MaaT013 as Salvage Therapy in Ruxolitinib Refractory GI-aGVHD Patients (ARES)

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.

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.

Study Overview

• Status: Recruiting
• Conditions: Acute Graft Versus Host Disease in Intestine; Steroid Refractory GVHD
• Intervention / Treatment: Drug: MaaT013

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.

• Study Type: Interventional
• Enrollment (Estimated): 75
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: MaaT Pharma; Phone Number: +0033663590186; Email: eplantamura@maat-pharma.com
• Study Contact Backup: Name: Mélanie Tilte; Email: mtilte@maat-pharma.com

Study Locations

• Austria
  • Innsbruck, Austria
    • Recruiting
    • Medizinische Universitat Innsbruck
    • Contact: Jakob Rudzki, MD
  • Linz, Austria
    • Recruiting
    • Ordensklinikum Linz Elisabethinen
    • Contact: Johannes Clausen, MD
• Belgium
  • Brugge, Belgium
    • Recruiting
    • Algemeen Ziekenhuis Sint-Jan Brugge-Oostende - Campus Sint-Jan
    • Contact: Alexander Schauwlieghe, MD
  • Brussel, Belgium
    • Recruiting
    • Universitair Ziekenhuis Brussel
    • Contact: Ann De Becker, MD
  • Gent, Belgium
    • Recruiting
    • Universitair Ziekenhuis Gent
    • Contact: Tessa Kerre, MD
  • Liège, Belgium
    • Recruiting
    • Centre Hospitalier Universitaire de Liege
    • Contact: Evelyne Willems, MD
• France
  • Amiens, France
    • Recruiting
    • Centre Hospitalier Universitaire Amiens-Picardie - Site Sud
    • Contact: Amandine Charbonnier, MD
  • Angers, France
    • Recruiting
    • Centre Hosptitalier Universitaire d'Angers
    • Contact: Sylvie François
  • Caen, France
    • Recruiting
    • CHU de Caen
    • Contact: Sylvain CHANTEPIE, MD
  • Grenoble, France
    • Recruiting
    • Centre Hospitalier Universitaire Grenoble Alpes
    • Contact: Martin Carré, MD
  • Montpellier, France
    • Recruiting
    • Hopital Lapeyronie
    • Contact: Jean-Jacques Tudesq, MD
  • Nice, France
    • Recruiting
    • Hôpital l'Archet
    • Contact: Michael Loschi
  • Paris, France
    • Recruiting
    • APHP St Antoine
    • Contact: Florent Malard, Dr
    • Principal Investigator: FLORENT MALARD
  • Pessac, France
    • Recruiting
    • Hopital Haut-Lévêque
    • Contact: Clémence Médiavilla
  • Pierre-Bénite, France
    • Recruiting
    • Centre Hospitalier Lyon-Sud
    • Contact: Hélène Labussière-Wallet
  • Poitiers, France
    • Recruiting
    • Centre Hospitalier Universitaire de Poitiers
    • Contact: Déborah Desmier
  • Rennes, France
    • Recruiting
    • Hopital Pontchaillou
    • Contact: Marc Bernard
  • Saint-Priest-en-Jarez, France
    • Recruiting
    • Institut de Cancérologie Lucien Neuwirth
    • Contact: Jérôme Cornillon, MD
  • Toulouse, France
    • Recruiting
    • Institut Universitaire Du Cancer de Toulouse Oncopole
    • Contact: Anne Huynh, MD
  • Vandœuvre-lès-Nancy, France
    • Recruiting
    • Hôpitaux de Brabois
    • Contact: Marie-Thérèse Rubio
• Germany
  • Berlin, Germany
    • Recruiting
    • Helios Klinikum Berlin-Buch
    • Contact: Judith Niederland, MD
  • Mannheim, Germany
    • Recruiting
    • Universitätsmedizin Mannheim
    • Contact: Daniela Heidenreich
  • Regensburg, Germany
    • Recruiting
    • Universitätsklinikum Regensburg
    • Contact: Hendrik Poeck, MD, PhD
  • Ulm, Germany
    • Recruiting
    • Universitätsklinik Ulm - Oberen Eselsberg
    • Contact: Verena Wais, MD
• Italy
  • Ancona, Italy
    • Recruiting
    • Azienda Ospedaliera Regionale San Carlo
    • Contact: Attilio Olivieri, MD
  • Bologna, Italy
    • Recruiting
    • Azienda Ospedaliero-Universitaria di Bologna Policlinico Sant Orsola-Malpighi
    • Contact: Francesca Bonifazi, MD
  • Milano, Italy
    • Recruiting
    • IRCCS Ospedale San Raffaele
    • Contact: Fabio Ciceri, MD
  • Reggio Calabria, Italy
    • Recruiting
    • Grande Ospedale Metropolitano Bianchi Melacrino Morelli
    • Contact: Massimo Martino, MD
  • Udine, Italy
    • Recruiting
    • Presidio Ospedaliero Universitario Santa Maria della Misericordia
    • Contact: Francesca Patriarca, MD
• Spain
  • Barcelona, Spain
    • Recruiting
    • Hospital de la Santa Creu i Sant Pau
    • Contact: Irene Garcia-Cadenas
  • Barcelona, Spain
    • Recruiting
    • Institut Catala d'Oncologia - Hospital Duran i Reynals (ICO L'Hospitalet)
    • Contact: Annalisa Paviglianiti, MD
  • El Palmar, Spain
    • Recruiting
    • Hospital Clinico Universitario Virgen de la Arrixaca
    • Contact: Andres Sanchez Salinas, MD
  • Granada, Spain
    • Recruiting
    • Hospital Universitario Virgen de las Nieves
    • Contact: Manuel Jurado Chacon
  • Madrid, Spain
    • Recruiting
    • Hospital Universitario La Paz
    • Contact: Karem Humala, MD
  • Madrid, Spain
    • Recruiting
    • Hospital Universitario Ramón y Cajal
    • Contact: Javier Lopez Jiménez, MD
  • Murcia, Spain
    • Recruiting
    • Hospital General Universitario Morales Meseguer
    • Contact: Oriana Lopez Godino, MD
  • Pamplona, Spain
    • Recruiting
    • Clinica Universidad de Navarra - Pamplona
    • Contact: Jose Rifon Roca, MD
  • Salamanca, Spain
    • Recruiting
    • Complejo Asistencial Universitario de Salamanca - Hospital Clinico
    • Contact: Lucia Lopez-Corral
  • Santander, Spain
    • Recruiting
    • Hospital Universitario Marques de Valdecilla
    • Contact: Maria Arancha Bermudez
  • Sevilla, Spain
    • Recruiting
    • Instituto de Biomedicina de Sevilla
    • Contact: Jose Antonio Perez Simon
  • Valencia, Spain
    • Recruiting
    • Hospital Clinico Universitario de Valencia
    • Contact: Carlos Solano Vercet, MD
  • Valencia, Spain
    • Recruiting
    • Hospital Universitari i Politecnic La Fe
    • Contact: Jaime Sanz

