| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| high or very high risk MDS in adult patients |
| Patients adultes atteints d’un syndrome myélodysplasique (SMD) de risque élevé ou très élevé |
|
| E.1.1.1 | Medical condition in easily understood language |
| high or very high risk MDS |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10028533 |
| E.1.2 | Term | Myelodysplastic syndrome |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Safety run-in (Part 1):
To determine whether sabatolimab is safe when added to azacitidine +
venetoclax in participants with high or very high risk MDS as per IPSS-R
criteria
Cohort 2 of the Safety run-in (Part 1) and Expansion (Part 2):
To determine the complete remission (CR) rate of sabatolimab (800 mg
Q4W) in combination with azacitidine and venetoclax |
«Run-in» (phase 1) :
Déterminer la sécurité d’emploi du sabatolimab lorsqu’il est administré en association avec l’azacitidine et le vénétoclax chez des patients atteints d’un SMD de risque élevé ou très élevé selon l’IPSS-R.
Cohorte 2 de la phase 1 de « Run-in » et de phase 2 d’expansion :
Déterminer le taux de RC obtenu avec le sabatolimab (administré à la dose de 800 mg toutes les 4 semaines) en association avec l’azacitidine et le vénétoclax |
|
| E.2.2 | Secondary objectives of the trial |
Safety run-in (Part 1) and Expansion (Part 2):
-To assess Complete Remission (CR) + marrow complete remission (mCR) rate
-To assess Overall Response Rate (ORR) defined as [CR + mCR + partial remission (PR) + HI]
-To assess the improvement of RBC/platelets transfusion independence
-To assess the safety and tolerability of sabatolimab in combination with
azacitidine and venetoclax
-To further characterize the pharmacokinetics of sabatolimab
-To characterize the immunogenicity of sabatolimab in combination with
azacitidine and venetoclax
Cohort 2 of the Safety run-in (Part 1) and Expansion (Part 2):
-To assess Duration of CR
-To assess Duration of CR/mCR
-To assess Duration of response
-To assess Time to CR/mCR
-To assess Progression Free Survival (PFS)
-To assess Leukemia-Free survival (LFS)
-To assess Event-Free Survival (EFS)
-To assess Overall Survival
Expansion (Part 2):
-To evaluate changes from baseline in fatigue |
«Run-in» (phase 1) et "Expansion" (phase 2) :
• Taux de RC + rémission complète médullaire [RCm]
• Taux de réponse globale (TRG) : RC + RCm + rémission partielle (RP) + amélioration hématologique (c'est-à-dire la proportion de patients présentant au minimum une amélioration hématologique)
• Amélioration en termes d’indépendance transfusionnelle (globules rouges/plaquettes)
• Profil de tolérance du sabatolimab en association avec l’azacitidine et le vénétoclax
• Pharmacocinétique (PK) du sabatolimab en association avec l’azacitidine et le vénétoclax
• Immunogénicité du sabatolimab en association avec l’azacitidine et le vénétoclax
Cohorte 2 de la Phase 1 et Phase 2 :
• Durée de la RC
• Délai d’obtention de la RC/RCm
• Durée de la RC/RCm
• Durée de la réponse
• Survie sans progression
• Survie sans leucémie
• Survie sans événement
• Survie globale
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed informed consent must be obtained prior to participation in the study
2. Age ≥ 18 years at the date of signing the informed consent form (ICF)
3. Morphologically confirmed diagnosis of myelodysplastic syndrome (MDS)
based on 2016 WHO classification by local investigator assessment with one of the following Prognostic Risk Categories, based on the revised International Prognostic Scoring System (IPSS-R):
Very high (> 6 points)
High (> 4.5-6 points)
4. Not immediately eligible for hematopoietic stem-cell transplantation (HSCT) or intensive chemotherapy at the time of screening due to individual clinical factors such as age, comorbidities and performance status, donor availability
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
Additional inclusion criteria as per full protocol may apply |
Pour l’inclusion dans l’étude, les patients doivent être affiliés à un régime de sécurité sociale (y compris la Couverture Médicale Universelle – CMU) ou être bénéficiaires d’un tel régime, et doivent remplir tous les critères suivants :
