Trial Outcomes & Findings for Phase 1b/2 Safety and Efficacy of APR-246 w/Azacitidine for tx of TP53 Mutant Myeloid Neoplasms (NCT NCT03072043)

NCT ID: NCT03072043

Last Updated: 2022-01-24

Results Overview

Maximum Tolerated Dose, defined as the dose level below which dose limiting toxicity (DLT) is manifested in ≥33% of the patients or at dose level 3 if DLT is manifested in \<33% of the patients.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

55 participants

Primary outcome timeframe

Up to 12 months

Results posted on

2022-01-24

Participant Flow

Participant milestones

Participant milestones
Measure	Phase 1b Dose Level 1 Participants treated at level 1: APR-246 50mg/kg lean body weight (LBW) + Azacitidine 75mg/m\^2	Phase 1B Dose Level 2 Participants treated at dose level 2: APR-246 75mg/kg lean body weight (LBW) + Azacitidine 75mg/m\^2	Phase 1B Dose Level 3 / Phase 2 MTD Participants treated at dose level 3/Phase 2 MTD : APR-246 100 mg/kg lean body weight (LBW) + Azacitidine 75mg/m\^2
Overall Study STARTED	3	3	49
Overall Study COMPLETED	3	3	40
Overall Study NOT COMPLETED	0	0	9

Reasons for withdrawal

Reasons for withdrawal
Measure	Phase 1b Dose Level 1 Participants treated at level 1: APR-246 50mg/kg lean body weight (LBW) + Azacitidine 75mg/m\^2	Phase 1B Dose Level 2 Participants treated at dose level 2: APR-246 75mg/kg lean body weight (LBW) + Azacitidine 75mg/m\^2	Phase 1B Dose Level 3 / Phase 2 MTD Participants treated at dose level 3/Phase 2 MTD : APR-246 100 mg/kg lean body weight (LBW) + Azacitidine 75mg/m\^2
Overall Study Death	0	0	3
Overall Study Adverse Event	0	0	2
Overall Study Withdrawal by Subject	0	0	4

Baseline Characteristics

Phase 1b/2 Safety and Efficacy of APR-246 w/Azacitidine for tx of TP53 Mutant Myeloid Neoplasms

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Phase 1B Dose Level 1 n=3 Participants Participants treated at level 1: APR-246 50mg/kg lean body weight (LBW) + Azacitidine 75mg/m\^2	Phase 1B Dos Level 2 n=3 Participants Participants treated at dose level 2: APR-246 75mg/kg lean body weight (LBW) + Azacitidine 75mg/m\^2	Phase 1B Dose Level 3/ MTD n=49 Participants Participants treated at dose level 3/MTD : APR-246 100 mg/kg lean body weight (LBW) + Azacitidine 75mg/m\^2	Total n=55 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	1 Participants n=5 Participants	1 Participants n=7 Participants	20 Participants n=5 Participants	22 Participants n=4 Participants
Age, Categorical >=65 years	2 Participants n=5 Participants	2 Participants n=7 Participants	29 Participants n=5 Participants	33 Participants n=4 Participants
Sex: Female, Male Female	2 Participants n=5 Participants	3 Participants n=7 Participants	24 Participants n=5 Participants	29 Participants n=4 Participants
Sex: Female, Male Male	1 Participants n=5 Participants	0 Participants n=7 Participants	25 Participants n=5 Participants	26 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants	4 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	3 Participants n=5 Participants	1 Participants n=7 Participants	45 Participants n=5 Participants	49 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants	2 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants	2 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants	2 Participants n=4 Participants
Race (NIH/OMB) White	2 Participants n=5 Participants	3 Participants n=7 Participants	42 Participants n=5 Participants	47 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants	4 Participants n=4 Participants
Region of Enrollment United States	3 participants n=5 Participants	3 participants n=7 Participants	49 participants n=5 Participants	55 participants n=4 Participants

PRIMARY outcome

Timeframe: Up to 12 months

Maximum Tolerated Dose, defined as the dose level below which dose limiting toxicity (DLT) is manifested in ≥33% of the patients or at dose level 3 if DLT is manifested in \<33% of the patients.

