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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/study/NCT03940352
Registration number
NCT03940352
Ethics application status
Date submitted
2/05/2019
Date registered
7/05/2019
Date last updated
3/07/2024
Titles & IDs
Public title
HDM201 in Combination With MBG453 or Venetoclax in Patients With Acute Myeloid Leukemia (AML) or High-risk Myelodysplastic Syndrome (MDS)
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Scientific 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)
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Secondary ID [1]
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2018-004001-62
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Secondary ID [2]
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CHDM201H12101C
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Acute Myeloid Leukemia (AML)
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High-risk Myelodysplastic Syndrome (MDS)
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Condition category
Condition code
Cancer
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Leukaemia - Acute leukaemia
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Cancer
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Leukaemia - Chronic leukaemia
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Cancer
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Children's - Leukaemia & Lymphoma
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Blood
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Haematological diseases
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Blood
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Other blood disorders
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Other
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Research that is not of generic health relevance and not applicable to specific health categories listed above
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - HDM201
Treatment: Other - MBG453
Treatment: Drugs - Venetoclax
Experimental: treatment arm1: HDM201+MBG453 - Phase Ib (escalation)
Experimental: treatment arm2: HDM201+venetoclax - Phase Ib (escalation)
Treatment: Drugs: HDM201
Capsule
Treatment: Other: MBG453
LIVI (Liquid in vial) Concentrate for Solution for infusion
Treatment: Drugs: Venetoclax
Tablet
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Intervention code [1]
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Treatment: Drugs
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Intervention code [2]
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Treatment: Other
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) as a measure of safety
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Assessment method [1]
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Month 24 is assumed to be study end
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Timepoint [1]
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at month 24
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Primary outcome [2]
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Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) as a measure of safety
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Assessment method [2]
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Month 24 is assumed to be study end
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Timepoint [2]
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at month 24
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Primary outcome [3]
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Incidence of dose limiting toxicities (DLTs) of treatment
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Assessment method [3]
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end of first cycle
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Timepoint [3]
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at day 28
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Primary outcome [4]
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Frequency of dose interuptions
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Assessment method [4]
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Month 24 is assumed to be study end
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Timepoint [4]
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at month 24
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Primary outcome [5]
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Frequency of dose reductions
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Assessment method [5]
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Month 24 is assumed to be study end
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Timepoint [5]
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at month 24
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Primary outcome [6]
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Dose intensities
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Assessment method [6]
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measured in mg/ day Month 24 is assumed to be study end
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Timepoint [6]
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at month 24
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Secondary outcome [1]
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Overall Response Rate (ORR)
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Assessment method [1]
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Month 24 is assumed to be study end
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Timepoint [1]
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at month 24
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Secondary outcome [2]
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Best Overall Response (BOR)
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Assessment method [2]
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Month 24 is assumed to be study end
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Timepoint [2]
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at month 24
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Secondary outcome [3]
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Event Free Survival (EFS) for AML (Cheson 2003) or Progression Free Survival (PFS) for MDS (Cheson 2006)
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Assessment method [3]
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Month 24 is assumed to be study end
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Timepoint [3]
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at month 24
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Secondary outcome [4]
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Relapse Free Survival (RFS) for AML (Cheson 2003) or Time To Response (TTR) for MDS (Cheson 2006)
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Assessment method [4]
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Month 24 is assumed to be study end
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Timepoint [4]
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at month 24
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Secondary outcome [5]
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Duration Of Response (DOR) for AML (Cheson 2003) and MDS (Cheson 2006)
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Assessment method [5]
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Month 24 is assumed to be study end
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Timepoint [5]
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at month 24
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Secondary outcome [6]
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Presence of anti-MBG453 antibodies (treatment arm 1 HD201+MBG453)
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Assessment method [6]
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Timepoint [6]
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at Day 1, Day 29 and at month 24
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Secondary outcome [7]
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Concentration of HDM201 (Treatment arm 1 HDM201+MBG453 and treatment arm 2 HDM201+venetoclax)
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Assessment method [7]
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Timepoint [7]
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at Day 1, Day 2, Day 5, Day 6 and Day 29
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Secondary outcome [8]
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Concentration of MBG453 (treatment arm 1 HDM201+MBG453)
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Assessment method [8]
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Timepoint [8]
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at Day 1, Day 2, Day 8, Day 11, Day 15, Day 29 and at month 24
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Secondary outcome [9]
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Concentration of venetoclax (treatment arm 2 HDM201+venetoclax)
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Assessment method [9]
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Timepoint [9]
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at Day 1, Day 2, Day 3, Day 5, Day 6, Day 8, Day 9, Day 14, Day 15 and Day 29
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Secondary outcome [10]
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PK parameter (AUC) of HDM201 (Treatment arm 1 HDM201+MBG453 and treatment arm 2 HDM201+venetoclax)
