Early Intervention With Acalabrutinib in Patients With High Risk CLL

Study Overview
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Brief Summary
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This study evaluates the effectiveness of acalabrutinib treatment in patients with chronic lymphocytic leukemia (CLL) deemed at high risk for Richter's Transformation (RT). This is a single arm study. Enrolled patients will initiate therapy with acalabrutinib and will dose continuously. While on study, subjects will be monitored monthly for the first 3 months, then every three months thereafter until disease progression, discontinuation due to toxicity, death, or study completion.

Detailed Description
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This is a multi-center, single arm, Phase II clinical trial to investigate the effectiveness of acalabrutinib treatment within 6 months of chronic lymphocytic leukemia (CLL) diagnosis for patients with CLL deemed at high risk for Richter's Transformation (RT).

Official Title
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A Phase II Trial of Early Intervention With Acalabrutinib in Patients With CLL at High Risk for Richter's Transformation

Conditions
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CLL/SLL, Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Drug: Acalabrutinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must be able to voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study specific procedures. The time from diagnosis to consent should be ≤6 months. Subject must be ≥ 18 years of age. Subject must have diagnosis of CLL/SLL based upon 2018 iwCLL Guidelines. Rai stage 0-2 disease without indication for treatment as defined by the 2018 iwCLL guidelines Subject must have high risk CLL as defined by any one of the following: NOTCH1 mutated (classic frameshift mutation only) Unmutated V4-39 B cell receptor usage Pathogenic c-MYC mutations Complex karyotype, (by CpG/oligodeoxynucleotide stimulation) Deletion 17p, or presence of TP53 mutation Subject has an Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 2. PT/PTT/INR within 1.5 x the ULN Adequate renal function defined by serum creatinine less than 2 x ULN Adequate hepatic function: ALT/AST less than 2x ULN Tbili less than 1.5 X ULN unless bilirubin elevation is due to Gilbert's syndrome (total bilirubin <3) Subject must have adequate bone marrow function. Absolute neutrophil count ≥1.0 x103/μL Hemoglobin ≥ 11.0 g/dL Platelets ≥ 100 x 103/μL Exclusion Criteria: Previous exposure to any systemic anti-cancer therapy as a treatment for CLL, including but not limited to chemotherapy, immunotherapy, radiotherapy, or investigational therapy. Note, patients treated with chemotherapy for a prior non-hematologic malignancy if more than 5 years earlier are eligible. Subject with a history of malignancy except for non-melanoma skin cancers. Subjects treated with curative intent via methods of local resection and or locally targeted anticancer treatment and are free of malignancy for at least 5 years from treatment end will be allowed to enroll. Subject requires chronic immunosuppressive therapy for any reason or was treated with immunosuppressive therapy within 6 months of study entry. Subjects with a history of autoimmune hemolytic anemia or immune thrombocytopenia purpura. Subject has prolymphocytic leukemia. Active bleeding, or history of bleeding diathesis (e.g., hemophilia or von Willebrand disease) Subject requires warfarin or equivalent vitamin K antagonist Uncontrolled or active significant infection, History of or suspected or confirmed PML Clinically 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. Subjects with controlled, asymptomatic atrial fibrillation during screening can enroll on study. Patients with stroke or CNS hemorrhage within 6 months Pregnant or breastfeeding Women of childbearing potential (WCBP) who are sexually active with heterosexual partners must agree to use highly effective methods of contraception during treatment and for 2 days after the last dose of acalabrutinib. Major surgical procedure within 28 days of first dose of study drug. If a subject had surgery, they must have recovered adequately from any toxicity or complications before the first dose of study drug. Has difficulty with or is unable to swallow oral medication or has significant gastrointestinal disease that would limit absorption of oral medication. Subject is known to be positive for human immunodeficiency virus (HIV) Active hepatitis C, as confirmed by being positive for Hep C RNA by PCR Active hepatitis B infection documented by a positive PCR for Hep B DNA. If hepatitis B serology is positive for hepatitis B core antibody, but Hep B DNA PCR is negative, patient is eligible to enroll. Subject requires strong CYP 3A4/5 inhibitors or inducers (Appendix B). Subject requires proton pump inhibitors. (Subjects that can transition to an H2 antagonist are allowed to enroll.)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Acalabrutinib<br>Acalabrutinib 100 mg will be administered orally twice daily continuously in 28-day cycles until treatment is discontinued for any reason. | Drug: Acalabrutinib<br>* Acalabrutinib, oral, 100 mg BID, continuous<br>* Other names: ACP-196;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of subjects who do not develop Richter's Transformation (RT) within 5 years of study drug administration |  | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival | Measured from time of study drug administration to time of progression, transformation to a more aggressive histology, treatment discontinuation due to toxicity, or death from any cause. | 5 years | 
| Progression-free survival | Measured from time of study drug administration to progression or death, measured in months. | 5 years | 
| Progression-free survival in patients with TP53 disruption | For subjects with TP53 disruption present at baseline, measured from time of study drug administration to progression or death, measured in months. | 5 years | 
| Overall survival | Measured from time of study drug administration to death from any cause, measured in months. | 5 years | 
| Percentage of subjects who do not develop Richter's Transformation within 2 years of study drug administration |  | 2 years | 
| Median time to development of RT | Measured from time of study drug administration | 5 years | 
| Safety of early interventional acalabrutinib in patients with chronic lymphocytic leukemia (CLL) at high risk for Richter's Transformation | Percentage of subjects who experience 1 or more adverse events. | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CLL, untreated