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APR-246 in Combination With Ibrutinib or Venetoclax-R in Subjects With TP53-Mutant R / R Non-Hodgkin Lymphomas (NHL)

Trial Status: Active

Study to determine the preliminary safety, tolerability, and pharmacokinetic (PK) profile of APR-246 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.

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 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.

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..

Massachusetts

Boston
Brigham and Women's Hospital
Status: ACTIVE
Dana-Farber Cancer Institute
Status: ACTIVE

New York

New York
Memorial Sloan Kettering Cancer Center
Status: ACTIVE
Contact: Anthony R. Mato
Phone: 212-639-8596

Texas

Dallas
UT Southwestern / Simmons Cancer Center-Dallas
Status: ACTIVE
Contact: Marcella West Aguilar
Phone: 214-648-1479
Houston
M D Anderson Cancer Center
Status: ACTIVE

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

Lead Organization
Aprea Therapeutics

  • Primary ID A20-11197
  • Secondary IDs NCI-2020-11625
  • Clinicaltrials.gov ID NCT04419389