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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
11/06/2024

Titles & IDs
Public title
HDM201 in Combination With MBG453 or Venetoclax in Patients With Acute Myeloid Leukemia (AML) or High-risk Myelodysplastic Syndrome (MDS)
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)
Secondary ID [1] 0 0
2018-004001-62
Secondary ID [2] 0 0
CHDM201H12101C
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Myeloid Leukemia (AML) 0 0
High-risk Myelodysplastic Syndrome (MDS) 0 0
Condition category
Condition code
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma
Blood 0 0 0 0
Haematological diseases
Blood 0 0 0 0
Other blood disorders
Other 0 0 0 0
Research that is not of generic health relevance and not applicable to specific health categories listed above

Intervention/exposure
Study type
Interventional
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
Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Treatment: Other
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) as a measure of safety
Timepoint [1] 0 0
at month 24
Primary outcome [2] 0 0
Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) as a measure of safety
Timepoint [2] 0 0
at month 24
Primary outcome [3] 0 0
Incidence of dose limiting toxicities (DLTs) of treatment
Timepoint [3] 0 0
at day 28
Primary outcome [4] 0 0
Frequency of dose interuptions
Timepoint [4] 0 0
at month 24
Primary outcome [5] 0 0
Frequency of dose reductions
Timepoint [5] 0 0
at month 24
Primary outcome [6] 0 0
Dose intensities
Timepoint [6] 0 0
at month 24
Secondary outcome [1] 0 0
Overall Response Rate (ORR)
Timepoint [1] 0 0
at month 24
Secondary outcome [2] 0 0
Best Overall Response (BOR)
Timepoint [2] 0 0
at month 24
Secondary outcome [3] 0 0
Event Free Survival (EFS) for AML (Cheson 2003) or Progression Free Survival (PFS) for MDS (Cheson 2006)
Timepoint [3] 0 0
at month 24
Secondary outcome [4] 0 0
Relapse Free Survival (RFS) for AML (Cheson 2003) or Time To Response (TTR) for MDS (Cheson 2006)
Timepoint [4] 0 0
at month 24
Secondary outcome [5] 0 0
Duration Of Response (DOR) for AML (Cheson 2003) and MDS (Cheson 2006)
Timepoint [5] 0 0
at month 24
Secondary outcome [6] 0 0
Presence of anti-MBG453 antibodies (treatment arm 1 HD201+MBG453)
Timepoint [6] 0 0
at Day 1, Day 29 and at month 24
Secondary outcome [7] 0 0
Concentration of HDM201 (Treatment arm 1 HDM201+MBG453 and treatment arm 2 HDM201+venetoclax)
Timepoint [7] 0 0
at Day 1, Day 2, Day 5, Day 6 and Day 29
Secondary outcome [8] 0 0
Concentration of MBG453 (treatment arm 1 HDM201+MBG453)
Timepoint [8] 0 0
at Day 1, Day 2, Day 8, Day 11, Day 15, Day 29 and at month 24
Secondary outcome [9] 0 0
Concentration of venetoclax (treatment arm 2 HDM201+venetoclax)
Timepoint [9] 0 0
at Day 1, Day 2, Day 3, Day 5, Day 6, Day 8, Day 9, Day 14, Day 15 and Day 29
Secondary outcome [10] 0 0
PK parameter (AUC) of HDM201 (Treatment arm 1 HDM201+MBG453 and treatment arm 2 HDM201+venetoclax)
Timepoint [10] 0 0
at month 6
Secondary outcome [11] 0 0
PK parameter (Cmax) of HDM201 (Treatment arm 1 HDM201+MBG453 and treatment arm 2 HDM201+venetoclax)
Timepoint [11] 0 0
at month 6
Secondary outcome [12] 0 0
PK parameter (Tmax) of HDM201 (Treatment arm 1 HDM201+MBG453 and treatment arm 2 HDM201+venetoclax)
Timepoint [12] 0 0
at month 6
Secondary outcome [13] 0 0
PK parameter (AUC) of MBG453 (treatment arm 1 HDM201+MBG453)
Timepoint [13] 0 0
at month 6
Secondary outcome [14] 0 0
PK parameter (Cmax) of MBG453 (treatment arm 1 HDM201+MBG453)
Timepoint [14] 0 0
at month 6
Secondary outcome [15] 0 0
PK parameter (Tmax) of MBG453 (treatment arm 1 HDM201+MBG453)
Timepoint [15] 0 0
at month 6
Secondary outcome [16] 0 0
PK parameter (AUC) of venetoclax (treatment arm 2 HDM201+venetoclax)
Timepoint [16] 0 0
at month 6
Secondary outcome [17] 0 0
PK parameter (Cmax) of venetoclax (treatment arm 2 HDM201+venetoclax)
Timepoint [17] 0 0
at month 6
Secondary outcome [18] 0 0
PK parameter (Tmax) of venetoclax (treatment arm 2 HDM201+venetoclax)
Timepoint [18] 0 0
at month 6
Secondary outcome [19] 0 0
Changes from baseline in GDF-15 (Treatment arm 1 HDM201+MBG453 and treatment arm 2 HDM201+venetoclax)
Timepoint [19] 0 0
at Day 1 and Day 2
Secondary outcome [20] 0 0
Changes from baseline in soluble TIM-3 (Treatment arm 1 HDM201+MBG453)
Timepoint [20] 0 0
at month 6

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.

Main
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
24/06/2019
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
14/06/2024
Actual
Sample size
Target
Accrual to date
Final
52
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
Novartis Investigative Site - Melbourne
Recruitment postcode(s) [1] 0 0
3004 - Melbourne
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
North Carolina
Country [2] 0 0
Finland
State/province [2] 0 0
Helsinki
Country [3] 0 0
Germany
State/province [3] 0 0
Heidelberg
Country [4] 0 0
Germany
State/province [4] 0 0
Wuerzburg
Country [5] 0 0
Italy
State/province [5] 0 0
MI
Country [6] 0 0
Italy
State/province [6] 0 0
RM
Country [7] 0 0
Singapore
State/province [7] 0 0
Singapore
Country [8] 0 0
Spain
State/province [8] 0 0
Madrid

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Novartis Pharmaceuticals
Address
Country

Ethics approval
Ethics application status

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.
Trial website
https://clinicaltrials.gov/study/NCT03940352
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT03940352