Advanced Solid Tumor, Chronic Lymphocytic Leukemia, Diffuse Large B Cell Lymphoma, Follicular Lymphoma, Mantle Cell Lymphoma, Marginal Zone Lymphoma, Small Lymphocytic Lymphoma
Conditions
Brief summary
The purpose of this study was to determine the maximum tolerated dose (MTD), recommended dose for expansion (RDFE), safety and tolerability of BGB-10188 as monotherapy in participants with relapsed/refractory (R/R) mature B-cell malignancies; in combination with zanubrutinib in participants with R/R follicular lymphoma (FL), R/R mantle cell lymphoma (MCL) or R/R diffuse large B-cell lymphoma (DLBCL); and in combination with tislelizumab in participants with advanced solid tumors.
Interventions
DRUGBGB-10188
Administered as specified in the treatment arm
DRUGZanubrutinib
Administered as specified in the treatment arm
DRUGTislelizumab
Administered as specified in the treatment arm
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
Key Inclusion Criteria: Parts A, B and C 1. Confirmed diagnosis of one of the following: * Part A: R/R CLL/SLL, R/R MZL, R/R FL, R/R MCL or R/R DLBCL * Part B: R/R FL, R/R MCL, or R/R DLBCL * Part C: R/R FL, R/R MCL, or R/R DLBCL CLL = chronic lymphocytic leukemia; SLL = small lymphocytic lymphoma; MZL = marginal zone lymphoma 2. Participants with MZL, FL, MCL, DLBCL, or SLL must have had at least one bi-dimensionally measurable nodal lesion greater than (\>) 1.5 centimeters (cm) in the longest diameter or extranodal lesion that is \> 1 cm in the longest diameter by computed tomography (CT) scan or magnetic resonance imaging (MRI), as defined by the Lugano Classification. Parts D and E 3. Part D: Histologically or cytologically confirmed unresectable locally advanced or metastatic solid tumors previously treated with standard systemic therapy (including prior chemotherapy, radiotherapy, target therapy, and immunotherapy as locally, or guidance approved therapy) or for which treatment is not available or not tolerated. Enrollment was limited to participants with advanced solid tumors for which there was clinical evidence of response to T-cell based immuno-oncology agents (e.g., non-small cell lung cancer \[NSCLC\], small cell lung cancer \[SCLC\], head and neck squamous cell cancer, hepatocellular carcinoma, gastric or gastroesophageal junction carcinoma, nasopharyngeal carcinoma, renal cell carcinoma, cervical cancer, triple-negative breast cancer, ovarian cancer (OC), endometrial carcinoma, esophageal cancer, melanoma, urothelial carcinoma or participant with confirmed microsatellite instability-high \[MSI-H\] or mismatch repair deficient \[dMMR\] solid tumor, etc.). Enrollment of tumor types beyond above situations required sponsor's approval. 4. Part E: Participants with histologically or cytologically confirmed epithelial OC (including fallopian or primary peritoneal cancer) previously treated with 1 to 3 lines of systemic anticancer treatment; must have been platinum resistant and checkpoint inhibitor (CPI) naïve. 5. Participants must have had measurable disease as assessed by RECIST v1.1. Key
Exclusion criteria
Parts A, B and C 1. History of allogeneic stem-cell transplantation or chimeric antigen receptor-T (CAR-T) cell therapy. 2. For participants with DLBCL in Part A, classified as T-cell/histiocyte-rich large B-cell lymphoma, high-grade B-cell lymphoma with myelocytomatosis viral oncogene homolog and B-cell lymphoma (BCL)-2 and/or BCL-6 rearrangements, high grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, Epstein-Barr virus positive DLBCL, and transformed DLBCL. Parts A, B, C, D and E 3. Prior exposure to PI3K inhibitor. For participants in Part B and Part C, prior exposure to BTK inhibitor and/or PI3K inhibitor. 4. Any approved anticancer therapy, including hormonal therapy, or any investigational agent or participation in another clinical study with therapeutic intent within 14 days before first dose. 5. Treatment with systemic immune-stimulatory agents (including, but not limited to, interferons and interleukin-2) within 2 weeks or 5 half-lives of the drug, whichever was later, before first dose. 6. Known human immunodeficiency virus (HIV) infection, or serologic status reflecting active viral hepatitis B (HBV) or viral hepatitis C (HCV) infection as follows: * HBsAg (+), or * HBcAb (+) and HBV DNA detected, or * Presence of HCV antibody. Participants with presence of HCV antibody were eligible if HCV ribonucleic acid (RNA) was undetectable NOTE: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: The Recommended Dose for Expansion (RDFE) of BGB-10188 Monotherapy in Hematologic Malignancies | Up to 28 days | The RDFE of BGB-10188 monotherapy in participants with hematologic malignancies was planned to be determined from safety, tolerability, pharmacokinetic (PK), and any other relevant and available data based on recommendations from the Safety Monitoring Committee. Part A dose-escalation enrolled participants with R/R CLL/SLL, MZL, FL, MCL, and DLBCL up to 540 mg, however the maximum tolerated dose was not reached and the RDFE could not be determined based on the data that were collected. |
