Phase III Randomized Study to Investigate the Use of Acalabrutinib in the Treatment of Patients With Early Stage CLL With High Risk of Early Disease Progression
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 22
- 试验地点
- 8
- 主要终点
- Event-Free Survival (EFS)
研究概览
简要总结
Study Phase III Randomized Study to Investigate the Use of Acalabrutinib in the Treatment of Patients with Early Stage CLL With High Risk of Early Disease Progression.
The study will consist of a screening phase, a treat¬ment/observation phase until progression, and a follow-up phase for progression in patients who discontinue treatment with Acalabrutinib without confirmed progression. Patients who progress will be followed for survival and initiation of subsequent antileukemic therapy. In the study, 130 patients from 20 centers in Spain with intermediate, high or very high risk will be randomized (1:1) to receive Acalabrutinib (n=65) or clinical observation (n=65). Acalabrutinib will be administered orally 100 mg twice daily on a continuous schedule.
Even though the majority of patients with CLL are currently diagnosed at early stages of the disease, there is a consensus that the standard of care in these patients is clinical observation (watch & wait) despite of the presence of risk factors for premature disease progression. Early treatment in patients with adverse prognostic parameters could prevent a disease evolving to a more advanced stage, and therefore more difficult to treat. So far, conventional chemotherapy did not show any benefit in terms of overall survival in patients with early stage CLL. (Dighiero 1998, Hoechstetter Leukemia 2017) Alongside this, treatment with chemotherapy may provoke two undesired effects: first, the occurrence of bone marrow toxicity that may hamper the subsequent administration of other treatments during the course of the disease; second, but not less relevant, genotoxic drug delivery may elicit a phenomenon of clonal selection leading to the appearance of CLL cells with genetic aberrations associated with refractoriness and aggressive outcome (i.e., TP53).
Against this background, it is of interest to investigate the role of new non-genotoxic drugs in the treatment of patients with CLL in early stages. Among different scores for selecting cases that are likely to progress rapidly, the German CLL Study Group (GCLLSG) risk score that includes 8 independent predictors for OS and PFS, differentiates patients with low-risk PFS vs. those with risk of early disease progression (median PFS 87 months vs. less than 27 months), allowing for a risk-adapted treatment approach in early stage CLL. (Pflug 2014, Langerbeins 2015).
Acalabrutinib, a second-generation, selective inhibitor of BTK, has shown substantial activity in patients with CLL. Acalabrutinib is a non-genotoxic drug active in cases with genetic lesions associated with chemorefratoriness and adverse outcome, including patients with alterations of TP53. Therefore, acalabrutinib represents a suitable compound for the treatment of patients with CLL in early stages with risk of early disease progression, including the high-risk CLL patient population with TP53 alterations.
详细描述
Randomized, open-label, parallel-group, multicenter, phase III trial with two arms, one with acalabrutinib (Arm A) and the other with the standard of care for the management of early Binet stage A patients "clinical observation (watch & wait)" (Arm B) in patients with untreated early stage CLL and risk factors for early disease progression. Early risk of disease progression will be defined by the GCLLSG prognostic index: intermediate (3-5), high (6-10) or very high (11-14) risk scores are required to be included in the study. Randomization will be managed through an IRT system:
- Arm A (65 patients): Patients assigned to arm A, will receive acalabrutinib as one capsule of 100 mg orally twice daily on a continuos schedule until disease progression, unacceptable toxicity or early withdrawal.
- Arm B (65 patients): Patients assigned to arm B, will remain on the w&w approach until disease progression or early withdrawal.
The enrolment period is estimated in 24 months. A treatment cycle is defined as lasting 28 days.
The duration of the study will be of 60 months from the inclusion of the first patient to the last patient has completed the last follow up visit.
- Periods of patient participation in the study
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
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
- •Adult patients with previously untreated CLL according to IWCLL criteria (Hallek, 2018).
- •Must understand and voluntarily sign an informed consent form.
- •Age ≥ 18 years at the time of signing the informed consent form and must be able to adhere to the study visit schedule and other Protocol requirements.
- •Diagnosis of CLL prior to inclusion in the study.
- •Binet clinical stage A and Rai 0 or
- •Absence of criteria for the initiation of chemotherapy, defined by the IWCLL guidelines for diagnosis and treatment of CLL (Hallek, 2018):
- •Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia.
- •Massive (i.e. ≥6 cm below the left costal margin) or progressive or symptomatic splenomegaly.
- •Massive nodes (i.e. ≥10 cm in longest diameter) or progressive or symptomatic lymphadenopathy.
- •Progressive lymphocytosis with an increase of ≥50% over a 2-month period, or lymphocyte doubling time (LDT) of less than 6 months.
- •A minimum of any one of the following disease-related symptoms: unintentional weight loss ≥10% within the previous 6 months, significant fatigue (i.e., ECOG PS 2 or worse; cannot work or unable to perform usual activities), fevers of ≥38.0°C for 2 or more weeks without other evidence of infection, or night sweats for more than 1 month without evidence of infection.
- •Autoimmune complications including anemia or thrombocytopenia poorly responsive to corticosteroids.
- •Symptomatic or functional extranodal involvement (e.g., skin, kidney, lung, spine).
- •GCLLSG prognostic index with intermediate (3-5), high (6-10) or very high (11-14) risk scores.
