APR-246 in Combination With Acalabrutinib or Venetoclax Based Therapy in Subjects With R/R Non Hodgkin Lymphomas (NHL)
Status and phase
Conditions
Treatments
Details and patient eligibility
About
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.
Full 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.
Enrollment
Sex
Ages
Volunteers
Inclusion and exclusion criteria
Inclusion Criteria:
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Is able to understand and is willing and able to comply with the study requirements and to provide written informed consent.
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Documented histologic diagnosis of R/R CLL, RT, or R/R MCL
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Safety Lead-In Cohort 1: Patients whose most recent regimen did not include BTK inhibitor therapy.
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Safety Lead-In Cohort 2: Patients whose most recent regimen did not include Bcl-2 inhibitor therapy.
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Safety Lead-In Cohort 3: APR-246 + venetoclax + rituximab in patients with RT
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Prothrombin time (or international normalized ratio) and partial thromboplastin time not to exceed 1.2 × the institution's normal range.
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Adequate BM function independent of growth factor or transfusion support, per local laboratory reference range at screening as follows:
- platelet count ≥ 75 000/mm3;
- absolute neutrophil count (ANC) ≥ 1000/mm3 unless cytopenia is clearly due to marrow involvement from CLL or MCL
- total hemoglobin ≥ 9 g/dL (without transfusion support within 2 weeks of screening);
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Adequate organ function as defined by the following laboratory values:
- Creatinine clearance ≥ 30 mL/min.
- 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.
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN, unless due to NHL organ involvement.
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Age ≥18 years at the time of signing the informed consent form.
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Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
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Projected life expectancy of ≥ 12 weeks.
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Women of childbearing potential and men with female partners of childbearing potential must be willing to use an effective form of contraception.
Exclusion Criteria:
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Patient with known allergies to xanthine oxidase inhibitors and/or rasburicase.
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For patients to receive rituximab on this protocol, prior allergy to rituximab is prohibited.
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No concomitant anticancer therapies, immunotherapies, cellular, or radiotherapy. No major surgery within 3 weeks prior to first dose of study treatment.
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Uncontrolled autoimmune hemolytic anemia (AIHA) or immune thrombocytopenia.
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Consumption of grapefruit, grapefruit products, Seville oranges, or star fruit within 7 days of starting study treatment.
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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.
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History of allogeneic or autologous stem cell transplant (SCT) or CAR-T therapy within the last 30 days or with any of the following:
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Active graft versus host disease (GVHD)
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Cytopenias from incomplete blood cell count recovery post-transplant;
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Need for anti-cytokine therapy for residual symptoms of neurotoxicity > grade 1 from CAR-T therapy;
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Ongoing immunosuppressive therapy.
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Known history of human immunodeficiency virus (HIV) serum positivity.
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Active hepatitis B/C.
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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.
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Known neurologic disorder or residual neurologic toxicities that may put patients at increased risk of neurologic toxicity in the opinion of the investigator.
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Cardiac abnormalities.
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Concomitant malignancies or previous malignancies with less than a 1 year disease- free interval at the time of signing consent.
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A female patient who is pregnant or breast-feeding.
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Active uncontrolled systemic infection.
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Received an investigational agent within 30 days or within 5 T1/2, whichever is shorter prior to the first dose of study treatment.
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Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of ibrutinib or venetoclax.
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Current treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers and/or strong P-gp inhibitors..
Trial design
Primary purpose
Allocation
Interventional model
Masking
1 participants in 4 patient groups
Trial contacts and locations
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Data sourced from clinicaltrials.gov
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