Evaluation of MaaT013 Efficacy in Gastrointestinal Acute Graft-Versus-Host Disease Refractory to Ruxolitinib: A Phase III Multicenter Open-Label Trial

Trial ID: 2024-513023-17-00
Protocol: MPOH06
Sponsor: MaaT PHARMA

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Diseases & Conditions

Acute graft versus host disease in intestine

Objectives

The primary objective of this study is to evaluate the **efficacy** of MaaT013 as assessed by the overall response rate (ORR) of gastrointestinal (GI) acute graft-versus-host disease (aGVHD) response at day 28 (D28). This is clinically relevant as it addresses the treatment of aGVHD in the GI tract for patients who are resistant or intolerant to ruxolitinib, providing a potential therapeutic option for this challenging condition.

Secondary objectives include:

To evaluate MaaT013 **safety**.
To evaluate ORR for GI at day 56 (D56) and month 3 (M3).
To evaluate ORR for all organs at D28, D56, and M3.
To evaluate the best ORR (for GI and all organs) achieved between day 0 (D0) and D28.
To assess the duration of response.
To assess overall survival (OS).
To assess progression-free survival (PFS).
To assess time to progression.
To assess steroid-free survival.
To evaluate the frequency of patients that tapered off corticosteroids (CS).
To measure the incidence of chronic graft-versus-host disease (GvHD).
To evaluate changes in patient-reported outcomes (PROs).
To evaluate MaaT013 activity on immune markers.

Participants

The clinical trial involves participants diagnosed with **acute graft-versus-host disease** (aGvHD) affecting the gastrointestinal tract, who are resistant or intolerant to ruxolitinib. The study population includes both male and female subjects aged 18 years and older. Participants have undergone allogeneic hematopoietic stem cell transplantation (Allo-HSCT) with any type of donor, stem cell source, GvHD prophylaxis, or conditioning regimen. The trial specifically targets individuals with aGvHD episodes involving the gastrointestinal system, classified as grades II to IV according to MAGIC guidelines, with or without other organ involvement. The trial population is selected based on resistance to steroids and either resistance to or intolerance of ruxolitinib. The sponsor has not provided the total number of participants. The study includes a vulnerable population, and all participants or their legally acceptable representatives have provided informed and written consent. No specific lifestyle considerations such as diet or physical activity are mentioned in the trial data.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of **MaaT013**, a **rectal solution** containing **allogeneic faecal microbiota, pooled**, as a salvage therapy for patients with acute graft-versus-host disease (aGvHD) affecting the gastrointestinal (GI) tract, who are resistant or intolerant to ruxolitinib. This is a multi-center, open-label, Phase III trial. The primary objective is to assess the overall response rate (ORR) of GI aGVHD at day 28. Secondary endpoints include evaluating the safety of MaaT013, ORR for GI at day 56 and month 3, ORR for all organs at various time points, duration of response, overall survival, progression-free survival, time to progression, steroid-free survival, frequency of corticosteroid tapering, incidence of chronic GvHD, and changes in patient-reported outcomes.

The trial follows a structured sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), history of allo-HSCT, and resistance or intolerance to steroids and ruxolitinib. Participants will undergo regular follow-up visits to monitor treatment response and safety, with assessments at day 28, day 56, and month 3. The end-of-study visit will conclude the participant's involvement, which is expected to last up to 28 days, aligning with the maximum treatment period of MaaT013. Conditions that may lead to early termination from the study include significant adverse events or withdrawal of consent.

The trial is expected to run until October 2025, with recruitment having commenced in March 2022. Participants will be randomly assigned to receive the investigational product, ensuring a controlled evaluation of its therapeutic potential. The study's design does not include a double-blind component, as it is open-label, allowing both researchers and participants to be aware of the treatment being administered. The trial's methodology is robust, focusing on clinically relevant outcomes to provide comprehensive data on the efficacy and safety of MaaT013 in this patient population.

Treatment

The clinical trial involves the administration of **MaaT013**, an experimental medication formulated as a **rectal solution**. The active substance in MaaT013 is **allogeneic faecal microbiota, pooled**, which is classified as a structurally diverse substance. This investigational product is developed by MAAT PHARMA and is designated as an orphan drug under the number EU/3/18/2083. The pharmaceutical form of MaaT013 is specifically designed for **rectal use**. The dosing regimen for MaaT013 involves a maximum daily dose of 150 ml, with a total maximum dose of 600 ml over a treatment period not exceeding 28 days. The administration schedule is tailored to ensure optimal therapeutic outcomes while monitoring participant compliance throughout the trial.

In addition to the experimental treatment, the study may include non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments, depending on the specific protocol requirements. These treatments are utilized to provide a baseline for evaluating the efficacy of MaaT013. Participant compliance with the dosing schedule and administration route is closely monitored to ensure adherence to the study protocol and to accurately assess the therapeutic efficacy of the investigational product.

Efficacy

The efficacy of MaaT013 in the treatment of **gastrointestinal (GI) acute graft-versus-host disease (aGVHD)** will be assessed primarily by evaluating the overall response rate (ORR) at day 28 (D28). This primary endpoint focuses on the response of GI aGVHD to the treatment. Secondary endpoints include evaluating the ORR for GI at day 56 (D56) and month 3 (M3), as well as the ORR for all organs at D28, D56, and M3. The best ORR achieved between day 0 (D0) and D28 will also be assessed. Additional secondary endpoints involve assessing the duration of response, overall survival (OS), progression-free survival (PFS), time to progression, and steroid-free survival. The frequency of patients tapering off corticosteroids (CS), the incidence of chronic GvHD, and changes in patient-reported outcomes (PROs) will also be evaluated.

