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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04623216
Recruitment Status : Recruiting
First Posted : November 10, 2020
Last Update Posted : December 15, 2021
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
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

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Biological: Sabatolimab Drug: Azacitidine Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 59 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : September 14, 2021
Estimated Primary Completion Date : June 11, 2024
Estimated Study Completion Date : November 3, 2026


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 Name: 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 Name: 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 Name: 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 Name: 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 Name: MBG453




Primary Outcome Measures :
  1. Incidence of dose limiting toxicities (Safety Run-in in adult cohorts 1 and 2 only) [ Time Frame: From Cycle 1 Day 1 to end of Cycle 2; Cycle =28 Days ]
    Assessment of tolerability of sabatolimab in adults in the post allogenic stem cell transplantation setting

  2. Percentage of adult subjects with absence of hematologic relapse per Investigator assessment (Safety Run-in and Expansion) [ Time Frame: From cycle 1day 1 to end of cycle 6, cycle =28 Days) ]
    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)

  3. Incidence of dose limiting toxicities (Safety confirmation in adolescent cohort 5 only) [ Time Frame: From Cycle 1 Day 1 to end of Cycle 2; Cycle =28 Days ]
    Assessment of tolerability of sabatolimab in adolescent patients in the post allogeneic stem cell transplantation setting


Secondary Outcome Measures :
  1. Incidence of grade III or IV acute Graft versus Host Disease (aGvHD) [ Time Frame: From start of treatment to up to 36 months from last patient first treatment. ]
    Assessment of the treatment emergent grade III or IV aGvHD.

  2. Incidence of moderate to severe Chronic GVHD (cGvHD) [ Time Frame: From start of treatment to up to 36 months from last patient first treatment. ]
    Assessment of the treatment emergent moderate or severe cGvHD.

  3. Peak of Serum Concentration (Cmax) sabatolimab [ Time Frame: 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 ]
    Maximal serum concentration of sabatolimab

  4. Trough serum concentration (Cmin) sabatolimab [ Time Frame: 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 ]
    Concentration of sabatolimab prior to next dosing or after end of treatment.

  5. Anti-drug antibody (ADA) prevalence on-treatment [ Time Frame: Throughout study until 150 day safety follow-up ]
    Immunogenicity to sabatolimab on treatment and after treatment.

  6. ADA prevalence at baseline [ Time Frame: prior to first dose of sabatolimab on cycle 1 cycle= 28 days ]
    Immunogenicity to sabatolimab prior to sabatolimab exposure

  7. Time from start of treatment to the date of first documented GvHD- free/ relapse- free survival [ Time Frame: 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 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

  8. Time from start of treatment to the date of first documented hematologic relapse or death due to any cause, whichever occurs first [ Time Frame: 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 ]
    Time to relapse from complete remission (CR/CRi) or death whichever occurs first

  9. Incidence of grade 3 immune-related adverse events not attributed to GvHD [ Time Frame: Throughout the study until 150 day safety follow up period ]
    Assessment of severe immune-related adverse events not attributed to GvHD

  10. Percentage of participants with measurable residual disease (MRD) positive at baseline who become MRD negative [ Time Frame: From start of treatment until end of cycle 6 (cycle = 28 Days) ]
    MRD conversion rate



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   12 Years to 99 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04623216


Contacts
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Contact: Novartis Pharmaceuticals 1-888-669-6682 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111

Locations
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France
Novartis Investigative Site Recruiting
Paris Cedex 10, France, 75475
Germany
Novartis Investigative Site Recruiting
Freiburg, Germany, 79106
Novartis Investigative Site Recruiting
Hamburg, Germany, 20246
Novartis Investigative Site Recruiting
Muenster, Germany, 48149
Italy
Novartis Investigative Site Recruiting
Bergamo, BG, Italy, 24128
Novartis Investigative Site Recruiting
Bologna, BO, Italy, 40138
Spain
Novartis Investigative Site Recruiting
Barcelona, Catalunya, Spain, 08035
Novartis Investigative Site Recruiting
Las Palmas de Gran Canaria, Spain, 35010
Novartis Investigative Site Recruiting
Madrid, Spain, 28009
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT04623216    
Other Study ID Numbers: CMBG453F12201
2020-000869-17 ( EudraCT Number )
First Posted: November 10, 2020    Key Record Dates
Last Update Posted: December 15, 2021
Last Verified: December 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.

URL: http://www.clinicalstudydatarequest.com

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
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
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Azacitidine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors