Relapsed Diffuse Large B-cell Lymphoma, Refractory Diffuse Large B-cell Lymphoma
Conditions
Keywords
Lymphoma, Tumor, Large B-cell Lymphoma
Brief summary
The primary purpose of this study is to assess the safety and tolerability of ociperlimab (BGB-A1217) in combination with tislelizumab (BGB-A317) or rituximab in participants with relapsed or refractory (R/R) diffuse large B cell lymphoma (DLBCL)
Interventions
DRUGOciperlimab
administered intravenously
DRUGTislelizumab
Administered intravenously once every 3 weeks
DRUGRituximab
Administered intravenously once every 3 weeks
Sponsors
BeiGene
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histologically confirmed DLBCL NOS (Not Otherwise Specified), Epstein-Barr virus (EBV) + DLBCL NOS, or high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (double/triple-hit lymphoma \[DHL/THL\]), based on the World Health Organization (WHO) 2016 classification of tumors of hematopoietic and lymphoid tissue 1. Cohort 1: participants must have positive tumor programmed cell death ligand-1 (PD-L1) immunohistochemistry (IHC) testing results as determined by local pathologist 2. Cohort 2: Participants must have negative tumor PD-L1 IHC results as determined by a local pathologist in the dose confirmation stage. The dose expansion stage can enroll participants regardless of PD-L1 expression. 2. Previously received ≥ 1 line of adequate systemic anti DLBCL therapy, defined as an anti CD20 antibody based chemoimmunotherapy for ≥ 2 consecutive cycles, unless participants had PD before Cycle 2. 3. Relapsed or refractory disease before study entry, defined as either: 1. Recurrent disease after having achieved disease remission (complete response or partial response) during or at the completion of the latest treatment regimen. 2. Stable disease or progressive disease (PD) at the completion of the latest treatment regimen. 4. Ineligible for high dose therapy/hematopoietic stem cell transplantation 5. Measurable disease as assessed by computed tomography (CT) or magnetic resonance imaging (MRI) and defined as at least 1 lymph node \> 1.5 cm in the longest diameter and/or at least 1 extranodal lesion \> 1.0 cm in the longest diameter, and measurable lesion (s) in 2 perpendicular diameters
Exclusion criteria
1. Current or history of central nervous system lymphoma 2. Histologically transformed lymphoma 3. Receipt of the following treatment: 1. Systemic chemotherapy, targeted small molecule therapy or radiation therapy within 4 weeks (or 5 half lives, whichever is shorter) before first dose of study drug 2. Recent treatment with another monoclonal antibody within 4 weeks before first dose of study drug 3. Investigational treatment within 4 weeks (or 5 half lives, whichever is shorter) before first dose of study drug 4. Treatment with autologous stem cell transplantation within 6 months before first dose of study drug 5. Treatment with allogeneic hematopoietic stem cell transplantation or organ transplantation 6. Treatment with anti-programmed cell death protein-1 (PD-1), anti PD-L1, anti PD-L2, anti T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT), anti CTLA4 or other antibody or drug specifically targeting T cell costimulation or checkpoint pathways. 4. Active autoimmune diseases or history of autoimmune diseases that may relapse, with the following exceptions: 1. Controlled Type 1 diabetes 2. Hypothyroidism (provided that it is managed with hormone replacement therapy only) 3. Controlled celiac disease 4. Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, or alopecia) 5. Any other disease that is not expected to recur in the absence of external triggering factors Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | From first dose of study drug up to 30 days after last dose, maximum time on treatment was 98 weeks. | An AE 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 study drug(s), whether considered related to study drug(s) or not. An 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 * Was a congenital anomaly/birth defect * Was considered a significant medical AE by the investigator based on medical judgement (eg, may jeopardize the patient or may require medical/surgical intervention to prevent one of the outcomes listed above). |
| Recommended Phase 2 Dose (RP2D) of Ociperlimab When Administered in Combination With Tislelizumab or Rituximab | 21 days | The highest dose evaluated for which the estimated toxicity rate is closest to the target toxicity rate of 33.3% |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DOR) | Up to the data cutoff date of 30 August 2024; maximum time on study was 28 months. | DOR is defined as the time from the date that response criteria were first met to the date that progressive disease is objectively documented per Lugano Classification (2014), as assessed by the investigator, or death, whichever occurred first. Median DOR was estimated using the Kaplan-Meier method. |
| Time to Response (TTR) | From first dose of study drug to the data cutoff date of 30 August 2024; maximum time on study was 28 months. | TTR is defined as the time from study treatment start to date of the earliest qualifying response (partial response or better) per Lugano Classification (2014) as assessed by the investigator |
