Clinical trial NCT04769895: MaaT013 As Salvage Therapy in Ruxolitinib Refractory GI-aGVHD Patients
Official title: Evaluation of the Efficacy of MaaT013 As Salvage Therapy in Acute GVHD Patients with Gastrointestinal Involvement, Refractory to Ruxolitinib; a Multi-center Open-label Phase III Trial.
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Acute Graft Versus Host Disease in Intestine
Steroid Refractory GVHD
Keywords: Microbiotherapy
Fecal microbiota transfer
Gastro intestinal acute GVHD
ruxolinib refractory
Lead sponsor: MaaT Pharma
Sponsor class: INDUSTRY
First posted: 2021-02-25
Enrollment: 66
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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:

* 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
* 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.

Primary outcomes:
measure: ORR of gastro intestinal-aGvHD
timeFrame: Day 28
Secondary outcomes:
measure: Safety and tolerability
timeFrame: Day 28
measure: Safety and tolerability
timeFrame: Month 3
measure: Safety and tolerability
timeFrame: Month 12
measure: aGvHD ORR
timeFrame: Day 28, Day 56 and Month 3
measure: GI aGvHD ORR
timeFrame: Day 56 and Month 3
measure: Best response rates
timeFrame: until Month 3
measure: Survival rates
timeFrame: Month and Month12
measure: Duration of response
timeFrame: Month 12
measure: chronic GvHD incidence and severity
timeFrame: Month 12
Other outcomes:
measure: Exploratory endpoint
timeFrame: Day 28
Locations:
city: Innsbruck
country: Austria
facility: Medizinische Universität Innsbruck
city: Linz
country: Austria
facility: Ordensklinikum Linz Elisabethinen
city: Brugge
country: Belgium
facility: Algemeen Ziekenhuis Sint-Jan Brugge-Oostende - Campus Sint-Jan
city: Brussels
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Brussel
country: Belgium
facility: Universitair Ziekenhuis Brussel
city: Gent
country: Belgium
facility: Universitair Ziekenhuis Gent
city: Liège
country: Belgium
facility: Centre Hospitalier Universitaire de Liège
city: Amiens
country: France
facility: Centre Hospitalier Universitaire Amiens-Picardie - Site Sud
city: Angers
country: France
facility: Centre Hosptitalier Universitaire d'Angers
city: Caen
country: France
facility: CHU de Caen
city: Grenoble
country: France
facility: Centre Hospitalier Universitaire Grenoble Alpes
city: Lille
country: France
facility: CHRU Lille - Hopital Claude Huriez
city: Marseille
country: France
facility: Institut Paoli Calmettes
city: Montpellier
country: France
facility: Hôpital Lapeyronie
city: Nice
country: France
facility: Hôpital l'Archet
city: Paris
country: France
facility: APHP St Antoine
city: Pessac
country: France
facility: Hôpital Haut-Lévêque
city: Pierre-Bénite
country: France
facility: Centre Hospitalier Lyon-Sud
city: Poitiers
country: France
facility: Centre Hospitalier Universitaire de Poitiers
city: Rennes
country: France
facility: Hôpital Pontchaillou
city: Saint-Priest-en-Jarez
country: France
facility: Institut de Cancérologie Lucien Neuwirth
city: Toulouse
country: France
facility: Institut Universitaire du Cancer de Toulouse Oncopole
city: Vandœuvre-lès-Nancy
country: France
facility: Hôpitaux de Brabois
city: Berlin
country: Germany
facility: Helios Klinikum Berlin-Buch
city: Mannheim
country: Germany
facility: Universitätsmedizin Mannheim
city: Regensburg
country: Germany
facility: Universitätsklinikum Regensburg
city: Ulm
country: Germany
facility: Universitätsklinik Ulm - Oberen Eselsberg
city: Würzburg
country: Germany
facility: Universitatsklinikum Wurzburg
city: Ancona
country: Italy
facility: Azienda Ospedaliera Regionale San Carlo
city: Bologna
country: Italy
facility: Azienda Ospedaliero-Universitaria di Bologna Policlinico Sant Orsola-Malpighi
city: Genova
country: Italy
facility: Istituto di Ricovero e Cura a Carattere Scientifico - Ospedale Policlinico San Martino
city: Milano
country: Italy
facility: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
city: Milano
country: Italy
facility: IRCCS Ospedale San Raffaele
city: Reggio Calabria
country: Italy
facility: Grande Ospedale Metropolitano Bianchi Melacrino Morelli
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli
city: Torino
country: Italy
facility: Azienda Ospedaliero-Universitaria Citta della Salute e della Scienza di Torino
city: Udine
country: Italy
facility: Presidio Ospedaliero Universitario Santa Maria della Misericordia
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Barcelona
country: Spain
facility: Institut Català d'Oncologia - Hospital Duran i Reynals (ICO L'Hospitalet)
city: El Palmar
country: Spain
facility: Hospital Clínico Universitario Virgen de la Arrixaca
city: Granada
country: Spain
facility: Hospital Universitario Virgen de las Nieves
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
city: Murcia
country: Spain
facility: Hospital General Universitario Morales Meseguer
city: Pamplona
country: Spain
facility: Clinica Universidad de Navarra - Pamplona
city: Salamanca
country: Spain
facility: Complejo Asistencial Universitario de Salamanca - Hospital Clínico
city: Santander
country: Spain
facility: Hospital Universitario Marqués de Valdecilla
city: Sevilla
country: Spain
facility: Instituto de Biomedicina de Sevilla
city: Valencia
country: Spain
facility: Hospital Clínico Universitario de Valencia
city: Valencia
country: Spain
facility: Hospital Universitari i Politècnic La Fe
Study officials:
affiliation: APHP
name: Florent Malard, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: