Trial Outcomes & Findings for APR-246 in Combination With Venetoclax and Azacitidine in TP53-Mutant Myeloid Malignancies (NCT NCT04214860)
NCT ID: NCT04214860
Last Updated: 2025-03-17
Results Overview
1\. Dose-limiting toxicities (DLTs), classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 5.0).
Recruitment status
COMPLETED
Study phase
PHASE1
Target enrollment
51 participants
Primary outcome timeframe
From baseline until event occures, i.e. through study completion, an average of 1 year
Results posted on
2025-03-17
Participant Flow
Cohort 2 APR-246 + VEN + AZA Safey Lead-In and Expansion data was combined for reporting purposes.
Participant milestones
| Measure |
Cohort 1
APR-246 4.5 g/day
APR-246: APR-246 4.5 g/day day 1-4
Venetoclax: Venetoclax 400 mg once daily days 1-28
Safety Lead-In
|
Cohort 2
PR-246 4.5 g/day
APR-246: APR-246 4.5 g/day day 1-4
Venetoclax: Venetoclax 400 mg once daily days 1-28
Azacitidine: Azacitidine 75 mg/m² on days 1-7.
Safety Lead-In + Expansion
|
|---|---|---|
|
Overall Study
STARTED
|
6
|
45
|
|
Overall Study
COMPLETED
|
6
|
43
|
|
Overall Study
NOT COMPLETED
|
0
|
2
|
Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
APR-246 in Combination With Venetoclax and Azacitidine in TP53-Mutant Myeloid Malignancies
Baseline characteristics by cohort
| Measure |
Cohort 1
n=6 Participants
APR-246 4.5 g/day
APR-246: APR-246 4.5 g/day
Venetoclax: Venetoclax 400 mg once daily
|
Cohort 2
n=43 Participants
APR-246 4.5 g/day
APR-246: APR-246 4.5 g/day
Venetoclax: Venetoclax 400 mg once daily
Azacitidine: Subcutaneous injection, or intravenous infusion
|
Total
n=49 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
|
|
Age, Categorical
Between 18 and 65 years
|
2 Participants
n=5 Participants
|
16 Participants
n=7 Participants
|
18 Participants
n=5 Participants
|
|
Age, Categorical
>=65 years
|
4 Participants
n=5 Participants
|
27 Participants
n=7 Participants
|
31 Participants
n=5 Participants
|
|
Age, Continuous
|
69 years
n=5 Participants
|
67 years
n=7 Participants
|
67 years
n=5 Participants
|
|
Sex: Female, Male
Female
|
4 Participants
n=5 Participants
|
20 Participants
n=7 Participants
|
24 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
2 Participants
n=5 Participants
|
23 Participants
n=7 Participants
|
25 Participants
n=5 Participants
|
|
Race (NIH/OMB)
American Indian or Alaska Native
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Asian
|
1 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
1 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
|
0 Participants
n=5 Participants
|
1 Participants
n=7 Participants
|
1 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Black or African American
|
1 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
1 Participants
n=5 Participants
|
|
Race (NIH/OMB)
White
|
3 Participants
n=5 Participants
|
37 Participants
n=7 Participants
|
40 Participants
n=5 Participants
|
|
Race (NIH/OMB)
More than one race
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Unknown or Not Reported
|
1 Participants
n=5 Participants
|
5 Participants
n=7 Participants
|
6 Participants
n=5 Participants
|
|
Region of Enrollment
United States
|
6 participants
n=5 Participants
|
43 participants
n=7 Participants
|
49 participants
n=5 Participants
|
PRIMARY outcome
Timeframe: From baseline until event occures, i.e. through study completion, an average of 1 year1\. Dose-limiting toxicities (DLTs), classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 5.0).
