Acute Myeloid Leukemia Clinical Trial
A Study of Siremadlin Alone and in Combination With Donor Lymphocyte Infusion in Acute Myeloid Leukemia Post-allogeneic Stem Cell Transplant
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.
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 38 participants and will start with a dose confirmation of siremadlin monotherapy (Part 1) to determine the siremadlin recommended dose, followed by a treatment strategy of siremadlin/DLI (Part 2).
In part 1, approximately 12 participants will be enrolled in 2 cohorts (starting dose 30 mg/day on days 1-5 of a 28-day treatment cycle, dose level +1 at 40 mg/day and dose level -1 at 20 mg/day) and participants will be treated for a maximum of 24 cycles. In part 2, participants will follow a treatment strategy, which contains three consecutive phases for a maximum of 24 cycles in total:
A priming phase with siremadlin monotherapy at the recommended dose determined in Part 1 (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.
Enrollment in part 2 will start after obtaining Health Authority's approval as applicable.
The decision of DLI administration in part 2 in eligible participants for combination will be at the discretion of the treating investigator per standard of practice/institutional guidelines.
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
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)
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
Other protocol defined inclusion/exclusion criteria may apply.
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There are 13 Locations for this study
Murdoch Western Australia, 6150, Australia
Augsburg , 86179, Germany
Freiburg , 79106, Germany
Haifa , 31096, Israel
Tel Aviv , 64239, Israel
Bergamo BG, 24128, Italy
Bologna BO, 40138, Italy
Sevilla Andalucia, 41013, Spain
Valencia , 46026, Spain
Cardiff , CF14 , United Kingdom
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