A Study of Siremadlin Alone and in Combination With Donor Lymphocyte Infusion in Acute Myeloid Leukemia Post-allogeneic Stem Cell Transplant

NCT05447663 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: CHDM201K122012021-003596-34
• Study Type: interventional
• Target: 8
• Locations: 3 countries
• Sites: 6

Brief Summary

The purpose of this study was to confirm a safe dose and schedule as well as the preliminary efficacy of siremadlin alone, and in combination with donor lymphocyte infusion (DLI), in adult participants with Acute Myeloid Leukemia (AML) who were in remission following allogeneic stem cell transplantation (allo-SCT) but were at high risk for relapse based on the presence of pre-transplant risk factors.

Conditions

Acute Myeloid Leukemia; Allogeneic Stem Cell Transplantation

Keywords

Acute Myeloid Leukemia; Acute myeloid leukemia post allogeneic stem cell transplantation; AML; allogeneic stem cell transplantation; HDM201; siremadlin; donor lymphocyte infusion; DLI; MDM2; p53; allo-SCT

Outcome Measures

Primary Outcomes (3)

• Rate of Dose Limiting Toxicities (DLTs) With Siremadlin Monotherapy in Part 1 (Dose Confirmation With Siremadlin Monotherapy)

  To determine the dose and schedule of siremadlin monotherapy that are tolerable without unacceptable toxicities as defined by the incidence of DLT during the first cycle of treatment in part 1. 'A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value assessed, by the Investigator, to be at least possibly related to study treatment (siremadlin monotherapy and/or siremadlin in combination with Donor lymphocyte infusion (DLI)), and as unrelated to disease, disease progression, inter-current illness, or concomitant medications, that occurs during the DLT observation period and meets severity criteria as per protocol.

  from cycle 1 day 1 (C1D1) to end of Cycle 1 (cycle = 28days)

• Time to Dose Limiting Toxicity (DLT) With Siremadlin in Combination With Donor Lymphocyte Infusion (DLI), in Part 2

  To determine the dose and schedule of siremadlin in combination with DLI that are tolerable without unacceptable toxicities (siremadlin recommended dose for combination), defined as time from start of combination phase to first DLT observed during the entire combination phase.

  From Day 1 of combination Cycle 1 to Day 42 of the last cycle of combination phase (up to 3 cycles of siremadlin/DLI combination). Cycle duration: 42 days

• Percentage of Participants Who Are Alive and Maintained Complete Remission (CR) or Complete Response With Incomplete Hematological Recovery (CRi) With no Evidence of Hematologic Relapse (Part 2)

  This involves evaluating the preliminary efficacy of siremadlin (as monotherapy, in priming and/or maintenance, with or without siremadlin in combination with DLI) on the prevention of hematologic relapse.

  Over 6 months from start of study treatment strategy (part 2 - siremadlin/DLI treatment strategy)

Secondary Outcomes (11)

• Participants Who Are Alive and Maintained CR or CRi With no Evidence of Hematologic Relapse (Part 1 -Siremadlin Monotherapy at the Recommended Dose for Part 2 )

  Over 6 months from start of siremadlin monotherapy (part 1)

• Time From Start of Study Treatment to the Date of First Documented Hematologic Relapse or Death Due to Any Cause, Whichever Occurs First

  From start of study treatment to up to 36 months from last patient first treatment

• Cumulative Incidence of AML Relapse at 1 Year and 2 Years After Start of Study Treatment

  1 year and 2 years after start of study treatment

• Time From Start of Study Treatment to the Date of Death From Any Cause

  From start of study treatment to up to 36 months from last patient first treatment

• Incidence of Graft Versus Host Disease (GvHD)

  From start of study treatment up to approx. 8 months

Study Arms (1)

Siremadlin (HDM201)

EXPERIMENTAL

Participants with AML post allogeneic stem cell transplantation (allo-SCT) received siremadlin monotherapy in part 1 and were to have received siremadlin monotherapy as well as in combination with donor lymphocyte infusion in part 2.

Drug: Siremadlin

Interventions

Siremadlin DRUG

Siremadlin was administered at a starting dose of 30 mg/day on days 1-5 of a 28-day treatment cycle (Part 1).

