STIMULUS-MDS3: A Study of Sabatolimab in Combination With Azacitidine and Venetoclax in High or Very High Risk MDS Participants

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04812548

Collaborator

(none)

Enrollment

Locations

Arm

54.2

Anticipated Duration (Months)

5.1

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndrome (MDS)	Drug: sabatolimab Drug: azacitidine Drug: venetoclax	Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

76 participants

Allocation:

N/A

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

May 31, 2021

Anticipated Primary Completion Date :

Dec 5, 2025

Anticipated Study Completion Date :

Dec 6, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: sabatolimab + azacitidine + venetoclax 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 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. Drug: azacitidine 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). Drug: venetoclax 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.

Arm

Intervention/Treatment

Experimental: sabatolimab + azacitidine + venetoclax

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

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.

Drug: azacitidine

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).

Drug: venetoclax

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.

Outcome Measures

Primary Outcome Measures

Incidence of dose limiting toxicities (DLTs) (Safety run-in patients only) [From Cycle 1 Day 8 to end of Cycle 2 (Cycle = 28 Days)]
Assessment of tolerability of MBG in combination with venetoclax and azacitidine
Percentage of participants (receiving 800mg sabatolimab) achieving complete remission (CR) per investigator assessment [Throughout study completion, up to 3 years]
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.

Secondary Outcome Measures

Percentage of subjects achieving a complete remission (CR) + morphologic complete remission (mCR): Safety run-in (Part 1) and Expansion (Part 2) [Throughout study completion, an average of 3 years]
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)
Overall Response Rate (ORR) of participants who achieved hematologic improvement (HI) or better as best response [Throughout study completion, an average of 3 years]
The percentage of participants achieving [CR + mCR + partial remission (PR) + hematologic improvement (HI)], per modified IWG-MDS Cheson 2006 criteria
Percentage of participants who are RBC/platelets transfusion independent [Continuously collected from start of treatment up to 3 years from last patient first treatment]
Improvement in red blood cells (RBC)/platelets transfusion independence as per IWG-MDS by dose level
Duration of transfusion independence [Continuously collected from start of treatment up to 3 years from last patient first treatment]
Transfusion independence as per IWG-MDS by dose level
Peak Serum Concentration (Cmax) MBG453 [Continuously collected for patients during treatment with sabatolimab up to 150 days after last treatment]
Maximal concentration of MBG453
Trough Serum Concentration (Cmin) MBG453 [Continuously collected for patients during treatment with sabatolimab up to 150 days after last treatment]
Concentration of sabatolimab prior to next dosing or after end of treatment
Anti-drug Antibody (ADA) prevalence at baseline and ADA incidence on-treatment by dose level [Continuously collected for patients during treatment with sabatolimab up to 150 days after last treatment]
Immunogenicity of sabatolimab prior to sabatolimab exposure and during treatment
Duration of complete remission (CR) [Throughout study completion, an average of 3 years]
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
Time to complete remission(CR)/marrow complete remission (mCR) [Throughout study completion, an average of 3 years]
Time to CR/mCR is defined as time from start of treatment to first occurrence of CR or mCR as per investigator assessment
Duration of CR/mCR [Throughout study completion, an average of 3 years]
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
Duration of response for participants who achieved hematologic improvement (HI) or better [Throughout study completion, an average of 3 years]
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
Progression-Free Survival (PFS) [Throughout study completion, an average of 3 years]
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
Leukemia-Free Survival (LFS) [Throughout study completion, an average of 3 years]
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]
Event-Free Survival (EFS) [Throughout study completion, an average of 3 years]
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
Overall Survival (OS) [Date of start of treatment to date of death due to any reason (for up to 3 years from last patient first treatment)]
Time from start of treatment to death due to any cause
Changes in fatigue (Part 2 - Expansion) [Throughout the Expansion Phase, an average of 3 years]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope National Medical Center Medical Oncology & Therapeutic	Duarte	California	United States	91010
2	University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030
3	Novartis Investigative Site	Melbourne	Victoria	Australia	3004
4	Novartis Investigative Site	Brasschaat		Belgium	2930
5	Novartis Investigative Site	Marseille		France	13273
6	Novartis Investigative Site	Nice Cedex		France	06202
7	Novartis Investigative Site	Duesseldorf		Germany	40479
8	Novartis Investigative Site	Leipzig		Germany	04103
9	Novartis Investigative Site	Stuttgart		Germany	70376
10	Novartis Investigative Site	Alexandroupolis	Evros	Greece	681 00
11	Novartis Investigative Site	Patras		Greece	265 00
12	Novartis Investigative Site	Nyiregyhaza		Hungary	4400
13	Novartis Investigative Site	Firenze	FI	Italy	50134
14	Novartis Investigative Site	Genova	GE	Italy	16132
15	Novartis Investigative Site	Barcelona	Catalunya	Spain	08036