Clinical trial NCT04812548: A Study of Sabatolimab in Combination With Azacitidine and Venetoclax in High or Very High Risk MDS Participants
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Myelodysplastic Syndrome (MDS)
Keywords: MGM453
Phase II
sabatolimab
TIM-3
venetoclax
azacitidine
Myelodysplastic syndrome
MDS
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2021-03-23
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief 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).

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Rate of Dose Limiting Toxicities (DLTs) - All Grades (Safety run-in Patients Only)
timeFrame: From Cycle 1 Day 8 to end of Cycle 2 (Cycle = 28 Days)
measure: Percentage of Participants (Receiving 800mg Sabatolimab) Achieving Complete Remission (CR) Per Investigator Assessment
timeFrame: up to approx. 23 months
Secondary outcomes:
measure: Percentage of Subjects Achieving a Complete Remission (CR) + Morphologic Complete Remission (mCR): Safety run-in (Part 1)
timeFrame: up to approx. 23 months
measure: Overall Response Rate (ORR) of Participants Who Achieved Hematologic Improvement (HI) or Better as Best Response
timeFrame: up to approx. 23 months
measure: Percentage of Participants Who Are RBC/Platelets Transfusion Independent
timeFrame: up to approx. 23 months
measure: Duration of Transfusion Independence
timeFrame: up to approx. 23 months
measure: Peak Serum Concentration (Cmax) of Sabatolimab
timeFrame: Continuously collected for patients during treatment with sabatolimab up to 150 days after last treatment, approx. 23 months
measure: Trough Serum Concentration (Cmin) Sabatolimab
timeFrame: Continuously collected for patients during treatment with sabatolimab up to 150 days after last treatment, approx. 23 months
measure: Anti-drug Antibody (ADA) Prevalence at Baseline and ADA Incidence On-treatment by Dose Level
timeFrame: Continuously collected for patients during treatment with sabatolimab up to 150 days after last treatment, approx. 23 months
measure: Duration of Complete Remission (CR)
timeFrame: up to approx. 23 months
measure: Time to Complete Remission(CR)/Marrow Complete Remission (mCR)
timeFrame: up to approx. 23 months
measure: Duration of Complete Response (CR)/Marrow Complete Response (mCR)
timeFrame: up to approx. 23 months
measure: Duration of Response for Participants Who Achieved Hematologic Improvement (HI) or Better
timeFrame: up to approx. 23 months
measure: Progression-Free Survival (PFS)
timeFrame: up to approx. 23 months
measure: Leukemia-Free Survival (LFS)
timeFrame: up to approx. 23 months
measure: Event-Free Survival (EFS)
timeFrame: up to approx. 23 months
measure: Overall Survival (OS)
timeFrame: Date of start of treatment to date of death due to any reason, for up to approx. 23 months
measure: Changes in Fatigue (Part 2 - Expansion)
timeFrame: throughout study until progressive disease, death or study discontinuation, approx. 3 years
Other outcomes:
Locations:
city: Brasschaat
country: Belgium
facility: Novartis Investigative Site
city: Marseille
country: France
facility: Novartis Investigative Site
city: Nice
country: France
facility: Novartis Investigative Site
city: Duesseldorf
country: Germany
facility: Novartis Investigative Site
city: Stuttgart
country: Germany
facility: Novartis Investigative Site
city: Alexandroupolis
country: Greece
facility: Novartis Investigative Site
state: Evros
city: Patras
country: Greece
facility: Novartis Investigative Site
city: Nyiregyhaza
country: Hungary
facility: Novartis Investigative Site
city: Genova
country: Italy
facility: Novartis Investigative Site
state: GE
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: