Sabatolimab as a Treatment for Patients With Acute Myeloid Leukemia and Presence of Measurable Residual Disease After Allogeneic Stem Cell Transplantation.

Study Overview
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Brief Summary
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The primary purpose of this study is to test the hypothesis that preemptive treatment with sabatolimab, alone or in combination with azacitidine, when administered to participants with AML/secondary AML who are in complete remission with positive measurable residual disease post-allogeneic hematopoietic stem cell transplantation (MRD+ post-aHSCT), can enhance the graft versus leukemia (GvL) response and prevent or delay hematologic relapse without an unacceptable level of treatment-emergent toxicities, including clinically significant acute and/or chronic graft-versus-host disease (GvHD) and immune-related adverse events

Detailed Description
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This is a phase Ib/II, open label, multi-center study of sabatolimab as monotherapy and in combination with azacitidine, in participants with AML/secondary AML who have received one aHSCT and achieved complete remission but MRD+, by local assessment, anytime between day 100 and day 365 post-aHSCT and at least 2 weeks after immunosuppressive medications have been tapered off. The study will enroll approximately 59 participants and will be conducted in two parts: Part 1 is a Safety Run-in of approximately 20 participants, to assess whether sabatolimab as monotherapy at the two tested dose levels (400 mg and 800 mg intravenously Q4W) is safe when administered in the post-aHSCT setting. For each dose level, once the required number of evaluable participants has been confirmed, enrollment will be halted until participants have completed the DLT observation period (≥ 8 weeks following the first dose). Following the observation period for DLTs, a Safety Review Meeting will be conducted after each dose level to assess safety and determine the recommended dose for expansion to proceed with enrollment of additional cohorts in Part 2 of the study. Part 2 consists of sabatolimab monotherapy expansion cohort of approximately 13 participants, sabatolimab in combination with azacitidine cohort of approximately 20 participants, and an adolescent cohort of approximately 6 participants (≥ 12 years but < 18 years of age) with sabatolimab as monotherapy. Sabatolimab will be administered at the recommended dose for expansion determined in Part 1.

Official Title
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A Phase Ib/II, Open Label Study of Sabatolimab as a Treatment for Patients With Acute Myeloid Leukemia and Presence of Measurable Residual Disease After Allogeneic Stem Cell Transplantation

