Trial Outcomes & Findings for A Study of Siremadlin Alone and in Combination With Donor Lymphocyte Infusion in Acute Myeloid Leukemia Post-allogeneic Stem Cell Transplant (NCT NCT05447663)

Last Updated: 2025-05-16

Results Overview

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.

Recruitment status

TERMINATED

Study phase

PHASE1/PHASE2

Target enrollment

8 participants

Primary outcome timeframe

from cycle 1 day 1 (C1D1) to end of Cycle 1 (cycle = 28days)

Results posted on

2025-05-16

Participant Flow

38 participants were planned to be enrolled; 12 participants in Part 1 and 26 participants in Part 2; however, due to permanent recruitment halt, the enrollment was stopped after the 1st dose escalation meeting. The study was conducted in 6 centers in 3 countries: Germany, Italy and Spain.

Prior to dosing at Cycle 1 Day 1, participants who fulfilled all the inclusion/exclusion criteria were enrolled via IRT and a treatment number was provided for the study treatment siremadlin.

Participant milestones

Participant milestones
Measure	Siremadlin (HDM201) 30mg Participants with AML post allogeneic stem cell transplantation (allo-SCT) received 30mg siremadlin monotherapy
Overall Study STARTED	8
Overall Study Entered Post-treatment Follow-up	7
Overall Study Did Not Enter Post-treatment Follow-up	1
Overall Study On 10mg (Due to Concomitant Medication to Prevent Overexposure)	1
Overall Study COMPLETED	0
Overall Study NOT COMPLETED	8

Reasons for withdrawal

Reasons for withdrawal
Measure	Siremadlin (HDM201) 30mg Participants with AML post allogeneic stem cell transplantation (allo-SCT) received 30mg siremadlin monotherapy
Overall Study Study terminated by Sponsor	5
Overall Study Death	2
Overall Study Withdrawal by Subject	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Siremadlin (HDM201) 30mg n=8 Participants Participants with AML post allogeneic stem cell transplantation (allo-SCT) received 30mg siremadlin monotherapy
Age, Continuous	52.0 years STANDARD_DEVIATION 17.96 • n=5 Participants
Sex: Female, Male Female	3 Participants n=5 Participants
Sex: Female, Male Male	5 Participants n=5 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	7 Participants n=5 Participants
Race/Ethnicity, Customized Hispanic or Latino	1 Participants n=5 Participants

PRIMARY outcome

Timeframe: from cycle 1 day 1 (C1D1) to end of Cycle 1 (cycle = 28days)

Population: Dose Determining Set (DDS): The Dose Determining Set (DDS) includes participants in the dose determination phase who met specific treatment cycles, exposure criteria, follow-up/DLT observation, and safety evaluations, or experienced a DLT during the observation period. Only the 30 mg siremadlin arm was opened for enrollment, and patients needing dose reduction during Cycle 1 were not analyzed separately.

Outcome measures

Outcome measures
Measure	Siremadlin (HDM201) 30mg n=7 Participants Participants with AML post allogeneic stem cell transplantation (allo-SCT) received 30mg siremadlin monotherapy in part 1	Siremadlin (HDM201) 30mg Participants with AML post allogeneic stem cell transplantation (allo-SCT) received 30mg siremadlin monotherapy
Rate of Dose Limiting Toxicities (DLTs) With Siremadlin Monotherapy in Part 1 (Dose Confirmation With Siremadlin Monotherapy)	1 Participants	—

PRIMARY outcome

Timeframe: 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

Population: Part 2 did not open for enrollment due to recruitment halt, so no data was analyzed hence no data to report.

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.

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: Over 6 months from start of study treatment strategy (part 2 - siremadlin/DLI treatment strategy)

Population: Part 2 did not open for enrollment due to recruitment halt, so no data was analyzed hence no data to report.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Over 6 months from start of siremadlin monotherapy (part 1)

Population: Participants who received siremadlin monotherapy at the recommended dose for Part 2. The recommended dose for Part 2 could not be determined and therefore there were no patients meeting the reporting criteria for this endpoint.

This involves evaluating the preliminary efficacy of siremadlin monotherapy at the recommended dose for part 2 on prevention of hematologic relapse

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From start of study treatment to up to 36 months from last patient first treatment

Population: Part 2 did not open for enrollment due to recruitment halt, so no data was analyzed hence no data to report.

Assessment of relapse free survival (RFS) in part 2

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 1 year and 2 years after start of study treatment

Population: Participants who received siremadlin at the recommended dose (RD) for Part 2 and had available efficacy data at 1 year and 2 years after start of study treatment. The RD for Part 2 could not be determined and there were no patients with efficacy data collected at 1 year and 2 years after start of study treatment. Therefore, there were no patients meeting the reporting criteria for this endpoint.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From start of study treatment to up to 36 months from last patient first treatment

Population: Part 2 did not open for enrollment due to recruitment halt, so no data was analyzed hence no data to report.