| Part B: The RDFE of BGB-10188 in Combination With Zanubrutinib in Hematologic Malignancies | Up to 28 days | The RDFE of BGB-10188 in combination with zanubrutinib was planned to be determined from safety, tolerability, PK, and any other relevant and available data obtained, based on recommendation of the Safety Monitoring Committee. The RDFE could not be determined since not all planned dose cohorts in this part of the study were enrolled and not enough data were collected to establish the RDFE. |
| Part D: The RDFE of BGB-10188 in Combination With Tislelizumab in Advanced Solid Tumors | Up to 28 days | The RDFE of BGB-10188 in combination with tislelizumab was determined based on the totality of safety, tolerability, PK, and any other relevant and available data that were obtained from the dose escalation phase for Part E. |
| Part E: Overall Response Rate (ORR) as Per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 | Up to 10.0 months | ORR was defined as the percentage of participants who had complete response (CR) or partial response (PR). Per RECIST v.1.1., CR was defined as disappearance of all target lesions, non-target lesions and no new lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<) 10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
| Number of Participants With Treatment Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), and AEs Leading to Discontinuation | Part A: 47.2 Months; Part B: 24 Months; Part D: 15.2 Months; Part E: 10 Months | An AE was defined as any unfavorable and unintended sign, symptom, or disease associated with the use of study drugs, whether considered related to study drugs or not. An SAE was any untoward medical occurrence that, at any dose, resulted in death, was life-threatening, required hospitalization or prolongation of existing hospitalization, resulted in disability, was a congenital anomaly or was considered a medically significant. TEAE was an AE that has an onset date or a worsening in severity from baseline on or after the first dose of study drug. Severity of AEs was assessed according to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) v.5.0, which consists of: Grade 1 Mild; Grade 2 Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Death due to AE. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Parts A and B: ORR as Assessed by Investigator | Part A: up to 47.2 months and Part B: up to 24 months | ORR was defined as the percentage of participants who had CR or PR as determined from investigator-derived tumor assessments per RECIST v. 1.1. Per RECIST v.1.1., CR was defined as disappearance of all target lesions, non-target lesions and no new lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
| Part A: Observed Maximum Plasma Concentration (Cmax) of BGB-10188 After a Single Dose | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, and 168 hours post-dose on Day -7 (each cycle = 28 days) | Cmax of BGB-10188 after a single dose was determined. |
| Part A: Cmax of BGB-10188 at Steady State | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose on Cycle 1 Day 15 (each cycle = 28 days) | Cmax of BGB-10188 at steady state was determined. |
| Part A: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) After Single Dose | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8,12, and 24 hours post-dose on Day-7 (each cycle = 28 days) | Area under the plasma concentration-time curve of BGB-10188 from time 0 to 24 hours (AUC0-24) was determined. |
| Part B: Duration of Response (DOR) | Up to 24 months | DOR was defined as the time from the first determination of an overall response per RECIST v1.1 until the first documentation of progression (PD) or death, whichever came first. Median DOR was estimated using the Kaplan-Meier method. Per RECIST v1.1., CR was defined as disappearance of all target lesions, non-target lesions, and no new lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. |
| Part B: Time to Response (TTR) | Up to 24 months | TRR was defined as the time from treatment initiation to the first documentation of response. Per RECIST v.1.1., CR was defined as disappearance of all target lesions, non-target lesions, and no new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in short axis to \< 10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
| Part B: Cmax of BGB-10188 After a Single Dose | Pre-dose, 0.5,1, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Cycle 1 Day 1 (each cycle = 28 days) | Cmax of BGB-10188 after a single dose when given in combination with zanubrutinib was determined. |
| Part B: Cmax of BGB-10188 at Steady State | Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Cycle 1 Day 15 (each cycle = 28 days) | Cmax of BGB-10188 at steady state when given in combination with zanubrutinib was determined. |
| Part B: AUC 0-24 h of BGB-10188 After a Single Dose | Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Cycle 1 Day 1 (each cycle = 28 days) | AUC 0-24 h of BGB-10188 after a single dose when given in combination with zanubrutinib was determined. |
| Part D: Overall Response Rate (ORR) | Up to 15.2 months | ORR was defined as the percentage of participants who had CR or PR as determined from investigator-derived tumor assessments per RECIST v. 1.1. Per RECIST v.1.1., CR was defined as disappearance of all target lesions, non-target lesions, and no new lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
