Clinical Trials /

HDM201 in Combination With MBG453 or Venetoclax in Patients With Acute Myeloid Leukemia (AML) or High-risk Myelodysplastic Syndrome (MDS)

NCT03940352

Description:

This is a phase 1b, multi-arm, open-label study of HDM201 in combination with MBG453 or venetoclax in subjects with AML or high-risk MDS. For all subjects, TP53wt status must be characterized by, at a minimum, no mutations noted in exons 5, 6, 7 and 8. Two treatment arms will enroll subjects in parallel to characterize the safety, tolerability, PK, PD and preliminary antitumor activity of HDM201+MBG453 (treatment arm 1) and HDM201+venetoclax (treatment arm 2). - In the treatment arm 1, subjects will receive HDM201 in combination with MBG453. - In the treatment arm 2, subjects will receive HDM201 in combination with venetoclax. Venetoclax dose will be gradually increased (ramp-up) over a period of 4 to 5 days to achieve the daily target dose tested that will be subsequently continued. Upon the completion of the escalation part, MTD(s) and/or RD(s) of HDM201 in combination with MBG453 or venetoclax in AML and high-risk MDS subjects will be determined for each treatment arm.

Related Conditions:
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: HDM201 in Combination With MBG453 or Venetoclax in Patients With Acute Myeloid Leukemia (AML) or High-risk Myelodysplastic Syndrome (MDS)
  • Official Title: A Phase Ib, Multi-arm, Open-label, Study of HDM201 in Combination With MBG453 or Venetoclax in Adult Subjects With Acute Myeloid Leukemia (AML) or High-risk Myelodysplastic Syndrome (MDS)

Clinical Trial IDs

  • ORG STUDY ID: CHDM201H12101C
  • SECONDARY ID: 2018-004001-62
  • NCT ID: NCT03940352

Conditions

  • Acute Myeloid Leukemia (AML)
  • High-risk Myelodysplastic Syndrome (MDS)

Interventions

DrugSynonymsArms
HDM201treatment arm1: HDM201+MBG453
MBG453treatment arm1: HDM201+MBG453
Venetoclaxtreatment arm2: HDM201+venetoclax

Purpose

This is a phase 1b, multi-arm, open-label study of HDM201 in combination with MBG453 or venetoclax in subjects with AML or high-risk MDS. For all subjects, TP53wt status must be characterized by, at a minimum, no mutations noted in exons 5, 6, 7 and 8. Two treatment arms will enroll subjects in parallel to characterize the safety, tolerability, PK, PD and preliminary antitumor activity of HDM201+MBG453 (treatment arm 1) and HDM201+venetoclax (treatment arm 2). - In the treatment arm 1, subjects will receive HDM201 in combination with MBG453. - In the treatment arm 2, subjects will receive HDM201 in combination with venetoclax. Venetoclax dose will be gradually increased (ramp-up) over a period of 4 to 5 days to achieve the daily target dose tested that will be subsequently continued. Upon the completion of the escalation part, MTD(s) and/or RD(s) of HDM201 in combination with MBG453 or venetoclax in AML and high-risk MDS subjects will be determined for each treatment arm.

Trial Arms

NameTypeDescriptionInterventions
treatment arm1: HDM201+MBG453ExperimentalPhase Ib (escalation)
  • HDM201
  • MBG453
treatment arm2: HDM201+venetoclaxExperimentalPhase Ib (escalation)
  • HDM201
  • Venetoclax

Eligibility Criteria

        Main Inclusion Criteria:

          -  Male or female patients ≥ 18 years of age at the date of ICF signature who present
             with one of the following:

               1. Relapsed/refractory AML following ≥1 prior therapies (but ≤3 prior therapies) who
                  have relapsed or exhibited refractory disease (primary failure) and are deemed by
                  the Investigator not to be candidates for standard therapy, including
                  re-induction with cytarabine or other established chemotherapy regimens for
                  patients with AML (patients who are suitable for standard re-induction
                  chemotherapy or hematopoietic stem cell transplantation and willing to receive it
                  are excluded)

               2. First line AML patient unfit for standard induction chemotherapy (includes both
                  de novo and secondary AML), except in countries where approved therapies are
                  available. Patients who are suitable for hematopoietic stem cell transplantation
                  and willing to receive it are excluded.

               3. High-risk MDS patient (high and very high-risk groups according to rIPSS) who
                  have failed hypomethylating agent therapy.

          -  ECOG performance status ≤ 1

          -  TP53wt tumor. At minimum exons 5, 6, 7 and 8 in the TP53 gene must be sequenced and
             determined to contain no mutations. The TP53 status must be obtained from a
             bone-marrow sample, collected no longer than 3 months before signing the main ICF.

          -  Patient must be a candidate for serial bone marrow aspirate and/or biopsy according to
             the institutional guidelines and be willing to undergo a bone marrow aspirate and/or
             biopsy at screening, during and at the end of therapy on this study. Exceptions may be
             considered after documented discussion with Novartis.

