Study of Ociperlimab (BGB-A1217) in Combination With Tislelizumab in Advanced Solid Tumors

BeiGene446 enrolled

Overview

The primary objectives of this study were: to assess the safety and tolerability, to determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) and to determine the recommended Phase 2 dose (RP2D) of BGB-A1217 (known as ociperlimab) in combination with tislelizumab in participants with advanced solid tumors in phase 1. Primary objective of Phase 1b was to assess overall response rate (ORR) determined by Investigator per Response Evaluation Criteria in Solid Tumors (RECIST) version (v).1.1 for patients in each dose-expansion cohort.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

446

Conditions

Locally Advanced and Metastatic Solid Tumors

Interventions

OciperlimabDRUG

Administered as an intravenous (IV) injection

TislelizumabDRUG

Administered as an IV injection

PemetrexedDRUG

Administered in accordance with local guidelines, prescribing information/summary of product

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Key Inclusion Criteria: Phase 1 Key Inclusion Criteria 1. Had Eastern Cooperative Oncology Group (ECOG) Performance Status less than or equal to (\<=) 1. 2. Greater than or equal to (\>=) measurable lesion per RECIST v1.1. 3. Had adequate organ function. 4. Phase 1- Participants with histologically or cytologically confirmed advanced, metastatic, unresectable solid tumors who had previously received standard systemic therapy or for which treatment is not available, not tolerated or refused. Phase 1b Key Inclusion Criteria 1. Signed informed consent form (ICF) and able to comply with study requirements. 2. Age \>= 18 years (or the legal age of consent) at the time the ICF was signed. 3. Histologically or cytologically confirmed tumor types in the following disease cohorts: Cohort 1: stage IV squamous NSCLC Cohort 2: stage IV non-squamous NSCLC Cohort 3: stage IV squamous or non-squamous NSCLC with PD-L1 positive. Cohort 4: extensive-stage SCLC Cohort 5: stage IIIB, IIIC or IV NSCLC Cohort 6: stage IV ESCC Cohort 7: stage IV EAC Cohort 8: recurrent or metastatic HNSCC incurable by local therapies Cohort 9: stage IV G/GEJ adenocarcinoma. Cohort 10: stage IV squamous or non-squamous NSCLC with PD-L1 positive. 4. ECOG Performance Status \<= 1 5. Adequate organ function 6. Were willing to use highly effective method of birth control Phase 1 Key Exclusion Criteria: 1. Active brain or leptomeningeal metastasis. 2. Active autoimmune diseases or history of autoimmune diseases that could have relapsed. 3. Had severe chronic or active infections requiring systemic antibacterial, antifungal or antiviral therapy, including tuberculosis infection, etc. (antiviral therapy is permitted for patients with hepatocellular carcinoma). 4. Concurrent participation in another therapeutic clinical trial. 5. Received prior therapies targeting TIGIT. Phase 1b Key Exclusion Criteria: 1. Participants with any prior therapy for recurrent/metastatic disease. 2. Non-squamous NSCLC patients with sensitizing epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK) fusion, and c-ros oncogene 1 (ROS1) fusion. 3. Gastric cancer participants with squamous or with positive HER2 expression. 4. Prior therapy with any drug specifically targeting T-cell co-stimulation or checkpoint pathways. (anti-PD(L)1 exception for Cohort 5). 5. Active leptomeningeal disease or uncontrolled brain metastasis. 6. Active autoimmune diseases or history of autoimmune diseases that may relapse. 7. With severe chronic or active infections requiring systemic antibacterial, antifungal or antiviral therapy, including tuberculosis infection, etc. (antiviral therapy is permitted for participants with hepatocellular carcinoma). 8. Concurrent participation in another therapeutic clinical study. NOTE: Other protocol-defined Inclusion/Exclusion criteria may apply.

Locations (65)

Outcomes

Primary Outcomes

Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)

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. A serious adverse event (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. Treatment-emergent adverse event (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 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.

