, severity, and duration of treatment-emergent adverse events (TEAE). Efficacy parameters will be measured at multiple timepoints, including Day 7, Day 14, Day 21, Day 28, Day 60, and Day 100, using validated clinical criteria and patient assessments.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Male or female subjects 18 years of age or older
Provide written informed consent form and agree to comply with study procedures
Have undergone first allogeneic hematopoietic stem cell transplant (HSCT) to treat a hematologic disease (malignant or non- malignant), from any donor source (matched and mismatched) using bone marrow, peripheral blood stem cells, or cord blood and any conditioning intensity
Have been clinically diagnosed with acute GvHD requiring systemic therapy with CS. Patients can be enrolled with only a clinically established diagnosis. Biopsy of involved organs with acute GvHD is encouraged but is not required and should not delay study entry. Enrollment/randomization includes commitment to continue steroids
HR-aGvHD must meet one of the following clinical features within 72 hours prior to randomization: A. High-risk as per Refined Minnesota Criteria: • Single organ involvement o Stage 4 skin o Stage 3-4 lower GI o Stage 1-4 liver • Multiple organ involvement o Stage 1-2 lower GI plus any liver o Stage 2 lower GI plus any skin o Stage 3-4 lower GI plus any liver or skin o Any three organ involvement OR B. One of the following: • Isolated stage 2 involvement of the lower GI tract • Stage 1 lower GI tract disease with skin involvement
Evidence of myeloid engraftment post allogeneic HSCT defined as three (3) consecutive days of achieving sustained ANC >500 x 10^6/L. Use of G-CSF and blood transfusion is allowed.
Life expectancy of at least one month, in the opinion of the investigator.
Investigator believes that the subject (or the subject’s legally acceptable representative[s]) understands the nature, scope and possible consequences of the study.

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Exclusion Criteria

Has received any systemic treatment for aGvHD other than corticosteroids +/- CNI (prophylaxis or treatment). Treatment with CS is allowed for up to 72 hours prior to Day 0.
Clinical presentation of chronic GvHD or overlap syndrome with both acute and chronic features of GvHD
Presence of relapsed primary malignancy since allogeneic HSCT
Have received more than one allogeneic HSCT
Clinically significant respiratory, renal or cardiac disease at screening including any of the following: a. requiring mechanical ventilation or having resting SO2 <90% on pulse oximetry b. serum creatinine >2mg/dL or eGFR <30ml/min (Cockroft Gault equation) c. uncontrolled hypertension d. Congestive heart failure New York Heart Association Class III or IV
Presence of cholestatic disorders or sinusoidal obstructive syndrome/veno-occlusive disease of the liver defined as persistent bilirubin abnormalities not attributable to aGvHD
Presence of any active uncontrolled infection requiring treatment and which in the opinion of the Investigator and/or Study medical monitor is likely to impact on the ability of the subject to participate in the trial. Infections are considered controlled if appropriate therapy has been used and, at the time of screening, no signs of progression are present.
Known infection with CMV, EBV, HBV, HCV, HIV or Tuberculosis. If the treatment for CMV, EBV, HBV, HCV has commenced the subject is eligible for study.
Any other medical or psychiatric condition which, in the opinion of the Investigator and/or Study medical monitor, makes the subject unsuitable for participation in the study or interfere with interpretation of study data.
Known sensitivity to dimethylsulfoxide (DMSO) or any other component of CYP-001.
Known or suspected current alcohol or substance abuse problem, in the opinion of the investigator.
Received any investigational treatment agent within 30 days or within 5 half-lives of Screening, whichever is greater.
Female subject of childbearing potential either not using or not willing to use an acceptable method of contraception to avoid pregnancy during the study and for 6 months after receipt of the last dose of investigational product. All female subjects are assumed to be of childbearing potential except: • Subjects aged > 60 years and postmenopausal. • Subjects aged 45 to 60 years (inclusive) with amenorrhea for ≥ 1 year with documented evidence of follicle-stimulating hormone level > 30 IU/L. If the follicle-stimulating hormone value is not available before randomization, a urine pregnancy test is required. • Subjects who are surgically sterile for at least 3 months before providing informed consent.
Pregnant, breastfeeding or not willing to cease breastfeeding.
Currently receiving a therapy not permitted during the study.
Involved in the planning and / or conduct of the study (applies to Cynata Therapeutics Limited staff, staff at the study site, and third-party vendors).