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
Overview
- Phase
- Phase 3
- Intervention
- Acalabrutinib
- Conditions
- Untreated Chronic Lymphocytic Leukemia
- Sponsor
- AstraZeneca
- Enrollment
- 155
- Locations
- 46
- Primary Endpoint
- Progression Free Survival (PFS) Assessed by BICR
- Status
- Active, not recruiting
- Last Updated
- last month
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.
Investigators
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
Arms & Interventions
Acalabrutinib
Acalabrutinib will be orally administered until disease progression or unacceptable toxicity
Intervention: Acalabrutinib
Rituximab and Chlorambucil
Chlorambucil orally administered and Rituximab via IV infusion for 6 cycles
Intervention: Rituximab
Rituximab and Chlorambucil
Chlorambucil orally administered and Rituximab via IV infusion for 6 cycles
Intervention: Chlorambucil
Outcomes
Primary Outcomes
Progression Free Survival (PFS) Assessed by BICR
Time Frame: Response evaluations performed every 12 weeks from Cycle 4 Day 1 to Cycle 25, then every 24 weeks until PD or death, up to DCO date of 03 January 2024 (a maximum of approximately 47.5 months)
PFS was defined as the time from randomization to PD (assessed by BICR according to International Workshop on Chronic Lymphocytic Leukaemia \[iwCLL\] 2018 guideline criteria) or death due to any cause. PD was defined as meeting at least 1 of the below criteria of groups(g) A or B. gA: increase of ≥50% from baseline (BL) or from response in lymph nodes or liver and/or spleen size; any constitutional symptoms; increase of ≥50% over nadir with absolute count ≥ 5×10\^9/liter (L) in circulating lymphocyte count (CLC); gB: decrease of ≥50% from BL secondary to CLL in platelet count; decrease of ≥2 gram per deciliter (g/dL) from BL secondary to CLL in hemoglobin (Hb); increase of CLL cells by ≥50% on successive biopsies in bone marrow (BM). Median PFS was calculated using Kaplan-Meier method and its confidence interval (CI) using Brookmeyer-Crowley method.
Secondary Outcomes
- Time to Next Treatment (TTNT)(Response evaluations performed every 12 weeks from Cycle 4 Day 1 to Cycle 25, then every 24 weeks until PD, and survival follow-ups performed every 12 weeks thereafter, up to DCO date of 03 January 2024 (a maximum of approximately 47.5 months))
- Overall Survival (OS)(From date of randomization until death due to any cause, up to DCO date of 03 January 2024 (a maximum of approximately 47.5 months))
- Minimal Residual Disease (MRD) Negativity Rate(At Cycle 9 (cycle duration: 28 days))
- Plasma Concentrations of Acalabrutinib and Its Metabolite ACP-5862(Pre-dose, and at 1, 2, 4 hours post-dose on Day 1 of Cycle 2 (cycle duration: 28 days))
- Overall Response Rate (ORR) Assessed by BICR and Investigator(Response evaluations performed every 12 weeks from Cycle 4 Day 1 to Cycle 25, then every 24 weeks until PD or death, up to DCO date of 03 January 2024 (a maximum of approximately 47.5 months))
- Duration of Response (DOR) Assessed by BICR and Investigator(Response evaluations performed every 12 weeks from Cycle 4 Day 1 to Cycle 25, then every 24 weeks until PD or death, up to DCO date of 03 January 2024 (a maximum of approximately 47.5 months))