The efficacy parameters will be measured and collected at specified timepoints, including D28, D56, and M3, using validated clinical assessment tools and patient-reported outcomes. The analysis will involve comparing the response rates and other efficacy measures at these timepoints to determine the effectiveness of MaaT013 as a salvage therapy in patients with GI aGVHD who are refractory to ruxolitinib. The trial is designed as a multi-center, open-label, phase III study, ensuring a comprehensive evaluation of the treatment's efficacy across different clinical settings.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Age ≥ 18 years old
Allo-HSCT with any type of donor, stem cell source, GvHD prophylaxis or conditioning regimen.
Acute GvHD episode with GI involvement per MAGIC guidelines (= grades II to IV), with or without involvement of other organs (Harris et al. 2016).
Patients resistant to steroids AND either resistant to OR with intolerance to ruxolitinib (intolerant patients: who had grade 3 or higher treatment-emergent and ruxolitinib-attributed adverse event that did not resolve within 7 days of discontinuing ruxolitinib): Resistance to steroids is defined as any of the following: - Lack of improvement (i.e., no decrease in stage in at least 1 involved organ system) after ≥ 5 days of treatment with CS at 2mg/kg/d methylprednisolone equivalent dose, - Progression (i.e., increase in any organ system or any new organ involvement) after ≥ 3 days of treatment with CS at 2 mg/kg/d methylprednisolone equivalent dose, - Patients treated with 1 mg/kg/d of CS because the physician deemed they would not tolerate 2 mg/kg/d and who correspond to the definition of SR patients, - Patients who previously began CS therapy at a lower dose (at least 1 mg/kg/d methylprednisolone equivalent) for skin or upper GI GvHD but develop new GvHD in another organ system, - Patients who cannot tolerate corticosteroid tapering, i.e., begin of CS at 2.0 mg/kg/d, demonstrate response, but show disease progress before a 50% decrease from the initial starting dose of CS is achieved. Resistance to ruxolitinib is defined as any of the following (Mohty et al. 2020): - Progression of GvHD compared to baseline after at least 5 days of treatment with ruxolitinib, based either on objective increase in stage/grade, or new organ involvement; - Lack of improvement in GvHD (partial response or better) compared to baseline after at least 14 days of treatment with ruxolitinib; - Loss of response, defined as objective worsening of GvHD determined by increase in stage, grade or new organ involvement at any time after initial improvement - Absence of complete response or very good partial response at day 28 after ruxolitinib Intolerance to ruxolitinib is defined as: - GvHD manifestations that persist without improvement in patients who had grade 3 or higher treatment-emergent and ruxolitinib-attributed adverse event that did not resolve within 7 days of discontinuing ruxolitinib.
Signature of informed and written consent by the subject or by the subject’s legally acceptable representative for patients under guardianship or trusteeship.

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Exclusion Criteria

Patients with known hypersensitivity to vancomycin or to any of the excipients listed in the corresponding SmPC
Patients with active CMV colitis
Patients who had previously received other lines of systemic aGvHD treatment other than CS and ruxolitinib.
Grade II-IV hyper-acute GvHD as defined by the MD Anderson’s criteria (Saliba et al. 2007) (aGvHD onset within 14 days after allo-HSCT)
Overlap chronic GvHD as defined by the NIH Consensus Criteria (Jagasia et al. 2015)
Relapsed/persistent malignancy requiring rapid immune suppression withdrawal
Active uncontrolled infection according to the attending physician
Severe organ dysfunction unrelated to underlying GvHD, including: - Cholestatic disorders or unresolved veno-occlusive disease of the liver (defined as persistent bilirubin abnormalities not attributable to GvHD and ongoing organ dysfunction, with the exception of Gilbert syndrome). - Clinically significant or uncontrolled cardiac disease including unstable angina, acute myocardial infarction within 6 months before Day 1 of study drug administration, New York Heart Association Class III or IV congestive heart failure, circulatory collapse requiring vasopressor or inotropic support that requires therapy. - Clinically significant respiratory disease that requires mechanical ventilation support or 50% oxygen.
Current or past (< 6 months) veno-occlusive disease or other uncontrolled complication unless otherwise agreed in writing by the sponsor.
Absolute neutrophil count <500/μL, confirmed within 3 days prior to pre-treatment start. Use of growth factor supplementation is allowed.
Absolute platelet count < 10 000/μL, confirmed within 3 days prior to pre-treatment start. Use of platelet infusion is allowed.
Patient with negative IgG EBV serology.
Current or past (< 6 months) evidence of toxic megacolon, bowel obstruction or gastrointestinal perforation.
Any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration of study drug and attending required study visits; pose a significant risk to the subject; or interfere with interpretation of study data.
Known allergy or intolerance to trehalose or maltodextrin.
Vulnerable patients such as: minors, persons deprived of liberty, persons in Intensive Care Unit unable to provide informed consent prior to the intervention.
Females of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication.
Breastfeeding females. Females of childbearing potential should be willing to use an acceptable method of birth control such as hormonal contraception (progestogen-only may be sufficient), male or female condom with or without spermicide, cap, diaphragm or sponge with spermicide for the course of the study. A combination of male condom with either cap, diaphragm or sponge with spermicide (double barrier methods) are also considered acceptable. Females of childbearing potential are those who have not been surgically sterilized or have not been free from menses for >1 year.
Other ongoing interventional protocol that might interfere with the current study’s primary endpoint.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Austria	Not Recruiting	22 Mar 2022	4
Belgium	Not Recruiting	22 Mar 2022	10
France	Not Recruiting	22 Mar 2022	31
Germany	Not Recruiting	22 Mar 2022	5
Italy	Not Recruiting	22 Mar 2022	5
Spain	Not Recruiting	22 Mar 2022	18