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

• Status: Not yet recruiting
• Trial end date: 2028-06-02
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Novartis Pharmaceuticals

Criteria

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.