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

NCT03940352 | Terminated Phase 1 FDA Drug

• 2 other identifiers: CHDM201H12101C2018-004001-62
• Study Type: interventional
• Target: 52
• Locations: 7 countries
• Sites: 9

Brief Summary

This was 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 had to be characterized by, at a minimum, no mutations noted in exons 5, 6, 7 and 8. Two treatment arms enrolled 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 received HDM201 in combination with MBG453.
• In the treatment arm 2, subjects received HDM201 in combination with venetoclax. Venetoclax dose was gradually increased (ramp-up) over a period of 4 to 5 days to achieve the daily target dose tested that was 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 was planned to be determined for each treatment arm.

Conditions

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

Keywords

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

Outcome Measures

Primary Outcomes (6)

• Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) as a measure of safety

  Month 24 is assumed to be study end

  at month 24

• Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) as a measure of safety

  Month 24 is assumed to be study end

  at month 24

• Incidence of dose limiting toxicities (DLTs) of treatment

  end of first cycle

  at day 28

• Frequency of dose interuptions

  Month 24 is assumed to be study end

  at month 24

• Frequency of dose reductions

  Month 24 is assumed to be study end

  at month 24

• Dose intensities

  measured in mg/ day Month 24 is assumed to be study end

  at month 24

Secondary Outcomes (20)

• Overall Response Rate (ORR)

  at month 24

• Best Overall Response (BOR)

  at month 24

• Event Free Survival (EFS) for AML (Cheson 2003) or Progression Free Survival (PFS) for MDS (Cheson 2006)

  at month 24

• Relapse Free Survival (RFS) for AML (Cheson 2003) or Time To Response (TTR) for MDS (Cheson 2006)

  at month 24

• Duration Of Response (DOR) for AML (Cheson 2003) and MDS (Cheson 2006)

  at month 24

Study Arms (2)

treatment arm1: HDM201+MBG453

EXPERIMENTAL

Phase Ib (escalation)

Drug: HDM201; Biological: MBG453

treatment arm2: HDM201+venetoclax

EXPERIMENTAL

Phase Ib (escalation)

Drug: HDM201; Drug: Venetoclax

Interventions

HDM201 DRUG

Capsule

treatment arm1: HDM201+MBG453; treatment arm2: HDM201+venetoclax

MBG453 BIOLOGICAL

LIVI (Liquid in vial) Concentrate for Solution for infusion

treatment arm1: HDM201+MBG453

Venetoclax DRUG

Tablet

treatment arm2: HDM201+venetoclax

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (9)

Duke University Medical Center .

Durham, North Carolina, 27710, United States

Location

Novartis Investigative Site

Melbourne, Victoria, 3004, Australia

Location

Novartis Investigative Site

Helsinki, FIN 00290, Finland

Location

Novartis Investigative Site

Heidelberg, 69120, Germany

Location

Novartis Investigative Site

Würzburg, 97080, Germany

Location

Novartis Investigative Site

Milan, MI, 20132, Italy

Location

Novartis Investigative Site

Roma, RM, 00161, Italy

Location

Novartis Investigative Site

Singapore, 119228, Singapore

Location

Novartis Investigative Site

Madrid, 28041, Spain

Location

Related Links

• Link to study results
• A Plain Language Trial Summary is available on www.novctrd.com

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

siremadlin; sabatolimab; venetoclax

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 2, 2019
• First Posted: May 7, 2019
• Study Start: June 24, 2019
• Primary Completion: August 20, 2024
• Study Completion: August 20, 2024
• Last Updated: October 10, 2025

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will not share

Locations

IT (2); SG (1); US (1); FI (1); AU (1); ES (1); DE (2)