Outcome measures
| Measure |
Cohort 1
n=6 Participants
APR-246 4.5 g/day
APR-246: APR-246 4.5 g/day day 1-4
Venetoclax: Venetoclax 400 mg once daily days 1-28
|
Cohort 2
n=43 Participants
PR-246 4.5 g/day
APR-246: APR-246 4.5 g/day day 1-4
Venetoclax: Venetoclax 400 mg once daily days 1-28
Azacitidine: Azacitidine 75 mg/m² on days 1-7.
|
|---|---|---|
|
To Evaluate the Tolerabililty and the Incidence of Treatment-Emergent Adverse Events of Administration of APR 246 in Combination With Venetoclax and Azacitidine in Patients With TP53 Mutant Myeloid Malignancies.
|
0 DLTs
|
0 DLTs
|
PRIMARY outcome
Timeframe: From baseline until event occures, i.e. through study completion, an average of 1 yearPopulation: Any Serious TEAEs
2\. Frequency of treatment-emergent adverse events (TEAEs), and serious adverse events (SAEs) related to APR-246 in combination with venetoclax and azacitidine during the trial.
Outcome measures
| Measure |
Cohort 1
n=6 Participants
APR-246 4.5 g/day
APR-246: APR-246 4.5 g/day day 1-4
Venetoclax: Venetoclax 400 mg once daily days 1-28
|
Cohort 2
n=43 Participants
PR-246 4.5 g/day
APR-246: APR-246 4.5 g/day day 1-4
Venetoclax: Venetoclax 400 mg once daily days 1-28
Azacitidine: Azacitidine 75 mg/m² on days 1-7.
|
|---|---|---|
|
To Evaluate the Tolerabililty and the Incidence of Treatment-Emergent Adverse Events of Administration of APR 246 in Combination With Venetoclax and Azacitidine in Patients With TP53 Mutant Myeloid Malignancies.
|
5 Participants
|
32 Participants
|
Adverse Events
Cohort 1
Serious events: 5 serious events
Other events: 6 other events
Deaths: 6 deaths
Cohort 2
Serious events: 32 serious events
Other events: 43 other events
Deaths: 26 deaths
Serious adverse events
| Measure |
Cohort 1
n=6 participants at risk
APR-246 4.5 g/day
APR-246: APR-246 4.5 g/day
Venetoclax: Venetoclax 400 mg once daily
|
Cohort 2
n=43 participants at risk
APR-246 4.5 g/day
APR-246: APR-246 4.5 g/day
Venetoclax: Venetoclax 400 mg once daily
Azacitidine: Subcutaneous injection, or intravenous infusion
|
|---|---|---|
|
Infections and infestations
Pneumonia
|
0.00%
0/6 • 18 months
|
14.0%
6/43 • 18 months
|
|
Infections and infestations
Sepsis
|
33.3%
2/6 • 18 months
|
9.3%
4/43 • 18 months
|
|
Infections and infestations
Diverticulitis
|
0.00%
0/6 • 18 months
|
4.7%
2/43 • 18 months
|
|
Infections and infestations
abdominal abscess
|
0.00%
0/6 • 18 months
|
2.3%
1/43 • 18 months
|
|
Infections and infestations
Bacteremia
|
0.00%
0/6 • 18 months
|
2.3%
1/43 • 18 months
|
|
Infections and infestations
Cellulitis
|
0.00%
0/6 • 18 months
|
2.3%
1/43 • 18 months
|
|
Infections and infestations
Clostridium difficile colitis
|
0.00%
0/6 • 18 months
|
2.3%
1/43 • 18 months
|
|
Infections and infestations
