Locally Advanced or Metastatic Solid Tumors for Phase 1, Dose Escalation and Phase 2 Safety Lead-in, HNSCC for Phase 2 Dose Expansion, NSCLC for Phase 2 Dose Expansion
Conditions
Brief summary
This was an open-label, multicenter, nonrandomized Phase 1 and 2 clinical trial evaluating various combinations of surzebiclimab (BGB-A425) and/or alcestobart (LBL-007) with tislelizumab.
Detailed description
Blocking antibodies targeting programmed cell death protein-1 (PD-1) have achieved remarkable results in the treatment of many types of tumors. However, based upon the rate of primary and secondary resistance to PD-1 blockade, it was apparent that additional immuno-regulatory mechanism(s) underlie tumor immune escape. Indeed, research shows that the T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) pathway cooperates with PD-1 to maximize the suppression of effector tumor infiltrating lymphocytes (TILs) as well as promote resistance to anti-PD-1 therapy. Therefore, TIM-3 represents an ideal target with the potential to significantly improve and/or extend the therapeutic benefit of anti-PD-1 therapy to a greater number of participants. TIM-3, Lymphocyte activation gene-3 (LAG-3), and PD-1 function as immune checkpoint receptors in the overlapping regulation of immune tolerance and have been shown to be co-overexpressed on the TILs from the participant samples of various solid tumors. Furthermore, emerging clinical data and preclinical data demonstrate co-expression of TIM-3, LAG-3, PD-1 often yield T cells exhausted immunophenotype (i.e., cytokine expression, proliferation etc.). Cancer cells take advantage of PD-1, TIM-3, and LAG-3 in inhibiting immune cells' function, and escape the immune surveillance. Based upon the overlapping expression profiles and immuno-regulatory functions, TIM-3 and LAG-3 mediated adaptive resistance, there was strong scientific rationale that simultaneous targeting of these checkpoint blockers, could potentially increase therapeutic benefit and might help to overcome the resistance arising due to anti-PD-(L)-1 therapy. Hence, this study evaluated the safety and preliminary efficacy of surzebiclimab (anti TIM-3), alcestobart (Anti-LAG-3) in combination with tislelizumab (anti PD-1) in patients with advanced solid tumors. This was an open-label, multicenter, nonrandomized Phase 1 and Phase 2 clinical trial. Phase 1 determined the recommended phase 2 dose (RP2D) for the combination of surzebiclimab and tislelizumab. Phase 2 safety lead-in determined the RP2D for the combination of surzebiclimab, tislelizumab and/or alcestobart. Phase 2 dose expansion continued to evaluate the safety but also focus on the efficacy of the doublet or triplet treatment combination in select tumor types.
Interventions
DRUGSurzebiclimab
Humanized immunoglobulin G1 (IgG1)-variant monoclonal antibody against TIM-3
DRUGTislelizumab
Humanized, IgG4-variant monoclonal antibody against PD-1
DRUGAlcestobart
Human anti LAG-3 antibody
Sponsors
BeiGene
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Open Label
Intervention model description
This was an open-label, multicenter, nonrandomized Phase 1 and Phase 2 clinical trial. Phase 1 determined the recommended phase 2 dose (RP2D) for the combination of surzebiclimab, and tislelizumab. Phase 2 safety lead-in determined the RP2D for the combination of alcestobart and tislelizumab with or without surzebiclimab. Phase 2 dose expansion continued to evaluate the safety but also focus on the efficacy of the double or triplet treatment combination in select tumor types.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Participants were aged \>=18 years. * Adequate organ function. * Eastern Cooperative Oncology Group (ECOG) performance status \<=1. * Must have been able to provide a recently obtained archival tumor tissue or fresh tumor biopsy. * The phase 1 dose escalation and phase 2 safety lead-in enrolled participants with histologically/cytologically confirmed advanced/metastatic solid tumors who had previously received standard systemic therapy per local guidelines, unless it was not available, not tolerated or determined not appropriate based on investigators judgement, and had at least 1 evaluable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. * The phase 2 dose expansion enrolled participants with recurrent/metastatic HNSCC (Cohorts 1 and 4) and advanced/metastatic NSCLC (Cohorts 2 and 5), with disease progression that occurred \>=10 weeks from the initiation of anti-PD-1/PD-L1 treatment for locally advanced or metastatic disease and had at least 1 measurable lesion outside of the central nervous system per RECIST v1.1. Key
Exclusion criteria
* A history of severe hypersensitivity reactions to other monoclonal antibodies. * Active autoimmune disease or a history of autoimmune diseases that might relapse or a history of life-threatening toxicity related to prior immune therapy. * Any condition that required systemic treatment with either corticosteroids or other immunosuppressive medication \<=14 days before administration of study drug. * A history of interstitial lung disease, noninfectious pneumonitis or uncontrolled lung diseases. * Prior therapy targeting TIM-3 and/or LAG-3. * The phase 2 dose expansion NSCLC cohorts excluded participants with known sensitizing epidermal growth factor receptor (EGFR) mutation, v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation, anaplastic lymphoma kinase (ALK) fusion, or c-ros oncogene 1 (ROS1) fusion. NOTE: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2 (Safety Lead-In): RP2D of Alcestobart in Combination With Surzebiclimab and Tislelizumab | Up to 21 days | The RP2D or recommended dose for expansion of the combination treatment was determined based upon the MTD or MAD, and also considered the long-term tolerability, PK, efficacy, and any other relevant data as available. |
| Phase 2 (Dose Expansion): Overall Response Rate (ORR) | Maximum time on study: Cohort 1: up to 31.3 months, Cohort 2: up to 32.0 months, Cohort 4: up to11.3 months, Cohort 5: up to 15.9 months | ORR was defined as the percentage of participants who had complete response (CR) or partial response (PR). Per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1., CR was defined as disappearance of all target 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. |
| Phase 1: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Up to 30 days after last dose of study drug (maximum treatment duration: up to 32.7 months) | An Adverse Event (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. 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 up to 30 days following study drug discontinuation or initiation of the first new systemic anticancer therapy, whichever occurred first. 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. 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. |
| Phase 1: Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) of Surzebiclimab in Combination With Tislelizumab | Up to 28 days | The MAD was defined as the highest dose administered, where all dose levels were tolerated during dose escalation. The MTD was not reached in Phase 1, therefore the MAD was reported. |
| Phase 1: Recommended Phase 2 Dose (RP2D) of Surzebiclimab in Combination With Tislelizumab | Up to 28 days | The RP2D or recommended dose for expansion of the combination treatment was determined based upon the MTD or MAD, and also considered the long-term tolerability, PK, efficacy, and any other relevant data as available. |