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: MaaT013; Route of administration: rectal (enema) Study drug dose: 4 enemas in total: Week 1: D0-D1: vancomycin pre-treatment (250mg per os, 4 times a day for 2 days); D2: 1 dose; Between D3 to D5: 1 dose Week 2: 1 dose (7 +/- 2 days after the last dose) Week 3: 1 dose (7 +/- 2 days after the last dose) A supplementary dose can be prescribed in case of GvHD relapse or massive antibiotic use during the study.

Drug: MaaT013; MaaT013 is made of allogeneic, full-ecosystem pooled biotherapeutic intestinal microbiota

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ORR of gastro intestinal-aGvHD	Overall Response Rate (Complete Response + Very Good Partial Response + Partial Response)	Day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and tolerability	Incidence of AEs, treatment-emergent AEs (TEAEs), Serious Adverse Events (SAEs), deaths, and laboratory abnormalities related to MaaT013, using the National Cancer Institute-Common Terminology Criteria for AEs (NCI-CTCAE) v5.0., and results from physical examination from D1 to Day 28.	Day 28
Safety and tolerability	Incidence of AEs, treatment-emergent AEs (TEAEs), Serious Adverse Events (SAEs), deaths, and laboratory abnormalities related to MaaT013, using the National Cancer Institute-Common Terminology Criteria for AEs (NCI-CTCAE) v5.0.	Month 3
Safety and tolerability	incidence of SAE and key events	Month 12
aGvHD ORR	aGvHD overall response rate (CR, VGPR and PR) for all organs	Day 28, Day 56 and Month 3
GI aGvHD ORR	GI aGvHD overall response rate (CR, VGPR and PR)	Day 56 and Month 3
Best response rates	CR, VGPR and PR for GI and overall aGvHD	until Month 3
Survival rates	Progression-free survival, relapse-free survival, overall survival, steroid-free survival, immunosuppression-free survival	Month and Month12
Duration of response	Duration of response after D28	Month 12
chronic GvHD incidence and severity	Percentage of chronic GvHD incidence and severity	Month 12

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory endpoint	Evaluation of MaaT013 impact on blood GvHD immune markers	Day 28

Collaborators and Investigators

• Sponsor: MaaT Pharma
• Investigators: Principal Investigator: Florent Malard, MD, PhD, APHP

Study record dates

Study Major Dates

• Study Start (Actual): March 25, 2022
• Primary Completion (Estimated): September 30, 2023
• Study Completion (Estimated): September 30, 2024

Study Registration Dates

• First Submitted: February 22, 2021
• First Submitted That Met QC Criteria: February 22, 2021
• First Posted (Actual): February 25, 2021

Study Record Updates

• Last Update Posted (Actual): August 21, 2023
• Last Update Submitted That Met QC Criteria: August 17, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Microbiotherapy; Fecal microbiota transfer; Gastro intestinal acute GVHD; ruxolinib refractory
• Additional Relevant MeSH Terms: Immune System Diseases; Graft vs Host Disease
• Other Study ID Numbers: MPOH06

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No