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Biological: Sabatolimab
* Drug: Azacitidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent must be obtained prior to participation in the study. At the date of signing the informed consent form (ICF), eligible participants must be ≥ 18 years for the adult cohorts; and ≥ 12 years old but < 18 years old for the adolescent cohort (cohort 5), which will open after completion of Safety Run-in. Diagnosis of AML/secondary AML and received one prior aHSCT performed to control AML Participants in complete remission (< 5% bone marrow blasts, absence of circulating blasts, and absence of extramedullary disease) with measurable residual disease (MRD) positivity by local assessment, at any time between day 100 and day 365 after allogeneic stem cell transplantation. Ability to provide a fresh bone marrow aspirate sample collected within 28 days from enrollment/randomization, and immediately shipped to a Novartis designated central laboratory for MRD testing. Systemic GvHD (graft versus host disease) prophylaxis or treatment [immunosuppressive treatment (IST)] completely tapered for at least two weeks prior to study entry. Prednisone dose ≤ 5 mg/day or equivalent corticosteroid dose is allowed. Participants who are found with MRD positivity while still on or tapering systemic GvHD prophylaxis or treatment, MRD positivity must be re-confirmed at least 2 week after the last dose of IST For the adult cohorts, participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2. For the adolescent cohort, participants must have a Karnofsky (age ≥ 16 years) or Lansky (age < 16 years) performance status score ≥ 50%. Exclusion Criteria: Prior exposure to TIM-3 directed therapy at anytime. History of severe hypersensitivity reactions to any ingredient of study drug(s) (azacitidine, sabatolimab) or monoclonal antibodies (mAbs) and/or their excipients Active Hepatitis B (HBV) or Hepatitis C (HCV) infection. Participants whose disease is controlled under antiviral therapy should not be excluded. Active acute GvHD grade III-IV according to standard criteria (Harris 2016). Active moderate chronic GvHD of the lungs according to NIH consensus criteria. Active severe chronic GvHD according to NIH consensus criteria. History of another primary malignancy that is currently clinically significant or currently requires active intervention. Any concurrent severe and/or active uncontrolled infection requiring parenteral antibacterial, antiviral or antifungal therapy (such as severe pneumonia, meningitis, or septicemia) Active autoimmune disease requiring systemic therapy (e.g. corticosteroids). Topical, inhaled, nasal and ophthalmic steroids are not prohibited. Replacement corticosteroids therapy is allowed and not considered a form of systemic treatment Live vaccine administered within 30 days prior to the first day of study treatment (Cycle 1 Day 1) Other concurrent severe and/or uncontrolled medical conditions (e.g. uncontrolled diabetes mellitus, chronic obstructive or chronic restrictive pulmonary disease including dyspnoea at rest from any cause) or history of serious organ dysfunction or disease involving the heart, kidney, or liver Other protocol defined inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sabatolimab 400mg<br>Safety cohort 1: Participants in this arm will receive sabatolimab 400mg intravenously every 4 weeks. | Biological: Sabatolimab<br>* Sabatolimab is a solution in vial for IV infusion<br>* Other names: MBG453;|
| Experimental: Sabatolimab 800mg<br>Safety cohort 2: Participants in this arm will receive sabatolimab 800mg intravenously every 4 weeks. | Biological: Sabatolimab<br>* Sabatolimab is a solution in vial for IV infusion<br>* Other names: MBG453;|
| Experimental: Sabatolimab + Azacitidine<br>Expansion cohort 3: Participants in this arm will receive sabatolimab at the recommended dose for expansion in combination with azacitidine. | Biological: Sabatolimab<br>* Sabatolimab is a solution in vial for IV infusion<br>* Other names: MBG453;Drug: Azacitidine<br>* Azacitidine comes in Vial for IV infusion or subcutaneous administration<br>|
| Experimental: Sabatolimab<br>Expansion cohort 4: Participants in this arm will receive sabatolimab at the recommended dose for expansion. | Biological: Sabatolimab<br>* Sabatolimab is a solution in vial for IV infusion<br>* Other names: MBG453;|
| Experimental: Sabatolimab (adolescent cohort)<br>Adolescent safety cohort (cohort 5): ≥12 to < 18 year old adolescent participants in this arm will receive sabatolimab at the recommended dose for expansion. | Biological: Sabatolimab<br>* Sabatolimab is a solution in vial for IV infusion<br>* Other names: MBG453;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose limiting toxicities (Safety Run-in in adult cohorts 1 and 2 only) | Assessment of tolerability of sabatolimab in adults in the post allogenic stem cell transplantation setting | From Cycle 1 Day 1 to end of Cycle 2; Cycle =28 Days | 
| Percentage of adult subjects with absence of hematologic relapse per Investigator assessment (Safety Run-in and Expansion) | Assessment of Complete Remission Maintenance Rate (no evidence of bone marrow blasts ≥5%; no evidence of reappearance of blasts in the blood; no evidence of development of extramedullary disease) | From cycle 1day 1 to end of cycle 6, cycle =28 Days) | 
| Incidence of dose limiting toxicities (Safety confirmation in adolescent cohort 5 only) | Assessment of tolerability of sabatolimab in adolescent patients in the post allogeneic stem cell transplantation setting | From Cycle 1 Day 1 to end of Cycle 2; Cycle =28 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of grade III or IV acute Graft versus Host Disease (aGvHD) | Assessment of the treatment emergent grade III or IV aGvHD. | From start of treatment to up to 36 months from last patient first treatment. | 
| Incidence of moderate to severe Chronic GVHD (cGvHD) | Assessment of the treatment emergent moderate or severe cGvHD. | From start of treatment to up to 36 months from last patient first treatment. | 
| Peak of Serum Concentration (Cmax) sabatolimab | Maximal serum concentration of sabatolimab | Cycle 1 day1 or day 5 (end of infusion) and cycle 3 day 1 or day 5(end of infusion) for adult cohorts and cycle 1 day 1 (end of infusion) and cycle 3 day 1(end of infusion) for adolescent cohort, cycle =28 days | 
| Trough serum concentration (Cmin) sabatolimab | Concentration of sabatolimab prior to next dosing or after end of treatment. | Day 1 or Day 5 of cycle 1, 3, 6 and 24 for adult cohorts and day 1 of Cycle 1, 2, 3, 6, 9, 12, 18 and 24 for adolescent cohort, and through treatment completion, an average of 15 months; cycle=28 days | 
| Anti-drug antibody (ADA) prevalence on-treatment | Immunogenicity to sabatolimab on treatment and after treatment. | Throughout study until 150 day safety follow-up | 
| ADA prevalence at baseline | Immunogenicity to sabatolimab prior to sabatolimab exposure | prior to first dose of sabatolimab on cycle 1 cycle= 28 days | 
| Time from start of treatment to the date of first documented GvHD- free/ relapse- free survival | Time from start of treatment to the date of first documented occurrence or worsening of treatment emergent grade III or IV aGvHD or moderate to severe cGvHD requiring initiation of systemic treatment, morphologic/hematologic relapse, or death due to any cause, whichever occurs first | Every 2 weeks until week 9 then every 4 weeks until week 25, and then every 8 weeks until end of treatment, and then every 12 weeks for up to 36 months from last patient first treatment. | 
| Time from start of treatment to the date of first documented hematologic relapse or death due to any cause, whichever occurs first | Time to relapse from complete remission (CR/CRi) or death whichever occurs first | Every 4 weeks (starting on week 5) until week 13, then every 12 weeks until week 49 and every 24 weeks thereafter up to 36 months from last patient first treatment | 
| Incidence of grade 3 immune-related adverse events not attributed to GvHD | Assessment of severe immune-related adverse events not attributed to GvHD | Throughout the study until 150 day safety follow up period | 
| Percentage of participants with measurable residual disease (MRD) positive at baseline who become MRD negative | MRD conversion rate | From start of treatment until end of cycle 6 (cycle = 28 Days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sabatolimab, MBG453, TIM-3, Azacitidine, Acute Myeloid Leukemia, AML, aHSCT, Allogeneic Hematopoietic Stem Cell Transplantation, Measurable Residual Disease, MRD, Phase Ib/II, Acute myeloid leukemia Hematopoietic stem cell transplantation