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

Acute Myeloid Leukemia (AML) Clinical Trial

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 Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03940352
• Other study ID #: CHDM201H12101C
• Secondary ID: 2018-004001-62
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: June 24, 2019
• Est. completion date: June 14, 2024

Study information

• Verified date: June 2024
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 52
• Est. completion date: June 14, 2024
• Est. primary completion date: June 14, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

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

Intervention

Drug:
• HDM201
Capsule

Biological:
• MBG453
LIVI (Liquid in vial) Concentrate for Solution for infusion

Drug:
• Venetoclax
Tablet

Locations

Country	Name	City	State
Australia	Novartis Investigative Site	Melbourne	Victoria
Finland	Novartis Investigative Site	Helsinki
Germany	Novartis Investigative Site	Heidelberg
Germany	Novartis Investigative Site	Wuerzburg
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Roma	RM
Singapore	Novartis Investigative Site	Singapore
Spain	Novartis Investigative Site	Madrid
United States	Duke University Medical Center .	Durham	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Australia,  Finland,  Germany,  Italy,  Singapore,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	Incidence of dose limiting toxicities (DLTs) of treatment	end of first cycle	at day 28
Primary	Frequency of dose interuptions	Month 24 is assumed to be study end	at month 24
Primary	Frequency of dose reductions	Month 24 is assumed to be study end	at month 24
Primary	Dose intensities	measured in mg/ day Month 24 is assumed to be study end	at month 24
Secondary	Overall Response Rate (ORR)	Month 24 is assumed to be study end	at month 24
Secondary	Best Overall Response (BOR)	Month 24 is assumed to be study end	at month 24
Secondary	Event Free Survival (EFS) for AML (Cheson 2003) or Progression Free Survival (PFS) for MDS (Cheson 2006)	Month 24 is assumed to be study end	at month 24
Secondary	Relapse Free Survival (RFS) for AML (Cheson 2003) or Time To Response (TTR) for MDS (Cheson 2006)	Month 24 is assumed to be study end	at month 24
Secondary	Duration Of Response (DOR) for AML (Cheson 2003) and MDS (Cheson 2006)	Month 24 is assumed to be study end	at month 24
Secondary	Presence of anti-MBG453 antibodies (treatment arm 1 HD201+MBG453)		at Day 1, Day 29 and at month 24
Secondary	Concentration of HDM201 (Treatment arm 1 HDM201+MBG453 and treatment arm 2 HDM201+venetoclax)		at Day 1, Day 2, Day 5, Day 6 and Day 29
Secondary	Concentration of MBG453 (treatment arm 1 HDM201+MBG453)		at Day 1, Day 2, Day 8, Day 11, Day 15, Day 29 and at month 24
Secondary	Concentration of venetoclax (treatment arm 2 HDM201+venetoclax)		at Day 1, Day 2, Day 3, Day 5, Day 6, Day 8, Day 9, Day 14, Day 15 and Day 29
Secondary	PK parameter (AUC) of HDM201 (Treatment arm 1 HDM201+MBG453 and treatment arm 2 HDM201+venetoclax)	Cycle 6	at month 6
Secondary	PK parameter (Cmax) of HDM201 (Treatment arm 1 HDM201+MBG453 and treatment arm 2 HDM201+venetoclax)	Cycle 6	at month 6
Secondary	PK parameter (Tmax) of HDM201 (Treatment arm 1 HDM201+MBG453 and treatment arm 2 HDM201+venetoclax)	Cycle 6	at month 6
Secondary	PK parameter (AUC) of MBG453 (treatment arm 1 HDM201+MBG453)	Cycle 6	at month 6
Secondary	PK parameter (Cmax) of MBG453 (treatment arm 1 HDM201+MBG453)	Cycle 6	at month 6
Secondary	PK parameter (Tmax) of MBG453 (treatment arm 1 HDM201+MBG453)	Cycle 6	at month 6
Secondary	PK parameter (AUC) of venetoclax (treatment arm 2 HDM201+venetoclax)	Cycle 6	at month 6
Secondary	PK parameter (Cmax) of venetoclax (treatment arm 2 HDM201+venetoclax)	Cycle 6	at month 6
Secondary	PK parameter (Tmax) of venetoclax (treatment arm 2 HDM201+venetoclax)	Cycle 6	at month 6
Secondary	Changes from baseline in GDF-15 (Treatment arm 1 HDM201+MBG453 and treatment arm 2 HDM201+venetoclax)		at Day 1 and Day 2
Secondary	Changes from baseline in soluble TIM-3 (Treatment arm 1 HDM201+MBG453)	Cycle 6	at month 6