Study of Acalabrutinib Versus Chlorambucil Plus Rituximab in Adult Subjects With Previously Untreated Chronic Lymphocytic Leukemia
- Conditions
- Untreated Chronic Lymphocytic Leukemia
- Interventions
- Registration Number
- NCT04075292
- Lead Sponsor
- AstraZeneca
- 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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 155
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Acalabrutinib Acalabrutinib Acalabrutinib will be orally administered until disease progression or unacceptable toxicity Rituximab and Chlorambucil Rituximab Chlorambucil orally administered and Rituximab via IV infusion for 6 cycles Rituximab and Chlorambucil Chlorambucil Chlorambucil orally administered and Rituximab via IV infusion for 6 cycles
- Primary Outcome Measures
Name Time Method Progression Free Survival (PFS) Assessed by BICR 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 Outcome Measures
Name Time Method 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) TTNT was defined as the time from the date of randomization to the date of initiation of non-protocol-specified anti-CLL therapy (either medication or radiotherapy for CLL) or death from any cause, whichever occurred first. Median TTNT was calculated using Kaplan-Meier method and its CI was calculated using Brookmeyer-Crowley method.
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) OS was defined as the time from the date of randomization until death due to any cause. The median OS was calculated using Kaplan-Meier method and its CI was calculated using Brookmeyer-Crowley method.
Minimal Residual Disease (MRD) Negativity Rate At Cycle 9 (cycle duration: 28 days) The MRD negative rate was defined as the percentage of participants with MRD-negativity (defined as \<1 CLL cell per 10,000 leukocytes) measured in the peripheral blood by flow cytometry.
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) Blood samples were collected to determine the concentration of acalabrutinib and its metabolite ACP-5862 in plasma.
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) ORR:percentage of participants with complete response(CR),CR with incomplete BM recovery(CRi), partial response(PR)/nodular PR(nPR) assessed by BICR;investigator per IWCLL 2018 criteria at/before initiation of subsequent anti-cancer therapy.CR:No lymph nodes(target lesions)≥1.5 centimeter(cm), spleen\<13cm,normal liver;CLC,no constitutional symptoms,platelets≥100,000/microliter(μL),Hb≥11.0 g/dL,BM:normocellular,no CLL cells\&B-lymphoid nodules.PR:atleast 2 gA parameters;1 gB parameter need to improve if previously abnormal.If only 1 parameter of both gA,B was abnormal prior to therapy,only 1 needs to improve.gA:Decrease≥50% from BL in lymph nodes,liver \& or spleen size,CLC;any constitutional symptoms, gB:platelet≥100,000/μL or increase 50% over BL;Hb≥11g/dL or increase≥50% over BL;BM:presence of CLL cells/B-lymphoid nodules/not done.CRi:all CR criteria+persistent anemia,thrombocytopenia or neutropenia unrelated to CLL,related to drug toxicity.nPR:CR+presence of B-lymphoid nodules in BM.
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) DOR was defined as the time from response (date of first documented response) to PD or death (absence of PD) as judged by BICR and investigator. PD was defined as meeting at least 1 of the below criteria of group A or group B. Group A: Increase of ≥ 50% from 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/L in CLC; group B: decrease of ≥50% from BL secondary to CLL in platelet count; decrease of ≥2 g/dL from BL secondary to CLL in hemoglobin; increase of CLL cells by ≥50% on successive biopsies in marrow. Median DOR was calculated using Kaplan-Meier method and its CI using Brookmeyer-Crowley method.
Trial Locations
- Locations (1)
Research Site
🇻🇳Ho Chi Minh, Vietnam