MaaT013 as Salvage Therapy in Ruxolitinib Refractory GI-aGVHD Patients

Steroid Refractory GVHD Clinical Trial

— ARES  

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.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04769895
• Other study ID #: MPOH06
• Status: Recruiting
• Phase: Phase 3
• Start date: March 25, 2022
• Est. completion date: September 30, 2024

Study information

• Verified date: August 2023
• Source: MaaT Pharma
• Contact: MaaT Pharma
• Phone: +0033663590186
• Email: eplantamura[@]maat-pharma.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 75
• Est. completion date: September 30, 2024
• Est. primary completion date: September 30, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Acute Graft Versus Host Disease in Intestine
• Graft vs Host Disease
• Steroid Refractory GVHD

Intervention

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

Locations

Country	Name	City	State
Austria	Medizinische Universität Innsbruck	Innsbruck
Austria	Ordensklinikum Linz Elisabethinen	Linz
Belgium	Algemeen Ziekenhuis Sint-Jan Brugge-Oostende - Campus Sint-Jan	Brugge
Belgium	Universitair Ziekenhuis Brussel	Brussel
Belgium	Universitair Ziekenhuis Gent	Gent
Belgium	Centre Hospitalier Universitaire de Liège	Liège
France	Centre Hospitalier Universitaire Amiens-Picardie - Site Sud	Amiens
France	Centre Hosptitalier Universitaire d'Angers	Angers
France	CHU de Caen	Caen
France	Centre Hospitalier Universitaire Grenoble Alpes	Grenoble
France	Hôpital Lapeyronie	Montpellier
France	Hôpital l'Archet	Nice
France	APHP St Antoine	Paris
France	Hôpital Haut-Lévêque	Pessac
France	Centre Hospitalier Lyon-Sud	Pierre-Bénite
France	Centre Hospitalier Universitaire de Poitiers	Poitiers
France	Hôpital Pontchaillou	Rennes
France	Institut de Cancérologie Lucien Neuwirth	Saint-Priest-en-Jarez
France	Institut Universitaire du Cancer de Toulouse Oncopole	Toulouse
France	Hôpitaux de Brabois	Vandœuvre-lès-Nancy
Germany	Helios Klinikum Berlin-Buch	Berlin
Germany	Universitätsmedizin Mannheim	Mannheim
Germany	Universitätsklinikum Regensburg	Regensburg
Germany	Universitätsklinik Ulm - Oberen Eselsberg	Ulm
Italy	Azienda Ospedaliera Regionale San Carlo	Ancona
Italy	Azienda Ospedaliero-Universitaria di Bologna Policlinico Sant Orsola-Malpighi	Bologna
Italy	IRCCS Ospedale San Raffaele	Milano
Italy	Grande Ospedale Metropolitano Bianchi Melacrino Morelli	Reggio Calabria
Italy	Presidio Ospedaliero Universitario Santa Maria della Misericordia	Udine
Spain	Hospital de la Santa Creu i Sant Pau	Barcelona
Spain	Institut Català d'Oncologia - Hospital Duran i Reynals (ICO L'Hospitalet)	Barcelona
Spain	Hospital Clínico Universitario Virgen de la Arrixaca	El Palmar
Spain	Hospital Universitario Virgen de las Nieves	Granada
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitario Ramón y Cajal	Madrid
Spain	Hospital General Universitario Morales Meseguer	Murcia
Spain	Clinica Universidad de Navarra - Pamplona	Pamplona
Spain	Complejo Asistencial Universitario de Salamanca - Hospital Clínico	Salamanca
Spain	Hospital Universitario Marqués de Valdecilla	Santander
Spain	Instituto de Biomedicina de Sevilla	Sevilla
Spain	Hospital Clínico Universitario de Valencia	Valencia
Spain	Hospital Universitari i Politècnic La Fe	Valencia

Sponsors (1)

Lead Sponsor	Collaborator
MaaT Pharma

Countries where clinical trial is conducted

Austria,  Belgium,  France,  Germany,  Italy,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Exploratory endpoint	Evaluation of MaaT013 impact on blood GvHD immune markers	Day 28
Primary	ORR of gastro intestinal-aGvHD	Overall Response Rate (Complete Response + Very Good Partial Response + Partial Response)	Day 28
Secondary	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
Secondary	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
Secondary	Safety and tolerability	incidence of SAE and key events	Month 12
Secondary	aGvHD ORR	aGvHD overall response rate (CR, VGPR and PR) for all organs	Day 28, Day 56 and Month 3
Secondary	GI aGvHD ORR	GI aGvHD overall response rate (CR, VGPR and PR)	Day 56 and Month 3
Secondary	Best response rates	CR, VGPR and PR for GI and overall aGvHD	until Month 3
Secondary	Survival rates	Progression-free survival, relapse-free survival, overall survival, steroid-free survival, immunosuppression-free survival	Month and Month12
Secondary	Duration of response	Duration of response after D28	Month 12
Secondary	chronic GvHD incidence and severity	Percentage of chronic GvHD incidence and severity	Month 12