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

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.

ClinicalTrials.gov Identifier: NCT05447663

Novartis Reference Number: CHDM201K12201

Last Update: Jan 25, 2023

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All compounds are either investigational or being studied for (a) new use(s). Efficacy and safety have not been established. There is no guarantee that they will become commercially available for the use(s) under investigation. 

Study Description

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 
Acute Myeloid Leukemia
Allogeneic Stem Cell Transplantation
Phase 
Phase 1
Phase 2
Overall status 
Recruiting
Start date 
Jan 30, 2023
Completion date 
Mar 30, 2028
Gender 
All
Age(s)
18 Years and older (Adult, Older Adult)

Interventions

Drug
Siremadlin
30-40 mg QD siremadlin capsules, orally (1-5 days of 28 or 42 days cycle)

Eligibility 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.

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.

Study Locations

Israel
Novartis Investigative Site
Recruiting
Tel Aviv, 6423906
-
Israel
Italy
Novartis Investigative Site
Recruiting
Bologna, 40138
BO
Italy
Spain
Novartis Investigative Site
Recruiting
Sevilla, 41013
Andalucia
Spain

Contacts

Name: 
Novartis Pharmaceuticals
Phone: 
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