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NCT03734016: ALPINE

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

Completed Phase 3 Results posted Last updated 30 March 2025
What this trial tests

Phase 3 trial testing Zanubrutinib in Chronic Lymphocytic Leukemia in 652 participants. Completed in 28 February 2024.

Timeline
1 November 2018
Primary endpoint
8 August 2022
28 February 2024

Quick facts

Lead sponsorBeiGene
PhasePhase 3
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingnone
Primary purposetreatment
Enrollment652
Start date1 November 2018
Primary completion8 August 2022
Estimated completion28 February 2024
Sites115 locations across France, Italy, Netherlands, New Zealand, Belgium, Sweden, United Kingdom, Germany

Drugs / interventions tested

Conditions studied

Sponsor

BeiGene — full company profile →

Who can join

18 and older, any sex, with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Overall Response Rate (ORR) Assessed by the Investigator Primary · 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.

GroupValue95% CI
Zanubrutinib83.579.0 – 87.3
Ibrutinib74.269.0 – 78.8
ORR Assessed by the Independent Review Committee (IRC) Primary · 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

GroupValue95% CI
Zanubrutinib86.282.0 – 89.8
Ibrutinib75.770.7 – 80.3
Progression-free Survival (PFS) Assessed by the Investigator Secondary · 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.

GroupValue95% CI
ZanubrutinibNA34.3 – NA
Ibrutinib34.233.3 – NA
Progression-free Survival Assessed by the Independent Review Committee Secondary · 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.

GroupValue95% CI
ZanubrutinibNA34.3 – NA
Ibrutinib35.033.2 – 44.3
Percentage of Participants With Atrial Fibrillation or Atrial Flutter Secondary · 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".

GroupValue95% CI
Zanubrutinib5.23.1 – 8.3
Ibrutinib13.39.8 – 17.5
Duration of Response Assessed by the Independent Review Committee Secondary · 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.

GroupValue95% CI
ZanubrutinibNA31.3 – NA
Ibrutinib33.932.2 – 41.4
Duration of Response (DOR) Assessed by the Investigator Secondary · 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.

GroupValue95% CI
ZanubrutinibNA31.3 – NA
Ibrutinib33.933.9 – NA
Time to Treatment Failure Secondary · 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.

GroupValue95% CI
ZanubrutinibNANA – NA
IbrutinibNA34.4 – NA
Rate of Partial Response With Lymphocytosis (PR-L) or Higher Assessed by the Independent Review Committee Secondary · 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.

GroupValue95% CI
Zanubrutinib91.788.2 – 94.5
Ibrutinib83.178.5 – 87.0
Rate of Partial Response With Lymphocytosis (PR-L) or Higher Assessed by the Investigator Secondary · 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 dec

GroupValue95% CI
Zanubrutinib89.986.1 – 93.0
Ibrutinib82.577.9 – 86.4
Overall Survival (OS) Secondary · 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.

GroupValue95% CI
ZanubrutinibNANA – NA
IbrutinibNANA – NA
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 Secondary · 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

GHS/QoL Scale at Week 24
GroupValue95% CI
Zanubrutinib8.186.25 – 10.12
Ibrutinib5.183.20 – 7.17
GHS/QoL Scale at Week 48
GroupValue95% CI
Zanubrutinib7.285.41 – 9.15
Ibrutinib5.933.97 – 7.89
Physical Functioning Scale at Week 24
GroupValue95% CI
Zanubrutinib6.554.96 – 8.15
Ibrutinib4.733.08 – 6.38
Physical Functioning Scale at Week 48
GroupValue95% CI
Zanubrutinib5.463.87 – 7.04
Ibrutinib4.312.65 – 5.97
Role Functioning Scale at Week 24
GroupValue95% CI
Zanubrutinib6.954.85 – 9.06
Ibrutinib6.324.14 – 8.50
Role Functioning Scale at Week 48
GroupValue95% CI
Zanubrutinib6.814.61 – 9.02
Ibrutinib5.012.69 – 7.33

Adverse events — posted to ClinicalTrials.gov

Time frame: All-cause mortality was collected through the end of study, maximum time on study was 60.5 months. Adverse events were collected 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.. Reporting threshold: 3%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Zanubrutinib
Serious: 172/324 (53%)
Deaths: 69/327
Ibrutinib
Serious: 196/324 (60%)
Deaths: 83/325

Serious adverse events (299 terms)