Outcome measures

Outcome measures
Measure	Phase 1b Dose Escalation n=12 Participants Participants will receive intravenous infusions of APR-246 as a lead-in phase on days -14 to -11 starting at Dose Level 1 prior to starting cycle #1 of combination therapy with azacitidine. Combination therapy will consist of APR-246 on days 1-4 and azacitidine on days 4-10 (or days 4-5 and 8-12) of a 28 day cycle. APR-246: Phase 1b: Dose escalation of APR-246 via intravenous (IV) infusion, with starting dose of 50 mg/kg lean body weight (LBW). Phase 2: APR-246 at maximum tolerated dose (MTD). Azacitidine: Azacitidine is administered subcutaneously (SC) or via IV at 75 mg/m\^2.	Phase 1B Dose Level 2 All participants treated at dose level 2: APR-246 75mg/kg lean body weight (LBW) + Azacitidine 75mg/m\^2	Phase 1B: Dose Level 3 / Phase 2 MTD All participants treated at dose level 3/ Phase 2 MTD : APR-246 100 mg/kg lean body weight (LBW) + Azacitidine 75mg/m\^2
Phase 1b: Maximum Tolerated Dose (MTD)	4500 mg/day	—	—

PRIMARY outcome

Timeframe: Up to 12 months

Population: 45 participants were evaluable for response

Complete Response Rate as defined by the 2006 International Working Group (IWG) criteria.

Outcome measures

Outcome measures
Measure	Phase 1b Dose Escalation n=45 Participants Participants will receive intravenous infusions of APR-246 as a lead-in phase on days -14 to -11 starting at Dose Level 1 prior to starting cycle #1 of combination therapy with azacitidine. Combination therapy will consist of APR-246 on days 1-4 and azacitidine on days 4-10 (or days 4-5 and 8-12) of a 28 day cycle. APR-246: Phase 1b: Dose escalation of APR-246 via intravenous (IV) infusion, with starting dose of 50 mg/kg lean body weight (LBW). Phase 2: APR-246 at maximum tolerated dose (MTD). Azacitidine: Azacitidine is administered subcutaneously (SC) or via IV at 75 mg/m\^2.	Phase 1B Dose Level 2 All participants treated at dose level 2: APR-246 75mg/kg lean body weight (LBW) + Azacitidine 75mg/m\^2	Phase 1B: Dose Level 3 / Phase 2 MTD All participants treated at dose level 3/ Phase 2 MTD : APR-246 100 mg/kg lean body weight (LBW) + Azacitidine 75mg/m\^2
Phase 2: Complete Response (CR) Rate	53 percentage of patients Interval 38.0 to 68.0	—	—

SECONDARY outcome

Timeframe: Up to 24 months

Population: 45 participants were evaluable for response.

Duration of response defined as the time between achieving response and progression of disease.

Outcome measures

Outcome measures
Measure	Phase 1b Dose Escalation n=45 Participants Participants will receive intravenous infusions of APR-246 as a lead-in phase on days -14 to -11 starting at Dose Level 1 prior to starting cycle #1 of combination therapy with azacitidine. Combination therapy will consist of APR-246 on days 1-4 and azacitidine on days 4-10 (or days 4-5 and 8-12) of a 28 day cycle. APR-246: Phase 1b: Dose escalation of APR-246 via intravenous (IV) infusion, with starting dose of 50 mg/kg lean body weight (LBW). Phase 2: APR-246 at maximum tolerated dose (MTD). Azacitidine: Azacitidine is administered subcutaneously (SC) or via IV at 75 mg/m\^2.	Phase 1B Dose Level 2 All participants treated at dose level 2: APR-246 75mg/kg lean body weight (LBW) + Azacitidine 75mg/m\^2	Phase 1B: Dose Level 3 / Phase 2 MTD All participants treated at dose level 3/ Phase 2 MTD : APR-246 100 mg/kg lean body weight (LBW) + Azacitidine 75mg/m\^2
Phase 2: Duration of Response	8 months Interval 6.5 to 11.2	—	—

SECONDARY outcome

Timeframe: Up to 24 months

Population: All participants who received at least one dose of study drug

OS:The length of time from the start of treatment until death by any cause.

