MaaT013 as Salvage Therapy in Ruxolitinib Refractory GI-aGVHD Patients
MaaT013 as Salvage Therapy in Ruxolitinib Refractory GI-aGVHD Patients
MaaT013 showed interesting results in steroids and ruxolitinib-resistant aGVHD patients with
 gut involvement (55% ORR at D28) and 47% and 39% OS at 6 and 12 months respectively (Malard
 2020), therefore warrant being tested as salvage therapy in steroid and JAK
 inhibitors-resistant GI-aGvHD patients. Given the absence of an approved 3rd line strategy or
 2nd line strategy in ruxolitinib intolerant patients and the extremely poor prognosis of
 these patients, who are mostly left with no viable therapeutic option, a single-arm
 open-label design was proposed.
Standard first-line therapy for the treatment of acute GVHD involves corticosteroids, usually
 methyl-prednisolone at a dose of 2 mg/kg per day (Martin PJ R. J., 2012; Van Lint MT, 1998).
 Despite initial responses (around 60%), fewer than half of patients have durable complete
 responses, and those patients who do not respond or progress after an initial response have
 high mortality (Weisdorf D, 1990; Alousi AM, 2009; Bolanos-Meade J, 2014). Moreover,
 prolonged high-dose corticosteroids (CS) exposure is associated with deleterious
 complications and long-term morbidity (Mohty M, 2010).

 For these reasons, there is great interest in identifying effective therapies for
 corticosteroid-resistant aGvHD and improve outcomes.

 Recently, ruxolitinib (Jakafi®), which has an Orphan Drug status in the USA, was granted an
 approval on 24 May 2019 from the FDA based on study INCB 18424-271 (NCT02953678). This
 open-label, single-arm study enrolled 72 grade 2-4 SR-aGvHD patients who were treated with 5
 mg (possibly increased to 10mg) ruxolitinib b.d. Of the 72 patients, 49 were included in the
 efficacy evaluation that led the FDA to grant market authorization. Of these 49 patients,
 Overall Response Rate (ORR - Complete + Very Good Partial + Partial Responses) after 28 days
 was 100%, 40.7% and 44.4% for patients with Grade 2, Grade 3, and Grade 4 aGVHD respectively.
 The overall survival (OS) estimate at 6 months was 51.0% for the entire cohort.

 The more recent REACH2 phase 3 randomized trial (NCT02913261) investigating ruxolitinib
 versus best available therapy in patients with corticosteroid-refractory acute GVHD has
 further established the role of ruxolitinib in the treatment of corticosteroid-refractory
 acute GvHD. The ORR at day 28 was higher in the ruxolitinib than in the control group (62%
 versus 39%; odds ratio, 2.64; 95%CI, 1.65-4.22; P<0.001). Similarly, the durable overall
 response at day 56 was higher in the ruxolitinib than in the control group (40% versus 22%;
 odds ratio, 2.38; 95% CI, 1.43-3.94; P<0.001) (Zeiser R, 2020) In the REACH1 and REACH2
 trials, 45% and 38% of patients, failed to respond to ruxolitinib at day 28, respectively.
 Moreover, in the REACH2 trial, the overall response at day 56 after initiation of therapy
 decreased from 62.3% at D28 after initiation of therapy to 39.4% at D56, suggesting a clear
 unmet medical need for those patients who failed to respond at D28, or worsened afterwards
 (Zeiser R. 2020). More importantly, results from the REACH1 trial showed only a 22%
 probability of survival at 2 months in ruxolitinib-non responder patients (Jagasia 2020).

 MaaT013 is made of allogeneic, full-ecosystem pooled biotherapeutic intestinal microbiota
 manufactured by MaaT Pharma in Lyon, France, according to GMP requirements. The intestinal
 microbiota material in its natural environment is derived from healthy, strictly-vetted and
 selected donors, following the European consensus recommendations (Cammarota 2016) with the
 purpose of minimizing the risk associated with fecal material transplants (FMT) for clinical
 research. Thus, prior to donation, donors undergo a thorough medical evaluation and
 laboratory screening including SARS-CoV-2 detection, to avoid any known contamination risk.
 MaaT013 is administered as an enema.

 MaaT013 showed interesting results in steroids and ruxolitinib-resistant aGVHD patients with
 gut involvement (55% ORR at D28) and 47% and 39% OS at 6 and 12 months respectively (Malard
 2020), therefore warrant being tested as salvage therapy in steroid and JAK
 inhibitors-resistant GI-aGvHD patients. Given the absence of an approved 3rd line strategy or
 2nd line strategy in ruxolitinib intolerant patients and the extremely poor prognosis of
 these patients, who are mostly left with no viable therapeutic option, a single-arm
 open-label design was proposed.
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

 -  Patients resistant to steroids AND either resistant to OR with intolerance to
 ruxolitinib OR with contra-indication to ruxolitinib:

 Exclusion Criteria:

 -  Grade IV hyper-acute GvHD

 -  Overlap chronic GvHD

 -  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).

 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, or arrhythmia that requires therapy.

 Clinically significant respiratory disease that requires mechanical ventilation support or
 50% oxygen.

 -  Current or past veno-occlusive disease or other uncontrolled complication unless
 otherwise agreed in writing by the sponsor.

 -  Absolute neutrophil count <500/µL for 3 consecutive days. Use of growth factor
 supplementation is allowed.

 -  Absolute platelet count < 10 000/µL. Use of platelet infusion is allowed.

 -  Patient with negative IgG EBV serology.

 -  Current or past 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. Females of
 childbearing potential should be willing to use 2 methods of birth control or be
 surgically sterile or abstain from procreative sexual activity for the course of the
 study. Females of childbearing potential are those who have not been surgically
 sterilized or have not been free from menses for >1 year. Males should agree to
 abstain from procreative sexual activity starting with the first dose of study therapy
 through the end of the study.

 -  Other ongoing interventional protocol that might interfere with the current study's
 primary endpoint.