Fungal Infection
|
0.00%
0/6 • 18 months
|
2.3%
1/43 • 18 months
|
|
Infections and infestations
Infusion Site Infection
|
0.00%
0/6 • 18 months
|
2.3%
1/43 • 18 months
|
|
Infections and infestations
Periorbital Celluitis
|
0.00%
0/6 • 18 months
|
2.3%
1/43 • 18 months
|
|
Infections and infestations
Septic Shock
|
0.00%
0/6 • 18 months
|
2.3%
1/43 • 18 months
|
|
Infections and infestations
Sinusitis Fungal Infection
|
0.00%
0/6 • 18 months
|
2.3%
1/43 • 18 months
|
|
Infections and infestations
Parotitis
|
16.7%
1/6 • 18 months
|
0.00%
0/43 • 18 months
|
|
Infections and infestations
Respiratory Syncytial Virus Infection
|
16.7%
1/6 • 18 months
|
0.00%
0/43 • 18 months
|
|
Blood and lymphatic system disorders
Febrile Neutropenia
|
33.3%
2/6 • 18 months
|
30.2%
13/43 • 18 months
|
|
Blood and lymphatic system disorders
Anemia
|
0.00%
0/6 • 18 months
|
2.3%
1/43 • 18 months
|
|
Gastrointestinal disorders
Nausea
|
0.00%
0/6 • 18 months
|
7.0%
3/43 • 18 months
|
|
Gastrointestinal disorders
Vomiting
|
0.00%
0/6 • 18 months
|
4.7%
2/43 • 18 months
|
|
Gastrointestinal disorders
Abdominal Pain
|
0.00%
0/6 • 18 months
|
2.3%
1/43 • 18 months
|
|
Gastrointestinal disorders
Inguinal Hernia
|
0.00%
0/6 • 18 months
|
2.3%
1/43 • 18 months
|
|
Gastrointestinal disorders
Obstruction Gastric
|
0.00%
0/6 • 18 months
|
2.3%
1/43 • 18 months
|
|
Gastrointestinal disorders
Rectal Hemorrhage
|
0.00%
0/6 • 18 months
|
2.3%
1/43 • 18 months
|
|
Gastrointestinal disorders
Diarrhea
|
16.7%
1/6 • 18 months
|
0.00%
0/43 • 18 months
|
|
Gastrointestinal disorders
Upper Gastrointestinal Hemorrhage
|
16.7%
1/6 • 18 months
|
0.00%
0/43 • 18 months
|
|
General disorders
Disease progression
|
16.7%
1/6 • 18 months
|
2.3%
1/43 • 18 months
|
|
General disorders
Mucosal Inflammation
|
16.7%
1/6 • 18 months
|
2.3%
1/43 • 18 months
|
|
General disorders
Death
|
0.00%
0/6 • 18 months
|
2.3%
1/43 • 18 months
|
|
General disorders
Gait Disturbance
|
0.00%
0/6 • 18 months
|
2.3%
1/43 • 18 months
|
|
General disorders
Pyrexia
|
0.00%
0/6 • 18 months
|
2.3%
1/43 • 18 months
|
|
Cardiac disorders
Angina Pectoris
|
0.00%
0/6 • 18 months
|
2.3%
1/43 • 18 months
|
|
Cardiac disorders
Cardiac Arrest
|
0.00%
0/6 • 18 months
|
2.3%
1/43 • 18 months
|
|
Cardiac disorders
Myocardial Infarction
|
0.00%
0/6 • 18 months
|
2.3%
1/43 • 18 months
|
|
Cardiac disorders
Pericarditis
|
0.00%
0/6 • 18 months
|
2.3%
1/43 • 18 months
|
|
Cardiac disorders
Tachycaridia
|
16.7%
1/6 • 18 months
|
0.00%
0/43 • 18 months
|
|
Respiratory, thoracic and mediastinal disorders
Acute Respiratory distress Syndrome
|
0.00%
0/6 • 18 months
|
4.7%
2/43 • 18 months
|
|
Respiratory, thoracic and mediastinal disorders
Dyspnoea
|
0.00%
0/6 • 18 months
|
2.3%
1/43 • 18 months
|
|
