Early Stage CLL With High Risk of Early Disease Progression MedDRA version: 21.0 Level: LLT Classification code 10008976 Term: Chronic lymphocytic leukemia System Organ Class: 100000004864
Conditions
Sponsors
Fundación PETHEMA
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Adult patients with previously untreated CLL according to IWCLL criteria (Hallek, 2018) 2. Must understand and voluntarily sign an informed consent form. 3. 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. 4. Diagnosis of CLL < 6 months prior to inclusion in the study 5. Binet clinical stage A and Rai 0 or 1 6. 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; 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 (eg, skin, kidney, lung, spine). 7. GCLLSG prognostic index with intermediate (3-5), high (6-10) or very high (11-14) risk scores. 8. Must have an Eastern Cooperative Oncology Group (ECOG) performance status score of =1. 9. 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): a. 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. b. Placement of an intrauterine device (IUD) or an intrauterine syste
Exclusion criteria
Exclusion criteria: 1. Prior treatment for CLL. 2. Meets any criteria for the initiation of treatment defined by the IWCLL guidelines for diagnosis and treatment of CLL (Hallek, 2018). 3. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) and/or Hepatitis C Virus (HCV) infection. 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. 4. Estimated Glomerular Filtration Rate (Cockcroft-Gault Appendix C) = 40 mL/min/1.73m2 5. Absolute neutrophil count (ANC) 2.5 x upper limit of normal (ULN). 8. Serum total bilirubin >1.5 x ULN, except in cases of Gilbert’s syndrome. 9. Prothrombin time/INR or aPTT (in the absence of Lupus anticoagulant) >2 x ULN. 10. Active bleeding, history of bleeding diathesis (eg, hemophilia or von Willebrand disease). 11. Requires treatment with proton pump inhibitors (eg, 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. 12. Unable to swallow capsules, or has disease significantly affecting gastrointestinal function that would limit absorption of oral medication. 13. 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. 14. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) within 7 days of first dose of study drug. 15. Systemic infection that has not resolved prior to initiating study treatment in spite of adequate anti-infective therapy. 16. Pregnant or lactating females. 17. Participation in any clinical study or having taken any investigational therapy within 28 days prior to initiating study therapy. 18. 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) 19. Presence of autoimmune haemolytic anaemia or autoimmune thrombocytopenia, or a positive direct antiglobulin test result. 20. Chronic use of steroids in excess of prednisone 20mg/day or its equivalent 21. Major surgery within the last 28 days prior to registration.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To compare the event-free survival (EFS) rate between acalabrutinib and clinical observation (watch & wait). 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. These will be counted as an event for EFS. [Time Frame: from randomization until progression, initiation of subsequent treatment for CLL or death by any cause, whichever occurs first]. ; Secondary Objective: • Response rates (Overall response rate (ORR); Complete Remission (CR); CR with incomplete marrow recovery (CRi); nodular partial remission (nPR); Partial Remission (PR). • Progression-free survival (PFS). [Time Frame: the time from randomization until symptomatic disease progression (as defined by the updated iwCLL-guidelines) or death from any cause, whichever occurs first]. • Overall survival (OS). [Time Frame: time between the day of randomization to death from may cause]. Patients alive or lost to follow-up will be censored. • Time to next treatment (TTNT). [Time Frame: time from randomization until the date of initiation of subsequent treatment for CLL or death from any cause] • Immunological recovery • Safety of acalabrutinib: type, frequency, and severity of adverse events (AEs) and relationship of AEs to acalabrutinib ;Primary end point(s): Event Free Survival 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. These will be counted as event for EFS.;Timepoint(s) of evaluation of this end point: Throughout the study | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - ORR is defined as the proportion of patients who achieve a CR, CRi, nPR, or PR over the course of the study. Patients who achieve a PR with lymphocytosis will be included in the ORR. The rate of MRD-negative disease will also be calculated. The IWCLL guidelines (Hallek, 2018) will be used to measure response in CLL subjects. Isolated treatment related lymphocytosis will not be considered as disease progression as recommended by the IWCLL guidelines (Hallek, 2018). Response rates will be shown by the frequency and percentage distribution, and by using the 95%CI - PFS is defined as the time from the date of treatment initiation to confirmed disease progression (IWCLL 2018 criteria) or death from any cause, whichever occurs first. Patients who withdraw from the study or are considered lost to follow-up without prior documentation of disease progression will be censored on the date of the last adequate disease assessment. Patients who start new anticancer therapy before documentation of disease progression will be censored on the date of the last adequate disease assessment that is on or before the start date of the new anticancer therapy. - OS is defined as the time from the date of treatment initiation to death due to any cause. Patients who are known to be alive or whose survival status is unknown will be censored at the last date the patient is known to be alive. - Time to next treatment (TTNT). [Time Frame: time from randomization until the date of initiation of subsequent treatment for CLL or death from any cause] Distribution of PFS, OS, and TTNT will be summarized using the Kaplan-Meier estimate of median and its corresponding 95% CIs. ;Timepoint(s) of evaluation of this end point: Throughout the study | — |
Countries
Spain
Contacts
Public ContactClinical Trial Department
Dynamic Science S.L.
Outcome results
None listed