| Phase 2 (Safety Lead-In): Number of Participants With TEAEs and SAEs | Up to 30 days after last dose of study drug (maximum duration of treatment: up to 19.6 months in Cohort A and up to 21.5 months in Cohort B) | 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. 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 up to 30 days following study drug discontinuation or initiation of the first new systemic anticancer therapy, whichever occurred first. 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. Severity of AEs was assessed according to 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. |
| Phase 2 (Safety Lead-In): MTD or MAD of Alcestobart in Combination With Tislelizumab | Up to 21 days | The MAD was defined as the highest dose administered, where all dose levels were tolerated during dose escalation. The MTD was not reached in Phase 2, therefore the MAD was reported. |
| Phase 2 (Safety Lead-In): MTD or MAD of Alcestobart in Combination With Surzebiclimab and Tislelizumab | Up to 21 days | The MAD was defined as the highest dose administered, where all dose levels were tolerated during dose escalation. The MTD was not reached in Phase 2, therefore the MAD was reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2 (Dose Expansion): Cmax of Surzebiclimab | Cycle 1 Day 1 and Cycle 5 Day 1 at pre-dose, end of infusion (EOI), 6 hours, 1, 3, 7, 14, and 21 days after EOI (each cycle was 21 days) | — |
| Phase 1: Minimum Observed Plasma Concentration (Cmin) of Surzebiclimab | Cycle 1 Day 1 and Cycle 5 Day 1 at pre-dose, end of infusion (EOI), 6 hours, 1, 3, 7, 14, 21, and 28 (cycle 1 only) days after EOI (Cycle 1 was 28 days; Cycle 2 and thereafter were 21 days) | Cmin of surzebiclimab was determined. |
| Phase 2 (Dose Expansion): Cmin of Surzebiclimab | Cycle 1 Day 1 and Cycle 5 Day 1 at pre-dose, end of infusion (EOI), 6 hours, 1, 3, 7, 14, and 21 days after EOI | — |
| Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Surzebiclimab | Cycle 1 Day 1 and Cycle 5 Day 1 at pre-dose, end of infusion (EOI), 6 hours, 1, 3, 7, 14, 21, and 28 (cycle 1 only) days after EOI (Cycle 1 was28 days; Cycle 2 and thereafter were 21 days) | — |
| Phase 2 (Dose Expansion): Tmax of Surzebiclimab | Cycle 1 Day 1 and Cycle 5 Day 1 at pre-dose, end of infusion (EOI), 6 hours, 1, 3, 7, 14, and 21 days after EOI (each cycle was 21 days) | — |
| Phase 1: Half-Life (t1/2) of Surzebiclimab | Cycle 1 Day 1 at pre-dose, end of infusion (EOI), 6 hours, 1, 3, 7, 14, 21, and 28 days after EOI (Cycle 1 was 28 days) | — |
| Phase 2 (Dose Expansion): T1/2 of Surzebiclimab | Cycle 1 Day 1 at pre-dose, end of infusion (EOI), 6 hours, 1, 3, 7, 14, and 21 days after EOI (each cycle was 21 days) | — |
| Phase 1: Area Under Curve From 0 to 21 Days (AUC0-21d) of Surzebiclimab | Cycle 1 Day 1 and Cycle 5 Day 1 at pre-dose, end of infusion (EOI), 6 hours, 1, 3, 7, 14, and 21 days after EOI (Cycle 1 was 28 days; Cycle 2 and thereafter were 21 days) | — |
| Phase 2 (Dose Expansion): AUC0-21d of Surzebiclimab | Cycle 1 Day 1 and Cycle 5 Day 1 at pre-dose, end of infusion (EOI), 6 hours, 1, 3, 7, 14, and 21 days after EOI (each cycle duration= 21 days) | — |
| Phase 1: Clearance (CL/F) of Surzebiclimab | Cycle 1 Day 1 at pre-dose, end of infusion (EOI), 6 hours, 1, 3, 7, 14, 21, and 28 days after EOI (Cycle 1 was 28 days) | — |
| Phase 2 (Dose Expansion): CL/F of Surzebiclimab | Cycle 1 Day 1 at pre-dose, end of infusion (EOI), 6 hours, 1, 3, 7, 14, and 21 days after EOI | — |
| Phase 1: Volume of Distribution (Vz/F) of Surzebiclimab | Cycle 1 Day 1 at pre-dose, end of infusion (EOI), 6 hours, 1, 3, 7, 14, 21, and 28 days after EOI (Cycle 1 was 28 days) | — |
| Phase 2 (Dose Expansion): Vz/F of Surzebiclimab | Cycle 1 Day 1 at pre-dose, end of infusion (EOI), 6 hours, 1, 3, 7, 14, and 21 days after EOI | Vz/F of surzebiclimab was determined. |
| Phase 2 (Safety Lead-In): Cmax of Alcestobart | Cycle 1 Day 1 and Cycle 5 Day 1 at pre-dose, end of infusion (EOI), 6 hours, 1, 3, 7, 14, and 21 days after EOI (each cycle was 21 days) | — |