Respiratory, thoracic and mediastinal disorders
Pulmonary Mass
|
0.00%
0/6 • 18 months
|
2.3%
1/43 • 18 months
|
|
Respiratory, thoracic and mediastinal disorders
Respiratory Failure
|
16.7%
1/6 • 18 months
|
0.00%
0/43 • 18 months
|
|
Metabolism and nutrition disorders
Hyperphosphatemia
|
16.7%
1/6 • 18 months
|
2.3%
1/43 • 18 months
|
|
Metabolism and nutrition disorders
Failure to Thrive
|
0.00%
0/6 • 18 months
|
2.3%
1/43 • 18 months
|
|
Metabolism and nutrition disorders
Tumor Lysis Syndrome
|
0.00%
0/6 • 18 months
|
2.3%
1/43 • 18 months
|
|
Metabolism and nutrition disorders
Hypocalcemia
|
16.7%
1/6 • 18 months
|
0.00%
0/43 • 18 months
|
|
Metabolism and nutrition disorders
Hyperkelaemia
|
16.7%
1/6 • 18 months
|
0.00%
0/43 • 18 months
|
|
Musculoskeletal and connective tissue disorders
Muscular Weakness
|
16.7%
1/6 • 18 months
|
4.7%
2/43 • 18 months
|
|
Musculoskeletal and connective tissue disorders
Pain in extremity
|
0.00%
0/6 • 18 months
|
2.3%
1/43 • 18 months
|
|
Musculoskeletal and connective tissue disorders
Neck Pain
|
16.7%
1/6 • 18 months
|
0.00%
0/43 • 18 months
|
|
Nervous system disorders
Ataxia
|
0.00%
0/6 • 18 months
|
2.3%
1/43 • 18 months
|
|
Nervous system disorders
Syncope
|
0.00%
0/6 • 18 months
|
2.3%
1/43 • 18 months
|
|
Nervous system disorders
Tremor
|
0.00%
0/6 • 18 months
|
2.3%
1/43 • 18 months
|
|
Nervous system disorders
Hemorrahge intracranial
|
16.7%
1/6 • 18 months
|
0.00%
0/43 • 18 months
|
|
Psychiatric disorders
Confusional State
|
0.00%
0/6 • 18 months
|
4.7%
2/43 • 18 months
|
|
Psychiatric disorders
Delirium
|
0.00%
0/6 • 18 months
|
2.3%
1/43 • 18 months
|
|
Injury, poisoning and procedural complications
Subdural Harmatoma
|
0.00%
0/6 • 18 months
|
4.7%
2/43 • 18 months
|
|
Investigations
Blood Creatinine Increased
|
0.00%
0/6 • 18 months
|
2.3%
1/43 • 18 months
|
|
Investigations
Blood bilirubin Increased
|
16.7%
1/6 • 18 months
|
0.00%
0/43 • 18 months
|
|
Renal and urinary disorders
Nephrolithiasis
|
0.00%
0/6 • 18 months
|
2.3%
1/43 • 18 months
|
|
Renal and urinary disorders
Acute Kidney Injury
|
16.7%
1/6 • 18 months
|
0.00%
0/43 • 18 months
|
|
Hepatobiliary disorders
Cholecystitis
|
0.00%
0/6 • 18 months
|
2.3%
1/43 • 18 months
|
|
Immune system disorders
Cytokine release syndorme
|
0.00%
0/6 • 18 months
|
2.3%
1/43 • 18 months
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute Myeloid Leukemia
|
0.00%
0/6 • 18 months
|
2.3%
1/43 • 18 months
|
|
Skin and subcutaneous tissue disorders
Acute Febrile Neutrophilic Deramotsis
|
0.00%
0/6 • 18 months
|
2.3%
1/43 • 18 months
|
|
Vascular disorders
Hypotension
|
0.00%
0/6 • 18 months
|
2.3%
1/43 • 18 months
|
Other adverse events
| Measure |
Cohort 1
n=6 participants at risk
APR-246 4.5 g/day
APR-246: APR-246 4.5 g/day