        Main Exclusion Criteria:

        Patients eligible for this study must not meet any of the following criteria:

          -  Prior combination treatment with compounds having the same mode of action:

               -  mdm2 or mdm4 inhibitors combined with TIM-3 inhibitors (for patients enrolled in
                  treatment arm1)

               -  mdm2 or mdm4 inhibitors combined with Bcl-2 inhibitor (for patients enrolled in
                  treatment arm2)

          -  History of severe hypersensitivity reactions to any ingredient of study drug(s) and
             other monoclonal antibodies (mAbs) and/or their excipients.

          -  Patients with acute promyelocytic leukemia with PML-RARA.

          -  Allogeneic stem cell transplant (HSCT) within last 6 months and/or active GvHD
             requiring systemic immunosuppressive therapy.

          -  GI disorders impacting absorption of oral HDM201 or venetoclax.

          -  Evidence of active bleeding or bleeding diathesis or major coagulopathy (including
             familial).

          -  Patients with active, known or suspected autoimmune disease (treatment arm 1 only).

        Other eligibility criteria apply.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) as a measure of safety
Time Frame:at month 24
Safety Issue:
Description:Month 24 is assumed to be study end

Secondary Outcome Measures

Measure:Overall Response Rate (ORR)
Time Frame:at month 24
Safety Issue:
Description:Month 24 is assumed to be study end
Measure:Best Overall Response (BOR)
Time Frame:at month 24
Safety Issue:
Description:Month 24 is assumed to be study end
Measure:Event Free Survival (EFS) for AML (Cheson 2003) or Progression Free Survival (PFS) for MDS (Cheson 2006)
Time Frame:at month 24
Safety Issue:
Description:Month 24 is assumed to be study end
Measure:Relapse Free Survival (RFS) for AML (Cheson 2003) or Time To Response (TTR) for MDS (Cheson 2006)
Time Frame:at month 24
Safety Issue:
Description:Month 24 is assumed to be study end
Measure:Duration Of Response (DOR) for AML (Cheson 2003) and MDS (Cheson 2006)
Time Frame:at month 24
Safety Issue:
Description:Month 24 is assumed to be study end
Measure:Presence of anti-MBG453 antibodies (treatment arm 1 HD201+MBG453)
Time Frame:at Day 1, Day 29 and at month 24
Safety Issue:
Description:
Measure:Concentration of HDM201 (Treatment arm 1 HDM201+MBG453 and treatment arm 2 HDM201+venetoclax)
Time Frame:at Day 1, Day 2, Day 5, Day 6 and Day 29
Safety Issue:
Description:
Measure:Concentration of MBG453 (treatment arm 1 HDM201+MBG453)
Time Frame:at Day 1, Day 2, Day 8, Day 11, Day 15, Day 29 and at month 24
Safety Issue:
Description:
Measure:Concentration of venetoclax (treatment arm 2 HDM201+venetoclax)
Time Frame:at Day 1, Day 2, Day 3, Day 5, Day 6, Day 8, Day 9, Day 14, Day 15 and Day 29
Safety Issue:
Description:
Measure:PK parameter (AUC) of HDM201 (Treatment arm 1 HDM201+MBG453 and treatment arm 2 HDM201+venetoclax)
Time Frame:at month 6
Safety Issue:
Description:Cycle 6
Measure:PK parameter (Cmax) of HDM201 (Treatment arm 1 HDM201+MBG453 and treatment arm 2 HDM201+venetoclax)
Time Frame:at month 6
Safety Issue:
Description:Cycle 6
Measure:PK parameter (Tmax) of HDM201 (Treatment arm 1 HDM201+MBG453 and treatment arm 2 HDM201+venetoclax)
Time Frame:at month 6
Safety Issue:
Description:Cycle 6
Measure:PK parameter (AUC) of MBG453 (treatment arm 1 HDM201+MBG453)
Time Frame:at month 6
Safety Issue:
Description:Cycle 6
Measure:PK parameter (Cmax) of MBG453 (treatment arm 1 HDM201+MBG453)
Time Frame:at month 6
Safety Issue:
Description:Cycle 6
Measure:PK parameter (Tmax) of MBG453 (treatment arm 1 HDM201+MBG453)
Time Frame:at month 6
Safety Issue:
Description:Cycle 6
Measure:PK parameter (AUC) of venetoclax (treatment arm 2 HDM201+venetoclax)
Time Frame:at month 6
Safety Issue:
Description:Cycle 6
Measure:PK parameter (Cmax) of venetoclax (treatment arm 2 HDM201+venetoclax)
Time Frame:at month 6
Safety Issue:
Description:Cycle 6
Measure:PK parameter (Tmax) of venetoclax (treatment arm 2 HDM201+venetoclax)
Time Frame:at month 6
Safety Issue:
Description:Cycle 6
Measure:Changes from baseline in GDF-15 (Treatment arm 1 HDM201+MBG453 and treatment arm 2 HDM201+venetoclax)
Time Frame:at Day 1 and Day 2
Safety Issue:
Description:
Measure:Changes from baseline in soluble TIM-3 (Treatment arm 1 HDM201+MBG453)
Time Frame:at month 6
Safety Issue:
Description:Cycle 6

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Novartis Pharmaceuticals

Trial Keywords

  • Phase Ib
  • BHLRM
  • AML
  • MDS
  • HDM201
  • TP53
  • MBG453
  • TIM-3
  • venetoclax
  • Bcl-2

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