| Phase 2 (Safety Lead-In): Cmin of Alcestobart | Cycle 1 Day 1 and Cycle 5 Day 1 at pre-dose, end of infusion (EOI), 6 hours, 1, 3, 7, 14, and 21 days after EOI (each cycle was 21 days) | Cmin of alcestobart was determined. |
| Phase 2 (Safety Lead-In): Tmax of Alcestobart | Cycle 1 Day 1 and Cycle 5 Day 1 at pre-dose, end of infusion (EOI), 6 hours, 1, 3, 7, 14, and 21 days after EOI (each cycle was 21 days) | — |
| Phase 2 (Safety Lead-In): t1/2 of Alcestobart | Cycle 1 Day 1 at pre-dose, end of infusion (EOI), 6 hours, 1, 3, 7, 14, and 21 days after EOI (each cycle was 21 days) | — |
| Phase 2 (Safety Lead-In): AUC0-21d of Alcestobart | Cycle 1 Day 1 and Cycle 5 Day 1 at pre-dose, end of infusion (EOI), 6 hours, 1, 3, 7, 14, and 21 days after EOI (each cycle was 21 days) | — |
| Phase 2 (Safety Lead-In): CL/F of Alcestobart | Cycle 1 Day 1 at pre-dose, end of infusion (EOI), 6 hours, 1, 3, 7, 14, and 21 days after EOI | — |
| Phase 2 (Safety Lead-In): Vz/F of Alcestobart | Cycle 1 Day 1 at pre-dose, end of infusion (EOI), 6 hours, 1, 3, 7, 14, and 21 days after EOI | — |
| Phase 1: Serum Concentrations of Tislelizumab | Pre-dose and EOI (within 30 minutes) on Cycle 1 Day 8 and Cycle 5 Day 1, and pre-dose on Day 1 of Cycles 2, 3, 6, 9, 13, 17, and 25 (Cycle 1 was 28 days, Cycle 2 and thereafter were 21 days) | Serum concentrations of tislelizumab were measured using an enzyme-linked immunosorbent assay (ELISA). |
| Phase 2 (Dose Expansion): Serum Concentrations of Tislelizumab | Pre-dose on Day 1 of Cycles 1, 2, 5, 6, 9, 13, 17, 25 and at EOI (within 30 minutes) on Day 1 of Cycles 1 and 5 (each cycle was 21 days) | Serum concentrations of tislelizumab were measured using an enzyme-linked immunosorbent assay (ELISA). |
| Phase 1: Number of Participants With Anti-Drug Antibodies (ADA) to Surzebiclimab | Maximum time on study: up to 57.5 months | Immunogenic responses to surzebiclimab included: treatment emergent, treatment-induced and treatment boosted anti-drug antibodies (ADA) and neutralizing antibody (NAb) positive assessments. Treatment-emergent ADA was defined as the sum of treatment-boosted ADA and treatment-induced ADA participants. Treatment-induced ADA was defined as ADA-evaluable participants that were ADA-negative at baseline and ADA-positive after drug administration during the treatment or follow-up observation period. Treatment-boosted ADA was defined as the Baseline-positive ADA-evaluable participants with significant increases (4-fold or higher) in ADA titer after drug administration during the treatment or follow-up observation period. NAb positive was defined as ADA-evaluable participants with positive Nab at any time including baseline and/or after drug administration. |
| Phase 2 (Safety Lead-In) Cohort B: Number of Participants With Anti-Drug Antibodies to Surzebiclimab | Maximum time on study in Cohort B: up to 21.5 months | Immunogenic responses to surzebiclimab included: treatment-emergent, treatment-induced and treatment-boosted ADA and NAb positive assessments. Treatment-emergent ADA was defined as the sum of treatment-boosted ADA and treatment-induced ADA participants. Treatment-induced ADA was defined as ADA-evaluable participants that were ADA-negative at baseline and ADA-positive after drug administration during the treatment or follow-up observation period. Treatment-boosted ADA was defined as the baseline-positive ADA-evaluable participants with significant increases (4-fold or higher) in ADA titer after drug administration during the treatment or follow-up observation period. NAb positive was defined as ADA-evaluable participants with positive NAb at any time including baseline and/or after drug administration. |
