A Study of ACP-196 (Acalabrutinib) in Subjects With Relapsed/Refractory CLL and Intolerant of Ibrutinib Therapy

Study Overview
=================
Brief Summary
-----------------
A Phase 2 Study to evaluate the Efficacy and Safety of ACP-196 (acalabrutinib) in Subjects with Relapsed/Refractory CLL and Intolerant of Ibrutinib Therapy

Detailed Description
-----------------
A Multicenter, Open-Label, Phase 2 study evaluating the efficacy and safety of Acalabrutinib in subjects with relapsed/refractory CLL (N=60) who are intolerant of ibrutinib therapy.

Official Title
-----------------
A Phase 2 Study of the Efficacy and Safety of ACP-196 in Subjects With Relapsed/Refractory CLL and Intolerant of Ibrutinib Therapy

Conditions
-----------------
Chronic Lymphocytic Leukemia

Intervention / Treatment
-----------------
* Drug: ACP-196 (acalabrutinib)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Men and women ≥ 18 years of age. Prior diagnosis of CLL Must have received ≥ 1 prior therapy for CLL Intolerant of ibrutinib Documented disease progression after stopping ibrutinib therapy as defined by the IWCLL 2008 criteria Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty. ECOG performance status of ≤ 2. Exclusion Criteria: Ongoing AE attributed to ibrutinib therapy Treatment with systemic anticancer therapy for CLL is prohibited between discontinuation of ibrutinib and enrollment on this trial. Prior exposure to a BCL-2 inhibitor (eg, venetoclax/ABT- 199) 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. Significant cardiovascular disease such as uncontrolled or symptomatic untreated 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 QTc > 480 msec at screening. Exception: Subjects with controlled, asymptomatic atrial fibrillation during screening are allowed to enroll on study. 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. Evidence of active Richter's transformation or any evidence of disease progression on ibrutinib therapy or any BTK inhibitor. CNS involvement by CLL or related Richter's transformation. Known history of human immunodeficiency virus (HIV), serologic status reflecting active hepatitis B or C infection, or any uncontrolled active systemic infection. Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP) History of stroke or intracranial hemorrhage within 2 months before the first dose of study drug. History of bleeding diathesis. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening. Major surgical procedure within 28 days of first dose of study drug. Requires treatment with a strong CYP3A inhibitor

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ACP-196 (acalabrutinib)<br>ACP-196 (acalabrutinib) 100 mg to be administered orally (PO) twice a day BID | Drug: ACP-196 (acalabrutinib)<br>* ACP-196 100 mg to be administered orally (PO) twice a day BID.<br>* Other names: Acalabrutinib;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Overall Response Rate (ORR) of ACP-196 (Acalabrutinib) | The overall response rate (ORR) of ACP-196 (acalabrutinib) in subjects with relapsed / refractory CLL who are intolerant of ibrutinib therapy. ORR is defined as the proportion of subjects achieving a best overall response (BOR) of either complete remission (CR), complete remission with incomplete bone marrow recovery (CRi), nodular partial remission (nPR), or partial remission (PR) at or before initiation of subsequent anticancer therapy. ORR will be analyzed per investigator's assessment. | From date of the first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to approximately 4 years and 7 months). 1 cycle = 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival | The progression-free survival of ACP-196 (acalabrutinib) in subjects with relapsed / refractory CLL who are intolerant of ibrutinib therapy. PFS is calculated as date of disease progression or death (censoring date for censored subjects) - first dose date + 1. | From the date of the first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 5 years). | 
| Duration of Response | The duration of response of ACP-196 (acalabrutinib) in subjects with relapsed / refractory CLL who are intolerant of ibrutinib therapy. DOR is calculated as date of disease progression or death (censoring date for censored subjects) - date of achieving the first CR, CRi, nPR, or PR + 1. | From the date of the first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 5 years) | 
| Time-to-Next Treatment | The time to next treatment of ACP-196 (acalabrutinib) in subjects with relapsed / refractory CLL who are intolerant of ibrutinib therapy. TTNT is defined as the time from date of first acalabrutinib treatment to date of institution of subsequent anticancer therapy for CLL or death due to any cause, whichever comes first. Subjects who do not have the above specified events prior to the data cutoff date will be censored at the date of last visit. TTNT will be calculated as follows: (Earlier date of institution of subsequent anticancer therapy for CLL or date of death due to any cause) - date of first dose + 1. For censored subjects, date of last visit will replace earlier date of use of subsequent anticancer therapy for CLL or date of death due to any cause in the calculation. | From date of the first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 5 years) | 
| Overall Survival | The overall survival of ACP-319 (acalabrutinib) in subjects with relapsed/refractory CLL who are intolerant of ibrutinib therapy | From date of the first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 5 years). | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Ibrutinib Intolerant, Chronic Lymphocytic Leukemia