Outcome measures

Outcome measures
Measure	Phase 1b Dose Escalation n=3 Participants Participants will receive intravenous infusions of APR-246 as a lead-in phase on days -14 to -11 starting at Dose Level 1 prior to starting cycle #1 of combination therapy with azacitidine. Combination therapy will consist of APR-246 on days 1-4 and azacitidine on days 4-10 (or days 4-5 and 8-12) of a 28 day cycle. APR-246: Phase 1b: Dose escalation of APR-246 via intravenous (IV) infusion, with starting dose of 50 mg/kg lean body weight (LBW). Phase 2: APR-246 at maximum tolerated dose (MTD). Azacitidine: Azacitidine is administered subcutaneously (SC) or via IV at 75 mg/m\^2.	Phase 1B Dose Level 2 n=3 Participants All participants treated at dose level 2: APR-246 75mg/kg lean body weight (LBW) + Azacitidine 75mg/m\^2	Phase 1B: Dose Level 3 / Phase 2 MTD n=49 Participants All participants treated at dose level 3/ Phase 2 MTD : APR-246 100 mg/kg lean body weight (LBW) + Azacitidine 75mg/m\^2
Overall Survival (OS)	14.6 months Interval 2.4 to 16.0	11.6 months Interval 6.3 to 13.7	10.4 months Interval 0.7 to 17.9

SECONDARY outcome

Timeframe: Up to 24 months

Population: 45 participants were evaluable for response

Proportion of participants achieving hematological improvement (HI), partial response (PR), complete response (CR), and/or marrow CR (mCR) by the IWG 2006 criteria.

Outcome measures

Outcome measures
Measure	Phase 1b Dose Escalation n=45 Participants Participants will receive intravenous infusions of APR-246 as a lead-in phase on days -14 to -11 starting at Dose Level 1 prior to starting cycle #1 of combination therapy with azacitidine. Combination therapy will consist of APR-246 on days 1-4 and azacitidine on days 4-10 (or days 4-5 and 8-12) of a 28 day cycle. APR-246: Phase 1b: Dose escalation of APR-246 via intravenous (IV) infusion, with starting dose of 50 mg/kg lean body weight (LBW). Phase 2: APR-246 at maximum tolerated dose (MTD). Azacitidine: Azacitidine is administered subcutaneously (SC) or via IV at 75 mg/m\^2.	Phase 1B Dose Level 2 All participants treated at dose level 2: APR-246 75mg/kg lean body weight (LBW) + Azacitidine 75mg/m\^2	Phase 1B: Dose Level 3 / Phase 2 MTD All participants treated at dose level 3/ Phase 2 MTD : APR-246 100 mg/kg lean body weight (LBW) + Azacitidine 75mg/m\^2
Phase 2: Overall Response Rate	87 percent of participants Interval 73.0 to 95.0	—	—

Adverse Events

Phase 1b Dose Level 1

Serious events: 3 serious events

Other events: 3 other events

Deaths: 1 deaths

Phase 1B Dose Level 2

Serious events: 1 serious events

Other events: 3 other events

Deaths: 1 deaths

Phase 1B Dose Level 3/Phase 2 MTD

Serious events: 30 serious events

Other events: 47 other events

Deaths: 36 deaths

Serious adverse events

Other adverse events

Additional Information

David Sallman, MD

Moffitt Cancer Center

Phone: 813-745-6841

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Serious adverse events
Measure	Phase 1b Dose Level 1 n=3 participants at risk All participants treated at dose level 1: APR-246 50 mg/kg lean body weight (LBW) + Azacitidine 75 mg/m\^2	Phase 1B Dose Level 2 n=3 participants at risk All participants treated at dose level 2: APR-246 75 mg/kg lean body weight (LBW) + Azacitidine 75 mg/m\^2	Phase 1B Dose Level 3/Phase 2 MTD n=49 participants at risk All participants treated at dose level 3 \& Phase 2: APR-246 100 mg/kg lean body weight (LBW) + Azacitidine 75 mg/m\^2
Blood and lymphatic system disorders Blood and Lymphatic system disorders -Other	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	2.0% 1/49 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Blood and lymphatic system disorders Febrile neutropenia	33.3% 1/3 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	34.7% 17/49 • Number of events 34 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Cardiac disorders Atrial fibrillation	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	4.1% 2/49 • Number of events 2 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Cardiac disorders Chest pain -cardiac	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	4.1% 2/49 • Number of events 2 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Cardiac disorders Pericardial effusion	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	4.1% 2/49 • Number of events 2 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Ear and labyrinth disorders Ear and labyrinth disorders -Other	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	2.0% 1/49 • Number of events 2 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Gastrointestinal disorders Gastrointestinal disorders -Other	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	2.0% 1/49 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Gastrointestinal disorders Vomiting	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	2.0% 1/49 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
General disorders Death NOS	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	2.0% 1/49 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
General disorders Infusion related reaction	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	2.0% 1/49 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
General disorders Multi organ failure	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	4.1% 2/49 • Number of events 2 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Infections and infestations Abdominal infection	33.3% 1/3 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/49 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Infections and infestations Bladder infection	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	2.0% 1/49 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Infections and infestations Infection and Infestations - Other	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	33.3% 1/3 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	14.3% 7/49 • Number of events 9 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Infections and infestations Lung infection	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	14.3% 7/49 • Number of events 7 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Infections and infestations Sepsis	33.3% 1/3 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	10.2% 5/49 • Number of events 5 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Infections and infestations Skin inefection	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	2.0% 1/49 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Injury, poisoning and procedural complications Ankle fracture	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	2.0% 1/49 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Investigations Creatinine increased	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	2.0% 1/49 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Metabolism and nutrition disorders Dehydration	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	6.1% 3/49 • Number of events 3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Musculoskeletal and connective tissue disorders Bone pain	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	2.0% 1/49 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Musculoskeletal and connective tissue disorders Chest wall pain	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	2.0% 1/49 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Musculoskeletal and connective tissue disorders Generalized muscle weakness	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	6.1% 3/49 • Number of events 3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Nervous system disorders Encephalopathy	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	2.0% 1/49 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Nervous system disorders Stroke	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	2.0% 1/49 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Renal and urinary disorders Acute kidney injury	33.3% 1/3 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/49 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Respiratory, thoracic and mediastinal disorders Adult respiratory distress syndrome	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	2.0% 1/49 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Respiratory, thoracic and mediastinal disorders Aspiration	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	2.0% 1/49 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Respiratory, thoracic and mediastinal disorders Bronchopulmonary hemorrhage	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	2.0% 1/49 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	4.1% 2/49 • Number of events 2 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Respiratory, thoracic and mediastinal disorders Respiratory, thoracic and mediastinal disorders - Other	66.7% 2/3 • Number of events 2 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	6.1% 3/49 • Number of events 3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Vascular disorders Hypotension	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	33.3% 1/3 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/49 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Vascular disorders Thromboembolic event	33.3% 1/3 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	6.1% 3/49 • Number of events 3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Vascular disorders Vascular disorders -Other	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	4.1% 2/49 • Number of events 2 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
General disorders Pain	33.3% 1/3 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/49 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Vascular disorders Vascular disorders - Other	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	2.0% 1/49 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.