| Progression-free Survival (PFS) | From first dose of study drug to the data cutoff date of 30 August 2024; maximum time on study was 28 months. | PFS is defined as the time from first dose until first documentation of progression per Lugano Classification (2014), as assessed by the investigator, or death, whichever comes first. Median PFS was estimated using the Kaplan-Meier method. |
| Overall Response Rate (ORR) | From first dose of study drug to the data cutoff date of 30 August 2024; maximum time on study was 28 months. | ORR is defined as the percentage of participants who achieved a best overall response of partial response (PR) or complete response (CR) based on the Lugano classification as assessed by the investigator. Response was evaluated using computed tomography (CT) and metabolic imaging (fluorodeoxyglucose-positron emission tomography (FDGPET). CR: complete metabolic (no/minimal FDG uptake and no evidence of FDG-avid disease in bone marrow) and radiologic response (target lesions regressed to ≤ 1.5 cm in longest diameter with no extra-lymphatic sites of disease, no organ enlargement and normal bone marrow morphology), no new lesions, and no bone marrow involvement confirmed by bone marrow biopsies (if bone marrow was involved at baseline). PR is partial metabolic (reduced FDG uptake from Baseline) and radiologic response (≥ 50% decrease in size of measurable nodes and extranodal sites, no increase in lesions, and spleen regressed by \> 50% in length beyond normal) and no new lesions. |
| Serum Concentration of Ociperlimab | Predose and end of infusion (EOI) on Cycle 1 Day 1 (C1D1), Cycle 2 Day 1, Cycle 5 Day 1, Cycle 9 Day 1, and Cycle 17 Day 1 | — |
| Host Immunogenicity: Number of Participants With Anti-drug Antibodies (ADA) to Ociperlimab | From first dose of study treatment to 30 days after last dose; maximum time on treatment was 98 weeks | The number of participants with anti-drug antibodies to ociperlimab includes participants that were ADA-negative at Baseline and ADA-positive after drug administration during the treatment or follow-up observation period and participants who were positive at Baseline for ADA and with significant increases (4-fold or higher) in ADA titer after drug administration during the treatment or follow-up observation period. |
| Overall Survival (OS) | From first dose of study drug to the data cutoff date of 30 August 2024; maximum time on study was 28 months. | OS is defined as the time from first study drug administration to the date of death due to any cause. Median OS was estimated using the Kaplan-Meier method. |
| Complete Response Rate (CRR) | From first dose of study drug to the data cutoff date of 30 August 2024; maximum time on study was 28 months. | CRR is defined as the percentage of participants who achieved a complete response per the Lugano Classification (2014) as assessed by the investigator. |
Countries
China
Participant flow
Recruitment details
The study began in April 2022 and completed in August 2024. Fifty-three participants were enrolled in this study, and all received treatment.
Participants by arm
| Arm | Count |
|---|---|
| Ociperlimab + Tislelizumab Participants received ociperlimab 900 mg and tislelizumab 200 mg every three weeks (Q3W) by intravenous injection (IV) until confirmed progressive disease, death, withdrawal of consent, loss of follow-up, or the end of study. | 24 |
| Ociperlimab + Rituximab Participants received ociperlimab 900 mg and rituximab 375 mg/m\^2 Q3W by intravenous injection until confirmed progressive disease, death, withdrawal of consent, loss of follow-up, or the end of study. | 29 |
| Total | 53 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 13 | 14 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Study Ended by Sponsor | 9 | 13 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Total | Ociperlimab + Tislelizumab | Ociperlimab + Rituximab |
|---|---|---|---|
| Age, Continuous | 65.0 Years | 64.0 Years | 66.0 Years |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Grade 0 | 16 Participants | 8 Participants | 8 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Grade 1 | 37 Participants | 16 Participants | 21 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Grade 2 | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 53 Participants | 24 Participants | 29 Participants |
| Region of Enrollment China | 53 participants | 24 participants | 29 participants |
| Sex: Female, Male Female | 27 Participants | 14 Participants | 13 Participants |
| Sex: Female, Male Male | 26 Participants | 10 Participants | 16 Participants |
| Weight | 62.00 kg | 59.00 kg | 63.80 kg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 13 / 24 | 14 / 29 |
| other Total, other adverse events | 23 / 24 | 28 / 29 |
| serious Total, serious adverse events | 9 / 24 | 8 / 29 |
Outcome results
Primary
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
An AE 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 study drug(s), whether considered related to study drug(s) or not. An 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 * Was a congenital anomaly/birth defect * Was considered a significant medical AE by the investigator based on medical judgement (eg, may jeopardize the patient or may require medical/surgical intervention to prevent one of the outcomes listed above).
Time frame: From first dose of study drug up to 30 days after last dose, maximum time on treatment was 98 weeks.