Assessment of Overall survival (OS) in part 2

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From start of study treatment up to approx. 8 months

Population: Safety Set: Safety set includes all participants from the Full Analysis Set (FAS), i.e. all participants who received any study drug (i.e., at least one dose of siremadlin with or without DLI). Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.

Incidence of grade III or IV acute GvHD, and moderate to severe chronic GvHD in part 1. Part 2 never started.

Outcome measures

Outcome measures
Measure	Siremadlin (HDM201) 30mg n=8 Participants Participants with AML post allogeneic stem cell transplantation (allo-SCT) received 30mg siremadlin monotherapy in part 1	Siremadlin (HDM201) 30mg Participants with AML post allogeneic stem cell transplantation (allo-SCT) received 30mg siremadlin monotherapy
Incidence of Graft Versus Host Disease (GvHD) Grade 3 acute GvHD	2 Participants	—
Incidence of Graft Versus Host Disease (GvHD) Moderate chronic GvHD	1 Participants	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Siremadlin (HDM201) 30mg n=8 Participants Participants with AML post allogeneic stem cell transplantation (allo-SCT) received 30mg siremadlin monotherapy in part 1	Siremadlin (HDM201) 30mg Participants with AML post allogeneic stem cell transplantation (allo-SCT) received 30mg siremadlin monotherapy
Percentage of Participants With Permanent Study Treatment Discontinuation Due to GvHD or Other Adverse Events	3 Participants	—

SECONDARY outcome

Timeframe: From start of treatment up to approx. 8 months

Population: Participants who received siremadlin monotherapy at the recommended dose for Part 2, and participants enrolled in Part 2. The recommended dose for Part 2 could not be determined and Part 2 was not opened, and therefore there were no patients meeting the reporting criteria for this endpoint.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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]

Population: Pharmacokinetic Analysis Set (PAS): PAS includes all participants in the safety set who provide at least one evaluable PK concentration of siremadlin. One participant from the 30mg cohort received a siremadlin reduced dose of 10 mg due to coadministration of a strong CYP3A4 inhibitor as per protocol.

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.

Outcome measures

Outcome measures
Measure	Siremadlin (HDM201) 30mg n=1 Participants Participants with AML post allogeneic stem cell transplantation (allo-SCT) received 30mg siremadlin monotherapy in part 1	Siremadlin (HDM201) 30mg n=7 Participants Participants with AML post allogeneic stem cell transplantation (allo-SCT) received 30mg siremadlin monotherapy
Pharmacokinetic (PK) Characteristic AUC of Siremadlin AUClast: Cycle 1 Day 1	1497 hr*ng/mL Geometric Coefficient of Variation NA NA: Data could not be analyzed as there was only 1 patient	3077 hr*ng/mL Geometric Coefficient of Variation 39.7
Pharmacokinetic (PK) Characteristic AUC of Siremadlin AUC0-8hr: Cycle 1 Day 1	446 hr*ng/mL Geometric Coefficient of Variation NA NA: Data could not be analyzed as there was only 1 patient	1187.1 hr*ng/mL Geometric Coefficient of Variation 39.8
Pharmacokinetic (PK) Characteristic AUC of Siremadlin AUClast: Cycle 1 Day 5	—	1880.7 hr*ng/mL Geometric Coefficient of Variation 31.2
Pharmacokinetic (PK) Characteristic AUC of Siremadlin AUC0-8hr: Cycle 1 Day 5	—	1894 hr*ng/mL Geometric Coefficient of Variation 30.3

SECONDARY outcome

Timeframe: 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]

Population: Pharmacokinetics Analysis Set (PAS): PAS includes all participants in the safety set who provide at least one evaluable PK concentration of siremadlin. One participant from the 30mg cohort received a siremadlin reduced dose of 10 mg due to coadministration of a strong CYP3A4 inhibitor as per protocol.

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.

Outcome measures

Outcome measures
Measure	Siremadlin (HDM201) 30mg n=1 Participants Participants with AML post allogeneic stem cell transplantation (allo-SCT) received 30mg siremadlin monotherapy in part 1	Siremadlin (HDM201) 30mg n=7 Participants Participants with AML post allogeneic stem cell transplantation (allo-SCT) received 30mg siremadlin monotherapy
PK Characteristic Cmax of Siremadlin Cycle 1 Day 1	73.6 ng/mL Geometric Coefficient of Variation NA NA: Data could not be analyzed as there was only 1 patient	207.68 ng/mL Geometric Coefficient of Variation 36.2
PK Characteristic Cmax of Siremadlin Cycle 1 Day 5	—	296.92 ng/mL Geometric Coefficient of Variation 30.4

