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)
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 1
- 试验地点
- 4
- 主要终点
- 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.
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Participant)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •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.
排除标准
- •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..
研究组 & 干预措施
Safety Lead-In Cohort 1
APR-246 4.5 g/d + Acalabrutinib in Subjects with R/R CLL (APR 246 Monotherapy Lead-in; 4.5 g/d x 2)
干预措施: APR-246 (eprenetapopt) + Acalabrutinib in CLL (Drug)
Safety Lead-In Cohort 2
APR-246 4.5 g/d + Venetoclax + Rituximab in Subjects with R/R CLL (APR 246 Monotherapy Lead-in; 4.5 g/d x 2).
干预措施: APR-246 (eprenetapopt) 4.5 g/d + Venetoclax + Rituximab in CLL (Drug)
Expansion Cohorts
APR-246 4.5 g/d + (Acalabrutinib, OR, (Ven+R)) in Subjects with R/R TP53-mutant CLL, and/or MCL, and/or RT
干预措施: APR-246 (eprenetapopt) 4.5 g/d + (Acalabrutinib, OR, (Venetoclax +Rituximab)), in CLL and/or MCL and/or RT (Drug)
Safety Lead-In Cohort 3
APR-246 4.5 g/d + Venetoclax + Rituximab in Subjects with RT
干预措施: APR-246 (eprenetapopt) 4.5 g/d + Venetoclax + Rituximab in RT (Drug)
结局指标
主要结局
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.
时间窗: 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.
时间窗: Through study completion, approximately 6 months
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.
时间窗: 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).
次要结局
未报告次要终点