Population: The Safety Analysis Set is defined as all participants who received any dose of any study drug(s).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ociperlimab + Tislelizumab | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious Adverse Events | 9 Participants |
| Ociperlimab + Tislelizumab | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment Emergent Adverse Events | 24 Participants |
| Ociperlimab + Rituximab | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment Emergent Adverse Events | 28 Participants |
| Ociperlimab + Rituximab | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious Adverse Events | 8 Participants |
Primary
Recommended Phase 2 Dose (RP2D) of Ociperlimab When Administered in Combination With Tislelizumab or Rituximab
The highest dose evaluated for which the estimated toxicity rate is closest to the target toxicity rate of 33.3%
Time frame: 21 days
Population: Safety analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ociperlimab + Tislelizumab | Recommended Phase 2 Dose (RP2D) of Ociperlimab When Administered in Combination With Tislelizumab or Rituximab | 900 mg Q3W |
| Ociperlimab + Rituximab | Recommended Phase 2 Dose (RP2D) of Ociperlimab When Administered in Combination With Tislelizumab or Rituximab | 900 mg Q3W |
Secondary
Complete Response Rate (CRR)
CRR is defined as the percentage of participants who achieved a complete response per the Lugano Classification (2014) as assessed by the investigator.
Time frame: From first dose of study drug to the data cutoff date of 30 August 2024; maximum time on study was 28 months.
Population: Efficacy analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ociperlimab + Tislelizumab | Complete Response Rate (CRR) | 13.0 percentage of participants |
| Ociperlimab + Rituximab | Complete Response Rate (CRR) | 7.4 percentage of participants |
Secondary
Duration of Response (DOR)
DOR is defined as the time from the date that response criteria were first met to the date that progressive disease is objectively documented per Lugano Classification (2014), as assessed by the investigator, or death, whichever occurred first. Median DOR was estimated using the Kaplan-Meier method.
Time frame: Up to the data cutoff date of 30 August 2024; maximum time on study was 28 months.
Population: Efficacy analysis set; participants with a best overall response of CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ociperlimab + Tislelizumab | Duration of Response (DOR) | 13.34 Months |
| Ociperlimab + Rituximab | Duration of Response (DOR) | 7.82 Months |
Secondary
Host Immunogenicity: Number of Participants With Anti-drug Antibodies (ADA) to Ociperlimab
The number of participants with anti-drug antibodies to ociperlimab includes participants that were ADA-negative at Baseline and ADA-positive after drug administration during the treatment or follow-up observation period and participants who were positive at Baseline for ADA and with significant increases (4-fold or higher) in ADA titer after drug administration during the treatment or follow-up observation period.
Time frame: From first dose of study treatment to 30 days after last dose; maximum time on treatment was 98 weeks
Population: The Immunogenicity Analysis Set is defined as all participants who received any dose of any study drug(s), for whom both Baseline ADA and ≥ 1 postbaseline ADA results were available.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ociperlimab + Tislelizumab | Host Immunogenicity: Number of Participants With Anti-drug Antibodies (ADA) to Ociperlimab | 0 Participants |
| Ociperlimab + Rituximab | Host Immunogenicity: Number of Participants With Anti-drug Antibodies (ADA) to Ociperlimab | 1 Participants |
Secondary
Overall Response Rate (ORR)
ORR is defined as the percentage of participants who achieved a best overall response of partial response (PR) or complete response (CR) based on the Lugano classification as assessed by the investigator. Response was evaluated using computed tomography (CT) and metabolic imaging (fluorodeoxyglucose-positron emission tomography (FDGPET). CR: complete metabolic (no/minimal FDG uptake and no evidence of FDG-avid disease in bone marrow) and radiologic response (target lesions regressed to ≤ 1.5 cm in longest diameter with no extra-lymphatic sites of disease, no organ enlargement and normal bone marrow morphology), no new lesions, and no bone marrow involvement confirmed by bone marrow biopsies (if bone marrow was involved at baseline). PR is partial metabolic (reduced FDG uptake from Baseline) and radiologic response (≥ 50% decrease in size of measurable nodes and extranodal sites, no increase in lesions, and spleen regressed by \> 50% in length beyond normal) and no new lesions.
Time frame: From first dose of study drug to the data cutoff date of 30 August 2024; maximum time on study was 28 months.
Population: Efficacy Analysis Set is defined as all the participants who received any dose of any study drug(s), had evaluable disease at baseline, and had at least one evaluable post-baseline tumor assessment unless clinical progression or death occurred prior to first tumor assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ociperlimab + Tislelizumab | Overall Response Rate (ORR) | 17.4 percentage of participants |
| Ociperlimab + Rituximab | Overall Response Rate (ORR) | 18.5 percentage of participants |
Secondary
Overall Survival (OS)
OS is defined as the time from first study drug administration to the date of death due to any cause. Median OS was estimated using the Kaplan-Meier method.