Venetoclax: Venetoclax 400 mg once daily
|
Cohort 2
n=43 participants at risk
APR-246 4.5 g/day
APR-246: APR-246 4.5 g/day
Venetoclax: Venetoclax 400 mg once daily
Azacitidine: Subcutaneous injection, or intravenous infusion
|
|---|---|---|
|
Gastrointestinal disorders
Nasuea
|
100.0%
6/6 • 18 months
|
62.8%
27/43 • 18 months
|
|
Gastrointestinal disorders
Diarrhea
|
50.0%
3/6 • 18 months
|
55.8%
24/43 • 18 months
|
|
Gastrointestinal disorders
Vomiting
|
50.0%
3/6 • 18 months
|
46.5%
20/43 • 18 months
|
|
Blood and lymphatic system disorders
Febrile Neutropenia
|
66.7%
4/6 • 18 months
|
44.2%
19/43 • 18 months
|
|
Gastrointestinal disorders
Decreased Appetite
|
33.3%
2/6 • 18 months
|
41.9%
18/43 • 18 months
|
|
Gastrointestinal disorders
Constipation
|
50.0%
3/6 • 18 months
|
34.9%
15/43 • 18 months
|
|
Metabolism and nutrition disorders
Hypokalemia
|
50.0%
3/6 • 18 months
|
32.6%
14/43 • 18 months
|
|
Investigations
Platelet Count Decreased
|
33.3%
2/6 • 18 months
|
32.6%
14/43 • 18 months
|
|
Nervous system disorders
Dizziness
|
50.0%
3/6 • 18 months
|
30.2%
13/43 • 18 months
|
|
General disorders
Edema Peripheral
|
50.0%
3/6 • 18 months
|
30.2%
13/43 • 18 months
|
|
Vascular disorders
Hypotension
|
33.3%
2/6 • 18 months
|
30.2%
13/43 • 18 months
|
|
Blood and lymphatic system disorders
Anemia
|
16.7%
1/6 • 18 months
|
27.9%
12/43 • 18 months
|
|
Respiratory, thoracic and mediastinal disorders
Cough
|
66.7%
4/6 • 18 months
|
23.3%
10/43 • 18 months
|
|
General disorders
Fatgiue
|
33.3%
2/6 • 18 months
|
25.6%
11/43 • 18 months
|
|
Investigations
White Blood Cell Count Deceased
|
0.00%
0/6 • 18 months
|
27.9%
12/43 • 18 months
|
|
Infections and infestations
Pneumonia
|
33.3%
2/6 • 18 months
|
23.3%
10/43 • 18 months
|
|
Nervous system disorders
Headache
|
50.0%
3/6 • 18 months
|
20.9%
9/43 • 18 months
|
|
Metabolism and nutrition disorders
Hypophosphataemia
|
33.3%
2/6 • 18 months
|
20.9%
9/43 • 18 months
|
|
Metabolism and nutrition disorders
Hyponatraemia
|
50.0%
3/6 • 18 months
|
18.6%
8/43 • 18 months
|
|
Musculoskeletal and connective tissue disorders
Back pain
|
16.7%
1/6 • 18 months
|
20.9%
9/43 • 18 months
|
|
General disorders
chills
|
16.7%
1/6 • 18 months
|
20.9%
9/43 • 18 months
|
|
Musculoskeletal and connective tissue disorders
Arthralgia
|
33.3%
2/6 • 18 months
|
18.6%
8/43 • 18 months
|
|
Investigations
Neutrophil count decreased
|
33.3%
2/6 • 18 months
|
18.6%
8/43 • 18 months
|
|
Nervous system disorders
tremor
|
33.3%
2/6 • 18 months
|
18.6%
8/43 • 18 months
|
|
Psychiatric disorders
Confusional State
|
16.7%
1/6 • 18 months
|
18.6%
8/43 • 18 months
|
|
Cardiac disorders
Sinus Tachycardia
|
16.7%
1/6 • 18 months
|
18.6%
8/43 • 18 months
|
|
Metabolism and nutrition disorders
Hypomagnesaemia
|
33.3%
