Chronic Lymphocytic Leukemia, Mantle Cell Lymphoma, Non Hodgkin Lymphoma
Conditions
Keywords
APR-246, eprenetapopt
Brief summary
Study to determine the preliminary safety, tolerability, and pharmacokinetic (PK) profile of APR-246 in combination with either acalabrutinib or venetoclax + rituximab therapy in subjects with NHL, including relapsed and/or refractory (R/R) CLL and R/R MCL.
Detailed description
Phase 1, open-label, dose-finding and cohort expansion study to determine the preliminary safety, tolerability, and pharmacokinetic (PK) profile of APR-246 (eprenetapopt) in combination with either acalabrutinib or venetoclax + rituximab therapy in subjects with NHL, including relapsed and/or refractory (R/R) CLL and R/R MCL. The study includes a safety lead-in portion followed by an expansion portion in subjects with R/R CLL, Richter Transformation (RT), and R/R MCL.
Interventions
DRUGAPR-246 (eprenetapopt) + Acalabrutinib in CLL
APR-246 D1, 8 and 15 of each cycle Acalabrutinib will be given at a standard dose and schedule (APR 246 Monotherapy Lead-in; 4.5 g/d x 2)
DRUGAPR-246 (eprenetapopt) 4.5 g/d + Venetoclax + Rituximab in CLL
APR-246 D1, 8 and 15 of each cycle Venetoclax + Rituximab will be given at a standard dose and schedule (APR 246 Monotherapy Lead-in; 4.5 g/d x 2)
DRUGAPR-246 (eprenetapopt) 4.5 g/d + (Acalabrutinib, OR, (Venetoclax +Rituximab)), in CLL and/or MCL and/or RT
APR-246 D1, 8 and 15 of each cycle Acalabrutinib will be given at a standard dose and schedule Venetoclax and Rituxiab will be given at a standard dose and schedule
DRUGAPR-246 (eprenetapopt) 4.5 g/d + Venetoclax + Rituximab in RT
APR-246 4.5 g/d D1, 8 and 15 of each cycle Venetoclax + Rituximab will be given at a standard dose and schedule
Sponsors
Aprea Therapeutics
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Is able to understand and is willing and able to comply with the study requirements and to provide written informed consent. 2. Documented histologic diagnosis of R/R CLL, RT, or R/R MCL 3. Safety Lead-In Cohort 1: Patients whose most recent regimen did not include BTK inhibitor therapy. 4. Safety Lead-In Cohort 2: Patients whose most recent regimen did not include Bcl-2 inhibitor therapy. 5. Safety Lead-In Cohort 3: APR-246 + venetoclax + rituximab in patients with RT 6. Prothrombin time (or international normalized ratio) and partial thromboplastin time not to exceed 1.2 × the institution's normal range. 7. Adequate BM function independent of growth factor or transfusion support, per local laboratory reference range at screening as follows: 1. platelet count ≥ 75 000/mm3; 2. absolute neutrophil count (ANC) ≥ 1000/mm3 unless cytopenia is clearly due to marrow involvement from CLL or MCL 3. total hemoglobin ≥ 9 g/dL (without transfusion support within 2 weeks of screening); 8. Adequate organ function as defined by the following laboratory values: 1. Creatinine clearance ≥ 30 mL/min. 2. Total serum bilirubin ≤ 1.5 × upper limit of normal (ULN) unless due to Gilbert's syndrome, NHL organ involvement, controlled immune hemolysis or considered an effect of regular blood transfusions. 3. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN, unless due to NHL organ involvement. 9. Age ≥18 years at the time of signing the informed consent form. 10. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2. 11. Projected life expectancy of ≥ 12 weeks. 12. Women of childbearing potential and men with female partners of childbearing potential must be willing to use an effective form of contraception.
Exclusion criteria
13. Patient with known allergies to xanthine oxidase inhibitors and/or rasburicase. 14. For patients to receive rituximab on this protocol, prior allergy to rituximab is prohibited. 15. No concomitant anticancer therapies, immunotherapies, cellular, or radiotherapy. No major surgery within 3 weeks prior to first dose of study treatment. 16. Uncontrolled autoimmune hemolytic anemia (AIHA) or immune thrombocytopenia. 17. Consumption of grapefruit, grapefruit products, Seville oranges, or star fruit within 7 days of starting study treatment. 18. Concomitant steroids for disease related pain control are allowed at any dose but must be discontinued prior to any study treatment initiation. Chronic use of corticosteroids is allowed up to ≤ 20 mg prednisone daily for non-cancer related conditions at the time of study start. 19. History of allogeneic or autologous stem cell transplant (SCT) or CAR-T therapy within the last 30 days or with any of the following: 20. Active graft versus host disease (GVHD) 21. Cytopenias from incomplete blood cell count recovery post-transplant; 22. Need for anti-cytokine therapy for residual symptoms of neurotoxicity \> grade 1 from CAR-T therapy; 23. Ongoing immunosuppressive therapy. 24. Known history of human immunodeficiency virus (HIV) serum positivity. 25. Active hepatitis B/C. 26. Known central nervous system (CNS) involvement by lymphoma. Patients with previous treatment for CNS involvement who are neurologically stable and without evidence of disease may be eligible if a compelling clinical rationale is provided to sponsor. 27. Known neurologic disorder or residual neurologic toxicities that may put patients at increased risk of neurologic toxicity in the opinion of the investigator. 28. Cardiac abnormalities. 29. Concomitant malignancies or previous malignancies with less than a 1 year disease- free interval at the time of signing consent. 30. A female patient who is pregnant or breast-feeding. 31. Active uncontrolled systemic infection. 32. Received an investigational agent within 30 days or within 5 T1/2, whichever is shorter prior to the first dose of study treatment. 33. Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of ibrutinib or venetoclax. 34. Current treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers and/or strong P-gp inhibitors..
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To Determine the DLT of APR-246 in Combination With Acalabrutinib or in Combination With Venetoclax + Rituximab Therapy in Subjects With NHL, Including Subjects With R/R CLL, RT and R/R MCL. | Through study completion, approximately 1 year | The occurrence of DLTs, classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events . |
| To Assess the Frequency of Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Related to APR-246 in Combination With Acalabrutinib and With Venetoclax + Rituximab Therapy. | Through study completion, approximately 6 months | The frequency of TEAEs and SAEs related to APR-246 in combination with acalabrutinib and with venetoclax + rituximab therapy |
| To Determine the Maximum Tolerated Dose (MTD) and the Recommended Phase 2 Dose (RP2D) in Subjects With TP53 Mutant NHL, Including Subjects With R/R CLL, RT and R/R MCL. | Through study completion, approximately 1 year | The highest dose of APR-246 with acceptable toxicity (RP2D of APR-246) (the dose producing ≤ 20% of DLT). |
Countries
United States
Participant flow
Pre-assignment details
No patients were enrolled in Safety Lead-In Cohort 1, Safety Lead-In Cohort 3, and Expansion Phase.
Participants by arm
| Arm | Count |
|---|---|
| Safety Lead-In Cohort 2 APR-246 + Venetoclax + Rituximab in Subjects with R/R CLL.
APR-246 (eprenetapopt) + Venetoclax + Rituximab in CLL: APR-246 D1, 8 and 15 of each cycle Venetoclax + Rituximab will be given at a standard dose and schedule | 1 |
| Total | 1 |
Baseline characteristics
| Characteristic | Safety Lead-In Cohort 2 |
|---|---|
| Age, Continuous | 74 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 1 Participants |
| Region of Enrollment United States | 1 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 0 | 0 / 1 | 0 / 0 | 0 / 0 |
| other Total, other adverse events | 0 / 0 | 1 / 1 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 | 0 / 1 | 0 / 0 | 0 / 0 |
Outcome results
Primary
To Assess the Frequency of Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Related to APR-246 in Combination With Acalabrutinib and With Venetoclax + Rituximab Therapy.
The frequency of TEAEs and SAEs related to APR-246 in combination with acalabrutinib and with venetoclax + rituximab therapy
Time frame: Through study completion, approximately 6 months
Population: Study was terminated.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Safety Lead-In Cohort 2 | To Assess the Frequency of Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Related to APR-246 in Combination With Acalabrutinib and With Venetoclax + Rituximab Therapy. | 1 participants |
Primary
To Determine the DLT of APR-246 in Combination With Acalabrutinib or in Combination With Venetoclax + Rituximab Therapy in Subjects With NHL, Including Subjects With R/R CLL, RT and R/R MCL.
The occurrence of DLTs, classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events .
Time frame: Through study completion, approximately 1 year
Population: Data was not collected as study was terminated.
Primary
To Determine the Maximum Tolerated Dose (MTD) and the Recommended Phase 2 Dose (RP2D) in Subjects With TP53 Mutant NHL, Including Subjects With R/R CLL, RT and R/R MCL.
The highest dose of APR-246 with acceptable toxicity (RP2D of APR-246) (the dose producing ≤ 20% of DLT).
Time frame: Through study completion, approximately 1 year
Population: Data was not collected as study was terminated.