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

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

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.

Study Overview

• Status: Completed
• Conditions: Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma
• Intervention / Treatment: Drug: Zanubrutinib; Drug: Ibrutinib

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 652
• Phase: Phase 3

Contacts and Locations

Study Locations

• Poland
  • Bialystok, Poland, 15748
    • Interhem Opieka Szpitalna
  • Brzozow, Poland, 36-200
    • Szpital Specjalist W Brzozowie,Podkarpacki Osrodek Onkologiczny
  • Chorzow, Poland, 41-500
    • Samodzielny Publiczny Zaklad Opieki Zdrowotnej Zespol Szpitali Miejskich
  • Gdansk, Poland, 80-952
    • Uniwersyteckie Centrum Kliniczne
  • Gdask, Poland, 80-219
    • Copernicus Podmiot Leczniczy Sp Z Oo Wojewodzkie Centrum Onkologii
  • Krakow, Poland, 30-510
    • Malopolskie Centrum Medyczne Sc
  • Legnica, Poland, 59-220
    • Wojewodzki Szpital Specjalistyczny w Legnicy
  • Lodz, Poland, 93-510
    • Wielospecjalistyczne Centrum Onkologii I Traumatologii Im M Kopernika W Lodzi
  • Poznan, Poland, 60-569
    • Examen Sp Z Oo

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria

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

Key Exclusion Criteria

1. Known prolymphocytic leukemia or history of, or currently suspected, Richter's transformation
2. Clinically significant cardiovascular disease.
3. 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
4. History of severe bleeding disorder or history of spontaneous bleeding requiring blood transfusion or other medical intervention
5. History of stroke or intracranial hemorrhage within 180 days before first dose of study drug
6. Severe or debilitating pulmonary disease
7. Active fungal, bacterial, and/or viral infection requiring systemic therapy
8. Known central nervous system involvement by leukemia or lymphoma
9. Known infection with HIV or active viral hepatitis B or C infection
10. Moderate or severe hepatic impairment, ie, Child-Pugh class B or C
11. Major surgery within 4 weeks of the first dose of study drug
12. Prior treatment with a (Burton's Kinase) BTK inhibitor
13. Toxicity from prior anticancer therapy that has not recovered to ≤ Grade 1
14. Pregnant or lactating women
15. Vaccination with a live vaccine within 35 days prior to the first dose of study drug
16. Hypersensitivity to zanubrutinib, ibrutinib, or any of the other ingredients in either drug
17. Concurrent participation in another therapeutic clinical trial

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Zanubrutinib; Participants received 160 mg zanubrutinib orally twice daily until disease progression, intolerable toxicity, initiation of alternative anticancer therapy, investigator/Sponsor decision, need for prohibited medication, study withdrawal, or pregnancy	Drug: Zanubrutinib; 160 mg orally twice daily; Other Names: Brukinsa; BGB-3111
Active Comparator: Ibrutinib; Participants received Ibrutinib 420 mg orally once daily until disease progression, intolerable toxicity, initiation of alternative anticancer therapy, investigator/Sponsor decision, need for prohibited medication, study withdrawal, or pregnancy	Drug: Ibrutinib; Ibrutinib 420 mg orally once daily; Other Names: Imbruvica

