Advanced Solid Tumors
Conditions
Brief summary
This was an open-label, multicenter, non-randomized Phase 1b clinical trial for participants with histologically or cytologically confirmed locally advanced or metastatic tumors including non-squamous or squamous non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), ovarian cancer (OC), or melanoma.
Detailed description
All participants received sitravatinib 120 mg orally once daily in combination with tislelizumab 200 mg intravenously (IV) once every 3 weeks until occurrence of progressive disease, unacceptable toxicity, death, withdrawal of consent, or study termination by sponsor. Participants were enrolled according to their tumor type and prior anti-programmed cell death protein-1 (PD-1)/PD-L1 antibody treatment into the following cohorts: * Cohort A: Anti-PD-1/PD-L1 antibody refractory/resistant metastatic, non-squamous NSCLC * Cohort B: Anti-PD-1/PD-L1 antibody naïve metastatic, non-squamous NSCLC * Cohort C: Anti-PD-1/PD-L1 antibody refractory/resistant metastatic or advanced RCC * Cohort D: Metastatic or advanced RCC without prior systemic therapy * Cohort E: Anti-PD-1/PD-L1 antibody naïve recurrent and platinum resistant epithelial OC * Cohort F: Anti-PD-1/PD-L1 antibody treated metastatic, squamous NSCLC * Cohort G: Anti-PD-1/PD-L1 antibody refractory/resistant unresectable or metastatic melanoma * Cohort H: PD-L1 positive, locally advanced or metastatic, non-squamous NSCLC without prior systemic treatment in the metastatic setting * Cohort I: PD-L1 positive, locally advanced or metastatic, squamous NSCLC without prior systemic treatment in the metastatic setting
Interventions
DRUGSitravatinib
Administered orally as a capsule
DRUGTislelizumab
Administered intravenously
Sponsors
BeiGene
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Able to provide written informed consent and can understand and agree to comply with the requirements of the study and the Schedule of Assessments 2. Age ≥ 18 years on the day of signing the informed consent form (or the legal age of consent in the jurisdiction in which the study is taking place) 3. At least 1 measurable lesion as defined by RECIST v1.1 4. Provide archival tumor tissue (formalin-fixed paraffin-embedded block \[FFPE\] with tumor tissue or unstained slides), if available. 5. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1 6. Adequate hematologic and end-organ function 7. Participants with inactive/asymptomatic carrier, chronic, or active hepatitis B virus (HBV) must have HBV deoxyribonucleic acid (DNA) \< 500 IU/mL (or 2500 copies/mL) at Screening 8. Females of childbearing potential must be willing to use a highly effective method of birth control for the duration of the study, and ≥ 120 days after the last dose of study drugs and have a negative serum pregnancy test ≤ 7 days of first dose of study drugs 9. Non-sterile males must be willing to use a highly effective method of birth control for the duration of the study and for ≥ 120 days after the last dose of study drugs
Exclusion criteria
1. Unacceptable toxicity on prior anti-PD-1/PD-L1 treatment 2. Active leptomeningeal disease or uncontrolled brain metastasis 3. Active autoimmune diseases or history of autoimmune diseases that may relapse 4. Any active malignancy ≤ 2 years 5. Any condition that required systemic treatment with either corticosteroids (\> 10 mg daily of prednisone or equivalent) or other immunosuppressive medication ≤ 14 days before first dose of study drugs 6. History of interstitial lung disease, noninfectious pneumonitis or uncontrolled diseases, including pulmonary fibrosis, acute lung diseases, etc. 7. Severe chronic or active infections (including tuberculosis infection, etc.) requiring systemic antibacterial, antifungal or antiviral therapy, within 14 days prior to first dose of study drugs 8. Known history of human immunodeficiency virus (HIV) infection 9. Participants with active hepatitis C infection 10. Any major surgical procedure requiring general anesthesia ≤ 28 days before first dose of study drugs 11. Prior allogeneic stem cell transplantation or organ transplantation 12. Hypersensitivity to tislelizumab or sitravatinib, to any ingredient in the formulation, or to any component of the container 13. Bleeding or thrombotic disorders or use of anticoagulants such as warfarin or similar agents requiring therapeutic international normalized ratio (INR) monitoring within 6 months before first dose of study drugs 14. Concurrent participation in another therapeutic clinical trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs) | Up to approximately 4 years and 2 months | Number of participants with treatment-emergent AEs (TEAEs) and serious adverse events (SAEs), which includes laboratory tests, physical exams, electrocardiogram results and vital signs; TEAE was defined as an adverse event that had an onset date or a worsening in severity from baseline (pretreatment) on or after the first dose of study drug(s) up to 30 days following last dose of study drug(s) or initiation of a new anticancer therapy, whichever occurs first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | Up to approximately 4 years and 2 months | ORR is defined as the percentage of participants with confirmed complete response (CR) or partial response (PR) as determined by the investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Efficacy was evaluated by cohort, as pre-specified in the statistical analysis plan. |
