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

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ClinicalTrials.gov Identifier: NCT04769895
Recruitment Status : Recruiting
First Posted : February 25, 2021
Last Update Posted : August 21, 2023
Sponsor:
Information provided by (Responsible Party):
MaaT Pharma

Tracking Information
First Submitted Date  ICMJE February 22, 2021
First Posted Date  ICMJE February 25, 2021
Last Update Posted Date August 21, 2023
Actual Study Start Date  ICMJE March 25, 2022
Estimated Primary Completion Date September 30, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 22, 2021)
ORR of gastro intestinal-aGvHD [ Time Frame: Day 28 ]
Overall Response Rate (Complete Response + Very Good Partial Response + Partial Response)
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 22, 2021)
  • Safety and tolerability [ Time Frame: Day 28 ]
    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.
  • Safety and tolerability [ Time Frame: Month 3 ]
    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.
  • Safety and tolerability [ Time Frame: Month 12 ]
    incidence of SAE and key events
  • aGvHD ORR [ Time Frame: Day 28, Day 56 and Month 3 ]
    aGvHD overall response rate (CR, VGPR and PR) for all organs
  • GI aGvHD ORR [ Time Frame: Day 56 and Month 3 ]
    GI aGvHD overall response rate (CR, VGPR and PR)
  • Best response rates [ Time Frame: until Month 3 ]
    CR, VGPR and PR for GI and overall aGvHD
  • Survival rates [ Time Frame: Month and Month12 ]
    Progression-free survival, relapse-free survival, overall survival, steroid-free survival, immunosuppression-free survival
  • Duration of response [ Time Frame: Month 12 ]
    Duration of response after D28
  • chronic GvHD incidence and severity [ Time Frame: Month 12 ]
    Percentage of chronic GvHD incidence and severity
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: February 22, 2021)
Exploratory endpoint [ Time Frame: Day 28 ]
Evaluation of MaaT013 impact on blood GvHD immune markers
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE MaaT013 as Salvage Therapy in Ruxolitinib Refractory GI-aGVHD Patients
Official Title  ICMJE 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.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Acute Graft Versus Host Disease in Intestine
  • Steroid Refractory GVHD
Intervention  ICMJE Drug: MaaT013
MaaT013 is made of allogeneic, full-ecosystem pooled biotherapeutic intestinal microbiota
Study Arms  ICMJE 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.
Intervention: Drug: MaaT013
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 22, 2021)
75
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 30, 2024
Estimated Primary Completion Date September 30, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: MaaT Pharma +0033663590186 eplantamura@maat-pharma.com
Contact: Mélanie Tilte mtilte@maat-pharma.com
Listed Location Countries  ICMJE Austria,   Belgium,   France,   Germany,   Italy,   Spain
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04769895
Other Study ID Numbers  ICMJE MPOH06
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Current Responsible Party MaaT Pharma
Original Responsible Party Same as current
Current Study Sponsor  ICMJE MaaT Pharma
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Florent Malard, MD, PhD APHP
PRS Account MaaT Pharma
Verification Date August 2023

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP