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Completed

NCT Number: NCT03734016

A Study of Zanubrutinib (BGB-3111) Versus Ibrutinib in Participants With Relapsed/Refractory Chronic Lymphocytic Leukemia

This study is designed to compare the overall response rate of zanubrutinib versus ibrutinib in participants with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma.

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Key information

Conditions

Chronic Lymphocytic Leukemia Chronic Disease Disease Attributes Hematologic Diseases Hemic and Lymphatic Diseases Immune System Diseases Immunoproliferative Disorders Leukemia Leukemia, B-Cell Leukemia, Lymphocytic, Chronic, B-Cell Leukemia, Lymphoid Lymphatic Diseases Lymphoproliferative Disorders Neoplasms Neoplasms by Histologic Type Pathologic Processes Pathological Conditions, Signs and Symptoms Recurrence Small Lymphocytic Lymphoma

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

Calvary Mater Newcastle, Waratah, New South Wales, Australia

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About this study

This is a global, Phase 3, randomized study of zanubrutinib versus ibrutinib in 652 participants with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma.

The primary efficacy endpoint is overall response rate determined by investigator assessment. Participants were randomized in a 1:1 manner to either zanubrutinib or ibrutinib. Treatment with zanubrutinib and ibrutinib was open label.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Key Inclusion Criteria

  • Confirmed diagnosis of CLL or SLL that meets the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria
  • CLL/SLL requiring treatment per 2008 IWCLL criteria
  • Relapsed or refractory to at least 1 prior systemic therapy for CLL/SLL
  • Measurable disease by computerized tomography (CT)/magnetic resonance imaging (MRI)
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
  • Life expectancy ≥ 6 months
  • Adequate bone marrow function
  • Adequate renal and hepatic function

Key Exclusion Criteria

  • Known prolymphocytic leukemia or history of, or currently suspected, Richter's transformation
  • Clinically significant cardiovascular disease.
  • Prior malignancy within the past 3 years, except for curatively treated basal or squamous cell skin cancer, non-muscle-invasive bladder cancer, carcinoma in situ of the cervix or breast
  • History of severe bleeding disorder or history of spontaneous bleeding requiring blood transfusion or other medical intervention
  • History of stroke or intracranial hemorrhage within 180 days before first dose of study drug
  • Severe or debilitating pulmonary disease
  • Active fungal, bacterial, and/or viral infection requiring systemic therapy
  • Known central nervous system involvement by leukemia or lymphoma
  • Known infection with HIV or active viral hepatitis B or C infection
  • Moderate or severe hepatic impairment, ie, Child-Pugh class B or C
  • Major surgery within 4 weeks of the first dose of study drug
  • Prior treatment with a (Burton's Kinase) BTK inhibitor
  • Toxicity from prior anticancer therapy that has not recovered to ≤ Grade 1
  • Pregnant or lactating women
  • Vaccination with a live vaccine within 35 days prior to the first dose of study drug
  • Hypersensitivity to zanubrutinib, ibrutinib, or any of the other ingredients in either drug
  • Concurrent participation in another therapeutic clinical trial

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Treatment and study plan

Zanubrutinib

Drug

160 mg orally twice daily

Other names: BGB-3111, Brukinsa

Ibrutinib

Drug

Ibrutinib 420 mg orally once daily

Other names: Imbruvica

Primary outcomes

  1. Overall Response Rate (ORR) Assessed by the Investigator

    Time frame: From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).

    ORR is defined as the percentage of participants with a complete response (CR) / complete response with incomplete bone marrow recovery (CRi), nodular partial response (nPR) or partial response (PR) per investigator assessment.

    Disease response was assessed in accordance with the 2008 criteria of the International Workshop on CLL (IWCLL), with modification for treatment-related lymphocytosis in participants with CLL and in accordance with the Lugano classification in participants with SLL.

  2. ORR Assessed by the Independent Review Committee (IRC)

    Time frame: From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).

    ORR is defined as the percentage of participants with a complete response (CR) / complete response with incomplete bone marrow recovery (CRi), nodular partial response (nPR) or partial response (PR) assessed by a blinded independent review committee. Overall response was assessed by the IRC for the purpose of regulatory filing with the Food and Drug Administration (FDA).

    Disease response was assessed in accordance with the 2008 criteria of the International Workshop on CLL (IWCLL), with modification for treatment-related lymphocytosis in participants with CLL and in accordance with the Lugano classification in participants with SLL.

Secondary outcomes

  1. Progression-free Survival (PFS) Assessed by the Investigator

    Time frame: From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).

    PFS is defined as the time from randomization to the date of first documentation of disease progression or death, whichever occurred first. Median PFS was estimated using the Kaplan-Meier method.

  2. Progression-free Survival Assessed by the Independent Review Committee

    Time frame: From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).

    PFS is defined as the time from randomization to the date of first documentation of disease progression or death, whichever occurred first. Median PFS was estimated using the Kaplan-Meier method.

  3. Percentage of Participants With Atrial Fibrillation or Atrial Flutter

    Time frame: From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).