| Duration of Response (DOR) | Up to approximately 4 years and 2 months | DOR is defined as the time from the first determination of an objective response until the first documentation of progressive disease, whichever comes first, as assessed by the investigator using RECIST v1.1. Results are reported for cohorts with responders, defined as CR or PR. Efficacy was evaluated by cohort, as pre-specified in the statistical analysis plan. |
| Disease Control Rate (DCR) | Up to approximately 4 years and 2 months | DCR is defined as the percentage of participants with best overall response as CR, PR, or stable disease (SD) as assessed by the investigator using RECIST v1.1. Efficacy was evaluated by cohort, as pre-specified in the statistical analysis plan. |
| Progression-free Survival (PFS) | Up to approximately 4 years and 2 months | PFS is defined as the time from the date of first dose to the date of first documentation of progressive disease or death, whichever comes first, as assessed by the investigator using RECIST v1.1. Efficacy was evaluated by cohort, as pre-specified in the statistical analysis plan. |
| Maximum Plasma Concentration (Cmax) for Sitravatinib | Predose and up to 24 hours post dose on Cycle 1 Day 1 (C1D1) and Cycle 1 Day 21 (C1D21); 21 days per cycle | — |
| Clearance After Oral Administration (CL/F) for Sitravatinib | Predose and up to 24 hours post dose on C1D1 and C1D21; 21 days per cycle | — |
| Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Time Point (AUC(0-t)) for Sitravatinib | Predose and up to 24 hours post dose on C1D1 and C1D21; 21 days per cycle | — |
| Area Under the Plasma Concentration-time Curve During the Dosing Interval (AUC(0-tau)) for Sitravatinib | Predose and up to 24 hours post dose on C1D1 and C1D21; 21 days per cycle | — |
| Observed Accumulation Ratio (Ro) for AUC0-tau for Sitravatinib | Predose and up to 24 hours post dose on C1D1 and C1D21; 21 days per cycle | Presented as geometric mean ratio and confidence interval, transformed from the difference of least square means and confidence interval of the least square differences in the logarithmic scale by exponentiation |
| Observed Accumulation Ratio (Ro) for Cmax for Sitravatinib | Predose and up to 24 hours post dose on C1D1 and C1D21; 21 days per cycle | Presented as geometric mean ratio and confidence interval, transformed from the difference of least square means and confidence interval of the least square differences in the logarithmic scale by exponentiation |
| Time to Maximum Plasma Concentration (Tmax) for Sitravatinib | Predose and up to 24 hours post dose on C1D1 and C1D21; 21 days per cycle | — |
Countries
Australia, China
Participant flow
Recruitment details
This study enrolled participants across study centers in Australia and China.
Participants by arm
| Arm | Count |
|---|---|
| Sitravatinib + Tislelizumab Sitravatinib 120 mg was administered orally once daily in combination with tislelizumab 200 mg IV once every 3 weeks | 216 |
| Total | 216 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 158 |
| Overall Study | Lost to Follow-up | 5 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Progressive Disease | 1 |
| Overall Study | Rolled into extension study | 9 |
| Overall Study | Sponsor Decision | 31 |
| Overall Study | Withdrawal by Subject | 11 |
Baseline characteristics
| Characteristic | Sitravatinib + Tislelizumab |
|---|---|
| Age, Continuous | 60.2 Years STANDARD_DEVIATION 11.03 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 213 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 143 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 70 Participants |
| Sex: Female, Male Female | 103 Participants |
| Sex: Female, Male Male | 113 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 158 / 216 |
| other Total, other adverse events | 213 / 216 |
| serious Total, serious adverse events | 120 / 216 |
Outcome results
Primary
Number of Participants With Adverse Events (AEs)
Number of participants with treatment-emergent AEs (TEAEs) and serious adverse events (SAEs), which includes laboratory tests, physical exams, electrocardiogram results and vital signs; TEAE was defined as an adverse event that had an onset date or a worsening in severity from baseline (pretreatment) on or after the first dose of study drug(s) up to 30 days following last dose of study drug(s) or initiation of a new anticancer therapy, whichever occurs first.
