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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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.

Conditions
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Acute Myeloid Leukemia, Allogeneic Stem Cell Transplantation

Intervention / Treatment
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* Drug: Siremadlin


Participation Criteria
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Eligibility Criteria
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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. 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) 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Siremadlin (HDM201)<br>Participants with AML post allogeneic stem cell transplantation (allo-SCT) will receive siremadlin monotherapy in part 1 and siremadlin monotherapy as well as in combination with donor lymphocyte infusion in part 2 | Drug: Siremadlin<br>* 30-40 mg QD siremadlin capsules, orally (1-5 days of 28 or 42 days cycle)<br>* Other names: HDM201;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence 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 (siremadlin recommended dose for part 2), as defined by the incidence of DLT during the first cycle of treatment in part 1. | 28 days | 
| 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 | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants who are alive and maintained CR or CRi with no evidence of hematologic relapse | This involves evaluating the preliminary efficacy of siremadlin monotherapy at the recommended dose for part 2 on prevention of hematologic relapse | 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 | Assessment of relapse free survival (RFS) in part 2 | From start of study treatment to up to 36 months from last patient first treatment | 
| Cumulative incidence of AML relapse | Cumulative incidence of Acute Myeloid Leukemia (AML) relapse at one year and 2 years after the start of study treatment in part 1 and 2. | at 1 year and at 2 years after start of study treatment | 
| Time from start of study treatment to the date of death from any cause | Assessment of Overall survival (OS) in part 2 | From start of study treatment to up to 36 months from last patient first treatment | 
| Incidence of Graft versus Host Disease (GvHD) | Incidence of grade III or IV acute GvHD, and moderate to severe chronic GvHD in part 1 and 2. | From start of study treatment to up to 24 months from last patient first treatment | 
| Percentage of participants with permanent study treatment discontinuation due to GvHD or other adverse events | Percentage of participants with permanent discontinuation of study treatment due to GvHD or other adverse events in part 1 and 2. | From start of study treatment to up to 24 months from last patient first treatment | 
| 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 | Assessment of GvHD-free/relapse-free survival (GRFS) in part 1 and 2. | From start of treatment to up to 36 months from last patient first treatment | 
| Pharmacokinetic (PK) characteristic AUC of siremadlin | AUC is the area under the concentration vs. time curve in part 1 and 2. | From Cycle 1 Day 1 to Cycle 24 Day 1 in part 1 or from Cycle 1 Day 1 safety confirmation to Cycle 21 Day 1 maintenance in part 2; [each cycle is 28 days for monotherapy, and 42 days for combination] | 
| PK characteristic Cmax of siremadlin | The maximum (peak) observed plasma, blood, serum or other body fluid drug concentration following drug administration (mass x volume^-1) in part 1 and 2. | From Cycle 1 Day 1 to Cycle 24 Day 1 in part 1 or from Cycle 1 Day 1 safety confirmation to Cycle 21 Day 1 maintenance in part 2; [each cycle is 28 days for monotherapy, and 42 days for combination] | 
| PK characteristic Tmax of siremadlin | The time to reach maximum (peak) plasma, blood, serum or other body fluid drug concentration after drug administration (time) in part 1 and 2. | From Cycle 1 Day 1 to Cycle 24 Day 1 in part 1 or from Cycle 1 Day 1 safety confirmation to Cycle 21 Day 1 maintenance in part 2; [each cycle is 28 days for monotherapy, and 42 days for combination] | 
| PK characteristic Ctrough of siremadlin | Concentration that is just prior to the beginning of, or at the end of a dosing interval; corresponding to the pre-dose concentration in part 1 and 2. | From Cycle 1 Day 1 to Cycle 24 Day 1 in part 1 or from Cycle 1 Day 1 safety confirmation to Cycle 21 Day 1 maintenance in part 2; [each cycle is 28 days for monotherapy, and 42 days for combination] | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML, Acute Myeloid Leukemia, Acute myeloid leukemia post allogeneic stem cell transplantation, allogeneic stem cell transplantation, HDM201, siremadlin, donor lymphocyte infusion, DLI, MDM2, p53, allo-SCT