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

Myelodysplastic Syndrome (MDS) Clinical Trial

— STIMULUS-MDS3  

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04812548
• Other study ID #: CMBG453B12203
• Secondary ID: 2020-003669-21
• Status: Terminated
• Phase: Phase 2
• Start date: May 31, 2021
• Est. completion date: May 8, 2023

Study information

• Verified date: May 2024
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Description:

Approximately 76 people with high or very high risk myelodysplastic syndrome (MDS) and age ≥ 18 years were to be asked to join this study but due to the decision by Novartis to halt recruitment the study did not enroll the approximately 76 participants.

The primary purpose of Part 1 (Safety run-in) was 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) was to have evaluated efficacy of sabatolimab, when administered in combination with azacitidine and venetoclax in adult participants with high or very high risk MDS. But due to the decision by Novartis to halt recruitment at the end of the Safety run-in, the study enrolled participants in Part 1 only.

This study was to have consisted of two parts:

Safety Run-in Part:

The first approximately 18 participants to have joined the study would have been part of the safety run-in. The first approximately 6 participants would have been enrolled to the lower dose given every four weeks sabatolimab safety run-in cohort.

After these participants would have completed 2 cycles of treatment a decision would have been made to confirm whether the chosen combination of sabatolimab with azacitidine and venetoclax was considered safe to continue with approximately 12 participants, to have been enrolled to the higher dose given every four weeks safety run-in cohort. After these participants would have completed 2 cycles of treatment a decision would have been made to confirm whether the chosen combination of sabatolimab with azacitidine and venetoclax was considered safe to continue with expansion part of the study.

Expansion Part (which did not occur):

After the safety run-in part would have confirmed that the study treatment (higher dose of sabatolimab given every four weeks with azacitidine and venetoclax) was safe, about 58 more participants would have been enrolled in the expansion part to better investigate the efficacy of the study treatment.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 20
• Est. completion date: May 8, 2023
• Est. primary completion date: May 8, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Myelodysplastic Syndrome (MDS)
• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

Drug:
• sabatolimab
Sabatolimab was administered at a low dose (Safety run-in (Part 1) cohort 1) or a high dose (Safety run-in (Part 1) cohort 2) via i.v. infusion over 30 minutes on Day 8 of every treatment cycle. Cycle = 28 days
• azacitidine
A standard dose of azacitidine was 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 was permitted (alternative schedule).
• venetoclax
Venetoclax film-coated tablets was 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 was necessary.

Locations

Country	Name	City	State
Belgium	Novartis Investigative Site	Brasschaat
France	Novartis Investigative Site	Marseille
France	Novartis Investigative Site	Nice
Germany	Novartis Investigative Site	Duesseldorf
Germany	Novartis Investigative Site	Stuttgart
Greece	Novartis Investigative Site	Alexandroupolis	Evros
Greece	Novartis Investigative Site	Patras
Hungary	Novartis Investigative Site	Nyiregyhaza
Italy	Novartis Investigative Site	Genova	GE
Spain	Novartis Investigative Site	Barcelona	Catalunya

