A Study of Sabatolimab in Combination With Azacitidine and Venetoclax in High or Very High Risk MDS Participants

Study Overview
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Brief Summary
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The purpose of the study is to find out if the new drug sabatolimab when given in combination with azacitidine and venetoclax, is safe and has beneficial effects in participants with high or very high risk myelodysplastic syndrome (MDS) who are not suitable for treatment with intensive chemotherapy or a stem-cell transplant (HSCT).

Detailed Description
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Approximately 76 people with high or very high risk myelodysplastic syndrome (MDS) and age ≥ 18 years are being asked to join this study. The primary purpose of Part 1 (Safety run-in) is to rule out excessive toxicity of sabatolimab, when administered in combination with azacitidine and venetoclax. The primary purpose of the combined cohort 2 of the Safety run-in (Part 1) and Expansion (Part 2) is to evaluate efficacy of sabatolimab, when administered in combination with azacitidine and venetoclax in adult participants with high or very high risk MDS. This study will consist of two parts: Safety Run-in Part: The first approximately 18 participants to join the study will be a part of the safety run-in. The first approximately 6 participants will be enrolled to the lower dose given every four weeks sabatolimab safety run-in cohort. After these participants have completed 2 cycles of treatment a decision will be made to confirm whether the chosen combination of sabatolimab with azacitidine and venetoclax is considered safe to continue with approximately 12 participants, will be enrolled to the higher dose given every four weeks safety run-in cohort. After these participants have completed 2 cycles of treatment a decision will be made to confirm whether the chosen combination of sabatolimab with azacitidine and venetoclax is considered safe to continue with expansion part of the study. Expansion Part: After the safety run-in part confirms that the study treatment (higher dose of sabatolimab given every four weeks with azacitidine and venetoclax) is safe, about 58 more participants will be enrolled in the expansion part to better investigate the efficacy of the study treatment.

Official Title
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A Single-arm, Open-label, Phase II Study of Sabatolimab in Combination With Azacitidine and Venetoclax in Adult Participants With High or Very High Risk Myelodysplastic Syndromes (MDS) as Per IPSS-R Criteria

Conditions
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Myelodysplastic Syndrome (MDS)

Intervention / Treatment
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* Drug: sabatolimab
* Drug: azacitidine
* Drug: venetoclax


