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

Inclusion Criteria

• Is able to understand and is willing and able to comply with the study requirements and to provide written informed consent.
• Documented histologic diagnosis of R/R CLL, RT, or R/R MCL
• Safety Lead-In Cohort 1: Patients whose most recent regimen did not include BTK inhibitor therapy.
• Safety Lead-In Cohort 2: Patients whose most recent regimen did not include Bcl-2 inhibitor therapy.
• Safety Lead-In Cohort 3: APR-246 + venetoclax + rituximab in patients with RT
• Prothrombin time (or international normalized ratio) and partial thromboplastin time not to exceed 1.2 × the institution's normal range.
• 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);
• 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.
• Age ≥18 years at the time of signing the informed consent form.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
• Projected life expectancy of ≥ 12 weeks.
• Women of childbearing potential and men with female partners of childbearing potential must be willing to use an effective form of contraception.

Exclusion Criteria

• Patient with known allergies to xanthine oxidase inhibitors and/or rasburicase.
• For patients to receive rituximab on this protocol, prior allergy to rituximab is prohibited.
• No concomitant anticancer therapies, immunotherapies, cellular, or radiotherapy. No major surgery within 3 weeks prior to first dose of study treatment.
• Uncontrolled autoimmune hemolytic anemia (AIHA) or immune thrombocytopenia.
• Consumption of grapefruit, grapefruit products, Seville oranges, or star fruit within 7 days of starting study treatment.
• 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.
• History of allogeneic or autologous stem cell transplant (SCT) or CAR-T therapy within the last 30 days or with any of the following:
• Active graft versus host disease (GVHD)
• Cytopenias from incomplete blood cell count recovery post-transplant;
• Need for anti-cytokine therapy for residual symptoms of neurotoxicity > grade 1 from CAR-T therapy;
• Ongoing immunosuppressive therapy.
• Known history of human immunodeficiency virus (HIV) serum positivity.
• Active hepatitis B/C.
• 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.
• Known neurologic disorder or residual neurologic toxicities that may put patients at increased risk of neurologic toxicity in the opinion of the investigator.
• Cardiac abnormalities.
• Concomitant malignancies or previous malignancies with less than a 1 year disease- free interval at the time of signing consent.
• A female patient who is pregnant or breast-feeding.
• Active uncontrolled systemic infection.
• Received an investigational agent within 30 days or within 5 T1/2, whichever is shorter prior to the first dose of study treatment.
• Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of ibrutinib or venetoclax.
• Current treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers and/or strong P-gp inhibitors..