- •Must have an Eastern Cooperative Oncology Group (ECOG) performance status score of ≤
- •All sexually active subjects with the capacity to reproduce (male and female) must use high-efficacy contraceptive methods during the course of the study. These restrictions apply for 3 months after the last dose of acalabrutinib. High-efficacy contraceptive methods include:
- •Total abstinence when consistent with the subject's typical and preferred lifestyle (periodic abstinence [e.g. calendar methods, ovulation, symptothermal and post-ovulation methods] and the withdrawal method are not acceptable contraceptive methods).
- •Female sterilisation defined as surgical hysterectomy, bilateral oophorectomy, or tubal ligation at least six weeks prior to the study treatment (a simple oophorectomy does not meet the definition of female sterilisation).
- •Male sterilisation (at least six months before screening). A man who has undergone a vasectomy must be the only partner who is a study subject.
- •Combination of two of the following methods (a+b or a+c or b+c):
- •Use of oral, injected or implanted hormonal contraceptives, or other hormonal contraceptive methods that have a comparable efficacy (failure rate < 1%), for example, hormonal vaginal ring or transdermal hormonal contraceptive. If an oral contraceptive is used, women must use the same pill for a minimum of three months before taking the study treatment.
- •Placement of an intrauterine device (IUD) or an intrauterine system (IUS).
- •Barrier contraceptive methods: condom or cervical cap (cervical/vault diaphragm or cap) with foam/gel/film/spermicidal cream/vaginal suppository.
- •Female subjects of childbearing potential must have a negative serum pregnancy test at screening. Females of child bearing potential are defined as sexually mature women without prior hysterectomy or who have had any evidence of menses in the past 12 months. However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to other causes, including prior chemotherapy, anti-estrogens, or ovarian suppression.
排除标准
- •Prior treatment for CLL.
- •Meets any criteria for the initiation of treatment defined by the IWCLL guidelines for diagnosis and treatment of CLL (Hallek, 2018).
- •Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) and/or Hepatitis C Virus (HCV) infection and/or known history of progressive multifocal leukoencephalopathy (PML). Subjects who are hepatitis B core antibody (anti-HBc) positive and who are surface antigen negative will need to have a negative polymerase chain reaction (PCR). Those who are hepatitis B surface antigen (HbsAg) positive or hepatitis B PCR positive will be excluded. Subjects who are hepatitis C antibody positive will need to have a negative PCR result. Those who are hepatitis C PCR positive will be excluded.
- •Estimated Glomerular Filtration Rate (Cockcroft-Gault Appendix C) ≤ 40 mL/min/1.73m
- •Absolute neutrophil count (ANC) < 1.0 X 109/L.
- •Platelet count < 100 X 109/L.
- •Serum aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) or alanine transaminase (ALT)/serum glutamate pyruvate transaminase (SGPT) >2.5 x upper limit of normal (ULN).
- •Serum total bilirubin >1.5 x ULN, except in cases of Gilbert's syndrome.
- •Prothrombin time/INR or aPTT (in the absence of Lupus anticoagulant) >2 x ULN.
- •Active bleeding, history of bleeding diathesis (e.g., hemophilia or von Willebrand disease).
- •Requires treatment with proton pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrolment to this study.
- •Unable to swallow capsules, or has disease significantly affecting gastrointestinal function that would limit absorption of oral medication.
- •Currently active, clinically significant cardiovascular disease or a history of myocardial infarction within 3 months prior to enrolment. Exception: Subjects with controlled, asymptomatic atrial fibrillation during screening can enrol on study.
- •Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7 days of first dose of study drug.
- •Systemic infection that has not resolved prior to initiating study treatment in spite of adequate anti-infective therapy.
- •Pregnant or lactating females.
- •Participation in any clinical study or having taken any investigational therapy within 28 days prior to initiating study therapy.
- •Prior history of malignancies, other than CLL, unless the patient has been free of the disease for ≥ 3 years. Exceptions include the following:
- •Basal cell carcinoma of the skin
- •Squamous cell carcinoma of the skin
- •Carcinoma in situ of the cervix
- •Carcinoma in situ of the breast
- •Incidental histologic finding of prostate cancer (TNM stage of T1a or T1b)
- •Presence of autoimmune haemolytic anaemia or autoimmune thrombocytopenia, or a positive direct antiglobulin test result.
- •Chronic use of steroids in excess of prednisone 20mg/day or its equivalent.
- •Major surgery within the last 28 days prior to registration.
- •History of stroke or intracranial hemorrhage within 6 months prior to enrolment.
- •Requires treatment with strong CYP3A4/5 Inhibitors.
- •Known history of drug-specific hypersensitivity or anaphylaxis to study drug (including active product or excipient components).
- •Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of acalabrutinib, or put the study outcomes at undue risk.
研究组 & 干预措施
Arm A_Acalabrutinib
Patients assigned to arm A, will receive acalabrutinib as one capsule of 100 mg orally twice daily on a continuos schedule until disease progression, unacceptable toxicity or early withdrawal.
干预措施: Acalabrutinib 100 MG Oral Capsule (Drug)
结局指标
主要结局
Event-Free Survival (EFS)
时间窗: From randomization to 60 months
EFS is defined as the time between the date of randomization and time point of symptomatic disease progression with treatment indication according to the iwCLL-Guidelines, initiation of subsequent treatment for CLL or death by any cause, whichever occurs first.
次要结局
- Progression-Free Survival (PFS)(From randomization to 60 months)
- Time To Next Treatment (TTNT)(From randomization to 60 months)
- Overall Survival (OS)(From randomization to 60 months)
- Objetive Response Rate (ORR)(From randomization to 60 months)