ReactionSystemZanubrutinibIbrutinib
COVID-19 pneumoniaInfections and infestations
PneumoniaInfections and infestations
COVID-19Infections and infestations
Atrial fibrillationCardiac disorders
Urinary tract infectionInfections and infestations
AnaemiaBlood and lymphatic system disorders
PyrexiaGeneral disorders
DeathGeneral disorders
SepsisInfections and infestations
Prostate cancerNeoplasms benign, malignant and unspecified (incl cysts and polyps)
Cardiac arrestCardiac disorders
Myocardial infarctionCardiac disorders
ConstipationGastrointestinal disorders
Inguinal herniaGastrointestinal disorders
BronchitisInfections and infestations
CellulitisInfections and infestations
Herpes zosterInfections and infestations
Lower respiratory tract infectionInfections and infestations
Basal cell carcinomaNeoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma of skinNeoplasms benign, malignant and unspecified (incl cysts and polyps)
Cerebrovascular accidentNervous system disorders
SyncopeNervous system disorders
Acute kidney injuryRenal and urinary disorders
Acute respiratory failureRespiratory, thoracic and mediastinal disorders
Pleural effusionRespiratory, thoracic and mediastinal disorders
Other adverse events (101 terms — click to expand)

ReactionSystemZanubrutinibIbrutinib
COVID-19Infections and infestations
Upper respiratory tract infectionInfections and infestations
DiarrhoeaGastrointestinal disorders
HypertensionVascular disorders
NeutropeniaBlood and lymphatic system disorders
ArthralgiaMusculoskeletal and connective tissue disorders
AnaemiaBlood and lymphatic system disorders
FatigueGeneral disorders
ContusionInjury, poisoning and procedural complications
CoughRespiratory, thoracic and mediastinal disorders
Atrial fibrillationCardiac disorders
RashSkin and subcutaneous tissue disorders
Muscle spasmsMusculoskeletal and connective tissue disorders
PyrexiaGeneral disorders
PneumoniaInfections and infestations
ThrombocytopeniaBlood and lymphatic system disorders
Urinary tract infectionInfections and infestations
HeadacheNervous system disorders
NauseaGastrointestinal disorders
DizzinessNervous system disorders
PetechiaeSkin and subcutaneous tissue disorders
VomitingGastrointestinal disorders
ConstipationGastrointestinal disorders
EpistaxisRespiratory, thoracic and mediastinal disorders
Peripheral swellingGeneral disorders
BronchitisInfections and infestations
Neutrophil count decreasedInvestigations
Back painMusculoskeletal and connective tissue disorders
Pain in extremityMusculoskeletal and connective tissue disorders
InsomniaPsychiatric disorders
DyspepsiaGastrointestinal disorders
Oedema peripheralGeneral disorders
HypokalaemiaMetabolism and nutrition disorders
PruritusSkin and subcutaneous tissue disorders
FallInjury, poisoning and procedural complications
Weight decreasedInvestigations
Decreased appetiteMetabolism and nutrition disorders
HyperuricaemiaMetabolism and nutrition disorders
Abdominal painGastrointestinal disorders
AstheniaGeneral disorders

Most-reported serious reactions: COVID-19 pneumonia, Pneumonia, COVID-19, Atrial fibrillation, Urinary tract infection, Anaemia, Pyrexia, Death.

Data from ClinicalTrials.gov NCT03734016 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia.
    Brown JR, Eichhorst B, Hillmen P, Jurczak W, et al · · 2023 · cited 371× · PMID 36511784 · DOI 10.1056/nejmoa2211582
  2. Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL.
    Tam CS, Trotman J, Opat S, Burger JA, et al · · 2019 · cited 280× · PMID 31340982 · DOI 10.1182/blood.2019001160
  3. Comparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects.
    Estupiñán HY, Berglöf A, Zain R, Smith CIE. · · 2021 · cited 191× · PMID 33777941 · DOI 10.3389/fcell.2021.630942
  4. Small Molecule NF-κB Pathway Inhibitors in Clinic.
    Ramadass V, Vaiyapuri T, Tergaonkar V. · · 2020 · cited 154× · PMID 32708302 · DOI 10.3390/ijms21145164
  5. Managing toxicities of Bruton tyrosine kinase inhibitors.
    Lipsky A, Lamanna N. · · 2020 · cited 112× · PMID 33275698 · DOI 10.1182/hematology.2020000118
  6. Treatment of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma with the BTK inhibitor zanubrutinib: phase 2, single-arm, multicenter study.
    Xu W, Yang S, Zhou K, Pan L, et al · · 2020 · cited 99× · PMID 32393328 · DOI 10.1186/s13045-020-00884-4
  7. BTK inhibitors in the treatment of hematological malignancies and inflammatory diseases: mechanisms and clinical studies.
    Alu A, Lei H, Han X, Wei Y, et al · · 2022 · cited 88× · PMID 36183125 · DOI 10.1186/s13045-022-01353-w
  8. Advances in targeted therapy for malignant lymphoma.
    Wang L, Qin W, Huo YJ, Li X, et al · · 2020 · cited 88× · PMID 32296035 · DOI 10.1038/s41392-020-0113-2

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Other trials of Zanubrutinib

Trials testing the same drug.

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Trials by the same sponsor.

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Drug Landscape aggregates and links these public records for informational use only. Always verify against the primary source before clinical or regulatory decisions. Canonical URL: https://druglandscape.com/trial/NCT03734016.

Primary sources · FDA · ClinicalTrials.gov · EMA · SEC EDGAR · ChEMBL · Wikidata · full sourcing