Chronic Lymphocytic Leukemia Clinical Trial
Acalabrutinib Safety Study in Untreated and Relapsed or Refractory Chronic Lymphocytic Leukemia Patients
This is a global, Phase 3b, multicenter, open-label, single-arm study to evaluate the safety and efficacy of acalabrutinib 100 mg twice daily (bid) in approximately 540 participants with leukemia-cll/" >chronic lymphocytic leukemia (CLL). Participants will be enrolled into 3 cohorts: treatment-naive (TN), relapsed/refractory (R/R), and prior Bruton tyrosine kinase inhibitor (BTKi) therapy. Participants will remain on study treatment until completion of 48 cycles (28 days per cycle), disease progression, toxicity requiring discontinuation, withdrawal of consent, lost to Follow-up, death, or study termination by the sponsor whichever occurs first. The duration of the study will be approximately 72 months from the first participant enrolled. This duration includes an estimated 24-month recruitment time and an assumed 48 cycles of study treatment (28 days per cycle); additional study time will be accrued during the disease Follow up period for those participants remaining on study treatment after completion of 48 cycles prior to the final data cutoff (DCO) (the amount of time will vary by participant).
This is a Global, Phase 3b, multicenter, open-label, single-arm study to evaluate the safety and efficacy of acalabrutinib 100 mg bid in approximately 540 participants with CLL. Participants will be enrolled into 3 cohorts: treatment-naive (TN): participants who have had no prior treatment for CLL and who have either a score > 6 on the cumulative illness rating scale and/or have a creatinine clearance of 30 to 69 mL/min using the Cockcroft-Gault equation (minimum of 300 participants), relapsed/refractory (R/R): participants who have received prior treatment for CLL and who have either relapsed or refractory CLL (approximately 200 participants), and prior bruton tyrosine kinase inhibitor (BTKi) therapy: participants who have received prior ibrutinib for CLL and who discontinued the medication for any reason prior to disease progression (up to 40 participants). Overall response and progression assessments will be conducted by the investigator in accordance with the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2018 criteria. Overall response assessments will be based on evaluation of physical examinations, recording of symptoms, radiologic evaluations, and hematologic evaluations.
Treatment period consists of 48 cycles [each cycle is 28 days). Study treatment (acalabrutinib 100 mg bid) will be administered until disease progression, toxicity requiring discontinuation, completion of 48 cycles of study treatment, withdrawal of consent, loss to follow-up, death, or study termination by the sponsor, whichever comes first.
48 Cycles: From Cycle 1 to Cycle 6, in-clinic visits will occur every cycle and during each visit, in-clinic assessments will be carried out. From Cycle 6 to Cycle 12, in-clinic visits will occur every 3 cycles and during each visit, in-clinic assessments will be carried out. From Cycle 13 to Cycle 48, in-clinic visits will occur every 3 cycles and in-clinic assessments will be carried out every 6 cycles.
Safety follow up visits will occur approximately 30 days from the last dose of study treatment.
If a participant continues to derive benefit from treatment at the end of 48 cycles prior to the final DCO, they will continue to be provided with study treatment. Post-DCO, 2 options will be considered: patients may be transitioned to another study or may shift to a commercial supply of acalabrutinib/off-study acalabrutinib as permitted by local regulation. Subjects who switch to off-study acalabrutinib will be considered as having completed the study and therefore will not have any additional study assessments, including the disease Follow-up period.
The duration of the study will be approximately 72 months from the first participant enrolled. This duration includes an estimated 24-month recruitment time and an assumed 48 cycles of study treatment (28 days per cycle); additional study time will be accrued during the Follow-up period for those participants remaining on study treatment after completion of 48 cycles prior to the final DCO (the amount of time will vary by participant).
Men and women ≥18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place)
Diagnosis of CLL that meets all published diagnostic criteria (Hallek et al. 2018):
Monoclonal B-cells (either kappa or lambda light chain restricted) that are clonally co-expressing ≥1 B-cell marker (CD19, CD20, and CD23) and CD5 during screening
Prolymphocytes may comprise <55% of blood lymphocytes during screening
Presence of ≥5 × 10^9 B lymphocytes/L (5000/μL) in the peripheral blood (at any point since the initial diagnosis)
Active disease per at least 1 of the following iwCLL 2018 criteria
Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (hemoglobin <10 g/dL) and/or thrombocytopenia (platelets <100,000/μL).
Massive (i.e., ≥6 cm below the left costal margin), progressive, or symptomatic splenomegaly.
Massive nodes (i.e., ≥10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy
Progressive lymphocytosis with an increase of >50% over a 2-month period or a lymphocyte doubling time (LDT) of <6 months. LDT may be obtained by linear regression extrapolation of absolute lymphocyte count obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In subjects with initial blood lymphocyte counts of <30x10^9/L (30,000/μL), LDT should not be used as a single parameter to define indication for treatment. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (e.g., infections) should be excluded.
Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy
B-symptoms documented in the subject's chart with supportive objective measures, as appropriate, defined as ≥1 of the following disease-related symptoms or signs: o- Unintentional weight loss ≥10% within the previous 6 months before screening o- Significant fatigue (Eastern Cooperative Oncology Group [ECOG] performance status ≥2; inability to work or perform usual activities) o- Fevers higher than 100.5°F or 38.0°C for ≥2 weeks o- Night sweats for ≥1 month before screening without evidence of infection
Must meet 1 of the following criteria:
a. Have received no prior therapy for treatment of CLL and meets 1 of the following criteria: i. A score of >6 on the Cumulative Illness Rating Scale (CIRS) ii. Creatinine clearance of 30 to 69 mL/min using the Cockcroft-Gault equation b. Have previously received therapy for CLL and have either refractory or relapsed CLL c. Have received prior ibrutinib therapy (i.e., defined as a subject who discontinued a ibrutinib for any reason prior to disease progression) for CLL
ECOG performance status of ≤2
Female subjects of childbearing potential (i.e., not surgically sterile or postmenopausal) who are sexually active with a non-sterilized male partner must use ≥1 highly effective method of contraception from the time of screening and must agree to continue using such precautions for 2 days after the last dose of study treatment. Contraception measures and restrictions on sperm donation are not required for male subjects.
Fluorescence in situ hybridization (FISH) for which the next-generation sequencing (NGS) method is preferred) within 60 days during screening up to before the first dose reflecting the presence or absence of del(17p), 13q del, 11q del, and trisomy of chromosome 12 along with the percentage of cells with the deletion, along with TP53 sequencing. Subjects must also have molecular analysis to detect IGHV mutation status (NGS is the preferred method) at screening if not done at any time point before that since diagnosis.
Each subject (or legally authorized representative if allowed per local regulations) must be willing and able to adhere to the study visit schedule, understand and comply with other protocol requirements, and provide written informed consent and authorization to use protected health information.
Subjects who have had disease progression while on a BTKi for any malignant or nonmalignant condition
Prior malignancy (other than CLL), except for adequately treated basal cell or squamous cell skin cancer, in situ cancer, early stage prostate cancer, or other cancer from which the subject has been disease-free for ≥2 years
History of confirmed progressive multifocal leukoencephalopathy
Significant cardiovascular disease such as symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months before screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or corrected QT interval using Fridericia's formula (QTcF) >480 msec at screening. Note: Subjects with rate-controlled, asymptomatic atrial fibrillation are allowed to enroll in the study (For prior ibrutinib therapy cohort only).
Malabsorption syndrome, disease significantly affecting gastrointestinal (GI) function, resection of the stomach, extensive small bowel resection that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass.
Evidence of active Richter's transformation. If Richter's transformation is suspected (i.e., lactate dehydrogenase [LDH] increased, asymmetric fast lymph node growth or clinical suspicion), it should be ruled out with positron emission tomographycomputed tomography (PET-CT) and/or biopsy according to guidelines.
Central nervous system (CNS) involvement by CLL.
Known history of human immunodeficiency virus, serologic status reflecting active hepatitis B virus or hepatitis C virus infection, any uncontrolled active systemic infection along with subjects who are on ongoing anti-infective treatment and subjects who have received vaccination with a live attenuated vaccine within 4 weeks before the first dose of study treatment.
Subjects who are hepatitis B core antibody (anti-HBc) positive and who are hepatitis B surface antibody (anti-HBs) negative will need to have a negative hepatitis B virus PCR result before enrollment. Those who are hepatitis B surface antigen (HBsAg) positive or hepatitis B virus PCR positive will be excluded.
Subjects who are hepatitis C virus antibody positive will need to have a negative hepatitis C virus PCR result before enroll.lment. Those who are hepatitis C virus PCR positive will be excluded
Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura defined as declining hemoglobin or platelet count secondary to autoimmune destruction within the screening period or requirement for high doses of steroids (>20 mg daily of prednisone or equivalent for longer than 2 weeks).
History of stroke or intracranial hemorrhage within 6 months before the first dose of study treatment.
History of bleeding diathesis (e.g., hemophilia or von Willebrand disease)
Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening.
Major surgical procedure within 4 weeks before first dose of study treatment. Note: Subjects who have had major surgery must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study treatment.
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 enrollment in this study.
All subjects requiring or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7 days before first dose of study treatment. Based on the known metabolic/transport pathways involved in the disposition of acalabrutinib and the commonly known novel oral anticoagulants (eg, apixaban, rivaroxaban, and edoxaban), no clinically relevant interaction is expected following coadministration of these agents.
Absolute neutrophil count (ANC) <0.50 x 10^9/L or platelet count <30 x 10^9/L, unless proven due to CLL and raised above the limits by granulocyte colony-stimulating factor (G-CSF) therapy and/or pooled platelet transfusion
Total bilirubin >3.0x upper limit of normal (ULN); or aspartate aminotransferase or alanine aminotransferase >3.0x ULN. Exception will be for Gilbert syndrome; if an investigator feels that a subject's total bilirubin is elevated secondary to Gilbert's, the subject must have a documented unconjugated bilirubin being >80% of the total bilirubin number. The investigator must also document that hemolysis has been ruled out along with (near)-normal lactate dehydrogenase and haptoglobin
Estimated creatinine clearance of <30 mL/min, calculated using the formula of Cockcroft and Gault or by direct assessment (i.e., creatinine clearance or ethylene diamine tetra-acetic acid (EDTA) clearance measurement)
Breastfeeding or pregnant
Received any chemotherapy, external beam radiation, investigational drug, or any other anti-CLL therapy within 30 days before first dose of study treatment
Concurrent participation in another therapeutic clinical study
History of or ongoing interstitial lung disease
Requiring long-term (> 1 week) treatment with a strong cytochrome CYP3A inhibitor/inducer. In addition, the use of strong or moderate CYP3A inhibitors or inducers within 7 days of the first dose of study drug is prohibited.
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There are 106 Locations for this study
Chandler Arizona, 85224, United States
Long Beach California, 90806, United States
Redlands California, 92373, United States
Whittier California, 90603, United States
Fort Myers Florida, 33908, United States
Jacksonville Florida, 32256, United States
Saint Petersburg Florida, 33705, United States
Marietta Georgia, 30060, United States
Normal Illinois, 61761, United States
Peoria Illinois, 61615, United States
Fort Wayne Indiana, 46845, United States
Indianapolis Indiana, 46260, United States
Shreveport Louisiana, 71105, United States
Saint Cloud Minnesota, 56303, United States
Kansas City Missouri, 64132, United States
Bethlehem Pennsylvania, 18015, United States
Chattanooga Tennessee, 37404, United States
Nashville Tennessee, 37203, United States
Dallas Texas, 75235, United States
Adelaide , 5000, Australia
Bedford Park , 5042, Australia
Clayton , 3168, Australia
Fitzroy , 3065, Australia
Nedlands , 6009, Australia
South Brisbane , 4101, Australia
Belo Horizonte , 30130, Brazil
Curitiba , 81520, Brazil
Goiania , 74605, Brazil
Porto Alegre , 90035, Brazil
Porto Alegre , 90110, Brazil
Ribeirão Preto , 14048, Brazil
Sao Paulo , 01236, Brazil
São Paulo , 01323, Brazil
Calgary Alberta, T2N 4, Canada
Edmonton Alberta, T6G 1, Canada
Victoria British Columbia, V8R 6, Canada
Winnipeg Manitoba, R3E 0, Canada
Halifax Nova Scotia, B3H 1, Canada
Brampton Ontario, L6R 3, Canada
Newmarket Ontario, L3Y 2, Canada
Ottawa Ontario, K1H 8, Canada
Aalborg , 9100, Denmark
Aarhus , 8200, Denmark
Herlev , 2730, Denmark
København Ø , 2100, Denmark
Odense , 5000, Denmark
Roskilde , 4000, Denmark
Hus , 00029, Finland
Kuopio , 70210, Finland
Tampere , 33521, Finland
Bordeaux , 33076, France
Brest , 29609, France
Limoges , 87042, France
Reims , 51092, France
Tours , 37000, France
Vandoeuvre-Les-Nancy , 54511, France
Bayern , 63739, Germany
Essen , 45147, Germany
Homburg , 66421, Germany
Porta Westfalica , 32457, Germany
Schwäbisch Hall , 74523, Germany
Catanzaro , 88100, Italy
Milano , 20122, Italy
Roma , 00161, Italy
Roma , 00168, Italy
Siena , 53100, Italy
Busan , 49241, Korea, Republic of
Seoul , 03080, Korea, Republic of
Seoul , 03722, Korea, Republic of
Seoul , 06591, Korea, Republic of
Seoul , 135-7, Korea, Republic of
Ulsan , 44033, Korea, Republic of
Arnhem , 6815 , Netherlands
Dordrecht , 3318 , Netherlands
Utrecht , 3584 , Netherlands
Bergen , 5053, Norway
Oslo , 1478, Norway
Trondheim , 7006, Norway
Moscow , 11547, Russian Federation
Moscow , 12516, Russian Federation
Moscow , 12528, Russian Federation
Nizhny Novgorod , 60312, Russian Federation
Petrozavodsk , 18501, Russian Federation
Saint Petersburg , 19102, Russian Federation
Saint Petersburg , 19429, Russian Federation
Saint Petersburg , 19734, Russian Federation
Saint-Petersburg , 19711, Russian Federation
Smolensk , 21401, Russian Federation
St. Petersburg , 19702, Russian Federation
St. Petersburg , 19734, Russian Federation
Syktyvkar , 16790, Russian Federation
Barcelona , 08036, Spain
Madrid , 28006, Spain
Madrid , 28041, Spain
Marbella , 29603, Spain
Ourense , 32005, Spain
Oviedo , 33011, Spain
Vitoria , 01009, Spain
Zaragoza , 50009, Spain
Luleå , 97180, Sweden
Lund , 221 8, Sweden
Uppsala , 75185, Sweden
Taichung , 40705, Taiwan
Tainan , 704, Taiwan
Taipei , 10002, Taiwan
Taipei , 11217, Taiwan
Liverpool , L7 8X, United Kingdom
Newmarket , CB8 7, United Kingdom
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