APR-246 in Combination With Ibrutinib or Venetoclax-R in Subjects With TP53-Mutant R / R Non-Hodgkin Lymphomas (NHL)
- 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 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.
- 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.
- At least one TP53 mutation which is not benign or likely benign.
- 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.
- 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..
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 ibrutinib or venetoclax + rituximab therapy in subjects with
TP53-mutant 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 and R/R MCL.
Trial Phase Phase I/II
Trial Type Treatment
- Primary ID A20-11197
- Secondary IDs NCI-2020-11625
- Clinicaltrials.gov ID NCT04419389