Myeloid Malignancy
Conditions
Brief summary
This clinical trial is a Phase I, open-label, dose-finding and cohort expansion study to determine the safety and preliminary efficacy of APR-246 in combination with venetoclax and azacitidine in patients with myeloid malignancies.
Detailed description
This study will enroll adult male and female patients of age ≥ 18 years with documented diagnosis of AML, according to WHO classification, and documented TP53 mutation which is not benign or likely benign, who also meet the eligibility requirements of this protocol. The study will include a safety lead-in dose-finding portion followed by expansion portion. During the safety lead-in portion of the study, two cohorts will independently enroll patients following a 3 + 3 design. Each cohort will enroll up to 6 patients. The expansion portion will begin once the recommended phase II dose (RP2D) of APR-246 in combination with venetoclax and in combination with venetoclax and azacitidine have been determined in order to assess the antitumor activity of these combinations.
Interventions
DRUGAPR-246
APR-246 4.5 g/day
DRUGVenetoclax
Venetoclax 400 mg once daily
DRUGAzacitidine
Subcutaneous injection, or intravenous infusion
Sponsors
Aprea Therapeutics
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
The study will include a safety lead-in dose-finding portion followed by the expansion portion. During the safety lead-in portion of the study, two cohorts will independently enroll patients following a 3 + 3 design.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Signed informed consent and ability to comply with protocol requirements. 2. Documented diagnosis of AML according to World Health Organization WHO) classification 3. Adequate organ function as defined by the following laboratory values: 1. Creatinine clearance \> 30 mL/min 2. Total serum bilirubin \< 1.5 × ULN 3. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \< 3 × ULN 4. Age ≥18 years 5. At least one TP53 mutation 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 7. Projected life expectancy of ≥ 12 weeks. 8. Negative serum or urine pregnancy test 9. Females of childbearing potential and males with female partners of childbearing potential must be willing to use an effective form of contraception
Exclusion criteria
1. Prior treatment for TP53-mutant AML (\*dependent upon treatment arm assigned). 2. Known history of HIV or active hepatitis B or active hepatitis C infection. 3. Any of the following cardiac abnormalities: 1. Myocardial infarction within six months prior to registration; 2. New York Heart Association Class III or IV heart failure or known left ventricular ejection fraction (LVEF) \< 40%; 3. A history of familial long QT syndrome; 4. Symptomatic atrial or ventricular arrhythmias 5. QTcF ≥ 470 msec, unless due to underlying bundle branch block and/or pacemaker and with approval of the medical monitor. 4. Concomitant malignancies for which patients are receiving active therapy 5. Known active CNS involvement from AML. 6. Malabsorption syndrome 7. Pregnancy or lactation. 8. Active uncontrolled systemic infection (viral, bacterial or fungal).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. | From baseline until event occures, i.e. through study completion, an average of 1 year | 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). |
Countries
United States
Participant flow
Recruitment details
Cohort 2 APR-246 + VEN + AZA Safey Lead-In and Expansion data was combined for reporting purposes.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 APR-246 4.5 g/day
APR-246: APR-246 4.5 g/day
Venetoclax: Venetoclax 400 mg once daily | 6 |
| Cohort 2 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 | 43 |
| Total | 49 |
Baseline characteristics
| Characteristic | Cohort 2 | Total | Cohort 1 |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 27 Participants | 31 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants | 18 Participants | 2 Participants |
| Age, Continuous | 67 years | 67 years | 69 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 6 Participants | 1 Participants |
| Race (NIH/OMB) White | 37 Participants | 40 Participants | 3 Participants |
| Region of Enrollment United States | 43 participants | 49 participants | 6 participants |
| Sex: Female, Male Female | 20 Participants | 24 Participants | 4 Participants |
| Sex: Female, Male Male | 23 Participants | 25 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 6 / 6 | 26 / 43 |
| other Total, other adverse events | 6 / 6 | 43 / 43 |
| serious Total, serious adverse events | 5 / 6 | 32 / 43 |
Outcome results
Primary
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.
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).
Time frame: From baseline until event occures, i.e. through study completion, an average of 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | 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 |
| Cohort 2 | 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 |
Primary
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.
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.
Time frame: From baseline until event occures, i.e. through study completion, an average of 1 year
Population: Any Serious TEAEs
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | 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 |
| Cohort 2 | 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. | 32 Participants |