Time frame: Up to approximately 4 years and 2 months
Population: The Safety Analysis Set is defined as all participants who received at least 1 dose of any study drug (any component of the combination therapy)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sitravatinib + Tislelizumab | Number of Participants With Adverse Events (AEs) | At least 1 TEAE | 216 Participants |
| Sitravatinib + Tislelizumab | Number of Participants With Adverse Events (AEs) | At least 1 SAE | 120 Participants |
Secondary
Area Under the Plasma Concentration-time Curve During the Dosing Interval (AUC(0-tau)) for Sitravatinib
Time frame: Predose and up to 24 hours post dose on C1D1 and C1D21; 21 days per cycle
Population: The Sitravatinib PK Analysis Set includes all participants who contributed at least 1 quantifiable PK sample for sitravatinib
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Sitravatinib + Tislelizumab | Area Under the Plasma Concentration-time Curve During the Dosing Interval (AUC(0-tau)) for Sitravatinib | C1D1 | 1050.57 h*ng/mL | Geometric Coefficient of Variation 75.432 |
| Sitravatinib + Tislelizumab | Area Under the Plasma Concentration-time Curve During the Dosing Interval (AUC(0-tau)) for Sitravatinib | C1D21 | 2058.23 h*ng/mL | Geometric Coefficient of Variation 58.47 |
Secondary
Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Time Point (AUC(0-t)) for Sitravatinib
Time frame: Predose and up to 24 hours post dose on C1D1 and C1D21; 21 days per cycle
Population: The Sitravatinib PK Analysis Set includes all participants who contributed at least 1 quantifiable PK sample for sitravatinib
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Sitravatinib + Tislelizumab | Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Time Point (AUC(0-t)) for Sitravatinib | C1D1 | 414.01 h*ng/mL | Geometric Coefficient of Variation 115.833 |
| Sitravatinib + Tislelizumab | Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Time Point (AUC(0-t)) for Sitravatinib | C1D21 | 1539.96 h*ng/mL | Geometric Coefficient of Variation 83.01 |
Secondary
Clearance After Oral Administration (CL/F) for Sitravatinib
Time frame: Predose and up to 24 hours post dose on C1D1 and C1D21; 21 days per cycle
Population: The Sitravatinib PK Analysis Set includes all participants who contributed at least 1 quantifiable PK sample for sitravatinib
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Sitravatinib + Tislelizumab | Clearance After Oral Administration (CL/F) for Sitravatinib | C1D1 | 72.89 Liters/hour | Geometric Coefficient of Variation 148.368 |
| Sitravatinib + Tislelizumab | Clearance After Oral Administration (CL/F) for Sitravatinib | C1D21 | 58.30 Liters/hour | Geometric Coefficient of Variation 58.47 |
Secondary
Disease Control Rate (DCR)
DCR is defined as the percentage of participants with best overall response as CR, PR, or stable disease (SD) as assessed by the investigator using RECIST v1.1. Efficacy was evaluated by cohort, as pre-specified in the statistical analysis plan.
Time frame: Up to approximately 4 years and 2 months
Population: The Efficacy Evaluable Analysis Set consists of all treated participants in the Safety Analysis Set with measurable baseline assessment per RECIST 1.1 who had at least one evaluable post-baseline tumor assessment unless treatment was discontinued due to clinical disease progression or early death (within 13 weeks of the first dose date)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sitravatinib + Tislelizumab | Disease Control Rate (DCR) | Cohort A: NSCLC | 78.3 Percentage of participants |
| Sitravatinib + Tislelizumab | Disease Control Rate (DCR) | Cohort B: NSCLC | 85.7 Percentage of participants |
| Sitravatinib + Tislelizumab | Disease Control Rate (DCR) | Cohort C: RCC | 100.0 Percentage of participants |
| Sitravatinib + Tislelizumab | Disease Control Rate (DCR) | Cohort E: OC | 79.7 Percentage of participants |
| Sitravatinib + Tislelizumab | Disease Control Rate (DCR) | Cohort F: NSCLC | 90.9 Percentage of participants |
| Sitravatinib + Tislelizumab | Disease Control Rate (DCR) | Cohort G: Melanoma | 88.0 Percentage of participants |
| Sitravatinib + Tislelizumab | Disease Control Rate (DCR) | Cohort I: NSCLC | 78.3 Percentage of participants |
| Sitravatinib + Tislelizumab | Disease Control Rate (DCR) | Cohort D: RCC | 100.0 Percentage of participants |
| Sitravatinib + Tislelizumab | Disease Control Rate (DCR) | Cohort H: NSCLC | 85.0 Percentage of participants |
Secondary
Duration of Response (DOR)
DOR is defined as the time from the first determination of an objective response until the first documentation of progressive disease, whichever comes first, as assessed by the investigator using RECIST v1.1. Results are reported for cohorts with responders, defined as CR or PR. Efficacy was evaluated by cohort, as pre-specified in the statistical analysis plan.
