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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/study/NCT05447663
Registration number
NCT05447663
Ethics application status
Date submitted
28/06/2022
Date registered
7/07/2022
Date last updated
16/05/2025
Titles & IDs
Public title
A Study of Siremadlin Alone and in Combination With Donor Lymphocyte Infusion in Acute Myeloid Leukemia Post-allogeneic Stem Cell Transplant
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Scientific title
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.
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Secondary ID [1]
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2021-003596-34
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Secondary ID [2]
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CHDM201K12201
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Acute Myeloid Leukemia
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Allogeneic Stem Cell Transplantation
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Condition category
Condition code
Cancer
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Leukaemia - Acute leukaemia
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Cancer
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Leukaemia - Chronic leukaemia
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Cancer
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Children's - Leukaemia & Lymphoma
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Siremadlin
Experimental: Siremadlin (HDM201) - Participants with AML post allogeneic stem cell transplantation (allo-SCT) received siremadlin monotherapy in part 1 and were to have received siremadlin monotherapy as well as in combination with donor lymphocyte infusion in part 2.
Treatment: Drugs: Siremadlin
Siremadlin was administered at a starting dose of 30 mg/day on days 1-5 of a 28-day treatment cycle (Part 1).
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Rate of Dose Limiting Toxicities (DLTs) With Siremadlin Monotherapy in Part 1 (Dose Confirmation With Siremadlin Monotherapy)
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Assessment method [1]
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To determine the dose and schedule of siremadlin monotherapy that are tolerable without unacceptable toxicities as defined by the incidence of DLT during the first cycle of treatment in part 1. 'A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value assessed, by the Investigator, to be at least possibly related to study treatment (siremadlin monotherapy and/or siremadlin in combination with Donor lymphocyte infusion (DLI)), and as unrelated to disease, disease progression, inter-current illness, or concomitant medications, that occurs during the DLT observation period and meets severity criteria as per protocol.
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Timepoint [1]
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from cycle 1 day 1 (C1D1) to end of Cycle 1 (cycle = 28days)
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Primary outcome [2]
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Time to Dose Limiting Toxicity (DLT) With Siremadlin in Combination With Donor Lymphocyte Infusion (DLI), in Part 2
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Assessment method [2]
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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.
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Timepoint [2]
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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
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Primary outcome [3]
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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 (Part 2)
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Assessment method [3]
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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.
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Timepoint [3]
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Over 6 months from start of study treatment strategy (part 2 - siremadlin/DLI treatment strategy)
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Secondary outcome [1]
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Participants Who Are Alive and Maintained CR or CRi With no Evidence of Hematologic Relapse (Part 1 -Siremadlin Monotherapy at the Recommended Dose for Part 2 )
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Assessment method [1]
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This involves evaluating the preliminary efficacy of siremadlin monotherapy at the recommended dose for part 2 on prevention of hematologic relapse
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Timepoint [1]
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Over 6 months from start of siremadlin monotherapy (part 1)
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Secondary outcome [2]
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Time From Start of Study Treatment to the Date of First Documented Hematologic Relapse or Death Due to Any Cause, Whichever Occurs First
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Assessment method [2]
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Assessment of relapse free survival (RFS) in part 2
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Timepoint [2]
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From start of study treatment to up to 36 months from last patient first treatment
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Secondary outcome [3]
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Cumulative Incidence of AML Relapse at 1 Year and 2 Years After Start of Study Treatment
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Assessment method [3]
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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. Cumulative incidence of relapse (CIR) is defined as the time from start of study treatment to the date of first documented hematologic relapse. CIR was to be analyzed in the FAS population who initiated priming phase at siremadlin recommended dose (RD) in Part 2 and participants at the RD in Part 1.
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Timepoint [3]
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1 year and 2 years after start of study treatment
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Secondary outcome [4]
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Time From Start of Study Treatment to the Date of Death From Any Cause
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Assessment method [4]
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Assessment of Overall survival (OS) in part 2
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Timepoint [4]
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From start of study treatment to up to 36 months from last patient first treatment
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Secondary outcome [5]
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Incidence of Graft Versus Host Disease (GvHD)
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Assessment method [5]
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Incidence of grade III or IV acute GvHD, and moderate to severe chronic GvHD in part 1. Part 2 never started.
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Timepoint [5]
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From start of study treatment up to approx. 8 months
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Secondary outcome [6]
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Percentage of Participants With Permanent Study Treatment Discontinuation Due to GvHD or Other Adverse Events
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Assessment method [6]
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Percentage of participants with permanent discontinuation of study treatment due to GvHD or other adverse events in part 1. As part 2 was not started, there were no participants to analyze in part 2.
