APR-246 in Combination With Acalabrutinib or Venetoclax Based Therapy in Subjects With R/R Non Hodgkin Lymphomas (NHL)
Study Details
Study Description
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.
Condition or Disease | Intervention/Treatment | Phase |
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Phase 1/Phase 2 |
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.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Experimental: Safety Lead-In Cohort 1 APR-246 + Acalabrutinib in Subjects with R/R CLL. |
Drug: APR-246 (eprenetapopt) + Acalabrutinib in CLL
APR-246 D1, 8 and 15 of each cycle Acalabrutinib will be given at a standard dose and schedule
|
Experimental: Safety Lead-In Cohort 2 APR-246 + Venetoclax + Rituximab in Subjects with R/R CLL. |
Drug: APR-246 (eprenetapopt) + Venetoclax + Rituximab in CLL
APR-246 D1, 8 and 15 of each cycle Venetoclax + Rituximab will be given at a standard dose and schedule
|
Experimental: Expansion Cohorts 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
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
|
Experimental: Safety Lead-In Cohort 3 APR-246 + Venetoclax + Rituximab in Subjects with RT |
Drug: APR-246 (eprenetapopt) + Venetoclax + Rituximab in RT
APR-246 D1, 8 and 15 of each cycle Venetoclax + Rituximab will be given at a standard dose and schedule
|
Outcome Measures
Primary Outcome Measures
- 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. [Through study completion, approximately 1 year]
The occurrence of DLTs, classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events .
- 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. [Through study completion, approximately 1 year]
The frequency of TEAEs and SAEs related to APR-246 in combination with acalabrutinib and with venetoclax + rituximab therapy
- 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. [Through study completion, approximately 1 year]
The highest dose of APR-246 with acceptable toxicity (RP2D of APR-246) (the dose producing ≤ 20% of DLT).
Eligibility Criteria
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:
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platelet count ≥ 75 000/mm3;
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absolute neutrophil count (ANC) ≥ 1000/mm3 unless cytopenia is clearly due to marrow involvement from CLL or MCL
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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:
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Creatinine clearance ≥ 30 mL/min.
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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.
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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..
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Massachusetts General Hospital | Boston | Massachusetts | United States | 02114 |
2 | Dana Farber Cancer Institute | Boston | Massachusetts | United States | 02215 |
3 | Memorial Sloan Kettering Cancer Center | New York | New York | United States | 10065 |
4 | MD Anderson Cancer Center | Houston | Texas | United States | 77030 |
Sponsors and Collaborators
- Aprea Therapeutics
Investigators
- Study Director: Joachim Gullbo, MD, Theradex Oncology
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- A20-11197