Time frame: Up to 30 days after the last dose of study interventions (up to 35.7 months [Dose escalation cohorts] and up to 13.3 months [Dose verification cohorts])

Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs)

The DLTs were defined as high grade (Grade 3 or 4) non-hematologic toxicities (that is, \>= Grade 4 toxicity; Grade 3 toxicity that is clinically significant and does not resolve to baseline or \<=Grade 1 within 7 days of initiating optimal supportive care), or hematologic toxicities (Grade 4 neutropenia lasting \> 7 days; \>=Grade 3 febrile neutropenia; Grade 3 thrombocytopenia with clinically significant bleeding; Grade 4 thrombocytopenia lasting \> 7 days; \>=Grade 4 anemia occurring during the DLT assessment window and considered by the investigator to be related to ociperlimab and/or tislelizumab.

Time frame: Up to 28 days (for Dose escalation cohorts) and up to 21 days (for Dose verification cohorts)

Phase 1: Maximum Administered Dose (MAD) of Ociperlimab in Combination With Tislelizumab

MAD was defined as the highest dose of ociperlimab administered.

Time frame: Up to 28 days (Dose escalation cohort)

Data from ClinicalTrials.gov

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Secondary Outcomes

Phase 1: ORR as Per RECIST v.1.1

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. 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.

Time frame: Maximum time duration on study: up to 35.7 months (Dose escalation cohorts) and up to 13.3 months (Dose verification cohorts)

Phase 1: Duration of Response (DOR) as Per RECIST v.1.1

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. 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.

Time frame: From the first determination of an overall response until PD or death, whichever came first (Maximum time duration on study: up to 35.7 months [Dose escalation cohorts] and up to 13.3 months [Dose verification cohorts])

Phase 1: Disease Control Rate (DCR) as Per RECIST v.1.1

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. 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.

Phase 1 (Dose Escalation): Serum Concentrations of Ociperlimab

Serum concentrations of ociperlimab were measured. Post-dose refers to the data collected for 30 minutes post-infusion. "C" in the timeframe below refers to "Cycle" and D refers to "Day" and "h" refers to "hours".

Time frame: C1D1 (pre and post dose; 24 hours (h) 72h, 168h and 336 h post-dose), C2D1 (pre- and post-dose), C5D1 (pre and post dose,168h and 336 h post-dose), C6D1 (pre and post-dose), pre-dose on C9D1,C13D1,C17D1,C25D1 (Cycle 1= 28 days; Cycle 2 onwards= 21 days)

Phase 1 (Dose Escalation): Serum Concentrations of Tislelizumab

Serum Concentrations of Tislelizumab was determined. Post-dose refers to the data collected for 30 minutes post-infusion.

Time frame: Cycle 1, Day 8 (pre-dose), Cycle 1, Day 8 (post-dose), Cycle 2, Day 1 (pre-dose), Cycle 5 Day 1 (pre-dose), Cycle 5 Day 1 (post-dose), pre-dose of Cycle 6 Day 1, Cycle 9 Day 1, Cycle 13 Day 1, Cycle 17 Day 1, Cycle 25 Day 1 (each cycle = 21 days)

Phase 1 (Dose Verification): Serum Concentrations of Ociperlimab

Serum concentration of ociperlimab was determined. Post-dose refers to the data collected for 30 minutes post-infusion. "C" in the timeframe below refers to "Cycle" and D refers to "Day" and "h" refers to "hours".

Time frame: Pre-dose, post-dose, 24 h,72 h,168 h,336 h post-dose C1D1, Pre-dose, post-dose on C2D1, Pre-dose, post-dose,168 h, 336 h post-dose on C5D1, Pre-dose, post-dose on C6D1, pre-dose C9D1 and C13D1 (each cycle = 21 days)

Phase 1 (Dose Verification): Serum Concentrations of Tislelizumab

Serum concentrations of tislelizumab were determined. Post-dose refers to the data collected for 30 minutes post-infusion.