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Timepoint [6]
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From start of study treatment up to approx. 8 months
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Secondary outcome [7]
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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
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Assessment method [7]
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Assessment of GvHD-free/relapse-free survival (GRPF) in Part 1 and 2. According to the study protocol, time-to-event endpoints in Part 1 were planned to be analyzed using Kaplan-Meier method only for participants who received siremadlin at the recommended dose for Part 2.
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Timepoint [7]
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From start of treatment up to approx. 8 months
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Secondary outcome [8]
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Pharmacokinetic (PK) Characteristic AUC of Siremadlin
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Assessment method [8]
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AUC is the area under the concentration vs. time curve in part 1 and was based on plasma concentration. Part 2 did not open for enrollment due to recruitment halt and so no data was analyzed. AUClast: The AUC from time zero to the last quantifiable concentration point (Tlast) (mass x time x volume-1). AUC0-t: The area under the concentration vs. time Curve (AUC) from time zero to specified time point.
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Timepoint [8]
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AUC from time 0 to 8hr postdose, AUC0- 8hr (Cycle 1 Day 1, Cycle 1 Day 5) in part 1 [each cycle is 28 days for monotherapy]
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Secondary outcome [9]
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PK Characteristic Cmax of Siremadlin
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Assessment method [9]
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The maximum (peak) observed plasma drug concentration following drug administration (mass x volume\^-1) in part 1. Part 2 did not open for enrollment due to recruitment halt and so no data was analyzed.
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Timepoint [9]
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from 0 to 24 hrs post-dose (Cycle 1 Day 1), from 0 to 8 hr post-dose (Cycle 1 Day 5) in part 1 [each cycle is 28 days for monotherapy]
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Secondary outcome [10]
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PK Characteristic Tmax of Siremadlin
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Assessment method [10]
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The time to reach maximum (peak) plasma drug concentration after drug administration (time) in part 1. Part 2 did not open for enrollment due to recruitment halt and so no data was analyzed.
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Timepoint [10]
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from 0 to 24 hrs post-dose (Cycle 1 Day 1), from 0 to 8 hr post-dose (Cycle 1 Day 5) in part 1 [each cycle is 28 days for monotherapy]
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Secondary outcome [11]
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PK Characteristic Ctrough of Siremadlin
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Assessment method [11]
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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. Part 2 never started.
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Timepoint [11]
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Cycle 1 Day 1, Cycle 1 Day 5 in part 1; [each cycle is 28 days]
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Eligibility
Key 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)
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Minimum age
18
Years
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Maximum age
100
Years
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
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
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Not applicable
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Single group
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Other design features
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Phase
Phase 1
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Stopped early
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
23/02/2023
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
26/10/2023
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Sample size
Target
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Accrual to date
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Final
8
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Recruitment in Australia
Recruitment state(s)
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Recruitment outside Australia
Country [1]
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Germany
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State/province [1]
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Augsburg
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Country [2]
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Germany
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State/province [2]
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Freiburg
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Country [3]
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Italy
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State/province [3]
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BG
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Country [4]
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Italy
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State/province [4]
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BO
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Country [5]
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Spain
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State/province [5]
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Andalucia
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Country [6]
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Spain
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State/province [6]
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Valencia
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Funding & Sponsors
Primary sponsor type
Commercial sector/industry
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Name
Novartis Pharmaceuticals
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Address
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Country
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Ethics approval
Ethics application status
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Summary
Brief summary
The purpose of this study was 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 Acute Myeloid Leukemia (AML) who were in remission following allogeneic stem cell transplantation (allo-SCT) but were at high risk for relapse based on the presence of pre-transplant risk factors.
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Trial website
https://clinicaltrials.gov/study/NCT05447663
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Trial related presentations / publications
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Public notes
This record is viewable in the ANZCTR as it had previously listed Australia and/or New Zealand as a recruitment site, however these sites have since been removed
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Contacts
Principal investigator
Name
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Novartis Pharmaceuticals
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Address
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Novartis Pharmaceuticals
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Country
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Novartis Pharmaceuticals
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Address
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Country
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Phone
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1-888-669-6682
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Fax
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Email
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[email protected]
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Contact person for scientific queries
Data sharing statement
What supporting documents are/will be available?
No Supporting Document Provided
Type
Other Details
Attachment
Study protocol
https://cdn.clinicaltrials.gov/large-docs/63/NCT05447663/Prot_000.pdf
Statistical analysis plan
https://cdn.clinicaltrials.gov/large-docs/63/NCT05447663/SAP_001.pdf
Results publications and other study-related documents
No documents have been uploaded by study researchers.
Results are available at
https://clinicaltrials.gov/study/NCT05447663
Download to PDF