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

Belgium,  France,  Germany,  Greece,  Hungary,  Italy,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Rate of Dose Limiting Toxicities (DLTs) - All Grades (Safety run-in Patients Only)	A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value considered by the Investigator to be at least possibly related to sabatolimab as a single contributor or in combination with other component(s) of study treatment that occurs during the DLT observation period and meets severity criteria as per protocol.	From Cycle 1 Day 8 to end of Cycle 2 (Cycle = 28 Days)
Primary	Percentage of Participants (Receiving 800mg Sabatolimab) Achieving Complete Remission (CR) Per Investigator Assessment	This endpoint assessed 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.	up to approx. 23 months
Secondary	Percentage of Subjects Achieving a Complete Remission (CR) + Morphologic Complete Remission (mCR): Safety run-in (Part 1)	Assessed the durability of complete remission (CR) or morphologic complete remission (mCR) rate. mCR is defined as <=5% blasts and blast count decrease by >=50% compared to baseline as per modified IWG-MDS Cheson 2006 criteria.	up to approx. 23 months
Secondary	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. Partial response (PR): all complete response (CR) criteria except >=50% decrease from baseline in blasts in bone marrow AND blast count in bone marrow >5%. HI (erythroid response or platelet response or neutrophil response) must last at least 8 weeks.	up to approx. 23 months
Secondary	Percentage of Participants Who Are RBC/Platelets Transfusion Independent	Improvement in red blood cells (RBC)/platelets transfusion post-baseline as per International Working Group - Myelodysplastic syndromes (IWG-MDS) by dose level for the safety run-in part (Cohort 1 (400 mg Q4W) and Cohort 2 (800 mg Q4W)) and for participants treated with sabatolimab 800 mg (Q4W) (Cohort 2 of safety run-in and expansion parts). RBC/Platelets transfusion independence is defined as participants having received no RBC/Platelets transfusions during at least 8 consecutive weeks after start of treatment.	up to approx. 23 months
Secondary	Duration of Transfusion Independence	Sum of each period of the transfusion independence for participants with at least one period of transfusion independence post-baseline by dose level for the safety run-in part (Cohort 1 (400 mg Q4W) and Cohort 2 (800 mg Q4W)) and for participants treated with sabatolimab 800 mg (Q4W) (Cohort 2 of safety run-in and expansion parts) for both red blood cells and platelets. RBC/Platelets transfusion independence is defined as participants having received no RBC/platelets transfusions during at least 8 consecutive weeks after start of treatment.	up to approx. 23 months
Secondary	Peak Serum Concentration (Cmax) of Sabatolimab	Maximal concentration of sabatolimab for participants treated with sabatolimab by dose level for the safety run-in part (Cohort 1 (400 mg Q4W) and Cohort 2 (800 mg Q4W)).	Continuously collected for patients during treatment with sabatolimab up to 150 days after last treatment, approx. 23 months
Secondary	Trough Serum Concentration (Cmin) Sabatolimab	Concentration of sabatolimab prior to next dosing or after end of treatment by dose level for the safety run-in part (Cohort 1 (400 mg Q4W) and Cohort 2 (800 mg Q4W)).	Continuously collected for patients during treatment with sabatolimab up to 150 days after last treatment, approx. 23 months
Secondary	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, approx. 23 months
Secondary	Duration of Complete Remission (CR)	Duration of complete remission (CR) is defined as time from first occurrence of CR to relapse from CR, progression or death due to any cause whichever occurs first for the safety run-in part (Cohort 2 (800 mg Q4W)). 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.; Relapse from complete remission (CR)is when at least 1 of the following criteria is met: Return to baseline bone marrow blast percentage.; Decrease of = 50% from maximum remission/response levels in neutrophils AND neutrophils <1.0*10^9/L.; Decrease of = 50% from maximum remission/response levels in platelets AND platelets <100*10^9/L.; Decrease from maximum remission/response levels in Hgb concentration by = 1.5g/dL AND Hgb < 10g/dL.; Becoming transfusion dependent	up to approx. 23 months
Secondary	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 for the safety run-in part (Cohort 2 (800 mg Q4W)).	up to approx. 23 months
Secondary	Duration of Complete Response (CR)/Marrow Complete Response (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 for the safety run-in part (Cohort 2 (800 mg Q4W)).	up to approx. 23 months
Secondary	Duration of Response for Participants Who Achieved Hematologic Improvement (HI) or Better	The duration of response was derived for participants treated with sabatolimab at the higher dose who achieved HI or better as per investigator assessment and is defined from the first occurrence of complete response (CR), marrow complete response (mCR), partial response (PR) or hematologic improvement (HI) until relapse, progression or death due to any reason for the safety run-in part (Cohort 2 (800 mg Q4W)).	up to approx. 23 months
Secondary	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 for the safety run-in part (Cohort 2 (800 mg Q4W)).	up to approx. 23 months
Secondary	Leukemia-Free Survival (LFS)	Time from start of treatment to transformation to acute leukemias per investigator assessment [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 for the safety run-in part (Cohort 2 (800 mg Q4W)).	up to approx. 23 months
Secondary	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 for the safety run-in part (Cohort 2 (800 mg Q4W)).	up to approx. 23 months
Secondary	Overall Survival (OS)	Time from start of treatment to death due to any cause for the safety run-in part (Cohort 2 (800 mg Q4W)).	Date of start of treatment to date of death due to any reason, for up to approx. 23 months
Secondary	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 would have been taken via scores from 0 (not at all) to 4 (very much). The higher the score, the better the Quality of Life.	throughout study until progressive disease, death or study discontinuation, approx. 3 years