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

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ClinicalTrials.gov Identifier: NCT04812548
Recruitment Status : Recruiting
First Posted : March 23, 2021
Last Update Posted : August 26, 2022
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE February 23, 2021
First Posted Date  ICMJE March 23, 2021
Last Update Posted Date August 26, 2022
Actual Study Start Date  ICMJE May 31, 2021
Estimated Primary Completion Date May 13, 2026   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 19, 2021)
  • Incidence of dose limiting toxicities (DLTs) (Safety run-in patients only) [ Time Frame: 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 [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 19, 2021)
  • Percentage of subjects achieving a complete remission (CR) + morphologic complete remission (mCR): Safety run-in (Part 1) and Expansion (Part 2) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Continuously collected for patients during treatment with sabatolimab up to 150 days after last treatment ]
    Maximal concentration of MBG453
  • Trough Serum Concentration (Cmin) MBG453 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of Sabatolimab in Combination With Azacitidine and Venetoclax in High or Very High Risk MDS Participants
Official Title  ICMJE 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
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).
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Myelodysplastic Syndrome (MDS)
Intervention  ICMJE
  • 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.
Study Arms  ICMJE 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.

Interventions:
  • Drug: sabatolimab
  • Drug: azacitidine
  • Drug: venetoclax
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 19, 2021)
76
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 14, 2026
Estimated Primary Completion Date May 13, 2026   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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

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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Novartis Pharmaceuticals 1-888-669-6682 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111
Listed Location Countries  ICMJE Australia,   Belgium,   France,   Germany,   Greece,   Hungary,   Italy,   Spain,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04812548
Other Study ID Numbers  ICMJE CMBG453B12203
2020-003669-21 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description:

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data is currently available according to the process described on www.clinicalstudydatarequest.com.

URL: https://www.clinicalstudydatarequest.com
Current Responsible Party Novartis ( Novartis Pharmaceuticals )
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Novartis Pharmaceuticals
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date August 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP