Description:
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.
Title
- Brief Title: APR-246 in Combination With Acalabrutinib or Venetoclax Based Therapy in Subjects With R/R Non Hodgkin Lymphomas (NHL)
- Official Title: Phase 1 and Dose Expansion Study of APR-246 in Combination With Acalabrutinib or Venetoclax-based Therapy in Subjects With R/R NHL Including Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Lymphoma (MCL)
Clinical Trial IDs
- ORG STUDY ID:
A20-11197
- NCT ID:
NCT04419389
Conditions
- Non Hodgkin Lymphoma
- Chronic Lymphocytic Leukemia
- Mantle Cell Lymphoma
Interventions
Drug | Synonyms | Arms |
---|
APR-246 (eprenetapopt) + Acalabrutinib in CLL | | Safety Lead-In Cohort 1 |
APR-246 (eprenetapopt) + Venetoclax + Rituximab in CLL | | Safety Lead-In Cohort 2 |
APR-246 (eprenetapopt) + (Acalabrutinib, OR, (Venetoclax +Rituximab)), in CLL and/or MCL and/or RT | | Expansion Cohorts |
APR-246 (eprenetapopt) + Venetoclax + Rituximab in RT | | Safety Lead-In Cohort 3 |
Purpose
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.
Trial Arms
Name | Type | Description | Interventions |
---|
Safety Lead-In Cohort 1 | Experimental | APR-246 + Acalabrutinib in Subjects with R/R CLL. | - APR-246 (eprenetapopt) + Acalabrutinib in CLL
|
Safety Lead-In Cohort 2 | Experimental | APR-246 + Venetoclax + Rituximab in Subjects with R/R CLL. | - APR-246 (eprenetapopt) + Venetoclax + Rituximab in CLL
|
Expansion Cohorts | Experimental | APR-246 + (Acalabrutinib, OR, (Ven+R)) in Subjects with R/R TP53-mutant CLL, and/or MCL, and/or RT | - APR-246 (eprenetapopt) + (Acalabrutinib, OR, (Venetoclax +Rituximab)), in CLL and/or MCL and/or RT
|
Safety Lead-In Cohort 3 | Experimental | APR-246 + Venetoclax + Rituximab in Subjects with RT | - APR-246 (eprenetapopt) + Venetoclax + Rituximab in RT
|
Eligibility Criteria
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..
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | 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. |
Time Frame: | Through study completion, approximately 1 year |
Safety Issue: | |
Description: | The occurrence of DLTs, classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events . |
Details
Phase: | Phase 1/Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | Aprea Therapeutics |
Trial Keywords
Last Updated
August 6, 2021