2/6 • 18 months
|
16.3%
7/43 • 18 months
|
|
Psychiatric disorders
Insomnia
|
50.0%
3/6 • 18 months
|
14.0%
6/43 • 18 months
|
|
Blood and lymphatic system disorders
Neutropenia
|
0.00%
0/6 • 18 months
|
18.6%
8/43 • 18 months
|
|
Skin and subcutaneous tissue disorders
contusion
|
33.3%
2/6 • 18 months
|
14.0%
6/43 • 18 months
|
|
Metabolism and nutrition disorders
Hyperphospataemia
|
33.3%
2/6 • 18 months
|
14.0%
6/43 • 18 months
|
|
Gastrointestinal disorders
Abdominal Distension
|
0.00%
0/6 • 18 months
|
16.3%
7/43 • 18 months
|
|
Gastrointestinal disorders
Dysgeusia
|
0.00%
0/6 • 18 months
|
16.3%
7/43 • 18 months
|
|
Respiratory, thoracic and mediastinal disorders
Dyspnoea
|
50.0%
3/6 • 18 months
|
11.6%
5/43 • 18 months
|
|
Injury, poisoning and procedural complications
Fall
|
0.00%
0/6 • 18 months
|
16.3%
7/43 • 18 months
|
|
Musculoskeletal and connective tissue disorders
Muscular Weakness
|
50.0%
3/6 • 18 months
|
11.6%
5/43 • 18 months
|
|
Gastrointestinal disorders
Abdominal Pain
|
16.7%
1/6 • 18 months
|
14.0%
6/43 • 18 months
|
|
General disorders
Gait Disturbance
|
16.7%
1/6 • 18 months
|
14.0%
6/43 • 18 months
|
|
Infections and infestations
Rhinorrhoea
|
16.7%
1/6 • 18 months
|
14.0%
6/43 • 18 months
|
|
Infections and infestations
Sepsis
|
33.3%
2/6 • 18 months
|
11.6%
5/43 • 18 months
|
|
Gastrointestinal disorders
Stomatitis
|
33.3%
2/6 • 18 months
|
11.6%
5/43 • 18 months
|
|
Skin and subcutaneous tissue disorders
Pruritus
|
0.00%
0/6 • 18 months
|
14.0%
6/43 • 18 months
|
|
General disorders
Pyrexia
|
50.0%
3/6 • 18 months
|
9.3%
4/43 • 18 months
|
|
Cardiac disorders
Electrocardiogram QT prolonged
|
16.7%
1/6 • 18 months
|
11.6%
5/43 • 18 months
|
|
Respiratory, thoracic and mediastinal disorders
Epistaxis
|
33.3%
2/6 • 18 months
|
9.3%
4/43 • 18 months
|
|
Renal and urinary disorders
Dysuria
|
0.00%
0/6 • 18 months
|
11.6%
5/43 • 18 months
|
|
Skin and subcutaneous tissue disorders
Hyperhidrosis
|
0.00%
0/6 • 18 months
|
11.6%
5/43 • 18 months
|
|
Metabolism and nutrition disorders
Hypoalbuminemia
|
0.00%
0/6 • 18 months
|
11.6%
5/43 • 18 months
|
|
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
|
0.00%
0/6 • 18 months
|
11.6%
5/43 • 18 months
|
|
General disorders
Pain
|
0.00%
0/6 • 18 months
|
11.6%
5/43 • 18 months
|
|
General disorders
Pain in extremity
|
0.00%
0/6 • 18 months
|
11.6%
5/43 • 18 months
|
|
Musculoskeletal and connective tissue disorders
Asthenia
|
16.7%
1/6 • 18 months
|
9.3%
4/43 • 18 months
|
|
General disorders
Injection site reaction
|
16.7%
1/6 • 18 months
|
9.3%
4/43 • 18 months
|
|
Metabolism and nutrition disorders
Dehydration
|
33.3%
2/6 • 18 months
|
7.0%
3/43 • 18 months
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place
Restriction type: GT60