1. La signature du consentement éclairé doit être obtenue avant la participation à l’étude.
2. Age ≥ 18 ans au moment de la signature du consentement éclairé
3. Diagnostic de SMD confirmé morphologiquement d’après la classification OMS 2016 selon l’évaluation du médecin-investigateur, avec un score pronostique IPSS-R de risque :
• Très élevé (> 6 points)
• Elevé (> 4,5-6 points)
4. Ne pas être éligible dans l’immédiat, au moment de la sélection, à une greffe de CSH
ou à une chimiothérapie intensive en raison de facteurs cliniques individuels tels que
l’âge, les comorbidités et l’indice de performance, et de la disponibilité d’un donneur
5. Indice de performance ECOG (pour Eastern Cooperative Oncology Group) de 0, 1 ou 2
D'autres critères d'inclusion peuvent s'appliquer conformément au protocole complet
|
|
| E.4 | Principal exclusion criteria |
1. Prior exposure to TIM-3 directed therapy or any BCL-2 inhibitor (including
venetoclax) at any time
2. Prior therapy with immune check point inhibitors (e.g. anti-CTLA4, anti-
PD-1, anti-PD-L1, or anti-PD-L2) or cancer vaccines is not allowed if the last
dose of the drug was administered within 4 months prior to start of treatment
3. Previous first-line treatment for very high risk or high risk myelodysplastic syndromes (based on IPSS-R) with any antineoplastic agents, approved or
investigational, including for example chemotherapy, lenalidomide and
hypomethylating agents (HMAs) such as decitabine or azacitidine. However, a one single cycle of HMAs treatment only started prior to enrollment is allowed.
4. Live vaccine administered within 30 days prior to start of treatment
5. Current use or use within 14 days prior to start of treatment of systemic
steroid therapy (> 10 mg/day prednisone or equivalent) or any
immunosuppressive therapy. Topical, inhaled, nasal, ophthalmic steroids are
allowed. Replacement therapy, steroids given in the context of a transfusion,
are allowed and not considered a form of systemic treatment
6. History of severe hypersensitivity reactions to any ingredient of study drug(s) (azacitidine, venetoclax or sabatolimab) or monoclonal antibodies (mAbs) and/or their excipients
7. Participants with Myelodysplastic syndrome (MDS) based on 2016 WHO
classification with revised International Prognostic Scoring System (IPSS-R) ≤ 4.5
Other protocol-defined Inclusion/Exclusion may apply. |
1. Traitement antérieur par un agent ciblant TIM-3 ou par un inhibiteur de BCL-2 (incluant le vénétoclax), à n’importe quel moment
2. Le patient ne doit pas avoir reçu de traitement par des inhibiteurs de checkpoint immunitaire (par ex. anti-CTLA4, anti-PD-1, anti-PD-L1 ou anti-PD-L2) ou des vaccins anticancéreux au cours des 4 mois (dernière dose) précédant l’instauration du traitement à l’étude.
3. Traitement antérieur de première ligne d’un SMD de risque élevé ou très élevé (selon l’IPSS-R) par des agents anticancéreux, approuvés ou expérimentaux, incluant la chimiothérapie, le lénalidomide et des AHM (décitabine ou l’azacitidine).
Cependant, un traitement par un AHM, commencé avant l’inclusion, est autorisé uniquement si un seul cycle a été administré.
4. Administration de tout vaccin vivant au cours des 30 jours précédant l’instauration du traitement à l’étude
5. Traitement par corticoïdes systémiques en cours au moment de la sélection ou au cours des 14 jours précédant l’instauration du traitement à l’étude (> 10 mg/jour de prednisone ou équivalent) ou tout autre traitement immunosuppresseur. Les corticoïdes par voie topique, inhalés, par voie nasale ou ophtalmiques sont autorisés. Les traitements de substitution et les corticoïdes administrés dans le cadre d’une transfusion sont autorisés et ne sont pas considérés comme un traitement systémique.
6. Antécédents de réaction d’hypersensibilité sévère à l’un des composants des médicaments à l’étude (azacitidine, vénétoclax ou sabatolimab) ou à des anticorps monoclonaux et/ou à leurs excipients
7. Patient atteint d’un SMD avec un score IPSS-R ≤ 4,5
D'autres critères d'inclusion peuvent s'appliquer conformément au protocole complet |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety run-in (Cohort 1 and Cohort 2 of Part 1):
1. Incidence of DLTs between Cycle 1 Day 8 and end of Cycle 2
Cohort 2 of Safety run-in (Part 1) and Expansion (Part 2):
2. Proportion of participants from cohort 2 of Part 1 and Part 2 achieving CR according to investigator assessment |
Cohortes 1 et 2 de la phase 1 de « Run-in » :
1.L’incidence de toxicités limitant la dose (DLT) sera évaluée entre le Jour 8 du Cycle 1 et la fin du Cycle 2
Cohorte 2 de la phase 1 de « Run-in » et de phase 2 d’expansion :
2.La proportion de patients ayant une RC sera évaluée par le médecin-investigateur |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. From Cycle 1 Day 8 to end of Cycle 2; Cycle =28 Days
2. Cycle 3, Cycle 7, Cycle 10, Cycle 13 then every 6 cycles up to cycle 25 and thereafter every 12 cycles. During follow-up phase, efficacy assessment will be assessed every 3 months |
|
| E.5.2 | Secondary end point(s) |
Safety run-in (Part 1) and Expansion (Part 2)
1. Proportion of participants with [CR + marrow complete remission (mCR)] according to investigator assessment by dose level for the safety run-in part
(cohort 1 (400 mg Q4W) and cohort 2 (800 mg Q4W)) and for participants treated with sabatolimab 800 mg (Q4W) (cohort 2 of safety run-in and expansion parts)
2. ORR is the proportion of participants who achieved HI or better as best
response as per investigator assessment (per modified IWG-MDS Cheson 2006 criteria). ORR will be summarized by dose level for the safety run-in part
(cohort 1 (400 mg Q4W) and cohort 2 (800 mg Q4W)) and for participants treated with sabatolimab 800 mg (Q4W) (cohort 2 of safety run-in and expansion parts)
3. Proportion of participants who are RBC/platelets transfusion independent and duration of transfusion independence (Section 8.3) as per IWG-MDS by dose
level for the safety run-in part (cohort 1 (400 mg Q4W) and cohort 2 (800 mg Q4W)) and for participants treated with sabatolimab 800 mg (Q4W) (cohort 2 of
safety run-in and expansion parts).