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent must be obtained prior to participation in the study Age ≥ 18 years at the date of signing the informed consent form (ICF) Morphologically confirmed diagnosis of myelodysplastic syndrome (MDS) based on 2016 WHO classification (Arber et al, 2016) by local investigator assessment with one of the following Prognostic Risk Categories, based on the revised International Prognostic Scoring System (IPSS-R) (Greenberg et al 2012): Very high (> 6 points) High (> 4.5-6 points) 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 (de Witte et al 2017) Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 Exclusion Criteria: Prior exposure to TIM-3 directed therapy or any BCL-2 inhibitor (including venetoclax) at any time 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 Previous first-line treatment for very high risk or high risk myelodysplastic syndromes (based on IPSS-R,Greenberg et al 2012 and Arber et al, 2016) 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. Live vaccine administered within 30 days prior to start of treatment 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 History of severe hypersensitivity reactions to any ingredient of study drug(s) (azacitidine, venetoclax or sabatolimab) or monoclonal antibodies (mAbs) and/or their excipients Participants with Myelodysplastic syndrome (MDS) based on 2016 WHO classification (Arber et al, 2016) with revised International Prognostic Scoring System (IPSS-R) ≤ 4.5 Other protocol-defined Inclusion/Exclusion may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: sabatolimab + azacitidine + venetoclax<br>Part 1: Safety run-in consists of 2 subsequent cohorts of a lower dose (cohort 1) and s higher dose (cohort 2) of sabatolimab in combination with fixed dose of venetoclax and azacitidine. Cohort 2 will be open only after the review of safety data from cohort 1 indicates the regimen is safe. If the regimen using sabatolimab at the lower dose is not safe, the study will be stopped. Subsequently, if the review of safety data from participants enrolled in cohort 2 indicates that the regimen is safe, then Part 2 will be opened. Otherwise, if the regimen at the higher dose is not safe, the study will be also stopped. Part 2: Expansion will enroll additional participants to further investigate the regimen including sabatolimab at the higher dose, azacitidine and venetoclax. Participants data from Part 1 and Part 2 treated with the higher dose will be combined to determine the complete remission rate. | Drug: sabatolimab<br>* Sabatolimab will be administered at a low dose (Safety run-in (Part 1) cohort 1) or a high dose (Safety run-in (Part 1) cohort 2 and Expansion (Part 2)) via i.v. infusion over 30 minutes on Day 8 of every treatment cycle.<br>Drug: azacitidine<br>* A standard dose of azacitidine will be given subcutaneously or intravenously every day for seven consecutive days on days 1-7 of a confirmed treatment cycle. In keeping with standard clinical practice, the alternative schedules for five consecutive days on days 1-5, followed by a two day break, then two consecutive days on days 8-9 will be permitted (alternative schedule).<br>Drug: venetoclax<br>* Venetoclax film-coated tablets will be administered at a dose of 400 mg orally or corresponding reduced dose for concomitant use with P-gp inhibitors or moderate or strong CYP3A4 inhibitors, once a day, from C1D1 to C1D14 during the treatment cycle. No ramp-up for venetoclax is necessary.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose limiting toxicities (DLTs) (Safety run-in patients only) | Assessment of tolerability of MBG in combination with venetoclax and azacitidine | From Cycle 1 Day 8 to end of Cycle 2 (Cycle = 28 Days) | 
| Percentage of participants (receiving 800mg sabatolimab) achieving complete remission (CR) per investigator assessment | This endpoint will assess Complete Remission (CR) Rate of participants from Cohort 2 of Part 1 and Part 2 according to Investigator assessment per modified IWG-MDS - Cheson 2006 criteria. CR is defined as follows: bone marrow blasts <=5%, hemoglobin level ≥ 10 g/dL, platelets count ≥ 100*10^9/L, neutrophils count ≥ 1.0*10^9/L, absence of blasts in peripheral blood. | Throughout study completion, up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of subjects achieving a complete remission (CR) + morphologic complete remission (mCR): Safety run-in (Part 1) and Expansion (Part 2) | Assessing the durability of complete remission (CR) or morphologic complete remission (mCR) rate (defined as the proportion of participants with best overall response of either CR or mCR) | Throughout study completion, an average of 3 years | 
| Overall Response Rate (ORR) of participants who achieved hematologic improvement (HI) or better as best response | The percentage of participants achieving [CR + mCR + partial remission (PR) + hematologic improvement (HI)], per modified IWG-MDS Cheson 2006 criteria | Throughout study completion, an average of 3 years | 
| Percentage of participants who are RBC/platelets transfusion independent | Improvement in red blood cells (RBC)/platelets transfusion independence as per IWG-MDS by dose level | Continuously collected from start of treatment up to 3 years from last patient first treatment | 
| Duration of transfusion independence | Transfusion independence as per IWG-MDS by dose level | Continuously collected from start of treatment up to 3 years from last patient first treatment | 
| Peak Serum Concentration (Cmax) MBG453 | Maximal concentration of MBG453 | Continuously collected for patients during treatment with sabatolimab up to 150 days after last treatment | 
| Trough Serum Concentration (Cmin) MBG453 | Concentration of sabatolimab prior to next dosing or after end of treatment | Continuously collected for patients during treatment with sabatolimab up to 150 days after last treatment | 
| Anti-drug Antibody (ADA) prevalence at baseline and ADA incidence on-treatment by dose level | Immunogenicity of sabatolimab prior to sabatolimab exposure and during treatment | Continuously collected for patients during treatment with sabatolimab up to 150 days after last treatment | 
| Duration of complete remission (CR) | 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 | Throughout study completion, an average of 3 years | 
| Time to complete remission(CR)/marrow complete remission (mCR) | Time to CR/mCR is defined as time from start of treatment to first occurrence of CR or mCR as per investigator assessment | Throughout study completion, an average of 3 years | 
| Duration of CR/mCR | 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 | Throughout study completion, an average of 3 years | 
| Duration of response for participants who achieved hematologic improvement (HI) or better | The duration of response will be derived for participants treated with sabatolimab at the higher dose who achieve HI or better as per investigator assessment and is defined from the first occurrence of CR, mCR, PR or HI until relapse, progression or death due to any reason | Throughout study completion, an average of 3 years | 
| Progression-Free Survival (PFS) | 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 | Throughout study completion, an average of 3 years | 
| Leukemia-Free Survival (LFS) | 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] | Throughout study completion, an average of 3 years | 
| Event-Free Survival (EFS) | 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 | Throughout study completion, an average of 3 years | 
| Overall Survival (OS) | Time from start of treatment to death due to any cause | Date of start of treatment to date of death due to any reason (for up to 3 years from last patient first treatment) | 
| Changes in fatigue (Part 2 - Expansion) | Changes in fatigue as measured by the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue for participants treated with sabatolimab at the higher dose of the expansion part only. Measurements are taken via scores from 0 (not at all) to 4 (very much). The higher the score, the better the Quality of Life. | Throughout the Expansion Phase, an average of 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MGM453, Phase II, sabatolimab, TIM-3, venetoclax, azacitidine, Myelodysplastic syndrome (MDS), MDS