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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Recruiting
• CT.gov ID: NCT03940352
• Collaborator: (none)
• Enrollment: 80
• Locations: 10
• Arms: 2
• Anticipated Duration (Months): 42.2
• Patients Per Site: 8
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia (AML); High-risk Myelodysplastic Syndrome (MDS)	Drug: HDM201; Biological: MBG453; Drug: Venetoclax	Phase 1

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 80 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: Jun 24, 2019
• Anticipated Primary Completion Date: Dec 30, 2022
• Anticipated Study Completion Date: Dec 30, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: treatment arm1: HDM201+MBG453 Phase Ib (escalation)	Drug: HDM201; Capsule; Biological: MBG453; LIVI (Liquid in vial) Concentrate for Solution for infusion
Experimental: treatment arm2: HDM201+venetoclax Phase Ib (escalation)	Drug: HDM201; Capsule; Drug: Venetoclax; Tablet

Outcome Measures

Primary Outcome Measures

1. Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) as a measure of safety [at month 24]

   Month 24 is assumed to be study end

2. Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) as a measure of safety [at month 24]

   Month 24 is assumed to be study end

3. Incidence of dose limiting toxicities (DLTs) of treatment [at day 28]

   end of first cycle

4. Frequency of dose interuptions [at month 24]

   Month 24 is assumed to be study end

5. Frequency of dose reductions [at month 24]

   Month 24 is assumed to be study end

6. Dose intensities [at month 24]

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

Secondary Outcome Measures

1. Overall Response Rate (ORR) [at month 24]

   Month 24 is assumed to be study end

2. Best Overall Response (BOR) [at month 24]

   Month 24 is assumed to be study end

3. Event Free Survival (EFS) for AML (Cheson 2003) or Progression Free Survival (PFS) for MDS (Cheson 2006) [at month 24]

   Month 24 is assumed to be study end

4. Relapse Free Survival (RFS) for AML (Cheson 2003) or Time To Response (TTR) for MDS (Cheson 2006) [at month 24]

   Month 24 is assumed to be study end

5. Duration Of Response (DOR) for AML (Cheson 2003) and MDS (Cheson 2006) [at month 24]

   Month 24 is assumed to be study end

6. Presence of anti-MBG453 antibodies (treatment arm 1 HD201+MBG453) [at Day 1, Day 29 and at month 24]

7. 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]

8. 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]

9. 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]

10. PK parameter (AUC) of HDM201 (Treatment arm 1 HDM201+MBG453 and treatment arm 2 HDM201+venetoclax) [at month 6]

    Cycle 6

11. PK parameter (Cmax) of HDM201 (Treatment arm 1 HDM201+MBG453 and treatment arm 2 HDM201+venetoclax) [at month 6]

    Cycle 6

12. PK parameter (Tmax) of HDM201 (Treatment arm 1 HDM201+MBG453 and treatment arm 2 HDM201+venetoclax) [at month 6]

    Cycle 6

13. PK parameter (AUC) of MBG453 (treatment arm 1 HDM201+MBG453) [at month 6]

    Cycle 6

14. PK parameter (Cmax) of MBG453 (treatment arm 1 HDM201+MBG453) [at month 6]

    Cycle 6

15. PK parameter (Tmax) of MBG453 (treatment arm 1 HDM201+MBG453) [at month 6]

    Cycle 6

16. PK parameter (AUC) of venetoclax (treatment arm 2 HDM201+venetoclax) [at month 6]

    Cycle 6

17. PK parameter (Cmax) of venetoclax (treatment arm 2 HDM201+venetoclax) [at month 6]

    Cycle 6

18. PK parameter (Tmax) of venetoclax (treatment arm 2 HDM201+venetoclax) [at month 6]

    Cycle 6

19. Changes from baseline in GDF-15 (Treatment arm 1 HDM201+MBG453 and treatment arm 2 HDM201+venetoclax) [at Day 1 and Day 2]

20. Changes from baseline in soluble TIM-3 (Treatment arm 1 HDM201+MBG453) [at month 6]

    Cycle 6

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Duke University Medical Center	Durham	North Carolina	United States	27710
2	Novartis Investigative Site	Melbourne	Victoria	Australia	3004
3	Novartis Investigative Site	Helsinki		Finland	FIN 00290
4	Novartis Investigative Site	Heidelberg		Germany	69120
5	Novartis Investigative Site	Wuerzburg		Germany	97080
6	Novartis Investigative Site	Milano	MI	Italy	20132
7	Novartis Investigative Site	Roma	RM	Italy	00161
8	Novartis Investigative Site	Singapore		Singapore	119228
9	Novartis Investigative Site	Madrid		Spain	28041
10	Novartis Investigative Site	Basel		Switzerland	4031

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03940352
• Other Study ID Numbers: CHDM201H12101C; 2018-004001-62
• First Posted: May 7, 2019
• Last Update Posted: Jun 30, 2022
• Last Verified: Jun 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: Phase Ib; BHLRM; AML; MDS; HDM201; TP53; MBG453; TIM-3; venetoclax; Bcl-2
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Myelodysplastic Syndromes; Syndrome; Venetoclax

Study Results

No Results Posted as of Jun 30, 2022