Time frame: From first dose of study drug to the data cutoff date of 30 August 2024; maximum time on study was 28 months.
Population: Efficacy analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ociperlimab + Tislelizumab | Overall Survival (OS) | 13.2 Months |
| Ociperlimab + Rituximab | Overall Survival (OS) | 13.3 Months |
Secondary
Progression-free Survival (PFS)
PFS is defined as the time from first dose until first documentation of progression per Lugano Classification (2014), as assessed by the investigator, or death, whichever comes first. Median PFS was estimated using the Kaplan-Meier method.
Time frame: From first dose of study drug to the data cutoff date of 30 August 2024; maximum time on study was 28 months.
Population: Efficacy analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ociperlimab + Tislelizumab | Progression-free Survival (PFS) | 1.2 Months |
| Ociperlimab + Rituximab | Progression-free Survival (PFS) | 1.8 Months |
Secondary
Serum Concentration of Ociperlimab
Time frame: Predose and end of infusion (EOI) on Cycle 1 Day 1 (C1D1), Cycle 2 Day 1, Cycle 5 Day 1, Cycle 9 Day 1, and Cycle 17 Day 1
Population: Pharmacokinetic (PK) analysis set includes all participants who received any dose of study drug(s), for whom any quantifiable postdose PK concentrations were available. Results are reported for participants with available data at each time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ociperlimab + Tislelizumab | Serum Concentration of Ociperlimab | Predose C1D1 | NA μg/mL | — |
| Ociperlimab + Tislelizumab | Serum Concentration of Ociperlimab | EOI C1D1 | 323.96 μg/mL | Geometric Coefficient of Variation 21.81 |
| Ociperlimab + Tislelizumab | Serum Concentration of Ociperlimab | Predose C2D1 | 61.84 μg/mL | Geometric Coefficient of Variation 36.832 |
| Ociperlimab + Tislelizumab | Serum Concentration of Ociperlimab | EOI C2D1 | 371.62 μg/mL | Geometric Coefficient of Variation 24.589 |
| Ociperlimab + Tislelizumab | Serum Concentration of Ociperlimab | Predose C5D1 | 127.20 μg/mL | Geometric Coefficient of Variation 45.138 |
| Ociperlimab + Tislelizumab | Serum Concentration of Ociperlimab | EOI C5D1 | 450.52 μg/mL | Geometric Coefficient of Variation 10.707 |
| Ociperlimab + Tislelizumab | Serum Concentration of Ociperlimab | Predose C9D1 | 181.58 μg/mL | Geometric Coefficient of Variation 46.927 |
| Ociperlimab + Tislelizumab | Serum Concentration of Ociperlimab | Predose C17D1 | 320.00 μg/mL | — |
| Ociperlimab + Rituximab | Serum Concentration of Ociperlimab | Predose C1D1 | NA μg/mL | — |
| Ociperlimab + Rituximab | Serum Concentration of Ociperlimab | EOI C5D1 | 507.48 μg/mL | Geometric Coefficient of Variation 15.295 |
| Ociperlimab + Rituximab | Serum Concentration of Ociperlimab | EOI C1D1 | 296.48 μg/mL | Geometric Coefficient of Variation 18.832 |
| Ociperlimab + Rituximab | Serum Concentration of Ociperlimab | Predose C5D1 | 184.09 μg/mL | Geometric Coefficient of Variation 27.675 |
| Ociperlimab + Rituximab | Serum Concentration of Ociperlimab | Predose C2D1 | 63.68 μg/mL | Geometric Coefficient of Variation 38.413 |
| Ociperlimab + Rituximab | Serum Concentration of Ociperlimab | Predose C9D1 | 184.83 μg/mL | Geometric Coefficient of Variation 23.101 |
| Ociperlimab + Rituximab | Serum Concentration of Ociperlimab | EOI C2D1 | 389.27 μg/mL | Geometric Coefficient of Variation 18.555 |
Secondary
Time to Response (TTR)
TTR is defined as the time from study treatment start to date of the earliest qualifying response (partial response or better) per Lugano Classification (2014) as assessed by the investigator
Time frame: From first dose of study drug to the data cutoff date of 30 August 2024; maximum time on study was 28 months.
Population: Efficacy analysis set; participants with a best overall response of CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ociperlimab + Tislelizumab | Time to Response (TTR) | 2.09 months |
| Ociperlimab + Rituximab | Time to Response (TTR) | 2.04 months |