Other adverse events
Measure	Phase 1b Dose Level 1 n=3 participants at risk All participants treated at dose level 1: APR-246 50 mg/kg lean body weight (LBW) + Azacitidine 75 mg/m\^2	Phase 1B Dose Level 2 n=3 participants at risk All participants treated at dose level 2: APR-246 75 mg/kg lean body weight (LBW) + Azacitidine 75 mg/m\^2	Phase 1B Dose Level 3/Phase 2 MTD n=49 participants at risk All participants treated at dose level 3 \& Phase 2: APR-246 100 mg/kg lean body weight (LBW) + Azacitidine 75 mg/m\^2
Gastrointestinal disorders Nausea	33.3% 1/3 • Number of events 2 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	66.7% 2/3 • Number of events 8 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	65.3% 32/49 • Number of events 57 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Eye disorders Blurry vision	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	33.3% 1/3 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/49 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
General disorders Fever	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	24.5% 12/49 • Number of events 16 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
General disorders Flu like symptoms	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	33.3% 1/3 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	2.0% 1/49 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
General disorders Gait disturbance	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	14.3% 7/49 • Number of events 18 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
General disorders Generalized edema	33.3% 1/3 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	2.0% 1/49 • Number of events 4 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
General disorders Pain -Side pain	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	4.1% 2/49 • Number of events 2 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
General disorders Pain -Hip	33.3% 1/3 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	8.2% 4/49 • Number of events 4 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
General disorders Pain- Jaw	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	33.3% 1/3 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/49 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
General disorders Pain -Shoulder	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	8.2% 4/49 • Number of events 4 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
General disorders Pain -Muscle	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	2.0% 1/49 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
General disorders Pain -Chest	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	2.0% 1/49 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Renal and urinary disorders Dysuria	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	6.1% 3/49 • Number of events 3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Hepatobiliary disorders Hepatobiliary disorders - Other	33.3% 1/3 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/49 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Hepatobiliary disorders Port vein thrombosis	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	4.1% 2/49 • Number of events 2 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Immune system disorders Allergic reaction including pruritis	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	4.1% 2/49 • Number of events 2 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Immune system disorders Allergic Reaction - swollen tongue	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	2.0% 1/49 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Infections and infestations Infections and Infestations - Other	100.0% 3/3 • Number of events 3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	33.3% 1/3 • Number of events 4 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	24.5% 12/49 • Number of events 17 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Infections and infestations Lung infection	33.3% 1/3 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	8.2% 4/49 • Number of events 4 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Infections and infestations Rhinitis, infective	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	2.0% 1/49 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Infections and infestations Sinusitis	33.3% 1/3 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	4.1% 2/49 • Number of events 2 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Infections and infestations Skin infection	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	2.0% 1/49 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Infections and infestations Tooth infection	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	4.1% 2/49 • Number of events 2 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Infections and infestations Upper respiratory infection	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	33.3% 1/3 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	8.2% 4/49 • Number of events 4 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Infections and infestations Urinary tract infection	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	8.2% 4/49 • Number of events 4 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Injury, poisoning and procedural complications Fall	33.3% 1/3 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	33.3% 1/3 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	14.3% 7/49 • Number of events 8 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Cardiac disorders Chest pain - cardiac	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	8.2% 4/49 • Number of events 4 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Cardiac disorders Heart palpitations	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	33.3% 1/3 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	8.2% 4/49 • Number of events 4 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Cardiac disorders Sinus tachycardia	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	10.2% 5/49 • Number of events 5 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Ear and labyrinth disorders Ear pain	33.3% 1/3 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/49 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Ear and labyrinth disorders Ear and labyrinth disorders -Other	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	2.0% 1/49 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Eye disorders Eye disorders - Other	33.3% 1/3 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	4.1% 2/49 • Number of events 2 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Gastrointestinal disorders Constipation	33.3% 1/3 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	42.9% 21/49 • Number of events 24 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Gastrointestinal disorders Diarrhea	33.3% 1/3 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	33.3% 1/3 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	30.6% 15/49 • Number of events 24 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Gastrointestinal disorders Dry mouth	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	66.7% 2/3 • Number of events 2 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/49 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Gastrointestinal disorders Enterocolitis	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	33.3% 1/3 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	2.0% 1/49 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Gastrointestinal disorders Fecal incontinence	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	2.0% 1/49 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Gastrointestinal disorders Mucositis oral	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	66.7% 2/3 • Number of events 2 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	16.3% 8/49 • Number of events 10 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
Gastrointestinal disorders Vomiting	33.3% 1/3 • Number of events 1 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	33.3% 1/3 • Number of events 5 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	44.9% 22/49 • Number of events 37 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.
General disorders Edema- limbs	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	0.00% 0/3 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.	36.7% 18/49 • Number of events 21 • 2 years, 10 months All Serious Adverse Events are reported, regardless of causality. Serious Adverse Events were reported during screening period and within 100 days of discontinuation of dosing.