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

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

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

Study Overview

• Status: Active, not recruiting
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Biological: Sabatolimab; Drug: Azacitidine

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 27
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Novartis Pharmaceuticals; Phone Number: 1-888-669-6682; Email: novartis.email@novartis.com
• Study Contact Backup: Name: Novartis Pharmaceuticals; Phone Number: +41613241111

Study Locations

• France
  • Marseille, France, 13273
    • Novartis Investigative Site
• Germany
  • Freiburg, Germany, 79106
    • Novartis Investigative Site
  • Hamburg, Germany, 20246
    • Novartis Investigative Site
  • Leipzig, Germany, 04103
    • Novartis Investigative Site
  • Muenster, Germany, 48149
    • Novartis Investigative Site
• Italy
  • BG
    • Bergamo, BG, Italy, 24128
      • Novartis Investigative Site
  • BO
    • Bologna, BO, Italy, 40138
      • Novartis Investigative Site
  • BS
    • Brescia, BS, Italy, 25123
      • Novartis Investigative Site
  • RM
    • Roma, RM, Italy, 00165
      • Novartis Investigative Site
• Spain
  • Las Palmas de Gran Canaria, Spain, 35010
    • Novartis Investigative Site
  • Madrid, Spain, 28009
    • Novartis Investigative Site
  • Castilla Y Leon
    • Salamanca, Castilla Y Leon, Spain, 37007
      • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 99 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Signed informed consent must be obtained prior to participation in the study.
2. 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.
3. Diagnosis of AML/secondary AML and received one prior aHSCT performed to control AML
4. 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.
5. 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.
6. 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.
7. 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
8. 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:

1. Prior exposure to TIM-3 directed therapy at anytime.
2. History of severe hypersensitivity reactions to any ingredient of study drug(s) (azacitidine, sabatolimab) or monoclonal antibodies (mAbs) and/or their excipients
3. Active Hepatitis B (HBV) or Hepatitis C (HCV) infection. Participants whose disease is controlled under antiviral therapy should not be excluded.
4. Active acute GvHD grade III-IV according to standard criteria (Harris 2016).
5. Active moderate chronic GvHD of the lungs according to NIH consensus criteria. Active severe chronic GvHD according to NIH consensus criteria.
6. History of another primary malignancy that is currently clinically significant or currently requires active intervention.
7. Any concurrent severe and/or active uncontrolled infection requiring parenteral antibacterial, antiviral or antifungal therapy (such as severe pneumonia, meningitis, or septicemia)
8. 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
9. Live vaccine administered within 30 days prior to the first day of study treatment (Cycle 1 Day 1)
10. 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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sabatolimab 400mg; Safety cohort 1: Participants in this arm will receive sabatolimab 400mg intravenously every 4 weeks.	Biological: Sabatolimab; Sabatolimab is a solution in vial for IV infusion; Other Names: MBG453
Experimental: Sabatolimab 800mg; Safety cohort 2: Participants in this arm will receive sabatolimab 800mg intravenously every 4 weeks.	Biological: Sabatolimab; Sabatolimab is a solution in vial for IV infusion; Other Names: MBG453
Experimental: Sabatolimab + Azacitidine; Expansion cohort 3: Participants in this arm will receive sabatolimab at the recommended dose for expansion in combination with azacitidine.	Biological: Sabatolimab; Sabatolimab is a solution in vial for IV infusion; Other Names: MBG453; Drug: Azacitidine; Azacitidine comes in Vial for IV infusion or subcutaneous administration
Experimental: Sabatolimab; Expansion cohort 4: Participants in this arm will receive sabatolimab at the recommended dose for expansion.	Biological: Sabatolimab; Sabatolimab is a solution in vial for IV infusion; Other Names: MBG453
Experimental: Sabatolimab (adolescent cohort); 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; Sabatolimab is a solution in vial for IV infusion; Other Names: MBG453

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): September 14, 2021
• Primary Completion (Estimated): November 7, 2024
• Study Completion (Estimated): April 1, 2027

Study Registration Dates

• First Submitted: November 3, 2020
• First Submitted That Met QC Criteria: November 9, 2020
• First Posted (Actual): November 10, 2020

Study Record Updates

• Last Update Posted (Actual): March 15, 2024
• Last Update Submitted That Met QC Criteria: March 14, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Acute Myeloid Leukemia; AML; TIM-3; Azacitidine; MBG453; Allogeneic Hematopoietic Stem Cell Transplantation; MRD; Phase Ib/II; Sabatolimab; aHSCT; Measurable Residual Disease; Acute myeloid leukemia Hematopoietic stem cell transplantation
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Neoplastic Processes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Neoplasm, Residual; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Azacitidine
• Other Study ID Numbers: CMBG453F12201; 2020-000869-17 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data is currently available according to the process described on www.clinicalstudydatarequest.com.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No