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

Study Overview
=================
Brief Summary
-----------------
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.

Detailed 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.

Official Title
-----------------
Phase 1 and Dose Expansion Study of APR-246 in Combination With Acalabrutinib or Venetoclax-based Therapy in Subjects With R/R NHL Including Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Lymphoma (MCL)

Conditions
-----------------
Non Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, Mantle Cell Lymphoma

Intervention / Treatment
-----------------
* Drug: APR-246 (eprenetapopt) + Acalabrutinib in CLL
* Drug: APR-246 (eprenetapopt) + Venetoclax + Rituximab in CLL
* Drug: APR-246 (eprenetapopt) + (Acalabrutinib, OR, (Venetoclax +Rituximab)), in CLL and/or MCL and/or RT
* Drug: APR-246 (eprenetapopt) + Venetoclax + Rituximab in RT


Participation Criteria
=================
Eligibility Criteria
-----------------
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..

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Safety Lead-In Cohort 1<br>APR-246 + Acalabrutinib in Subjects with R/R CLL. | Drug: APR-246 (eprenetapopt) + Acalabrutinib in CLL<br>* APR-246 D1, 8 and 15 of each cycle Acalabrutinib will be given at a standard dose and schedule<br>|
| Experimental: Safety Lead-In Cohort 2<br>APR-246 + Venetoclax + Rituximab in Subjects with R/R CLL. | Drug: APR-246 (eprenetapopt) + Venetoclax + Rituximab in CLL<br>* APR-246 D1, 8 and 15 of each cycle Venetoclax + Rituximab will be given at a standard dose and schedule<br>|
| Experimental: Expansion Cohorts<br>APR-246 + (Acalabrutinib, OR, (Ven+R)) in Subjects with R/R TP53-mutant CLL, and/or MCL, and/or RT | Drug: APR-246 (eprenetapopt) + (Acalabrutinib, OR, (Venetoclax +Rituximab)), in CLL and/or MCL and/or RT<br>* 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<br>|
| Experimental: Safety Lead-In Cohort 3<br>APR-246 + Venetoclax + Rituximab in Subjects with RT | Drug: APR-246 (eprenetapopt) + Venetoclax + Rituximab in RT<br>* APR-246 D1, 8 and 15 of each cycle Venetoclax + Rituximab will be given at a standard dose and schedule<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the DLT of APR-246 in combination with acalabrutinib or in combination with venetoclax + rituximab therapy in subjects with NHL, including subjects with R/R CLL, RT and R/R MCL. | The occurrence of DLTs, classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events . | Through study completion, approximately 1 year | 
| To assess the frequency of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) related to APR-246 in combination with acalabrutinib and with venetoclax + rituximab therapy. | The frequency of TEAEs and SAEs related to APR-246 in combination with acalabrutinib and with venetoclax + rituximab therapy | Through study completion, approximately 1 year | 
| To determine the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) in subjects with TP53 mutant NHL, including subjects with R/R CLL, RT and R/R MCL. | The highest dose of APR-246 with acceptable toxicity (RP2D of APR-246) (the dose producing ≤ 20% of DLT). | Through study completion, approximately 1 year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
APR-246, eprenetapopt