Study of Acalabrutinib (ACP-196) Versus Ibrutinib in Previously Treated Participants With High Risk Chronic Lymphocytic Leukemia (CLL)

Study Overview
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Brief Summary
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This study is designed to evaluate progression-free survival (PFS) endpoint for acalabrutinib versus (vs) ibrutinib in previously treated chronic lymphocytic leukemia.

Official Title
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A Randomized, Multicenter, Open-Label, Non-Inferiority, Phase III Study of Acalabrutinib (ACP-196) Versus Ibrutinib in Previously Treated Subjects With High Risk Chronic Lymphocytic Leukemia

Conditions
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Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Drug: Acalabrutinib
* Drug: Ibrutinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women ≥ 18 years of age. ECOG performance status of 0 to 2. Diagnosis of CLL. Must have ≥ 1 of the following high-risk prognostic factors: Presence of 17p del by central laboratory. Presence of 11q del by central laboratory. Active disease meeting ≥ 1 of the following IWCLL 2008 criteria for requiring treatment Must have received ≥ 1 prior therapies for CLL. Meet the following laboratory parameters: Absolute neutrophil count (ANC) ≥ 750 cells/μL or ≥ 500 cells/μL in participants with documented bone marrow involvement, and independent of growth factor support 7 days before assessment. Platelet count ≥ 30,000 cells/μL without transfusion support 7 days before assessment. Participants with transfusion-dependent thrombocytopenia are excluded. Serum aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT)/serum glutamic-pyruvic transaminase (SGPT) ≤ 3.0 x upper limit of normal (ULN). Total bilirubin ≤ 1.5 x ULN. Estimated creatinine clearance ≥ 30 mL/min. Exclusion Criteria: Known CNS lymphoma or leukemia. Known prolymphocytic leukemia or history of, or currently suspected, Richter's syndrome. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura. Prior exposure to ibrutinib or to a B-cell receptor (BCR) inhibitor or a B-cell lymphoma-2 (BCL-2) inhibitor. Received any chemotherapy, external beam radiation therapy, anticancer antibodies, or investigational drug within 30 days before first dose of study drug. Prior radio- or toxin-conjugated antibody therapy. Prior allogeneic stem cell or autologous transplant. Major surgery within 4 weeks before first dose of study drug. Prior malignancy, except for adequately treated lentigo maligna melanoma, non-melanomatous skin cancer, in situ cervical carcinoma or other malignancy treated with no evidence of active disease > 3 years before Screening and at low risk for recurrence. Significant cardiovascular disease within 6 months of screening. Known history of infection with human immunodeficiency virus (HIV). History of stroke or intracranial hemorrhage within 6 months before randomization. History of bleeding diathesis. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists within 7 days of first dose of study drug. Requires treatment with a strong cytochrome P450 3A (CYP3A) inhibitor/inducer.
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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Acalabrutinib<br>Participants will receive oral acalabrutinib 100 mg twice daily (BID) until disease progression (PD), or unacceptable toxicity, or other reasons for discontinuation, whichever occurs first. | Drug: Acalabrutinib<br>* Participants will receive oral acalabrutinib as stated in arm description.<br>* Other names: ACP-196;|
| Active Comparator: Ibrutinib<br>Participants will receive oral ibrutinib 420 mg once daily (QD) until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurrs first. | Drug: Ibrutinib<br>* Participants will receive oral ibrutinib as stated in arm description.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) Based on Independent Review Committee (IRC) Assessment | The PFS is defined as the time from date of randomization to the date of first IRC-assessed PD or death due to any cause, whichever occurred first. PD (per International Workshop on Chronic Lymphocytic Leukemia [iwCLL] 2008 criteria): Lymphocytes >= 50% increase over baseline, or >= 50% increase in lymphadenopathy/hepatomegaly/splenomegaly, or >= 50% platelets or > 2 g/dL hemoglobin decreases from baseline secondary to chronic lymphocytic leukemia (CLL). The PFS is assessed using the Kaplan-Meier method. | Baseline (Days -28 to -1) through 55.2 months (maximum observed duration) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Infections Grade >= 3 | Number of participants with treatment-emergent infections Grade >=3 are reported. | Day 1 through 83.5 months (maximum observed duration) | 
| Number of Participants With Treatment-emergent Richter's Transformation | Richter's transformation is defined as the occurrence of an aggressive lymphoma in participants with a previous or concomitant diagnosis of CLL. Richter's transformation was assessed by central pathology. Number of participants with treatment-emergent Richter's transformation are reported. | Day 1 through 83.5 months (maximum observed duration) | 
| Number of Participants With Treatment-emergent Atrial Fibrillation | Number of participants with treatment-emergent atrial fibrillation (including atrial flutter) are reported. | Day 1 through 83.5 months (maximum observed duration) | 
| Overall Survival (OS) | The OS is defined as the time from date of randomization to date of death due to any cause. The OS is assessed using the Kaplan-Meier method. | Baseline (Days -28 to -1) through 83.7 months (maximum observed duration) | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. | Day 1 through 83.5 months (maximum observed duration) | 
| Number of Participants With Treatment-emergent Laboratory Abnormalities | Number of participants with treatment-emergent laboratory abnormalities are reported. Laboratory abnormality is defined as any abnormal finding during analysis of hematology and serum chemistry. | Day 1 through 83.5 months (maximum observed duration) | 
| Number of Participants With Abnormal Vital Signs Reported as TEAEs | Number of participants with abnormal vital signs reported as TEAEs are reported. Abnormal vital signs are defined as any abnormal finding in the vital sign parameters (body temperature, blood pressure, heart rate, and respiratory rate). | Day 1 through 83.5 months (maximum observed duration) | 
| Percentage of Participants With Lymphocytosis | Percentage of participants with at least one occurrence of treatment-related lymphocytosis defined as an elevation in ALC of >= 50% compared with baseline and a postbaseline assessment of > 5000/μL in the peripheral blood are reported. | Day 1 through 83.5 months (maximum observed duration) | 
| Number of Participants With Electrocardiogram (ECG) Abnormality at Baseline | Number of participants with ECG abnormality at baseline are reported. | Baseline (Days -28 to -1) | 
| Number of Participants With Shift From Baseline to Worst (Grade 3 and 4) Postbaseline in Eastern Cooperative Oncology Group (ECOG) Performance Status | The ECOG performance status assessed participant's performance status on 5 point scale: 0=Fully active/able to carry on all pre-disease activities without restriction; 1=restricted in physically strenuous activity, ambulatory/able to carry out light or sedentary work; 2=ambulatory (>50% of waking hours), capable of all self-care, unable to carry out any work activities; 3=capable of only limited self care, confined to bed/chair >50% of waking hrs; 4=completely disabled, cannot carry on any self care, totally confined to bed/chair; 5=death. Number of participants with shift from baseline (Days -28 to -1) to worst Grade 3 and 4 in ECOG performance status are reported. | Baseline (Days -28 to -1) through 83.5 months (maximum observed duration) |