| Phase 2 (Dose Expansion): Number of Participants With Anti-Drug Antibodies to Surzebiclimab | Maximum time on study: Cohort 1: up to 31.3 months, Cohort 2: up to 32.0 months, Cohort 4: up to 11.3 months, Cohort 5: up to 15.9 months | Immunogenic responses to surzebiclimab included: treatment-emergent, treatment-induced and treatment-boosted ADA and NAb positive assessments. Treatment-emergent ADA was defined as the sum of treatment-boosted ADA and treatment-induced ADA participants. Treatment-induced ADA was defined as ADA-evaluable participants that were ADA-negative at baseline and ADA-positive after drug administration during the treatment or follow-up observation period. Treatment-boosted ADA was defined as the baseline-positive ADA-evaluable participants with significant increases (4-fold or higher) in ADA titer after drug administration during the treatment or follow-up observation period. NAb positive was defined as ADA-evaluable participants with positive NAb at any time including baseline and/or after drug administration. |
| Phase 2 (Safety Lead-In): Number of Participants With Anti-Drug Antibodies to Alcestobart | Maximum time on study: Cohort A: up to 22.1 months; Cohort B: up to 21.5 months | Immunogenic responses to alcestobart included: treatment-emergent, treatment-induced and treatment-boosted ADA and NAb positive assessments. Treatment-emergent ADA was defined as the sum of treatment-boosted ADA and treatment-induced ADA participants. Treatment-induced ADA was defined as ADA-evaluable participants that were ADA-negative at baseline and ADA-positive after drug administration during the treatment or follow-up observation period. Treatment-boosted ADA was defined as the baseline-positive ADA-evaluable participants with significant increases (4-fold or higher) in ADA titer after drug administration during the treatment or follow-up observation period. NAb positive was defined as ADA-evaluable participants with positive NAb at any time including baseline and/or after drug administration. |
| Phase 2 (Dose Expansion) Cohorts 4 and 5: Number of Participants With Anti-Drug Antibodies to Alcestobart | Maximum time on study: Cohort 4: up to 11.3 months, Cohort 5: up to 15.9 months | Immunogenic responses to alcestobart included: treatment-emergent, treatment-induced and treatment-boosted ADA and NAb positive assessments. Treatment-emergent ADA was defined as the sum of treatment-boosted ADA and treatment-induced ADA participants. Treatment-induced ADA was defined as ADA-evaluable participants that were ADA-negative at baseline and ADA-positive after drug administration during the treatment or follow-up observation period. Treatment-boosted ADA was defined as the baseline-positive ADA-evaluable participants with significant increases (4-fold or higher) in ADA titer after drug administration during the treatment or follow-up observation period. NAb positive was defined as ADA-evaluable participants with positive NAb at any time including baseline and/or after drug administration. |
| Phase 1: Number of Participants With Anti-Drug Antibodies to Tislelizumab | Maximum time on study: up to 57.5 months | Immunogenic responses to tislelizumab included: treatment-emergent, treatment-induced and treatment-boosted ADA and NAb positive assessments. Treatment-emergent ADA was defined as the sum of treatment-boosted ADA and treatment-induced ADA participants. Treatment-induced ADA was defined as ADA-evaluable participants that were ADA-negative at baseline and ADA-positive after drug administration during the treatment or follow-up observation period. Treatment-boosted ADA was defined as the baseline-positive ADA-evaluable participants with significant increases (4-fold or higher) in ADA titer after drug administration during the treatment or follow-up observation period. NAb positive was defined as ADA-evaluable participants with positive NAb at any time including baseline and/or after drug administration. |
