High Risk Chronic Lymphocytic Leukemia MedDRA version: 21.0 Level: LLT Classification code 10008976 Term: Chronic lymphocytic leukemia System Organ Class: 100000004864
Conditions
Sponsors
Acerta Pharma B.V.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Men and women = 18 years of age. 2. Prior diagnosis of CLL that meets published diagnostic criteria as follows: a. Monoclonal B-cells (either kappa or lambda light chain restricted) that are clonally co-expressing = 1 B-cell marker (CD19, CD20, or CD23) and CD5. b. Prolymphocytes may comprise = 55% of blood lymphocytes. c. No evidence of cyclin D1 rearrangement or BCL-1 over expression. d. Presence of = 5 x 109 B lymphocytes/L (5000 µL) in the peripheral blood (at any point since diagnosis). 3. Must have received = 1 prior therapy for CLL and not be appropriate for treatment or retreatment with purine analogue-based therapy as defined by = 1 of the following criteria: a. Failure to respond (stable disease [SD] or disease progression on treatment) or progression-free interval of 1.5 cm as measured in the longest diameter in a site that has not been previously irradiated. An irradiated lesion may be assessed for measurable disease only if there has been documented progression in that lesion since radiotherapy has ended. 6. Documented disease progression after stopping ibrutinib therapy as defined by the IWCLL 2008 criteria. 7. Eastern Cooperative Oncology Group (ECOG) performance status of = 2. 8. Women who are sexually active and can bear children must agree to use highly effective forms of contraception during the study and for 2 days after the last dose of acalabrutinib. Highly effective forms of contraception are defined in the protocol. 9. This criterion has been removed as of Protocol Amendment 3. 10. This criterion has been removed as of Protocol Amendment 3. 11. Willing and able to participate in all required evaluations and procedures in this study protocol, including swallowing capsules without difficulty. 12. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local patient privacy regulations). Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 30 F.1.3 Elderly (>=65 years) yes F.1.3.1 Numbe
Exclusion criteria
Exclusion criteria: 1. Ongoing Grade 3 or 4 AE attributed to ibrutinib therapy. Note: Subjects may be eligible for enrollment once the ibrutinib-related AE improves to Grade = 2. 2. Treatment with systemic anticancer therapy for CLL is prohibited between discontinuation of ibrutinib and enrollment on this trial. 3. Prior exposure to a BCL-2 inhibitor (e.g., venetoclax/ABT-199). 4. Prior malignancy (other than CLL), except for adequately treated basal cell or squamous cell skin cancer, in situ cancer, or other cancer from which the subject has been disease free for = 2 years. 5. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or corrected QT interval (QTc) > 480 msec at screening. Exception: Subjects with controlled, asymptomatic atrial fibrillation during screening are allowed to enroll on study. 6. 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. 7. Evidence of active Richter's transformation or any evidence of disease progression on ibrutinib therapy or any BTK inhibitor. 8. CNS involvement by CLL or related Richter’s transformation. 9. Known history of HIV, serologic status reflecting active hepatitis B or C infection, or any uncontrolled active systemic infection. a) Subjects who are anti-hepatitis B core antibody (anti-HBc) positive and who are surface antigen negative will need to have a negative polymerase chain reaction (PCR) result before enrollment. Those who are hepatitis B surface antigen (HBsAg) positive or hepatitis B PCR positive will be excluded. b) Subjects who are hepatitis C antibody positive will need to have a negative PCR result before enrollment. Those who are hepatitis C PCR positive will be excluded. 10. Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP) 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). 11. History of stroke or intracranial hemorrhage within 2 months before the first dose of study drug. 12. History of bleeding diathesis (e.g., hemophilia or von Willebrand disease). 13. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening. 14. Major surgical procedure within 28 days of first dose of study drug. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug. 15. Requires treatment with a strong CYP3A inhibitor. 16. 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 to this study. 17. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon). 18. Absolute neutrophil count (ANC) < 0.75 x 1
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the efficacy of acalabrutinib in subjects with relapsed/refractory CLL who are intolerant of ibrutinib therapy;Secondary Objective: To evaluate the safety and tolerability of acalabrutinib in subjects with relapsed/refractory CLL who are intolerant of ibrutinib therapy EXPLORATORY OBJECTIVES: - To determine the effect of acalabrutinib on peripheral blood B cells, T cells, NK cells, and MDSCs. - To evaluate potential predictive biomarkers and mechanisms of resistance for the disease.;Primary end point(s): Efficacy will be evaluated based on the modified International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria (Appendix 2). The primary efficacy endpoint is ORR assessed by the investigators.;Timepoint(s) of evaluation of this end point: See section above. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): The secondary efficacy endpoints are: • Duration of response (DOR) • PFS • Time-to-next treatment (TTNT) • OS The safety of acalabrutinib will be characterized by laboratory assessments and the type, frequency, severity, and causal attribution of AEs, or AEs leading to discontinuation of study treatment. For consistency of interpretation, AEs and laboratory results will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), and the severity of both hematologic and nonhematologic AEs will be graded using the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 or higher. Standard definitions for seriousness will be applied (see Section 6.1). The occupancy of BTK by acalabrutinib will be measured in peripheral blood mononuclear cells (PBMCs) with the aid of a biotin-tagged acalabrutinib analogue probe. The effect of acalabrutinib on B cells, NK cells (CD56+), T cells (CD3+, CD4+, CD8+ levels), and MDSCs (HLA-DR- CD14+CD11b+ CD33+ levels) will also be evaluated. Genotyping for BTK, p53, and phospholipase C gamma (PLC?) mutations will be performed.;Timepoint(s) of evaluation of this end point: See section above. | — |
Countries
Belgium, France, Israel, Spain, United Kingdom, United States
Contacts
Public ContactACE-CL-208 Clinical Team
Acerta Pharma BV
Outcome results
None listed