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Siremadlin (HDM201) 30mg n=1 Participants Participants with AML post allogeneic stem cell transplantation (allo-SCT) received 30mg siremadlin monotherapy in part 1	Siremadlin (HDM201) 30mg n=7 Participants Participants with AML post allogeneic stem cell transplantation (allo-SCT) received 30mg siremadlin monotherapy
PK Characteristic Tmax of Siremadlin Cycle 1 Day	3.00 hour (hr) Interval 3.0 to 3.0	5.95 hour (hr) Interval 2.02 to 6.03
PK Characteristic Tmax of Siremadlin Cycle 1 Day 5	—	4.50 hour (hr) Interval 1.92 to 7.75

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Siremadlin (HDM201) 30mg n=1 Participants Participants with AML post allogeneic stem cell transplantation (allo-SCT) received 30mg siremadlin monotherapy in part 1	Siremadlin (HDM201) 30mg n=7 Participants Participants with AML post allogeneic stem cell transplantation (allo-SCT) received 30mg siremadlin monotherapy
PK Characteristic Ctrough of Siremadlin Cycle 1 Day 1 (Pre-dose)	0 ng/mL Standard Deviation 0	0 ng/mL Standard Deviation 0
PK Characteristic Ctrough of Siremadlin Cycle 1 Day 5 (Pre-dose)	—	146.77 ng/mL Standard Deviation 79.726

Adverse Events

Siremadlin (HDM201) 30mg

Serious events: 2 serious events

Other events: 8 other events

Deaths: 2 deaths

Serious adverse events

Serious adverse events
Measure	Siremadlin (HDM201) 30mg n=8 participants at risk Participants with AML post allogeneic stem cell transplantation (allo-SCT) received 30mg siremadlin monotherapy
Blood and lymphatic system disorders Thrombocytopenia	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Gastrointestinal disorders Diarrhoea	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Gastrointestinal disorders Oesophagitis	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
General disorders General physical health deterioration	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Infections and infestations Abdominal infection	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.

Other adverse events

Other adverse events
Measure	Siremadlin (HDM201) 30mg n=8 participants at risk Participants with AML post allogeneic stem cell transplantation (allo-SCT) received 30mg siremadlin monotherapy
Blood and lymphatic system disorders Anaemia	37.5% 3/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Blood and lymphatic system disorders Leukopenia	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Blood and lymphatic system disorders Neutropenia	75.0% 6/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Blood and lymphatic system disorders Thrombocytopenia	87.5% 7/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Cardiac disorders Tachycardia	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Ear and labyrinth disorders External ear pain	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Ear and labyrinth disorders Vertigo	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Eye disorders Corneal exfoliation	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Eye disorders Dry eye	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Eye disorders Eyelid oedema	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Gastrointestinal disorders Diarrhoea	50.0% 4/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Gastrointestinal disorders Nausea	50.0% 4/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Gastrointestinal disorders Vomiting	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
General disorders Fatigue	25.0% 2/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
General disorders Mucosal inflammation	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
General disorders Pyrexia	37.5% 3/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Immune system disorders Acute graft versus host disease	25.0% 2/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Immune system disorders Chronic graft versus host disease	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Infections and infestations COVID-19	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Infections and infestations Clostridium difficile colitis	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Infections and infestations Clostridium difficile infection	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Infections and infestations Nasopharyngitis	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Infections and infestations Oral herpes	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Infections and infestations Rhinitis	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Injury, poisoning and procedural complications Fall	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Injury, poisoning and procedural complications Lumbar vertebral fracture	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Injury, poisoning and procedural complications Upper limb fracture	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Investigations Alanine aminotransferase increased	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Investigations Aspartate aminotransferase increased	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Investigations Blood bilirubin increased	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Investigations Weight decreased	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Metabolism and nutrition disorders Hyperuricaemia	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Metabolism and nutrition disorders Hypoglycaemia	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Nervous system disorders Headache	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Nervous system disorders Psychomotor hyperactivity	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Psychiatric disorders Insomnia	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Reproductive system and breast disorders Endometrial thickening	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Reproductive system and breast disorders Vaginal haemorrhage	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Respiratory, thoracic and mediastinal disorders Dyspnoea	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Skin and subcutaneous tissue disorders Dermatitis	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Skin and subcutaneous tissue disorders Dry skin	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Skin and subcutaneous tissue disorders Pruritus	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Skin and subcutaneous tissue disorders Rash	37.5% 3/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
Vascular disorders Hypotension	12.5% 1/8 • Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after end of treatment (EOT) (responders and non-responders, regardless of when treatment was discontinued) were followed up to approx. 8 months to collect long term data survival including: survival, relapse/progression of the underlying hematologic disease. Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.

Additional Information

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Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of pooled data (i.e., data from all sites) in clinical trial or disclosure of trial results in their entirety.
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