APR-246 in Combination With Acalabrutinib or Venetoclax Based Therapy in Subjects With R/R Non Hodgkin Lymphomas (NHL)

Study Results

Results available

Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.

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Basic Information

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Recruitment Status

TERMINATED

Clinical Phase

PHASE1/PHASE2

Total Enrollment

1 participants

Study Classification

INTERVENTIONAL

Study Start Date

2021-03-02

Study Completion Date

2021-08-24

Brief Summary

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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.

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Detailed Description

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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.

Conditions

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Non Hodgkin Lymphoma Chronic Lymphocytic Leukemia Mantle Cell Lymphoma

Study Design

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Allocation Method

NON_RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

SINGLE

Participants

Study Groups

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Safety Lead-In Cohort 1

APR-246 4.5 g/d + Acalabrutinib in Subjects with R/R CLL (APR 246 Monotherapy Lead-in; 4.5 g/d x 2)

Group Type EXPERIMENTAL

APR-246 (eprenetapopt) + Acalabrutinib in CLL

Intervention Type DRUG

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)

Safety Lead-In Cohort 2

APR-246 4.5 g/d + Venetoclax + Rituximab in Subjects with R/R CLL (APR 246 Monotherapy Lead-in; 4.5 g/d x 2).

Group Type EXPERIMENTAL

APR-246 (eprenetapopt) 4.5 g/d + Venetoclax + Rituximab in CLL

Intervention Type DRUG

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)

Expansion Cohorts

APR-246 4.5 g/d + (Acalabrutinib, OR, (Ven+R)) in Subjects with R/R TP53-mutant CLL, and/or MCL, and/or RT

Group Type EXPERIMENTAL

APR-246 (eprenetapopt) 4.5 g/d + (Acalabrutinib, OR, (Venetoclax +Rituximab)), in CLL and/or MCL and/or RT

Intervention Type DRUG

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

Safety Lead-In Cohort 3

APR-246 4.5 g/d + Venetoclax + Rituximab in Subjects with RT

Group Type EXPERIMENTAL

APR-246 (eprenetapopt) 4.5 g/d + Venetoclax + Rituximab in RT

Intervention Type DRUG

APR-246 4.5 g/d D1, 8 and 15 of each cycle Venetoclax + Rituximab will be given at a standard dose and schedule

Interventions

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APR-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)

Intervention Type DRUG

APR-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)

Intervention Type DRUG

APR-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

Intervention Type DRUG

APR-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

Intervention Type DRUG

Eligibility Criteria

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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..

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No