Time frame: Cycle 1 Day 1 (pre-dose), Cycle 1 Day 1 (post-dose), Cycle 2 Day 1 (pre-dose), Cycle 5 Day 1 (pre-dose), Cycle 5 Day 1 (post-dose), Cycle 6 Day 1 (pre-dose), Cycle 9 Day 1 (pre-dose), Cycle 13 Day 1 (pre-dose) (each cycle = 21 days)

Phase 1: Number of Participants With Immunogenic Response to Ociperlimab and Tislelizumab

Immunogenic responses to ociperlimab and tislelizumab 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.

Time frame: Up to 32.2 months (Dose escalation cohorts) and up to 11 months (Dose verification cohorts)

Phase 1b: DOR as Per RECIST v.1.1

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.

Time frame: From the first determination of an overall response until PD or death, whichever came first (Maximum time duration on study: Up to 41.6 months [Cohorts 1 to 9] and up to 21.4 months [Cohort 10])

Phase 1b: DCR as Per RECIST v.1.1

DCR was defined as the percentage of participants with BOR, as per RECIST v.1.1, of a CR, PR, or SD. 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 \< 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 was defined as 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 1b: Progression Free Survival (PFS) as Per RECIST v.1.1

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. 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.

Time frame: From first dose of study drugs to the date of the first documentation of PD or death, whichever came first (Maximum time duration on study: up to 41.6 months [Cohorts 1 to 9] and up to 21.4 months [Cohort 10])

Phase 1b (Cohorts 1-10): Number of Participants With TEAEs and TESAEs

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.

Time frame: Up to 30 days after the last dose of study interventions (Maximum time duration on study: up to 41.6 months [Cohorts 1 to 9] and up to 21.4 months [Cohort 10])

Phase 1b (Cohort 1-9): Serum Concentrations of Ociperlimab

Serum concentrations of ociperlimab were determined. Post-dose refers to the data collected for 30 minutes post-infusion.

Time frame: Cycle 1 Day 1 (pre-dose), Cycle 1 Day 1 (post-dose), Cycle 2 Day 1 (pre-dose), Cycle 5 Day 1 (pre-dose and post-dose), pre-dose on Cycle 6 Day 1, Cycle 9 Day 1, Cycle 13 Day 1, Cycle 17 Day 1 and Cycle 25 Day 1 (each cycle = 21 days)

Phase 1b (Cohort 1-9): Serum Concentrations of Tislelizumab

Serum concentrations of tislelizumab were determined. Post-dose refers to the data collected for 30 minutes post-infusion.

Time frame: Cycle 1 Day 1 (pre-dose and post-dose), Cycle 2 Day 1 (pre-dose), Cycle 5 Day 1 (pre-dose and post-dose), pre-dose on Cycle 6 Day 1, Cycle 9 Day 1, Cycle 13 Day 1, Cycle 17 Day 1 and Cycle 25 Day 1 (each cycle = 21 days)

Phase 1b (Cohort 10): Serum Concentrations of Ociperlimab

Serum concentrations of ociperlimab were determined. Post-dose refers to the data collected for 30 minutes post-infusion and 'h' in the time-frame section refers to hours.

Time frame: Pre-dose, post-dose, 168 h, 336 h post-dose Cycle1 Day 1, Pre-dose on Cycle 2 Day 1, Pre-dose, post-dose (30 min) on Cycle 5 Day 1, Pre-dose on Cycle 6 Day 1, Cycle 9 Day 1, Cycle 13 Day 1, Cycle 17 Day 1, and Cycle 25 Day 1 (each cycle = 21 days)

Phase 1b (Cohort 10): Serum Concentrations of Tislelizumab

Serum concentrations of tislelizumab were determined. Post-dose refers to the data collected for 30 minutes post-infusion.

