Study of Acalabrutinib Versus Chlorambucil Plus Rituximab in Adult Subjects With Previously Untreated Chronic Lymphocytic Leukemia

Study Overview
=================
Brief Summary
-----------------
This is a randomized, multicenter, open-label, Phase 3 study to evaluate the efficacy and safety of Acalabrutinib versus Chlorambucil plus Rituximab in subjects with Previously Untreated Chronic Lymphocytic Leukemia.

Detailed Description
-----------------
Patients be randomized in a 1:1 ratio into 2 arms to receive either acalabrutinib monotherapy (Arm A) or rituximab in combination with chlorambucil (Arm B). The primary objective of this study is to compare the efficacy of acalabrutinib relative to chlorambucil plus rituximab in subjects with previously untreated chronic lymphocytic leukemia without del(17p) or TP53 mutation.

Official Title
-----------------
A Randomized, Multicenter, Open-Label, Phase 3 Study to Evaluate the Efficacy and Safety of Acalabrutinib Versus Chlorambucil Plus Rituximab in Subjects With Previously Untreated Chronic Lymphocytic Leukemia

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

Intervention / Treatment
-----------------
* Drug: Acalabrutinib
* Drug: Rituximab
* Drug: Chlorambucil


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Men and women: (a) ≥65 years of age OR (b) >18 and <65 years of age, provided that they meet at least one of the following criteria: (i) Creatinine clearance 30 to 69 mL/min using the Cockcroft-Gault equation (iwCLL guidelines) (ii) A score higher than 6 on the Cumulative Illness Rating Score-Geriatric (CIRS G) ECOG performance status of 0, 1, or 2 Diagnosis of CLL that meets published diagnostic criteria (Hallek 2018) Active disease per IWCLL 2018 criteria that requires treatment Adequate bone marrow function Adequate renal and hepatic function Exclusion Criteria: Known detected del(17p) or TP53 mutation Transformation of CLL to aggressive non-Hodgkin lymphoma (NHL) (eg, Richter's transformation, PLL, or diffuse large B cell lymphoma [DLBCL]), or central nervous system (CNS) involvement by leukemia History of prior malignancy except for the following: (a) Curatively treated basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of the cervix at any time prior to study (b) Other cancers not specified above which have been curatively treated by surgery and/or radiation therapy from which subject is disease-free for ≥3 years without further treatment Significant cardiovascular disease Known history of infection with human immunodeficiency virus (HIV) Serologic status reflecting active hepatitis B or C infection Any active systemic infection (eg, bacterial, viral, or fungal infection) requiring systemic treatment History of stroke or intracranial hemorrhage within 6 months before first dose of study drug Major surgical procedure within 30 days of first dose of study drug Any prior CLL-specific therapies Corticosteroid use >20 mg within 1 week before first dose of study drug, except as indicated for other medical conditions Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists For women only: breastfeeding or pregnant

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 130 Years

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Acalabrutinib<br>Acalabrutinib will be orally administered until disease progression or unacceptable toxicity | Drug: Acalabrutinib<br>* acalabrutinib 100 mg twice daily orally<br>|
| Active Comparator: Rituximab and Chlorambucil<br>Chlorambucil orally administered and Rituximab via IV infusion for 6 cycles | Drug: Rituximab<br>* Rituximab: 375 mg/m2 IV infusion on Day 1 of Cycle 1. 500 mg/m2 IV infusion on Day 1 for each of subsequent cycles (Cycles 2-6)<br>Drug: Chlorambucil<br>* Chlorambucil: 0.5 mg/kg body weight orally on Day 1 and Day 15 of Cycles 1-6<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) | Progression free survival is defined as time from randomization until progression or death due to any cause (whichever occurs first) | approximately 50 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate |  | approximately 50 months | 
| Duration of response |  | approximately 50 months | 
| Time to next treatment |  | approximately 50 months | 
| Overall survival |  | approximately 50 months | 
| Minimal residual disease negativity rate |  | approximately 50 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Chronic Lymphocytic Leukemia, Acalabrutinib, Progression-free Survival