Relapsed/Refractory Follicular Non-Hodgkin Lymphoma
Conditions
Keywords
Relapsed/Refractory Follicular non-Hodgkin Lymphoma
Brief summary
This clinical study examined the safety and efficacy of the combination of zanubrutinib and obinutuzumab versus obinutuzumab alone in adults with follicular lymphoma whose disease returned after or did not respond to prior therapy.
Detailed description
This study randomly assigned participants in a 2:1 ratio to receive either zanubrutinib plus obinutuzumab or obinutuzumab alone. The assignment considered how many prior treatments participants had received, whether their cancer had stopped responding to rituximab, and whether they were enrolled in Mainland China or other regions. Each treatment cycle lasted 28 days, with zanubrutinib taken by mouth twice daily and obinutuzumab given intravenously on a set schedule, followed by optional maintenance for up to 24 months. Participants who had obinutuzumab alone could have switched to the combination treatment if their disease worsened or did not respond after 12 months, if confirmed by an independent review.
Interventions
DRUGZanubrutinib
Oral administration as a capsule
DRUGObinutuzumab
Intravenous administration
Sponsors
BeiGene
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Participants had a histologically confirmed diagnosis of B-cell follicular lymphoma. * Participants had received two or more prior systemic treatments for follicular lymphoma. * Participants had previously received both an anti-cluster of differentiation 20 (anti-CD20) antibody and an appropriate alkylator-based combination therapy. * Participants had disease that had progressed after completion of the most recent therapy or was considered refractory to treatment. * Participants had measurable disease present. * Archival tissue confirming the diagnosis was available. * Participants had an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. * Participants had adequate renal and hepatic function. Key
Exclusion criteria
* Participants had prior exposure to a Bruton's tyrosine kinase (BTK) inhibitor. * Participants had known central nervous system involvement by leukemia or lymphoma. * Participants had evidence of transformation from follicular lymphoma to another aggressive histologic subtype. * Participants had undergone an allogeneic hematopoietic stem cell transplantation within 12 months of enrollment. * Participants had a prior malignancy within the past 2 years, except for those who had curatively treated basal cell or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast, or localized prostate cancer with a Gleason score of 6. * Participants had clinically significant cardiovascular disease. * Participants had undergone major surgery within 4 weeks prior to the start of study treatment. * Participants had an active fungal, bacterial, or viral infection requiring systemic treatment. * Participants had a history of severe bleeding disorder. Note: Other protocol-defined inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) by Independent Central Review (ICR) Assessment | From first dose to primary analysis data cutoff (08OCT2021) start of a new anticancer therapy, or the crossover date, whichever came first. Median follow-up was 12.45 months. | ORR was defined as the percentage of participants who achieved a best overall response of complete response (CR) or partial response (PR) per the Lugano Classification for Non-Hodgkin's Lymphoma. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) as Assessed by the Investigator | From first dose to primary analysis data cutoff (08OCT2021) start of a new anticancer therapy, or the crossover date, whichever came first. Median follow-up was 12.45 months. | ORR was defined as the percentage of participants who achieved a best overall response of complete response (CR) or partial response (PR) per the Lugano Classification for Non-Hodgkin's Lymphoma. |
| Duration of Response (DOR) as Determined by Investigator Assessment | From first dose to primary analysis data cutoff (08OCT2021) start of a new anticancer therapy, or the crossover date, whichever came first. Median follow-up was 12.45 months. | DOR was defined as the time from the date that a confirmed response (CR or PR) was first observed to the date of first documented disease progression or death, whichever occurred first. For participants in the monotherapy arm who crossed over to combination therapy, disease assessments after crossover were not included in the DOR calculation. Median DOR was estimated using the Kaplan-Meier method. |
| DOR as Determined by ICR | From first dose to primary analysis data cutoff (08OCT2021) start of a new anticancer therapy, or the crossover date, whichever came first. Median follow-up was 12.45 months. | DOR was defined as the time from the date that a confirmed response (CR or PR) was first observed to the date of first documented disease progression or death, whichever occurred first. For participants in the monotherapy arm who crossed over to combination therapy, disease assessments after crossover were not included in the DOR calculation. Median DOR was estimated using the Kaplan-Meier method. |