| Phase 2 (Safety Lead-In): Number of Participants With Anti-Drug Antibodies to Tislelizumab | Maximum time on study: Cohort A: up to 22.1 months; Cohort B: up to 21.5 months | Immunogenic responses to alcestobart included: treatment-emergent, treatment-induced and treatment-boosted ADA and NAb positive assessments. Treatment-emergent ADA was defined as the sum of treatment-boosted ADA and treatment-induced ADA participants. Treatment-induced ADA was defined as ADA-evaluable participants that were ADA-negative at baseline and ADA-positive after drug administration during the treatment or follow-up observation period. Treatment-boosted ADA was defined as the baseline-positive ADA-evaluable participants with significant increases (4-fold or higher) in ADA titer after drug administration during the treatment or follow-up observation period. NAb positive was defined as ADA-evaluable participants with positive NAb at any time including baseline and/or after drug administration. |
| Phase 2 (Dose Expansion): Number of Participants With Anti-Drug Antibodies to Tislelizumab | Maximum time on study: Cohort 1: up to 31.3 months, Cohort 2: up to 32.0 months, Cohort 4: up to 11.3 months, Cohort 5: up to 15.9 months | Immunogenic responses to tislelizumab included: treatment-emergent, treatment-induced and treatment-boosted ADA and NAb positive assessments. Treatment-emergent ADA was defined as the sum of treatment-boosted ADA and treatment-induced ADA participants. Treatment-induced ADA was defined as ADA-evaluable participants that were ADA-negative at baseline and ADA-positive after drug administration during the treatment or follow-up observation period. Treatment-boosted ADA was defined as the baseline-positive ADA-evaluable participants with significant increases (4-fold or higher) in ADA titer after drug administration during the treatment or follow-up observation period. NAb positive was defined as ADA-evaluable participants with positive NAb at any time including baseline and/or after drug administration. |
| Phase 2 (Safety Lead- In): Overall Response Rate (ORR) | Maximum time on study: Cohort A: up to 22.1 months; Cohort B: up to 21.5 months | ORR was defined as the percentage of participants who had CR or PR. Per RECIST v.1.1, CR was defined as disappearance of all target 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. |
| Phase 2 (Dose Expansion): Number of Participants With TEAEs and SAEs | Up to 30 days after last dose of study drug (maximum treatment duration: Cohort 1: up to 6.9 months, Cohort 2: up to 23.5 months, Cohort 4: up to 9.6 months, Cohort 5: up to 15.4 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 up to 30 days following study drug discontinuation or initiation of the first new systemic anticancer therapy, whichever occurred first. Severity of AEs was assessed according to 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. |
| Phase 1: Disease Control Rate (DCR) | Maximum time on study: up to 57.5 months | DCR was defined as the percentage of participants with a best overall response (BOR) of CR, PR, or stable disease (SD), per RECIST v.1.1. CR was defined as the disappearance of all target 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 progressive disease (PD), taking as reference the smallest sum diameters while on study. |
| Phase 2 (Safety Lead-In): Disease Control Rate (DCR) | Maximum time on study: Cohort A: up to 22.1 months; Cohort B: up to 21.5 months | DCR was defined as the percentage of participants with a BOR of CR, PR, or SD, per RECIST v.1.1. CR was defined as the disappearance of all target 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. 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. |
| Phase 2 (Dose Expansion): Disease Control Rate (DCR) | Maximum time on study: Cohort 1: up to 31.3 months, Cohort 2: up to 32.0 months, Cohort 4: up to 11.3 months, Cohort 5: up to 15.9 months | DCR was defined as the percentage of participants with a BOR of CR, PR, or SD, per RECIST v.1.1. CR was defined as the disappearance of all target 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. 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. |
