The primary purpose of this study was to test the hypothesis that preemptive treatment with sabatolimab, alone or in combination with azacitidine, when administered to participants with Acute myeloid leukemia (AML)/secondary AML who were in complete remission with positive measurable residual disease post-allogeneic hematopoietic stem cell transplantation (Minimal residual disease (MRD)+ post- Allogeneic hematopoietic stem cell transplantation (aHSCT)), could 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
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 had received one aHSCT and achieved complete remission but MRD+, by local assessment, anytime at \>= Day 60 after aHSCT and at least 2 weeks after immunosuppressive medications had been tapered off. The study was planned to enroll approximately 59 participants and be conducted in two parts: Part 1 was 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) was safe when administered in the post-aHSCT setting. For each dose level, once the required number of evaluable participants had been confirmed, enrollment would be halted until participants had completed the dose limiting toxicities (DLT) observation period (≥ 8 weeks following the first dose). Following the observation period for DLTs, a Safety Review Meeting was to 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 consisted 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 was to be administered at the recommended dose for expansion determined in Part 1. After initiating Part 2, Novartis took the decision to put enrollment in permanent halt and terminate the sabatolimab program. This decision was not driven by any safety concerns.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
24
Sabatolimab is a solution in vial for IV infusion
Azacitidine comes in Vial for IV infusion or subcutaneous administration
Novartis Investigative Site
Marseille, France
Novartis Investigative Site
Freiburg im Breisgau, Germany
Novartis Investigative Site
Hamburg, Germany
Novartis Investigative Site
Münster, Germany
Novartis Investigative Site
Bergamo, BG, Italy
Novartis Investigative Site
Bologna, BO, Italy
Novartis Investigative Site
Brescia, BS, Italy
Novartis Investigative Site
Roma, RM, Italy
Novartis Investigative Site
Barcelona, Catalonia, Spain
Rate of Dose Limiting Toxicities (Safety Run-in in Adult Sabatolimab 400mg & 800mg Only)
Assessment of tolerability of sabatolimab in adults and adolescents in the post allogenic stem cell transplantation setting. This was determined by the number of participants with at least one event - All grades. 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 that occurs during the DLT observation period and meets the severity criteria as per protocol.
Time frame: 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)
The percentage of adult participants for whom no evidence of hematologic relapse (no evidence of bone marrow blasts ≥5%, no evidence of reappearance of blasts in the blood; no evidence of development of extramedullary disease) has been documented after 6 cycles of study treatment or earlier discontinuation at the recommended dose of sabatolimab 800 mg.
Time frame: From Cycle 1 Day 1 to end of Cycle 6; Cycle = 28 Days
Rate of Dose Limiting Toxicities (Safety Confirmation in Adolescent Cohort Only)
Assessment of tolerability of sabatolimab in adolescent participants in the post allogeneic stem cell transplantation setting. This was determined by the number of participants with at least one event - All grades. 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 that occurs during the DLT observation period and meets the severity criteria as per protocol.
Time frame: From Cycle 1 Day 1 to end of Cycle 2; Cycle =28 Days
Incidence of Grade III or IV Acute Graft Versus Host Disease (aGvHD)
Assessment of the treatment emergent grade III or IV aGvHD. Acute GvHD: Grade IV acute GvHD, Stage ≥3 lower GI acute GvHD (consistent with Grade III acute GvHD) or Stage ≥3 liver acute GvHD (consistent with Grade III GvHD).
Time frame: 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. Chronic GvHD: Moderate chronic GvHD of the lungs, Severe chronic GvHD.
Time frame: From start of treatment to up to 36 months from last patient first treatment.
Peak of Serum Concentration (Cmax) Sabatolimab
Cmax is the maximal serum concentration of sabatolimab.
Time frame: Cycle 1 Day 5 (end of infusion) and Cycle 3 Day 1 or Day 5 (end of infusion) and Cycle 24 Day 1 (end of infusion); Cycle =28 Days
Trough Serum Concentration of (Cmin) Sabatolimab
Cmin is the concentration of sabatolimab prior to next dosing or after end of treatment.
Time frame: Adult cohorts: Pre-dose on Day 1 (safety run-in) or Day 5 (expansion) of Cycle 1, 3, 6 and 24 (safety run-in only); Adolescent cohort: Pre-dose on Day 1 of Cycle 1, 2, 3 and 6; Cycle = 28 Days
Graft Versus Host Disease (GvHD)-Free/Relapse-free Survival (GRFS)
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
Time frame: From start of treatment to up to 36 months from last patient first treatment
Relapse-free Survival (RFS)
Time from start of treatment to the date of first documented hematologic relapse or death due to any cause, whichever occurs first.
Time frame: From start of treatment to up to 36 months from last patient first treatment
Percentage of Participants With Measurable Residual Disease (MRD) Positive at Baseline Who Become MRD Negative
Percentage of participants with centrally confirmed MRD+ status at baseline converting to MRD- within the first 6 cycles of study treatment.
Time frame: From start of treatment until end of Cycle 6 (Cycle = 28 Days)
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