| Parts D and E: Duration of Response (DOR) | Part D: up to 15.2 months and Part E: up to 10.0 months | DOR was defined as the time from the first determination of an overall response per RECIST v1.1 until the first documentation of PD or death, whichever came first. Median DOR was estimated using the Kaplan-Meier method. Per RECIST v1.1., CR was defined as disappearance of all target lesions, non-target lesions, and no new lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum in the study. DOR for participants who had not progressed or died at the time of analysis was to be censored at the date of their last tumor assessment. |
| Parts D and E: Disease Control Rate (DCR) | Part D: up to 15.2 months and Part E: up to 10.0 months | DCR was defined as the percentage of participants with best overall response (BOR), as per RECIST v.1.1, of a CR, PR, or stable disease (SD). Per RECIST v.1.1., CR was defined as disappearance of all target lesions, non-target lesions, and no new lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. |
| Parts D and E: Time to Response (TTR) | Part D: up to 15.2 months and Part E: up to 10.0 months | TTR was defined as the time from treatment initiation to the first documentation of response. Per RECIST v.1.1., CR was defined as disappearance of all target lesions, non-target lesions, and no new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in short axis to \< 10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
| Part D: Cmax of BGB-10188 After a Single Dose | Pre-dose, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Cycle 1 Day 1 (each cycle = 28 days) | Cmax of BGB-10188 after a single dose when given in combination with tislelizumab was determined. |
| Part D: Cmax of BGB-10188 at Steady State | Pre-dose, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Cycle 2 Day 1 (each cycle = 21 days) | Cmax of BGB-10188 at steady state when given in combination with tislelizumab was determined. |
| Part D: AUC 0-24h of BGB-10188 After Single Dose | Pre-dose, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Cycle 1 Day 1 (each cycle = 28 days) | AUC 0-24 h of BGB-10188 after a single dose when given in combination with tislelizumab was determined. |
| Part D: AUC 0-24h of BGB-10188 at Steady State | Pre-dose, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Cycle 2 Day 1 (each cycle = 21 days) | AUC 0-24 h of BGB-10188 at steady state when given in combination with tislelizumab was determined. |
| Part E: Progression-Free Survival (PFS) | Up to 10.0 months | PFS was defined as the time from the date of the first dose of study drugs to the date of the first documentation of PD assessed by the investigator using RECIST v1.1 or death, whichever occurred first. Median PFS was estimated using the Kaplan-Meier method. Per RECIST v1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. |
| Part E: Clinical Benefit Rate (CBR) | Up to 10.0 months | CBR was defined as the percentage of participants with best overall response, as defined by RECIST v1.1, of a CR, PR, or at least 24 weeks of SD. Per RECIST v.1.1., CR was defined as disappearance of all target lesions, non-target lesions, and no new lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. |
| Part E: Cancer Antigen (CA)-125 Response Rate Per Gynecological Cancer Intergroup | Up to 10.0 months | CA-125 response rate was defined as the percentage of participants achieving a CA-125 response according to the Gynecological Cancer Center Intergroup criteria, in which a response had occurred if there was at least a 50% reduction in CA-125 levels from baseline. |
| Part E: Cmax of BGB-10188 After Single Dose | Pre-dose, 0.5, 1, 2, 4, 6, 8, 24 hours post-dose on Cycle 1 Day 1 (each cycle = 21 days) | Cmax of BGB-10188 after a single dose when given in combination with tislelizumab was determined. |
| Part E: Cmax of BGB-10188 at Steady State | Pre-dose, 0.5, 1, 2, 4, 6, 8, 24 hours post-dose on Cycle 2 Day 1 (each cycle = 21 days) | Cmax of BGB-10188 at steady state when given in combination with tislelizumab was determined. |
| Part E: AUC0-24h of BGB-10188 After Single Dose | Pre-dose, 0.5, 1, 2, 4, 6, 8, 24 hours post-dose of Cycle 1 Day 1 (each cycle = 21 days) | AUC0-24 h of BGB-10188 after a single dose when given in combination with tislelizumab was determined. |
Countries
Australia, China
Contacts
STUDY_DIRECTORStudy Director
BeiGene
Participant flow
Pre-assignment details
A total of 97 participants were enrolled, out of which 96 were randomized and treated. One participant was enrolled but not treated. Part C was cancelled by the sponsor and not initiated.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 69.6 years STANDARD_DEVIATION 4.04 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 84 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized Asian | 3 Participants |
| Race/Ethnicity, Customized Not Reported | 0 Participants |
| Race/Ethnicity, Customized White | 3 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 5 | 1 / 5 | 1 / 8 | 0 / 6 | 0 / 10 | 0 / 4 | 0 / 5 | 1 / 5 | 3 / 6 | 2 / 11 | 1 / 10 | 0 / 7 | 2 / 9 | 1 / 5 |
| other Total, other adverse events | 4 / 5 | 5 / 5 | 8 / 8 | 6 / 6 | 10 / 10 | 4 / 4 | 5 / 5 | 5 / 5 | 6 / 6 | 11 / 11 | 9 / 10 | 7 / 7 | 8 / 9 | 5 / 5 |
| serious Total, serious adverse events | 1 / 5 | 1 / 5 | 3 / 8 | 1 / 6 | 4 / 10 | 2 / 4 | 1 / 5 | 3 / 5 | 4 / 6 | 5 / 11 | 5 / 10 | 2 / 7 | 4 / 9 | 2 / 5 |
Outcome results
None listed