A Study of Sabatolimab and Magrolimab-based Treatment in AML or Higher Risk MDS Participants

Novartis Pharmaceuticals

Overview

This study is to determine the safety and preliminary efficacy of sabatolimab in combination with magrolimab and azacitidine in adult participants with 1L unfit Acute Myeloid Leukemia (AML) or with 1L higher risk Myelodysplastic Syndromes (MDS), and sabatolimab in combination with magrolimab in participants with relapsed or refractory (R/R) AML.

The primary purpose of the Safety run-in is to rule out excessive toxicity and investigate safety of the combination of sabatolimab with azacitidine and magrolimab in previously untreated participants with higher-risk MDS and unfit AML. The primary purpose of the combined Safety Run-in and Expansion is to assess the preliminary efficacy of the combination of sabatolimab with magrolimab with (cohort 1 and 2) or without (cohort 3) azacitidine in terms of achieving complete remission in 3 different indications: * Previously untreated participants with AML, who are unfit for intensive chemotherapy (1L unfit AML - cohort 1), * Previously untreated participants with higher-risk MDS (1L higher risk MDS - cohort 2), * Participants with R/R AML after having been previously treated with only first line venetoclax in combination with hypomethylating agent (VEN+HMA) (R/R AML - cohort 3).

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Conditions

Myelodysplastic Syndromes Acute Myeloid Leukemia

Interventions

SabatolimabDRUG

Solution for intravenous infusion

MagrolimabDRUG

Solution for intravenous infusion

AzacitidineDRUG

Solution for subcutaneous injection or intravenous infusion

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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. Newly diagnosed with AML based on 2016 WHO classification (Arber et al 2016) and not suitable for intensive chemotherapy defined as: age ≥75, ECOG performance Status 2 or 3, or any of the following comorbidities: severe cardiac comorbidity (including congestive heart failure, LVEF ≤ 50%, chronic stable Angina) , pulmonary comorbidity (DLCO ≤ 65% or FEVI ≤ 65%). moderate hepatic impairment (with total Bilirubin \>1.5 to 3x ULN) , renal impairment (eGFR≥ 30 ml/min/1.73m\^2 to 45 30 ml/min/1.73m\^2), or other comorbidity incompatible with intensive chemotherapy per Investigator assessment and approved by the Novartis Medical monitor) OR Morphologically confirmed diagnosis of myelodysplastic syndrome (MDS) based on 2016 WHO classification (Arber et al 2016), that is intermediate, high or very high risk (higher risk) based on the revised International Prognostic Scoring System (IPSS-R) (Greenberg et al 2012), previously untreated for higher risk MDS \[1L higher risk MDS\]: * Intermediate (\>3-4.5 points) * High (\> 4.5-6 points) * Very high (\> 6 points) OR (for expansion only) Participants with AML relapsed or refractory to venetoclax in combination with a hypomethylating agent (VEN+HMA) as defined by failure to achieve bone marrow blast \<5% after at least 2 cycles of VEN+HMA (refractory) or relapsed after having achieved BM blast \<5% following previous treatment with VEN+HMA as first and the only line of treatment for AML 4. Eastern Cooperative Oncology Group (ECOG) performance status must be 0-2 for participants ≥ 75 years of age, OR 0-3 for participants \< 75 years of age 5. White blood cell (WBC) count ≤ 20 x 10\^3/μL prior to first dose of study treatment (may be reduced with leukapheresis, hydroxyurea, or oral etoposide) 6. Hemoglobin ≥ 9 g/dL prior to initial dose of study treatment. Transfusions are allowed to meet hemoglobin eligibility prior to first dose of study treatment Exclusion Criteria: 1. Prior treatment with CD47 or signal regulatory protein alpha (SIRPα) targeting agents 2. Prior exposure to TIM-3 directed therapy 3. Prior therapy with immune checkpoint inhibitors (eg, anti-CTLA4, anti-PD-1, anti-PDL1, 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 the study treatment 4. For participants with higher risk MDS only: Previous first-line treatment for intermediate, high, very high risk (higher risk) MDS (based on IPSS-R) with any antineoplastic agents including for example chemotherapy and hypomethylating agents such as decitabine or azacitidine. For participants with newly diagnosed AML only: Previous treatment at any time, with any approved or investigational antineoplastic agents for AML or higher risk MDS. Prior and concurrent therapy with hydroxyurea or oral etoposide (to reduce WBC count), supportive care ruxolitinib, erythroid and/or myeloid growth factors are allowed. 5. Acute promyelocytic leukemia 6. Known inherited or acquired bleeding disorders 7. Patients with CNS leukemia or neurologic signs and symptoms suggestive of CNS leukemia (unless CNS leukemia had been excluded) Other protocol defined inclusion/exclusion criteria may apply

Outcomes

Primary Outcomes

Percentage of participants with dose limiting toxicities (only for participants enrolled in the safety run-in part)

Assessment of tolerability of sabatolimab and magrolimab given together with azacitidine

Time frame: Cycle 1 Day 1 to the end of Cycle 2 (up to 14 days from the planned cycle 3 Day 1) ; Cycle = 28 Days

Percentage of participants achieving complete remission (CR) according to Investigator assessment per treatment arm

Assessing the Complete Remission (CR) Rate in each treatment arm (including participants from safety run-in and expansion) per IWG -Cheson 2003 and ELN AML recommendations - Doehner 2017 (AML) and per modified IWG-MDS criteria- Cheson 2006 (MDS) in each treatment arm.

Time frame: Up to 4 years from last patient first treatment

Secondary Outcomes

Anti-drug-antibody prevalence at baseline

Measuring immunogenicity to sabatolimab and magrolimab prior to exposure

Time frame: prior to first dose of sabatolimab on week 2 Day 1 and first dose of magrolimab on week 1 day 1

Anti-drug-antibody prevalence on treatment

Measuring immunogenicity to sabatolimab and magrolimab on treatment and after treatment

Time frame: Throughout study until 90 day safety follow up for sabatolimab and 30 day safety follow up for magrolimab

Peak of Serum Concentration (Cmax) sabatolimab and magrolimab

Maximal serum concentration of sabatolimab and magrolimab

Time frame: Day 1 of week 2, 5, 13 for sabatolimab. Day 1 or week 1, 5, 13 for magrolimab

Trough serum concentration (Cmin) sabatolimab

Concentration of sabatolimab prior to next dosing or after end of treatment

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.