| Progression-free Survival (PFS) | From first dose to primary analysis data cutoff (08OCT2021) start of a new anticancer therapy, or the crossover date, whichever came first. Median follow-up was 12.45 months. | PFS was defined as the time from randomization to the date of first documented disease progression or death from any cause, whichever occurred first, as determined by the ICR or investigator assessment. For participants in the monotherapy arm who crossed over to combination therapy, disease assessments after crossover were not included in the PFS calculation. Median PFS was estimated using the Kaplan-Meier method. |
| Overall Survival (OS) | From first dose to primary analysis data cutoff (08OCT2021) start of a new anticancer therapy, or the crossover date, whichever came first. Median follow-up was 12.45 months. | OS was defined as the time from randomization to the date of death from any cause. Median OS was estimated using the Kaplan-Meier method. |
| Complete Response Rate | From first dose to primary analysis data cutoff (08OCT2021) start of a new anticancer therapy, or the crossover date, whichever came first. Median follow-up was 12.45 months. | CRR was defined as the percentage of participants who achieved a complete response or complete metabolic response as their best overall response, as determined by ICR and investigator assessment. Responses were assessed from randomization until the data cutoff date, the start of a new anticancer therapy, or the crossover date for participants in the monotherapy arm who switched to combination therapy. |
| Time to Response (TTR) | From first dose to primary analysis data cutoff (08OCT2021) start of a new anticancer therapy, or the crossover date, whichever came first. Median follow-up was 12.45 months. | TRR was defined as the time from randomization to the first date that response criteria (CR or PR) were met, as determined by ICR and investigator assessment. Only participants who achieved an overall response were included in the analysis. For participants in the monotherapy arm who crossed over to combination therapy, disease assessments after crossover were not included in the TRR calculation. |
| 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, Role Functioning, and Symptom Scores | Baseline, Week 12, and Week 24 | The EORTC QLQ-C30 includes 30 questions covering 5 functional scales (physical, role, emotional, cognitive, social), 1 global health scale, 3 symptom scales (fatigue, nausea/vomiting, pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, financial difficulties). Participants report their health over the past week. Most items use a 4-point scale (1 = Not at all to 4 = Very much), while 2 global QOL items use a 7-point scale (1 = Very poor to 7 = Excellent). Raw scores are linearly transformed to a 0-100 scale; higher GHS and functional scores and lower symptom scores indicate better quality of life. |
| Change From Baseline in European Quality of Life 5-Dimensions, 5-level (EQ-5D-5L) Visual Analogue Scale (VAS) | Baseline, Week 12, and Week 24 | The EQ-5D-5L measures health outcomes using a VAS to record 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. |
| Number of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | From first dose to 30 days after zanubrutinib, 90 days after obinutuzumab, or before new therapy, whichever came first, up to study cut-off (31 Dec 2024); maximum exposure was 28.7 months for obinutuzumab and 67.4 months for combination therapy. | An adverse event refers to any unintended or unfavorable sign, symptom, or condition (including abnormal lab results) that occurs during the study, regardless of whether it is linked to the study drug. |
| Area Under the Curve (AUCss) of Zanubrutinib at Steady State | Cycle 1 Day 1 and Cycle 2 Day 1: Predose (within 30 minutes before zanubrutinib dosing) and 2 hours (± 30 minutes) post-dose. | Pharmacokinetic exposure parameters were estimated for each participant using a population pharmacokinetic (PK) model. |
| Zanubrutinib Plasma Concentrations | Cycle 1 Day 1 and Cycle 2 Day 1: Predose (within 30 minutes before zanubrutinib dosing) and 2 hours (± 30 minutes) post-dose. | — |
| Minimum Observed Concentration (Cmin) of Zanubrutinib at Steady State | Cycle 1 Day 1 and Cycle 2 Day 1: Predose (within 30 minutes before zanubrutinib dosing) and 2 hours (± 30 minutes) post-dose. | Pharmacokinetic exposure parameters were estimated for each participant using a population pharmacokinetic (PK) model. |
| Maximum Observed Concentration (Cmax) of Zanubrutinib at Steady State | Cycle 1 Day 1 (2 hours postdose) and Cycle 2 Day 1 (predose and 2 hours postdose) | — |
Countries
Australia, Belarus, Bulgaria, Canada, China, Czechia, France, Germany, Italy, New Zealand, Poland, Russia, South Korea, Spain, Taiwan, United Kingdom, United States
Contacts
STUDY_DIRECTORStudy Director
BeiGene
Participant flow
Recruitment details
Participants were enrolled in multiple study centers in Australia, Europe, Asia, and North America.
