A study of efficacy and safety of siremadlin alone and in combination with donor lymphocyte infusion (DLI) in adults with acute myeloid leukemia (AML) who have received allogeneic stem cell transplant (allo-SCT) but are at high risk for relapse.

Phase 1

Conditions: Acute Myeloid Leukemia
MedDRA version: 21.0Level: LLTClassification code 10000886Term: Acute myeloid leukemiaSystem Organ Class: 100000004864
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2021-003596-34-IT

Lead Sponsor: OVARTIS PHARMA AG

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 32

Inclusion Criteria

1. Signed informed consent must be obtained prior to participation in the study.
2. Adults >= 18 years of age.
3. 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 non-haploidentical transplant for prevention of GvHD are eligible if they are between Day >=60 and <= Day 150 post-allo-SCT at study entry.
4. 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 complete morphologic
• remission (<5% leukemic blasts) at time of transplant (within 30 days of transplant / prior to starting conditioning regimen) but with evidence of residual leukemia.
5. 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 antithymocyte globulin (ATG) or alemtuzumab or post-transplant cyclophosphamide as a part of conditioning is allowed.
6. Donor lymphocytes are collected, cryopreserved and available for infusion (DLI), or obtaining donor lymphocytes for DLI is feasible.
7. Post-allo-SCT, participants must have achieved complete remission (CR) or CR with incomplete count recovery (CRi) with no current evidence of hematologic relapse (bone marrow blasts <5%; no circulating blasts in the blood; no evidence of extramedullary disease).
8. Systemic GvHD prophylaxis or treatment [immunosuppressive treatment (IST)] taper has been started prior to start of study treatment or has been completed.
9. Ability to provide a fresh bone marrow aspirate sample collected within 28 days from enrollment, and immediately shipped to a Novartis designated central laboratory for MRD testing.
10. Adequate liver function tests (AST and ALT <= 3 × ULN, total bilirubin <= 1.5 × ULN) and renal function (estimated Glomerular Filtration Rate (eGFR) = 45 mL/min/1.73 m2) (within 14 days prior to start of study treatment).
11. Evidence of adequate engraftment post allo-SCT: ANC >= 1.0x109/L, platelet count >= 75x109/L, hemoglobin >= 8 g/dL (within 14 days prior to start of study treatment).
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 16
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 16

Exclusion Criteria

1. Prior exposure to MDM-inhibitor.
2. Active acute GvHD of any grade (per Harris et al 2016) requiring systemic therapy at time of study treatment initiation.
3. Active chronic GvHD of any grade (per NIH criteria (Jagasia et al 2015) requiring systemic therapy at time of study treatment initiation.
4. Past history of grade III or IV acute GvHD (per Harris et al 2016) and/or past history of moderate or severe chronic GvHD (per NIH criteria (Jagasia et al 2015)).
5. Recipient of allo-SCT from a matched unrelated donor (MUD) with one or more antigen or allele mismatch at HLA-A, -B, -C, -DRB1 locus (HLA matching less than 8/8 antigens).
6. Recipient of allo-SCT from a haploidentical family donor.
7. Recipients of cord blood transplant as a graft source.
8. Prior systemic cancer-directed treatments or investigational modalities <= 5 half-lives or 4 weeks prior to starting study, whichever is shorter.
9. Prior systemic AML-directed treatments given at any time after allo-SCT (including DLI).
10. History of another primary malignancy that is currently clinically significant or currently requires active intervention. Participants who are receiving adjuvant therapy such as hormone therapy are eligible.
11. 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 CYP3A4 inducers during the entire study.
12. GI disorders that may prevent the intake and absorption of oral siremadlin (eg, diarrhea, uncontrolled nausea and/or vomiting, GI bleeding, etc).
13. 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.
14. Cardiac or cardiac repolarization abnormality, including but not limited to any of the following:
• History of myocardial infarction (MI), angina pectoris, or coronary artery bypass graft (CABG) within 6 months prior to starting study treatment.
• Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block).
• Baseline QTcF interval > 470 ms.
• Clinically significant and/or uncontrolled heart disease such as congestive heart failure requiring treatment (NYHA Grade III/IV).
15. Other concurrent severe and/or uncontrolled medical conditions or serious organ dysfunction or other co-morbidity that, in the opinion of the investigator, predisposes the participant o high risk of noncompliance with the protocol.

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method

Secondary Outcome Measures

Name	Time	Method

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