    Participants were considered as having an atrial fibrillation/flutter event if they had a treatment-emergent AE of either "atrial fibrillation" or "atrial flutter".

  4. Duration of Response Assessed by the Independent Review Committee

    Time frame: From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).

    DOR is defined as the time from the date that response criteria were first met to the date that disease progression was objectively documented or death, whichever occurred first, determined by independent central review. Median DOR was estimated using the Kaplan-Meier method.

  5. Duration of Response (DOR) Assessed by the Investigator

    Time frame: From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).

    DOR is defined as the time from the date that response criteria were first met to the date that disease progression was objectively documented or death, whichever occurred first, determined by investigator assessment. Median DOR was estimated using the Kaplan-Meier method.

  6. Time to Treatment Failure

    Time frame: From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).

    Time to treatment failure is defined as the time from randomization to discontinuation of study drug due to any reason. Median time to treatment failure was estimated by the Kaplan-Meier method.

  7. Rate of Partial Response With Lymphocytosis (PR-L) or Higher Assessed by the Independent Review Committee

    Time frame: From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).

    The rate of partial response with lymphocytosis or better is defined as the percentage of participants who achieved a complete response or a complete response with incomplete bone marrow recovery (CR/CRi), nodular partial response, partial response, or partial response with lymphocytosis assessed by the blinded IRC.

    Disease response was assessed per iwCLL 2008 criteria, with modification for treatment-related lymphocytosis for participants with CLL and per Lugano classification for participants with SLL.

  8. Rate of Partial Response With Lymphocytosis (PR-L) or Higher Assessed by the Investigator

    Time frame: From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).

    The rate of partial response with lymphocytosis or better is defined as the percentage of participants who achieved a complete response or complete response with incomplete bone marrow recovery (CR/CRi), nodular partial response, partial response, or partial response with lymphocytosis as assessed by the investigator.

    Disease response was assessed according to the iwCLL 2008 criteria, with modification for treatment-related lymphocytosis for participants with CLL and in accordance with Lugano classification for participants with SLL.

    Partial response with lymphocytosis: blood lymphocytes decreased < 50% or increased from baseline, and otherwise meeting criteria for PR.

  9. Overall Survival (OS)

    Time frame: From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).

    Overall survival is defined as the time from randomization to the date of death due to any cause. Median OS was estimated using the Kaplan-Meier method.

  10. Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL), Physical Functioning and Role Functioning Scores

    Time frame: Baseline and Weeks 24 and 48

    The EORTC QLQ-30 contains 30 questions that incorporate 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 1 global health status scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The participant answers questions about their health during the past week. There are 28 questions answered on a 4-point scale where 1 = Not at all (best) and 4 = Very Much (worst) and 2 global health quality of life (QOL) questions answered on a 7-point scale where 1 = Very poor and 7 = Excellent. Raw scores are transformed into a 0 to 100 scale via linear transformation. Higher scores in GHS and functional scales indicate better quality of life.

  11. Change From Baseline in EORTC QLQ-C30 Symptom Scales of Fatigue, Nausea and Vomiting, Pain, and Diarrhoea

    Time frame: Baseline and Weeks 24 and 48

    The EORTC QLQ-30 contains 30 questions that incorporate 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 1 global health status scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The participant answers questions about their health during the past week. There are 28 questions answered on a 4-point scale where 1 = Not at all (best) and 4 = Very Much (worst) and 2 global health quality of life (QOL) questions answered on a 7-point scale where 1 = Very poor and 7 = Excellent. Raw scores are transformed into a 0 to 100 scale via linear transformation. Lower scores in symptom scales indicate better quality of life.

  12. Change From Baseline in European Quality of Life 5-dimensions 5-levels Health Questionnaire (EQ-5D-5L) Visual Analog Scale (VAS)

    Time frame: Baseline and Weeks 24 and 48

    The EQ-5D-5L VAS measures a participant's self-rated health on a scale from 0 to 100, where 100 is 'the best health you can imagine' and 0 is 'the worst health you can imagine.' A higher score indicates better health outcomes.

  13. Number of Participants With Treatment-emergent Adverse Events (TEAE)

    Time frame: From first dose of study drug up to 30 days after last dose, up to the end of study data cutoff (28 February 2024); median (range) time on treatment was 41.2 (0.4-59.1) months in the zanubrutinib arm and 37.8 (0.1-60.4) months in the ibrutinib arm.

    An adverse event is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study drug, whether considered related to study drug or not.

    A serious adverse event (SAE) is any untoward medical occurrence that, at any dose:

    • Resulted in death
    • Was life-threatening
    • Required hospitalization or prolongation of existing hospitalization
    • Resulted in disability/incapacity
    • Resulted in a congenital anomaly/birth defect
    • Was considered a significant medical AE by the investigator based on medical judgment

Sponsors and collaborators

Lead sponsor

BeiGene

Industry

Registry information

Official study title

A Phase 3, Randomized Study of Zanubrutinib (BGB-3111) Compared With Ibrutinib in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Acronym: ALPINE

Important dates

Study start
2018
Primary completion
2022
Study completion
2024
First posted
Nov 7, 2018
Registry last updated
Mar 30, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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