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

Phase 1

Terminated

Conditions: Acute Myeloid Leukemia
Allogeneic Stem Cell Transplantation

Interventions: Drug: Siremadlin

Registration Number: NCT05447663

Lead Sponsor: Novartis Pharmaceuticals

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.

Detailed Description: 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.

The primary purpose of the study was 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 was initially planned to enroll approximately 38 participants starting 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).

After enrolling 8 participants (at the starting dose 30 mg/day on days 1-5 of a 28-day treatment cycle) in part 1, Novartis took the decision to put the enrollment in permanent halt and terminate the siremadlin program. For that reason, the enrollment in part 2 will not be open. The Novartis decision was not driven by any safety concerns.

In part 1 approximately 12 participants were planned to 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 were planned to be treated for a maximum of 24 cycles.

In part 2, participants were planned to 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 were not eligible for the combination phase of siremadlin/DLI could continue priming phase with siremadlin monotherapy.

* A combination phase of siremadlin in combination with DLI (siremadlin/DLI) for participants who were eligible to receive DLI (up to a total of 3 combination cycles).

* A maintenance phase with siremadlin monotherapy.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 8

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Siremadlin (HDM201)	Siremadlin	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.

Primary Outcome Measures

Name	Time	Method
Rate of Dose Limiting Toxicities (DLTs) With Siremadlin Monotherapy in Part 1 (Dose Confirmation With Siremadlin Monotherapy)	from cycle 1 day 1 (C1D1) to end of Cycle 1 (cycle = 28days)	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.
Time to Dose Limiting Toxicity (DLT) With Siremadlin in Combination With Donor Lymphocyte Infusion (DLI), in Part 2	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	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.
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)	Over 6 months from start of study treatment strategy (part 2 - siremadlin/DLI treatment strategy)	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.

Secondary Outcome Measures

Name	Time	Method
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 )	Over 6 months from start of siremadlin monotherapy (part 1)	This involves evaluating the preliminary efficacy of siremadlin monotherapy at the recommended dose for part 2 on prevention of hematologic relapse
Time From Start of Study Treatment to the Date of First Documented Hematologic Relapse or Death Due to Any Cause, Whichever Occurs First	From start of study treatment to up to 36 months from last patient first treatment	Assessment of relapse free survival (RFS) in part 2
Cumulative Incidence of AML Relapse at 1 Year and 2 Years After Start of Study Treatment	1 year and 2 years after start of study treatment	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.
Time From Start of Study Treatment to the Date of Death From Any Cause	From start of study treatment to up to 36 months from last patient first treatment	Assessment of Overall survival (OS) in part 2
Incidence of Graft Versus Host Disease (GvHD)	From start of study treatment up to approx. 8 months	Incidence of grade III or IV acute GvHD, and moderate to severe chronic GvHD in part 1. Part 2 never started.
Percentage of Participants With Permanent Study Treatment Discontinuation Due to GvHD or Other Adverse Events	From start of study treatment up to approx. 8 months	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.
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	From start of treatment up to approx. 8 months	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.
Pharmacokinetic (PK) Characteristic AUC of Siremadlin	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]	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.
PK Characteristic Cmax of Siremadlin	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]	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.
PK Characteristic Tmax of Siremadlin	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]	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.
PK Characteristic Ctrough of Siremadlin	Cycle 1 Day 1, Cycle 1 Day 5 in part 1; [each cycle is 28 days]	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.