4. Incidence and severity of AEs and SAEs, changes in laboratory values and vital signs, and incidence of notable ECG abnormalities by dose level for the safety
run-in part (cohort 1 (400 mg Q4W) and cohort 2 (800 mg Q4W)) and for participants treated with sabatolimab 800 mg (Q4W) (cohort 2 of safety run-in
and expansion parts)
5. Serum concentrations and pharmacokinetic parameters (see Section 8.5.2 ) for sabatolimab by dose level for the safety run-in part (cohort 1 (400 mg Q4W) and cohort 2 (800 mg Q4W)) and for participants treated with sabatolimab 800 mg (Q4W) (cohort 2 of safety run-in and expansion parts).
6. Anti-drug Antibody (ADA) prevalence at baseline and ADA incidence on-treatment by dose level for the safety run-in part (cohort 1 (400 mg Q4W) and cohort 2 (800 mg Q4W)) and for participants treated with sabatolimab 800 mg (Q4W) (cohort 2 of safety run-in and expansion parts).
Cohort 2 of Safety run-in (Part 1) and Expansion (Part 2):
1. Duration of CR is defined as time from first occurrence of CR to relapse from CR, progression or death due to any cause whichever occurs first for participants
treated with sabatolimab at 800 mg Q4W
2. Time to CR/mCR is defined as time from start of treatment to first occurrence of CR or mCR as per investigator assessment for participants treated with
sabatolimab at 800 mg Q4W
3. Duration of CR/mCR is defined as time from first occurrence of CR/mCR to relapse from CR, progression or death due to any cause whichever occurs first for participants treated with sabatolimab at 800 mg Q4W
4. Duration of response for participants who achieved HI or better per modified IWG-MDS Cheson 2006 criteria) as per investigator assessment until relapse or death. Participants who did not relapse or die are censored to last adequate response assessment for participants treated with sabatolimab at 800 mg Q4W
5. Time from start of treatment to disease progression (including transformation to acute leukemia per WHO 2016 classification), relapse from CR or death due to
any cause, whichever occurs first for participants treated with sabatolimab at 800 mg Q4W
6. Time from start of treatment to transformation to acute leukemia [as defined as ≥ 20% blasts in bone marrow/ peripheral blood (per WHO 2016 classification) or diagnosis of extramedullary acute leukemia or death due to any cause, whichever occurs first] for participants treated with sabatolimab at 800 mg Q4W
7. Time from start of treatment to lack of reaching CR within the first 6 cycles, relapse from CR or death due to any cause, whichever occurs first for participants treated with sabatolimab at 800 mg Q4W
8. Time from start of treatment to death due to any cause for participants treated with sabatolimab at 800 mg Q4W
Expansion (Part 2):
Changes in fatigue as measured by the FACIT-Fatigue for participants treated with sabatolimab at 800 mg Q4W of the expansion part only |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.-2.C3, 7,10,13 then every 6 cycles up to C25 thereafter every 12 cycles.fu phase, efficacy assessment every 3m
3.start of treatment up to 3y from LPFT
4.screening,each cycle of treatment & end of treatment visit
5.-6. Prior to first dose of MBG453 on C1D8,on C 2,3,6,9, 12,18,14, at end of treatment visit,at 30 and 150 d of safety follow-up
7.-12. Prior to first dose MBG453 on C1D8 , on Cycle 2, 3, 6, 9, 2, 18 and 14, at end of treatment visit and at 30 and 150 days of safety follow-up
13.Date of treatment start to lack of reaching CR within the first 6 cycles, relapse from CR or death
14.date of treatment start to date of death due to any reason (up to 3y from LPFT
15.C1 D1 , prior C2 (C1D28), prior C3 (C2 D28), prior to C4 ,prior to C6, prior to C7,end of treatment&every 24w
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| immunogenicity of sabatolimab given in combination with azacitidine and venetoclax |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| Hong Kong |
| Lebanon |
| United States |
| Belgium |
| France |
| Germany |
| Greece |
| Hungary |
| Italy |
| Spain |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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