Pre-assignment details
After enrollment, participants were randomized 2:1 to zanubrutinib plus obinutuzumab or obinutuzumab alone, stratified by prior therapy, rituximab-refractory status, and region. Treatment began within 5 days, in 28-day cycles. At investigator discretion, those on obinutuzumab monotherapy could cross over to zanubrutinib plus obinutuzumab if progressive disease or non-response was confirmed by independent central review.
Participants by arm
| Arm | Count |
|---|---|
| Obinutuzumab Obinutuzumab 1000 mg intravenously on Days 1, 8, and 15 of Cycle 1; Day 1 of Cycles 2 to 6; and then every 8 weeks until unacceptable toxicity, withdrawal of consent, loss of clinical benefit, or disease progression; each cycle is 28 days | 72 |
| Zanubrutinib + Obinutuzumab Zanubrutinib 160 milligrams (mg) twice a day orally with or without food; Obinutuzumab 1000 mg intravenously on Days 1, 8, and 15 of Cycle 1; Day 1 of Cycles 2 to 6; and then every 8 weeks until unacceptable toxicity, withdrawal of consent, loss of clinical benefit, or disease progression; each cycle is 28 days | 145 |
| Total | 217 |
Baseline characteristics
| Characteristic | Zanubrutinib + Obinutuzumab | Total | Obinutuzumab |
|---|---|---|---|
| Age, Continuous | 61.1 years STANDARD_DEVIATION 11.98 | 61.7 years STANDARD_DEVIATION 12.26 | 62.9 years STANDARD_DEVIATION 12.81 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 6 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 116 Participants | 176 Participants | 60 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 25 Participants | 35 Participants | 10 Participants |
| Race/Ethnicity, Customized Asian | 30 Participants | 47 Participants | 17 Participants |
| Race/Ethnicity, Customized Not Reported | 23 Participants | 31 Participants | 8 Participants |
| Race/Ethnicity, Customized White | 92 Participants | 139 Participants | 47 Participants |
| Sex: Female, Male Female | 70 Participants | 109 Participants | 39 Participants |
| Sex: Female, Male Male | 75 Participants | 108 Participants | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 33 / 72 | 51 / 145 | 16 / 36 |
| other Total, other adverse events | 62 / 71 | 130 / 143 | 32 / 36 |
| serious Total, serious adverse events | 22 / 71 | 75 / 143 | 20 / 36 |
Outcome results
Primary
Overall Response Rate (ORR) by Independent Review Committee (IRC) Assessment
ORR is defined as the percentage of participants who achieve either complete response (CR) or partial response (PR) as best overall response, as assessed by the IRC using Lugano Classification for Non-Hodgkin Lymphoma
Time frame: Through primary analysis data cut-off date of 08OCT2021 (up to approximately 3 years and 11 months)
Population: Intent-To-Treat (ITT) analysis set includes all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Obinutuzumab | Overall Response Rate (ORR) by Independent Review Committee (IRC) Assessment | 45.8 percentage of participants |
| Zanubrutinib + Obinutuzumab | Overall Response Rate (ORR) by Independent Review Committee (IRC) Assessment | 68.3 percentage of participants |
p-value: 0.0017Cochran-Mantel-Haenszel
Secondary
Apparent Clearance (CL/F) of Zanubrutinib
Time frame: Day 1 Cycle 1 and Day 2 Cycle 2: Predose
Secondary
Area Under the Curve From 0 to 12 Hours Post Dose (AUC0-12)
Time frame: Day 1 Cycle 1 and Day 2 Cycle 2: Pre-dose
Secondary
Complete Metabolic Response Rate
Time frame: Up to approximately 7 years
Secondary
Complete Response Rate
Time frame: Up to approximately 7 years
Secondary
Duration of Response (DOR)
Time frame: Up to approximately 7 years
Secondary
Health-Related Quality of Life (HRQOL) as Assessed by The 5-level EQ-5D Version (EQ-5D-5L)
Time frame: Up to approximately 7 years
Secondary
Health-Related Quality of Life (HRQOL) as Assessed by The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30)
Time frame: Up to approximately 7 years
Secondary
Occurrence and Severity of Treatment-emergent Adverse Events (TEAEs)
Safety and Tolerability
Time frame: Up to approximately 7 years
Secondary
Overall Response Rate (ORR) as Assessed by the Investigator
Time frame: Up to approximately 7 years
Secondary
Overall Survival (OS)
Time frame: Up to approximately 7 years
Secondary
Progression Free Survival (PFS)
Time frame: Up to approximately 7 years
Secondary
Time to Response (TTR)
Time frame: Up to approximately 7 years