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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT04812548




Registration number
NCT04812548
Ethics application status
Date submitted
23/02/2021
Date registered
23/03/2021
Date last updated
31/05/2023

Titles & IDs
Public title
A Study of Sabatolimab in Combination With Azacitidine and Venetoclax in High or Very High Risk MDS Participants
Scientific 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
Secondary ID [1] 0 0
2020-003669-21
Secondary ID [2] 0 0
CMBG453B12203
Universal Trial Number (UTN)
Trial acronym
STIMULUS-MDS3
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Myelodysplastic Syndrome (MDS) 0 0
Condition category
Condition code
Blood 0 0 0 0
Haematological diseases
Blood 0 0 0 0
Other blood disorders
Other 0 0 0 0
Research that is not of generic health relevance and not applicable to specific health categories listed above

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - sabatolimab
Treatment: Drugs - azacitidine
Treatment: Drugs - venetoclax

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.


Treatment: Drugs: 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.

Treatment: Drugs: 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).

Treatment: Drugs: 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.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Incidence of dose limiting toxicities (DLTs) (Safety run-in patients only)
Timepoint [1] 0 0
From Cycle 1 Day 8 to end of Cycle 2 (Cycle = 28 Days)
Primary outcome [2] 0 0
Percentage of participants (receiving 800mg sabatolimab) achieving complete remission (CR) per investigator assessment
Timepoint [2] 0 0
Throughout study completion, up to 3 years
Secondary outcome [1] 0 0
Percentage of subjects achieving a complete remission (CR) + morphologic complete remission (mCR): Safety run-in (Part 1) and Expansion (Part 2)
Timepoint [1] 0 0
Throughout study completion, an average of 3 years
Secondary outcome [2] 0 0
Overall Response Rate (ORR) of participants who achieved hematologic improvement (HI) or better as best response
Timepoint [2] 0 0
Throughout study completion, an average of 3 years
Secondary outcome [3] 0 0
Percentage of participants who are RBC/platelets transfusion independent
Timepoint [3] 0 0
Continuously collected from start of treatment up to 3 years from last patient first treatment
Secondary outcome [4] 0 0
Duration of transfusion independence
Timepoint [4] 0 0
Continuously collected from start of treatment up to 3 years from last patient first treatment
Secondary outcome [5] 0 0
Peak Serum Concentration (Cmax) MBG453
Timepoint [5] 0 0
Continuously collected for patients during treatment with sabatolimab up to 150 days after last treatment
Secondary outcome [6] 0 0
Trough Serum Concentration (Cmin) MBG453
Timepoint [6] 0 0
Continuously collected for patients during treatment with sabatolimab up to 150 days after last treatment
Secondary outcome [7] 0 0
Anti-drug Antibody (ADA) prevalence at baseline and ADA incidence on-treatment by dose level
Timepoint [7] 0 0
Continuously collected for patients during treatment with sabatolimab up to 150 days after last treatment
Secondary outcome [8] 0 0
Duration of complete remission (CR)
Timepoint [8] 0 0
Throughout study completion, an average of 3 years
Secondary outcome [9] 0 0
Time to complete remission(CR)/marrow complete remission (mCR)
Timepoint [9] 0 0
Throughout study completion, an average of 3 years
Secondary outcome [10] 0 0
Duration of CR/mCR
Timepoint [10] 0 0
Throughout study completion, an average of 3 years
Secondary outcome [11] 0 0
Duration of response for participants who achieved hematologic improvement (HI) or better
Timepoint [11] 0 0
Throughout study completion, an average of 3 years
Secondary outcome [12] 0 0
Progression-Free Survival (PFS)
Timepoint [12] 0 0
Throughout study completion, an average of 3 years
Secondary outcome [13] 0 0
Leukemia-Free Survival (LFS)
Timepoint [13] 0 0
Throughout study completion, an average of 3 years
Secondary outcome [14] 0 0
Event-Free Survival (EFS)
Timepoint [14] 0 0
Throughout study completion, an average of 3 years
Secondary outcome [15] 0 0
Overall Survival (OS)
Timepoint [15] 0 0
Date of start of treatment to date of death due to any reason (for up to 3 years from last patient first treatment)
Secondary outcome [16] 0 0
Changes in fatigue (Part 2 - Expansion)
Timepoint [16] 0 0
Throughout the Expansion Phase, an average of 3 years

Eligibility
Key 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 (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)

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 (de Witte et al
2017)

5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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,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.

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
(Arber et al, 2016) with revised International Prognostic Scoring System (IPSS-R) =
4.5

Other protocol-defined Inclusion/Exclusion may apply.

Study design
Purpose of the study
Treatment
Allocation to intervention
N/A
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
31/05/2021
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
8/05/2023
Sample size
Target
Accrual to date
Final
20
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 0 0
Belgium
State/province [1] 0 0
Brasschaat
Country [2] 0 0
France
State/province [2] 0 0
Marseille
Country [3] 0 0
France
State/province [3] 0 0
Nice Cedex
Country [4] 0 0
Germany
State/province [4] 0 0
Duesseldorf
Country [5] 0 0
Germany
State/province [5] 0 0
Stuttgart
Country [6] 0 0
Greece
State/province [6] 0 0
Evros
Country [7] 0 0
Greece
State/province [7] 0 0
Patras
Country [8] 0 0
Hungary
State/province [8] 0 0
Nyiregyhaza
Country [9] 0 0
Italy
State/province [9] 0 0
GE
Country [10] 0 0
Spain
State/province [10] 0 0
Catalunya

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Novartis Pharmaceuticals
Address
Country

Ethics approval
Ethics application status

Summary
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).
Trial website
https://clinicaltrials.gov/ct2/show/NCT04812548
Trial related presentations / publications
Public notes
This record is viewable in the ANZCTR as it had previously listed Australia and/or New Zealand as a recruitment site, however these sites have since been removed

Contacts
Principal investigator
Name 0 0
Novartis Pharmaceuticals
Address 0 0
Novartis Pharmaceuticals
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries