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

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

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).

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.

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