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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
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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
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Secondary ID [1]
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2020-003669-21
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Secondary ID [2]
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CMBG453B12203
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Universal Trial Number (UTN)
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Trial acronym
STIMULUS-MDS3
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Myelodysplastic Syndrome (MDS)
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Condition category
Condition code
Blood
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Haematological diseases
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Blood
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Other blood disorders
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Other
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Research that is not of generic health relevance and not applicable to specific health categories listed above
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Intervention/exposure
Study type
Interventional
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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.
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Incidence of dose limiting toxicities (DLTs) (Safety run-in patients only)
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Assessment method [1]
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Assessment of tolerability of MBG in combination with venetoclax and azacitidine
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Timepoint [1]
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From Cycle 1 Day 8 to end of Cycle 2 (Cycle = 28 Days)
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Primary outcome [2]
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Percentage of participants (receiving 800mg sabatolimab) achieving complete remission (CR) per investigator assessment
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Assessment method [2]
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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.
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Timepoint [2]
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Throughout study completion, up to 3 years
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Secondary outcome [1]
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Percentage of subjects achieving a complete remission (CR) + morphologic complete remission (mCR): Safety run-in (Part 1) and Expansion (Part 2)
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Assessment method [1]
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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)
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Timepoint [1]
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Throughout study completion, an average of 3 years
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Secondary outcome [2]
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Overall Response Rate (ORR) of participants who achieved hematologic improvement (HI) or better as best response
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Assessment method [2]
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The percentage of participants achieving [CR + mCR + partial remission (PR) + hematologic improvement (HI)], per modified IWG-MDS Cheson 2006 criteria
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Timepoint [2]
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Throughout study completion, an average of 3 years
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Secondary outcome [3]
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Percentage of participants who are RBC/platelets transfusion independent
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Assessment method [3]
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Improvement in red blood cells (RBC)/platelets transfusion independence as per IWG-MDS by dose level
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Timepoint [3]
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Continuously collected from start of treatment up to 3 years from last patient first treatment
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Secondary outcome [4]
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Duration of transfusion independence
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Assessment method [4]
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Transfusion independence as per IWG-MDS by dose level
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Timepoint [4]
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Continuously collected from start of treatment up to 3 years from last patient first treatment
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Secondary outcome [5]
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Peak Serum Concentration (Cmax) MBG453
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Assessment method [5]
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Maximal concentration of MBG453
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Timepoint [5]
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Continuously collected for patients during treatment with sabatolimab up to 150 days after last treatment
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Secondary outcome [6]
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Trough Serum Concentration (Cmin) MBG453
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Assessment method [6]
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Concentration of sabatolimab prior to next dosing or after end of treatment
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Timepoint [6]
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Continuously collected for patients during treatment with sabatolimab up to 150 days after last treatment
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Secondary outcome [7]
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Anti-drug Antibody (ADA) prevalence at baseline and ADA incidence on-treatment by dose level
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Assessment method [7]
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Immunogenicity of sabatolimab prior to sabatolimab exposure and during treatment
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Timepoint [7]
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Continuously collected for patients during treatment with sabatolimab up to 150 days after last treatment
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Secondary outcome [8]
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Duration of complete remission (CR)
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Assessment method [8]
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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
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Timepoint [8]
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Throughout study completion, an average of 3 years
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Secondary outcome [9]
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Time to complete remission(CR)/marrow complete remission (mCR)
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Assessment method [9]
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Time to CR/mCR is defined as time from start of treatment to first occurrence of CR or mCR as per investigator assessment
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Timepoint [9]
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Throughout study completion, an average of 3 years
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Secondary outcome [10]
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Duration of CR/mCR
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Assessment method [10]
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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
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Timepoint [10]
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Throughout study completion, an average of 3 years
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Secondary outcome [11]
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Duration of response for participants who achieved hematologic improvement (HI) or better
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Assessment method [11]
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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
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Timepoint [11]
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Throughout study completion, an average of 3 years
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Secondary outcome [12]
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Progression-Free Survival (PFS)
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Assessment method [12]
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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
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Timepoint [12]
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Throughout study completion, an average of 3 years
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Secondary outcome [13]
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Leukemia-Free Survival (LFS)
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Assessment method [13]
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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]
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Timepoint [13]
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Throughout study completion, an average of 3 years
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Secondary outcome [14]
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Event-Free Survival (EFS)
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Assessment method [14]
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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
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Timepoint [14]
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Throughout study completion, an average of 3 years
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Secondary outcome [15]
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Overall Survival (OS)
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Assessment method [15]
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Time from start of treatment to death due to any cause
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Timepoint [15]
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Date of start of treatment to date of death due to any reason (for up to 3 years from last patient first treatment)
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Secondary outcome [16]
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Changes in fatigue (Part 2 - Expansion)
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Assessment method [16]
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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.
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Timepoint [16]
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Throughout the Expansion Phase, an average of 3 years
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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
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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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.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
N/A
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Other
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Other design features
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Phase
Phase 2
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
31/05/2021
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
8/05/2023
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Sample size
Target
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Accrual to date
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Final
20
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Recruitment in Australia
Recruitment state(s)
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Recruitment outside Australia
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Belgium
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State/province [1]
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Brasschaat
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France
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State/province [2]
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Marseille
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France
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State/province [3]
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Nice Cedex
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Germany
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State/province [4]
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Duesseldorf
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Germany
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Stuttgart
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Greece
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Evros
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Greece
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Patras
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Hungary
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Nyiregyhaza
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Italy
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State/province [9]
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GE
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Spain
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Catalunya
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Novartis Pharmaceuticals
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Address
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Country
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Ethics approval
Ethics application status
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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).
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Trial website
https://clinicaltrials.gov/ct2/show/NCT04812548
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Trial related presentations / publications
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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
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Contacts
Principal investigator
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Novartis Pharmaceuticals
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Address
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Novartis Pharmaceuticals
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Fax
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Email
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Contact person for public queries
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Address
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Fax
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT04812548
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