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

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ClinicalTrials.gov Identifier: NCT03940352
Recruitment Status : Recruiting
First Posted : May 7, 2019
Last Update Posted : October 16, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE May 2, 2019
First Posted Date  ICMJE May 7, 2019
Last Update Posted Date October 16, 2019
Actual Study Start Date  ICMJE June 24, 2019
Estimated Primary Completion Date April 22, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 6, 2019)
  • Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) as a measure of safety [ Time Frame: at month 24 ]
    Month 24 is assumed to be study end
  • Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) as a measure of safety [ Time Frame: at month 24 ]
    Month 24 is assumed to be study end
  • Incidence of dose limiting toxicities (DLTs) of treatment [ Time Frame: at day 28 ]
    end of first cycle
  • Frequency of dose interuptions [ Time Frame: at month 24 ]
    Month 24 is assumed to be study end
  • Frequency of dose reductions [ Time Frame: at month 24 ]
    Month 24 is assumed to be study end
  • Dose intensities [ Time Frame: at month 24 ]
    measured in mg/ day Month 24 is assumed to be study end
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03940352 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 6, 2019)
  • Overall Response Rate (ORR) [ Time Frame: at month 24 ]
    Month 24 is assumed to be study end
  • Best Overall Response (BOR) [ Time Frame: at month 24 ]
    Month 24 is assumed to be study end
  • Event Free Survival (EFS) for AML (Cheson 2003) or Progression Free Survival (PFS) for MDS (Cheson 2006) [ Time Frame: at month 24 ]
    Month 24 is assumed to be study end
  • Relapse Free Survival (RFS) for AML (Cheson 2003) or Time To Response (TTR) for MDS (Cheson 2006) [ Time Frame: at month 24 ]
    Month 24 is assumed to be study end
  • Duration Of Response (DOR) for AML (Cheson 2003) and MDS (Cheson 2006) [ Time Frame: at month 24 ]
    Month 24 is assumed to be study end
  • Presence of anti-MBG453 antibodies (treatment arm 1 HD201+MBG453) [ Time Frame: at Day 1, Day 29 and at month 24 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • PK parameter (AUC) of HDM201 (Treatment arm 1 HDM201+MBG453 and treatment arm 2 HDM201+venetoclax) [ Time Frame: at month 6 ]
    Cycle 6
  • PK parameter (Cmax) of HDM201 (Treatment arm 1 HDM201+MBG453 and treatment arm 2 HDM201+venetoclax) [ Time Frame: at month 6 ]
    Cycle 6
  • PK parameter (Tmax) of HDM201 (Treatment arm 1 HDM201+MBG453 and treatment arm 2 HDM201+venetoclax) [ Time Frame: at month 6 ]
    Cycle 6
  • PK parameter (AUC) of MBG453 (treatment arm 1 HDM201+MBG453) [ Time Frame: at month 6 ]
    Cycle 6
  • PK parameter (Cmax) of MBG453 (treatment arm 1 HDM201+MBG453) [ Time Frame: at month 6 ]
    Cycle 6
  • PK parameter (Tmax) of MBG453 (treatment arm 1 HDM201+MBG453) [ Time Frame: at month 6 ]
    Cycle 6
  • PK parameter (AUC) of venetoclax (treatment arm 2 HDM201+venetoclax) [ Time Frame: at month 6 ]
    Cycle 6
  • PK parameter (Cmax) of venetoclax (treatment arm 2 HDM201+venetoclax) [ Time Frame: at month 6 ]
    Cycle 6
  • PK parameter (Tmax) of venetoclax (treatment arm 2 HDM201+venetoclax) [ Time Frame: at month 6 ]
    Cycle 6
  • 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 ]
  • Changes from baseline in soluble TIM-3 (Treatment arm 1 HDM201+MBG453) [ Time Frame: at month 6 ]
    Cycle 6
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE HDM201 in Combination With MBG453 or Venetoclax in Patients With Acute Myeloid Leukemia (AML) or High-risk Myelodysplastic Syndrome (MDS)
Official Title  ICMJE 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)
Brief Summary

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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Acute Myeloid Leukemia (AML)
  • High-risk Myelodysplastic Syndrome (MDS)
Intervention  ICMJE
  • Drug: HDM201
    Capsule
  • Biological: MBG453
    LIVI (Liquid in vial) Concentrate for Solution for infusion
  • Drug: Venetoclax
    Tablet
Study Arms  ICMJE
  • Experimental: treatment arm1: HDM201+MBG453
    Phase Ib (escalation)
    Interventions:
    • Drug: HDM201
    • Biological: MBG453
  • Experimental: treatment arm2: HDM201+venetoclax
    Phase Ib (escalation)
    Interventions:
    • Drug: HDM201
    • Drug: Venetoclax
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 6, 2019)
80
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 22, 2021
Estimated Primary Completion Date April 22, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Novartis Pharmaceuticals 1-888-669-6682 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111
Listed Location Countries  ICMJE Australia,   Finland,   Singapore,   Spain,   Switzerland
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03940352
Other Study ID Numbers  ICMJE CHDM201H12101C
2018-004001-62 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Novartis
Verification Date October 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP