Acalabrutinib Safety Study in Untreated and Relapsed or Refractory Chronic Lymphocytic Leukemia Patients
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 bid in approximately 600 participants with 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 follow-up
 period for those participants remaining on study treatment after completion of 48 cycles (the
 amount of time will vary by participant).
This is a Phase 3b, multicenter, open-label, single-arm study to evaluate the safety and
 efficacy of acalabrutinib 100 mg bid in approximately 600 participants with chronic
 lymphocytic leukemia (CLL). Participants will be enrolled into 3 cohorts: treatment-naive
 (TN) (minimum of 300 participants), relapsed/refractory (R/R) (approximately 200
 participants), and prior bruton tyrosine kinase inhibitor (BTKi) therapy (up to 70 to 100
 participants). Assessment of response and progression 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. Study treatment
 (acalabrutinib 100 mg bid) will be administered until disease progression, unacceptable
 toxicity, 48 cycles of study treatment, withdrawal of consent, loss to follow-up, death, or
 study termination by the sponsor, whichever comes first (each cycle is 28 days). In-clinic
 visits will occur every cycle for the first 6 cycles, and then every 3 cycles for the next 6
 cycles. After 12 cycles "in-clinic visits" will occur 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, they will continue to be
 provided with study treatment. This may include, but not be limited to, transition to a
 long-term extension trial, continuous supply in this trial (for eg in countries where
 regulatory approval is not obtained, or drug is not reimbursed) or switching to commercial
 drug as permitted by local regulations. Participants who remain in the trial after the
 completion of 48 cycles will be followed for disease progression, description of all
 subsequently administered anticancer therapies, and IWCLL indication for initiation of
 subsequent anticancer therapies q24w via standard practice until transition to regulatory
 approved off-study acalabrutinib, withdrawal of consent, lost to follow-up, death, or study
 termination by the sponsor. Participants 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).
Inclusion Criteria:

 1. Men and women ≥18 years of age (or the legal age of consent in the jurisdiction in
 which the study is taking place)

 2. Diagnosis of CLL that meets published diagnostic criteria (Hallek et al. 2018):

 1. 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

 2. Prolymphocytes may comprise <55% of blood lymphocytes

 3. Presence of ≥5 × 109 B lymphocytes/L (5000/μL) in the peripheral blood (at any
 point since the initial diagnosis)

 3. Active disease as per at least 1 of the following IWCLL 2018 criteria

 1. 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).

 2. Massive (i.e., ≥6 cm below the left costal margin), progressive, or symptomatic
 splenomegaly.

 3. Massive nodes (i.e., ≥10 cm in the longest diameter), progressive, or symptomatic
 lymphadenopathy

 4. 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 <30x109/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.

 5. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard
 therapy

 6. 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 before screening without evidence of infection o-
 Night sweats for ≥1 month before screening without evidence of infection

 4. 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 BTKi therapy (i.e., defined as a subject who discontinued a BTKi for
 any reason except disease progression) for CLL d. Criterion deleted.

 5. ECOG performance status of ≤2

 6. 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.

 7. Fluorescence in situ hybridization (FISH) within 60 days before or during screening
 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
 at any time point since diagnosis.

 8. 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.

 Exclusion Criteria:

 1. Subjects who have had disease progression while on a BTKi for any malignant or
 nonmalignant condition

 2. 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

 3. History of confirmed progressive multifocal leukoencephalopathy

 4. 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.

 5. Malabsorption syndrome, disease significantly affecting gastrointestinal 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.

 6. 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.

 7. Central nervous system (CNS) involvement by CLL.

 8. 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.

 1. 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.

 2. 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

 9. 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).

 10. History of stroke or intracranial hemorrhage within 6 months before the first dose of
 study treatment.

 11. History of bleeding diathesis (e.g., hemophilia or von Willebrand disease)

 12. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before
 screening.

 13. 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.

 14. 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.

 15. 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.

 16. Absolute neutrophil count (ANC) <0.50 x 109/L or platelet count <30 x 109/L, unless
 proven due to CLL and raised above the limits by granulocyte colony-stimulating factor
 (G-CSF) therapy and/or pooled platelet transfusion

 17. 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

 18. 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)

 19. Breastfeeding or pregnant

 20. Received any chemotherapy, external beam radiation, investigational drug, or any other
 anti-CLL therapy within 30 days before first dose of study treatment

 21. Concurrent participation in another therapeutic clinical study

 22. History of interstitial lung disease

 23. 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.