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

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

Tracking Information

• First Submitted Date: May 2, 2019
• First Posted Date: May 7, 2019
• Last Update Posted Date: October 16, 2019
• Actual Study Start Date: June 24, 2019
• Estimated Primary Completion Date: April 22, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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: Same as current
• Change History: Complete list of historical versions of study NCT03940352 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (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: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

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: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

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

Intervention

• Drug: HDM201
  Capsule
• Biological: MBG453
  LIVI (Liquid in vial) Concentrate for Solution for infusion
• Drug: Venetoclax
  Tablet

Study Arms

• 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

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: May 6, 2019): 80
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: April 22, 2021
• Estimated Primary Completion Date: April 22, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Novartis Pharmaceuticals; 1-888-669-6682; novartis.email@novartis.com

Contact: Novartis Pharmaceuticals; +41613241111

• Listed Location Countries: Australia, Finland, Singapore, Spain, Switzerland

Administrative Information

• NCT Number: NCT03940352
• Other Study ID Numbers: 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: Not Provided
• Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Study Sponsor: Novartis Pharmaceuticals
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Novartis
• Verification Date: October 2019