| Phase 1: Overall Response Rate (ORR) | Maximum time on study: up to 57.5 months | ORR was defined as the percentage of participants who had CR or PR. Per RECIST v.1.1, CR was defined as disappearance of all target 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. |
| Phase 2 (Dose Expansion): Duration of Response (DOR) | From the first determination of an overall response until PD or death, whichever came first (Maximum time on study [Cohort 1: up to 31.3 months, Cohort 2: up to 32.0 months, Cohort 4: up to 11.3 months, Cohort 5: up to 15.9 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 or death, whichever came first. DOR was estimated using the Kaplan-Meier method. Per RECIST v.1.1., CR was defined as disappearance of all target 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. |
| Phase 2 (Dose Expansion): Progression Free Survival (PFS) | Maximum time on study: Cohort 1: up to 31.3 months, Cohort 2: up to 32.0 months, Cohort 4: up to 11.3 months, Cohort 5: up to 15.9 months | Progression free survival was defined as the time from the date of the first dose of study drug(s) to the date of the first documentation of disease progression assessed by investigator or death, whichever occurred first as determined from investigator derived tumor assessments per RECIST 1.1. 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. |
| Phase 1: Maximum Observed Plasma Concentration (Cmax) of Surzebiclimab | Cycle 1 Day 1 and Cycle 5 Day 1 at pre-dose, end of infusion (EOI; within 30 minutes), 6 hours, 1, 3, 7, 14, 21, and 28 (cycle 1 only) days after EOI. Cycle 1 was 28 days and Cycle 5 was 21 days. | The maximum observed plasma concentration of surzebiclimab was measured in Cycle 1 and Cycle 5. |
Countries
Australia, France, Italy, South Korea, Spain, United States
Contacts
STUDY_DIRECTORStudy Director
BeiGene
Participant flow
Pre-assignment details
Based on the interim analysis of Cohorts 1, 2, 4, 5 in dose expansion, sponsor decided not to further investigate the combinations in renal cell carcinoma (RCC) and to not investigate alcestobart (LBL-007), double or triple treatment combination in programmed cell death protein-1 (PD-1) resistant non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC). Hence, Phase 2 (Dose Expansion) Cohorts 3, 6 and 7 were planned, but not initiated based on sponsor's decision.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 64.2 years STANDARD_DEVIATION 9.57 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized Asian | 27 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants |
| Race/Ethnicity, Customized Missing | 3 Participants |
| Race/Ethnicity, Customized More than one race | 0 Participants |
| Race/Ethnicity, Customized Other | 1 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants |
| Race/Ethnicity, Customized White | 98 Participants |
| Sex: Female, Male Female | 57 Participants |
| Sex: Female, Male Male | 13 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 | EG014 affected / at risk | EG015 affected / at risk | EG016 affected / at risk | EG017 affected / at risk | EG018 affected / at risk | EG019 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 1 | 1 / 1 | 0 / 3 | 1 / 5 | 1 / 7 | 2 / 4 | 1 / 7 | 1 / 3 | 1 / 1 | 0 / 1 | 2 / 4 | 3 / 6 | 2 / 6 | 0 / 3 | 3 / 6 | 4 / 6 | 15 / 21 | 11 / 22 | 11 / 20 | 8 / 20 |
| other Total, other adverse events | 1 / 1 | 1 / 1 | 3 / 3 | 4 / 5 | 7 / 7 | 4 / 4 | 7 / 7 | 3 / 3 | 1 / 1 | 1 / 1 | 4 / 4 | 6 / 6 | 6 / 6 | 3 / 3 | 4 / 6 | 6 / 6 | 20 / 21 | 20 / 22 | 20 / 20 | 20 / 20 |
| serious Total, serious adverse events | 1 / 1 | 1 / 1 | 3 / 3 | 2 / 5 | 3 / 7 | 2 / 4 | 1 / 7 | 0 / 3 | 1 / 1 | 1 / 1 | 3 / 4 | 3 / 6 | 4 / 6 | 1 / 3 | 4 / 6 | 3 / 6 | 9 / 21 | 8 / 22 | 6 / 20 | 9 / 20 |
Outcome results
None listed