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

Sponsor
Novartis Pharmaceuticals (Industry)
Overall Status
Not yet recruiting
CT.gov ID
NCT05447663
Collaborator
(none)
32
1
66.4

Study Details

Study Description

Brief Summary

The purpose of this study is 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 AML who are in remission following allogeneic stem cell transplantation (allo-SCT) but are at high risk for relapse based on the presence of pre-transplant risk factors.

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

Detailed Description

This is a Phase Ib/II, single arm, open label, multi-center study of siremadlin as monotherapy and in combination with DLI, in adult participants with AML who are in complete remission (CR) or CR with incomplete count recovery (CRi) post allo-SCT but are at high risk for relapse based on the presence of pre-transplant risk factors.

The primary purpose of the study is to confirm the safe dose and schedule of siremadlin monotherapy and in combination with DLI. The study is also designed to assess the preliminary efficacy in preventing hematologic relapse.

The study will enroll approximately 32 participants. Every participant will follow a treatment strategy, which contains three consecutive phases for a maximum of 24 cycles in total:

  • A priming phase with siremadlin monotherapy (for at least 2 cycles). Participants who are not eligible for the combination phase of siremadlin/DLI may continue priming phase with siremadlin monotherapy.

  • A combination phase of siremadlin in combination with DLI (siremadlin/DLI) for participants who are eligible to receive DLI (up to a total of 3 combination cycles).

  • A maintenance phase with siremadlin monotherapy.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
32 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase Ib/II, Open Label Study of Siremadlin Monotherapy and in Combination With Donor Lymphocyte Infusion as a Treatment for Patients With Acute Myeloid Leukemia Post-allogeneic Stem Cell Transplantation Who Are in Complete Remission But at High Risk for Relapse.
Anticipated Study Start Date :
Nov 21, 2022
Anticipated Primary Completion Date :
Jun 16, 2027
Anticipated Study Completion Date :
Jun 2, 2028

Arms and Interventions

Arm Intervention/Treatment
Experimental: Siremadlin (HDM201)

Participants with AML post allogeneic stem cell transplantation (allo-SCT) will receive siremadlin monotherapy and in combination with donor lymphocyte infusion

Drug: Siremadlin
30-40 mg QD siremadlin capsules, orally (1-5 days of 28 or 42 days cycle)
Other Names:
  • HDM201
  • Outcome Measures

    Primary Outcome Measures

    1. Incidence of Dose Limiting Toxicities (DLTs) with siremadlin monotherapy in priming phase [28 days]

      To determine the dose and schedule of siremadlin monotherapy that are tolerable without unacceptable toxicities (siremadlin recommended dose for priming), as defined by the incidence of DLT during the first cycle of priming phase.

    2. Time to Dose Limiting Toxicity (DLT) with siremadlin in combination with Donor Lymphocyte Infusion (DLI), in 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]

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

    3. 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 [Over 6 months from start of siremadlin [each cycle is 28 days for monotherapy, and 42 days for combination]]

      This involves evaluating the preliminary efficacy of siremadlin (priming monotherapy in combination with DLI after priming monotherapy, and as monotherapy maintenance subsequent to priming or in combination with DLI on the prevention of hematologic relapse.

    Secondary Outcome Measures

    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]

      Assessment of relapse free survival (RFS)

    2. Cumulative incidence of AML relapse [at 1 year and at 2 years after start of study treatment]

      Cumulative incidence of Acute Myeloid Leukemia (AML) relapse at one year and 2 years after the start of study treatment

    3. 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]

      Assessment of Overall survival (OS)

    4. Measurable residual disease (MRD) status of participants at baseline and within the first 6 months of study treatment [first 6 months of study treatment]

      Assessment of the effect of study treatment on MRD status within the first 6 months of study treatment

    5. Incidence of Graft versus Host Disease (GvHD) [From start of study treatment to up to 24 months from last patient first treatment]

      Incidence of grade III or IV acute GvHD, and moderate to severe chronic GvHD

    6. Percentage of participants with permanent study treatment discontinuation due to GvHD or other adverse events [From start of study treatment to up to 24 months from last patient first treatment]

      Percentage of participants with permanent discontinuation of study treatment due to GvHD or other adverse events

    7. Time from start of study treatment to the date of first documented occurrence or worsening of treatment emergent grade III or IV acute GvHD, or chronic GvHD requiring initiation of systemic immunosuppressive treatment [From start of treatment to up to 36 months from last patient first treatment]

      Assessment of GvHD-free/relapse-free survival (GRFS)

    8. Pharmacokinetic (PK) characteristic AUC of siremadlin [From Cycle 1 Day 1 to Cycle 21 Day 1; [each cycle is 28 days for monotherapy, and 42 days for combination]]

      AUC is the area under the concentration vs. time curve

    9. PK characteristic Cmax of siremadlin [From cycle 1 Day 1 to Cycle 21 Day 1; [each cycle is 28 days for monotherapy, and 42 days for combination]]

      The maximum (peak) observed plasma, blood, serum or other body fluid drug concentration following drug administration (mass x volume^-1).

    10. PK characteristic Tmax of siremadlin [From Cycle 1 Day 1 to Cycle 21 Day 1; [each cycle is 28 days for monotherapy, and 42 days for combination]]

      The time to reach maximum (peak) plasma, blood, serum or other body fluid drug concentration after drug administration (time).

    11. PK characteristic Ctrough of siremadlin [From Cycle 1 Day 1 to Cycle 21 Day 1;[each cycle is 28 days for monotherapy, and 42 days for combination]]

      Concentration that is just prior to the beginning of, or at the end of a dosing interval; corresponding to the pre-dose concentration.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • 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. Patients who received high-dose cyclophosphamide early post-transplant for prevention of GvHD are eligible if they are between ≥ Day 60 and ≤ Day 150 post-allo-SCT at study entry.

    • 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.

    • AML in morphologic complete remission (<5% leukemic blasts) at time of transplant (within 30 days of transplant / prior to starting conditioning regimen) but with evidence of residual leukemia.

    • 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

    • Post-allo-SCT, participants must have achieved CR or CRi with no current evidence of hematologic relapse

    • Systemic GvHD prophylaxis or treatment [immunosuppressive treatment (IST)] taper has been started prior to start of study treatment or has been completed

    • Eastern Cooperative Oncology Group (ECOG ) performance status 0, 1 or 2.

    • Laboratory test results indicating adequate liver and kidney function laboratory test results

    • Evidence of adequate engraftment: Absolute Neutrophil Count (ANC) ≥ 1.0x109/L, Platelets (PLT) ≥ 75x109/L, Hemoglobin (Hgb) ≥ 8 g/dL (within 14 days prior to start of study treatment)

    Exclusion criteria:
    • 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

    • 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 shorter

    • 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

    Other protocol defined inclusion/exclusion criteria may apply.

    Contacts and Locations

    Locations

    No locations specified.

    Sponsors and Collaborators

    • Novartis Pharmaceuticals

    Investigators

    • Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Novartis Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT05447663
    Other Study ID Numbers:
    • CHDM201K12201
    • 2021-003596-34
    First Posted:
    Jul 7, 2022
    Last Update Posted:
    Jul 7, 2022
    Last Verified:
    Jul 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Novartis Pharmaceuticals
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Jul 7, 2022