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR) as Determined by Investigator Assessment	ORR is percentage of participants with partial response (PR) or higher, (defined as Complete response/ Complete response with incomplete bone marrow recovery (CR/CRi) + PR + nodular PR) per investigator assessment using the "modified" 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) guidelines with modification for treatment-related lymphocytosis for participants with CLL and per Lugano Classification for non-Hodgkin lymphoma (NHL)) for participants with Small lymphocytic lymphoma (SLL)	Up to approximately 3 years and 9 months
ORR as Determined by Independent Review Committee (IRC)	ORR is the percentage of participants with PR or higher, (CR/CRi) + PR + nodular PR per IRC assessment using the "modified" 2008 IWCLL guidelines with modification for treatment-related lymphocytosis for participants with CLL and per Lugano Classification for NHL for participants with SLL	Up to approximately 3 years and 9 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival Determined by Independent Central Review		Up to 51 months
Progression-free Survival Determined by Investigator Assessment		Up to 51 months
Duration of Response Determined by Investigator Assessment		Up to 51 months
Duration of Response Determined by Independent Central Review		Up to 51 months
Time to Treatment Failure		Up to 51 months
Overall Survival		Up to 51 months
Patient Reported Outcomes as Assessed by EORTC-QLQ-C30		Up to 51 months
Patient Reported Outcomes as Assessed by EQ-5D-5L		Up to 51 months
Incidence of Adverse Events as Assessed by CTCAE v4.03 [Safety and Tolerability]		51 months
Rate of Partial Response With Lymphocytosis (PR-L) or Higher Determined by Independent Central Review	Proportion of participants who achieve a CR/CRi + PR + nodular PR + PR-L	Up to 51 months
Overall Response Rate Determined by Independent Central Review		51 months

Other Outcome Measures

Outcome Measure	Time Frame
Correlation Between Prognostic and Predictive Biomarkers and Clinical Outcomes	Up to 51 months

Collaborators and Investigators

• Sponsor: BeiGene
• Investigators: Study Director: Study Director, BeiGene

Publications and helpful links

General Publications

• Hillmen P, Brown JR, Eichhorst BF, Lamanna N, O'Brien SM, Qiu L, Salmi T, Hilger J, Wu K, Cohen A, Huang J, Tam CS. ALPINE: zanubrutinib versus ibrutinib in relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Future Oncol. 2020 Apr;16(10):517-523. doi: 10.2217/fon-2019-0844. Epub 2020 Mar 24.
• Brown JR, Eichhorst B, Hillmen P, Jurczak W, Kazmierczak M, Lamanna N, O'Brien SM, Tam CS, Qiu L, Zhou K, Simkovic M, Mayer J, Gillespie-Twardy A, Ferrajoli A, Ganly PS, Weinkove R, Grosicki S, Mital A, Robak T, Osterborg A, Yimer HA, Salmi T, Wang MD, Fu L, Li J, Wu K, Cohen A, Shadman M. Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. N Engl J Med. 2023 Jan 26;388(4):319-332. doi: 10.1056/NEJMoa2211582. Epub 2022 Dec 13.
• Hillmen P, Eichhorst B, Brown JR, Lamanna N, O'Brien SM, Tam CS, Qiu L, Kazmierczak M, Zhou K, Simkovic M, Mayer J, Gillespie-Twardy A, Shadman M, Ferrajoli A, Ganly PS, Weinkove R, Grosicki S, Mital A, Robak T, Osterborg A, Yimer HA, Salmi T, Ji M, Yecies J, Idoine A, Wu K, Huang J, Jurczak W. Zanubrutinib Versus Ibrutinib in Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma: Interim Analysis of a Randomized Phase III Trial. J Clin Oncol. 2023 Feb 10;41(5):1035-1045. doi: 10.1200/JCO.22.00510. Epub 2022 Nov 17.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2018
• Primary Completion (Actual): August 8, 2022
• Study Completion (Actual): February 28, 2024

Study Registration Dates

• First Submitted: November 2, 2018
• First Submitted That Met QC Criteria: November 6, 2018
• First Posted (Actual): November 7, 2018

Study Record Updates

• Last Update Posted (Actual): April 1, 2024
• Last Update Submitted That Met QC Criteria: March 28, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: CLL; relapsed; refractory; Chronic Lymphocytic Leukemia; SLL; Small Lymphocytic Lymphoma
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Hematologic Diseases; Leukemia, B-Cell; Chronic Disease; Lymphoma; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Tyrosine Kinase Inhibitors; Zanubrutinib; Ibrutinib
• Other Study ID Numbers: BGB-3111-305; 2018-001366-42 (EudraCT Number); CTR20190098 (Registry Identifier: Center for drug evaluation, CFDA)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No