Also known as: HDM201

Siremadlin (HDM201)

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants with AML diagnosis, who underwent one allo-SCT to treat AML and are currently at ≥ Day 60 but no later than Day 120 (≤ Day 120) post allo-SCT.
• Pre-allo-SCT - Participants must have any of the following risk factors that put them at high risk for relapse:
• AML in first CR (CR1) prior to allo-SCT with one of the following:
• Adverse risk genetic abnormalities per 2017 ELN risk stratification. Patients with TP53 mutant AML at diagnosis are eligible if they meet eligibility criteria.
• Therapy-related AML (t-AML).
• Secondary AML (sAML) \[AML secondary to antecedent myelodysplastic syndrome (MDS) or AML secondary to myeloproliferative neoplasm (MPN)\].
• AML in second or greater CR (≥CR2) prior to allo-SCT.
• Allo-SCT must have the following characteristics:
• Unmanipulated/T cell-replete bone marrow or peripheral blood stem cells as a graft source.
• Matched related (family) donor (MFD) or matched unrelated donor (MUD): Human Leukocyte Antigen (HLA) matching of donor and recipient should be at a minimum of 8/8 antigen or allele matched at HLA-A, -B, -C, -DRB1 loci.
• Any conditioning regimen intensity is permitted, the use of anti-thymocyte globulin (ATG) or alemtuzumab or post-transplant cyclophosphamide as a part of conditioning is allowed.
• Donor lymphocytes are collected, cryopreserved and available for infusion (DLI), or obtaining donor lymphocytes for DLI is feasible (applicable only for part 2)
• Post-allo-SCT, participants must have achieved CR or CRi with no current evidence of hematologic relapse
• Eastern Cooperative Oncology Group (ECOG ) performance status 0, 1 or 2.
• Laboratory test results indicating adequate liver and kidney function laboratory test results

You may not qualify if:

• Prior exposure to MDM-inhibitor
• Active acute GvHD (aGvHD) of any grade (per Harris et al 2016) and/or active chronic GvHD (cGvHD ) of any grade (per NIH criteria (Jagasia et al 2015)) requiring systemic therapy at time of study treatment initiation
• Past history of grade III or IV aGvHD and/or past history of moderate or severe cGvHD. History of lower grades of GvHD is permitted if GvHD resolved to grade 0 for at least 4 weeks prior to start of study treatment.
• Recipient of allo-SCT from MUD with ≥1 antigen or allele mismatch at HLA-A, -B, -C, -DRB1 locus (HLA matching \< 8/8 antigens)
• Recipient of allo-SCT from a haploidentical family donor; and recipients of cord blood transplant as a graft source
• Prior systemic AML-directed treatments given at any time after allo-SCT (including DLI)
• Prior systemic cancer-directed treatments or investigational modalities ≤ 5 half-lives or 4 weeks prior to starting study, whichever is longer
• GI disorders that may prevent the intake and absorption of oral siremadlin (eg, diarrhea, uncontrolled nausea/vomiting, GI bleeding, etc).
• Any concurrent severe and/or active uncontrolled bacterial, viral or fungal infection requiring parenteral antibacterial, antiviral or antifungal therapy. Prophylactic antimicrobial use (oral or parenteral) is allowed.
• Participants who require treatment with moderate or strong CYP3A inducers within 14 days prior to starting study treatment, or are expected to receive moderate or strong CYP3A inducers during the entire study
• Cardiac or cardiac repolarization abnormality, that are clinically significant

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (6)

Novartis Investigative Site

Augsburg, 86179, Germany

Location

Novartis Investigative Site

Freiburg im Breisgau, 79106, Germany

Location

Novartis Investigative Site

Bergamo, BG, 24127, Italy

Location

Novartis Investigative Site

Bologna, BO, 40138, Italy

Location

Novartis Investigative Site

Seville, Andalusia, 41013, Spain

Location

Novartis Investigative Site

Valencia, 46026, Spain

Location

Related Links

• A Plain Language Trial Summary is available on www.novctrd.com

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

siremadlin

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Results Point of Contact

• Title: Clinical Disclosure Office
• Organization: Novartis Pharmaceuticals

novartis.email@novartis.com

862-778-3000

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Study started out a phase l/ll study but because it was terminated, it never made it to phase ll.

Study Record Dates

• First Submitted: June 28, 2022
• First Posted: July 7, 2022
• Study Start: February 23, 2023
• Primary Completion: October 26, 2023
• Study Completion: October 26, 2023
• Last Updated: May 16, 2025
• Results First Posted: January 14, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will share

Locations

ES (2); DE (2); IT (2)