Time frame: Cycle 1 Day 1 (pre-dose and post-dose, Cycle 2 Day 1 (pre-dose), Cycle 5 Day 1 (pre-dose and post-dose), pre-dose of Cycle 6 Day 1, Cycle 9 Day 1, Cycle 13 Day 1, Cycle 17 Day 1 and Cycle 25 Day 1 (each cycle = 21 days)

Phase 1b (Cohort 1-10): Number of Participants With Immunogenic Response to Ociperlimab and Tislelizumab

Immunogenic responses to ociperlimab and 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.

Time frame: Up to 34.4 months (Cohorts 1 to 9) and up to 20.8 months (Cohort 10)

Phase 1b (Cohort 1-10): Percentage of Participants With ORR: TIGIT Biomarkers Expression

Archival or fresh tumor samples were collected for analysis of biomarkers for T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) and PD-L1 expression. The TIGIT expression on immune cells (IC) and the classification thresholds were different for various cohorts. For Cohort 4, TIGIT IC was categorized as \<1% or \>=1%; for Cohorts 1, 2, 3, 5, 6, 8, 9 and 10, TIGIT IC was categorized as \<5% or \>=5%. ORR is reported for each TIGIT subgroup as relevant in each cohort. Biomarker data were not analyzed and reported for participants in Cohort 7.

Time frame: Maximum time duration on study: up to 41.6 months (Cohorts 1 to 9) and up to 21.4 months (Cohort 10)

Phase 1b (Cohort 1-10): Percentage of Participants With ORR: PD-L1 Biomarkers Expression

Archival or fresh tumor samples were collected for analysis of biomarkers for T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) and PD-L1 expression. The PD-L1 expression scoring algorithm and the classification thresholds were also different for various cohorts as follows: For Cohort 1 and Cohort 2, PD-L1 TC \<1% or \>= 1%; for Cohorts 3, 5, and 10, PD-L1 TC \< 50% or \>=50%; for Cohort 4, PD-L1 tumor area positivity (TAP) \<1% or \>=1%; for Cohort 9, PD-L1 TAP \< 5% or \>= 5%; for Cohort 6 and 8, PD-L1 TAP \<10% or \>=10%. ORR is reported for each PD-L1 subgroup as relevant in each cohort. Biomarker data were not analyzed and reported for participants in Cohort 7.

Time frame: Maximum time duration on study: up to 41.6 months (Cohorts 1 to 9) and up to 21.4 months (Cohort 10)

Phase 1b (Cohort 1-10): PFS in TIGIT Biomarkers Expression

Archival or fresh tumor samples were collected for analysis of biomarkers for T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) and PD-L1 expression. The TIGIT expression on immune cells and the classification thresholds were different for various cohorts. For Cohort 4, TIGIT IC was categorized as \<1% or \>=1%; for Cohorts 1, 2, 3, 5, 6, 8, 9 and 10, TIGIT IC was categorized as \<5% or \>=5%. Median PFS (mPFS) is reported for each TIGIT subgroup as relevant in each cohort. Biomarker data were not analyzed and reported for participants in Cohort 7.

Time frame: Maximum time duration on study: up to 41.6 months (Cohorts 1 to 9) and up to 21.4 months (Cohort 10)

Phase 1b (Cohort 1-10): PFS in PD-L1 Biomarkers Expression

Archival or fresh tumor samples were collected for analysis of biomarkers for T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) and PD-L1 expression. The PD-L1 expression scoring algorithm and the classification thresholds were also different for various cohorts as follows: For Cohort 1 and Cohort 2, PD-L1 TC \<1% or \>= 1%; for Cohorts 3, 5, and 10, PD-L1 TC \< 50% or \>=50%; for Cohort 4, PD-L1 tumor area positivity (TAP) \<1% or \>=1%; for Cohort 9, PD-L1 TAP \< 5% or \>= 5%; for Cohort 6 and 8, PD-L1 TAP \<10% or \>=10%. mPFS is reported for each PD-L1 subgroup as relevant in each cohort. Biomarker data were not analyzed and reported for participants in Cohort 7.

Time frame: Maximum time duration on study: up to 41.6 months (Cohorts 1 to 9) and up to 21.4 months (Cohort 10)