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Assessment method [10]
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Cycle 6
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Timepoint [10]
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at month 6
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Secondary outcome [11]
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PK parameter (Cmax) of HDM201 (Treatment arm 1 HDM201+MBG453 and treatment arm 2 HDM201+venetoclax)
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Assessment method [11]
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Cycle 6
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Timepoint [11]
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at month 6
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Secondary outcome [12]
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PK parameter (Tmax) of HDM201 (Treatment arm 1 HDM201+MBG453 and treatment arm 2 HDM201+venetoclax)
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Assessment method [12]
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Cycle 6
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Timepoint [12]
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at month 6
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Secondary outcome [13]
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PK parameter (AUC) of MBG453 (treatment arm 1 HDM201+MBG453)
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Assessment method [13]
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Cycle 6
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Timepoint [13]
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at month 6
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Secondary outcome [14]
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PK parameter (Cmax) of MBG453 (treatment arm 1 HDM201+MBG453)
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Assessment method [14]
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Cycle 6
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Timepoint [14]
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at month 6
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Secondary outcome [15]
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PK parameter (Tmax) of MBG453 (treatment arm 1 HDM201+MBG453)
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Assessment method [15]
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Cycle 6
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Timepoint [15]
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at month 6
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Secondary outcome [16]
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PK parameter (AUC) of venetoclax (treatment arm 2 HDM201+venetoclax)
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Assessment method [16]
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Cycle 6
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Timepoint [16]
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at month 6
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Secondary outcome [17]
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PK parameter (Cmax) of venetoclax (treatment arm 2 HDM201+venetoclax)
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Assessment method [17]
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Cycle 6
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Timepoint [17]
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at month 6
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Secondary outcome [18]
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PK parameter (Tmax) of venetoclax (treatment arm 2 HDM201+venetoclax)
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Assessment method [18]
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Cycle 6
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Timepoint [18]
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at month 6
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Secondary outcome [19]
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Changes from baseline in GDF-15 (Treatment arm 1 HDM201+MBG453 and treatment arm 2 HDM201+venetoclax)
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Assessment method [19]
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Timepoint [19]
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at Day 1 and Day 2
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Secondary outcome [20]
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Changes from baseline in soluble TIM-3 (Treatment arm 1 HDM201+MBG453)
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Assessment method [20]
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Cycle 6
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Timepoint [20]
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at month 6
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Eligibility
Key inclusion criteria
Main
* 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.
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key 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.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Non-randomised trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 1
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Active, not recruiting
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
24/06/2019
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
31/07/2024
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Actual
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Sample size
Target
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Accrual to date
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Final
52
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Recruitment in Australia
Recruitment state(s)
VIC
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Recruitment hospital [1]
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Novartis Investigative Site - Melbourne
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Recruitment postcode(s) [1]
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3004 - Melbourne
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Recruitment outside Australia
Country [1]
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United States of America
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State/province [1]
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North Carolina
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Country [2]
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Finland
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State/province [2]
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Helsinki
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Germany
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State/province [3]
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Heidelberg
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Germany
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State/province [4]
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Wuerzburg
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Country [5]
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Italy
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State/province [5]
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MI
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Country [6]
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Italy
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State/province [6]
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RM
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Country [7]
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Singapore
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State/province [7]
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Singapore
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Country [8]
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Spain
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State/province [8]
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Madrid
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Funding & Sponsors
Primary sponsor type
Commercial sector/industry
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Name
Novartis Pharmaceuticals
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Address
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Country
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Ethics approval
Ethics application status
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Summary
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.
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Trial website
https://clinicaltrials.gov/study/NCT03940352
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Address
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Country
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Address
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Country
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Phone
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Fax
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Email
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Contact person for scientific queries
No information has been provided regarding IPD availability
What supporting documents are/will be available?
No Supporting Document Provided
Results publications and other study-related documents
No documents have been uploaded by study researchers.
Results not provided in
https://clinicaltrials.gov/study/NCT03940352
Download to PDF