Time frame: Up to approximately 4 years and 2 months
Population: The Efficacy Evaluable Analysis Set consists of all treated participants in the Safety Analysis Set with measurable baseline assessment per RECIST 1.1 who had at least one evaluable post-baseline tumor assessment unless treatment was discontinued due to clinical disease progression or early death (within 13 weeks of the first dose date)
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Sitravatinib + Tislelizumab | Duration of Response (DOR) | Cohort A: NSCLC | 3.1 Months |
| Sitravatinib + Tislelizumab | Duration of Response (DOR) | Cohort B: NSCLC | 17.9 Months |
| Sitravatinib + Tislelizumab | Duration of Response (DOR) | Cohort C: RCC | 11.4 Months |
| Sitravatinib + Tislelizumab | Duration of Response (DOR) | Cohort E: OC | 5.6 Months |
| Sitravatinib + Tislelizumab | Duration of Response (DOR) | Cohort F: NSCLC | 6.9 Months |
| Sitravatinib + Tislelizumab | Duration of Response (DOR) | Cohort G: Melanoma | 19.1 Months |
| Sitravatinib + Tislelizumab | Duration of Response (DOR) | Cohort H: NSCLC | 9.7 Months |
| Sitravatinib + Tislelizumab | Duration of Response (DOR) | Cohort I: NSCLC | 8.1 Months |
Secondary
Maximum Plasma Concentration (Cmax) for Sitravatinib
Time frame: Predose and up to 24 hours post dose on Cycle 1 Day 1 (C1D1) and Cycle 1 Day 21 (C1D21); 21 days per cycle
Population: The Sitravatinib Pharmacokinetic (PK) Analysis Set includes all participants who contributed at least 1 quantifiable PK sample for sitravatinib
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Sitravatinib + Tislelizumab | Maximum Plasma Concentration (Cmax) for Sitravatinib | C1D1 | 49.49 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 82.688 |
| Sitravatinib + Tislelizumab | Maximum Plasma Concentration (Cmax) for Sitravatinib | C1D21 | 98.36 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 68.908 |
Secondary
Objective Response Rate (ORR)
ORR is defined as the percentage of participants with confirmed complete response (CR) or partial response (PR) as determined by the investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Efficacy was evaluated by cohort, as pre-specified in the statistical analysis plan.
Time frame: Up to approximately 4 years and 2 months
Population: The Efficacy Evaluable Analysis Set consists of all treated participants in the Safety Analysis Set with measurable baseline assessment per RECIST 1.1 who had at least one evaluable post-baseline tumor assessment unless treatment was discontinued due to clinical disease progression or early death (within 13 weeks of the first dose date)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sitravatinib + Tislelizumab | Objective Response Rate (ORR) | Cohort A: NSCLC | 4.3 Percentage of participants |
| Sitravatinib + Tislelizumab | Objective Response Rate (ORR) | Cohort B: NSCLC | 23.8 Percentage of participants |
| Sitravatinib + Tislelizumab | Objective Response Rate (ORR) | Cohort C: RCC | 66.7 Percentage of participants |
| Sitravatinib + Tislelizumab | Objective Response Rate (ORR) | Cohort D: RCC | 0.0 Percentage of participants |
| Sitravatinib + Tislelizumab | Objective Response Rate (ORR) | Cohort E: OC | 28.8 Percentage of participants |
| Sitravatinib + Tislelizumab | Objective Response Rate (ORR) | Cohort F: NSCLC | 18.2 Percentage of participants |
| Sitravatinib + Tislelizumab | Objective Response Rate (ORR) | Cohort G: Melanoma | 36.0 Percentage of participants |
| Sitravatinib + Tislelizumab | Objective Response Rate (ORR) | Cohort H: NSCLC | 60.0 Percentage of participants |
| Sitravatinib + Tislelizumab | Objective Response Rate (ORR) | Cohort I: NSCLC | 30.4 Percentage of participants |
Secondary
Observed Accumulation Ratio (Ro) for AUC0-tau for Sitravatinib
Presented as geometric mean ratio and confidence interval, transformed from the difference of least square means and confidence interval of the least square differences in the logarithmic scale by exponentiation
Time frame: Predose and up to 24 hours post dose on C1D1 and C1D21; 21 days per cycle
Population: The Sitravatinib PK Analysis Set includes all participants who contributed at least 1 quantifiable PK sample for sitravatinib
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Sitravatinib + Tislelizumab | Observed Accumulation Ratio (Ro) for AUC0-tau for Sitravatinib | 1.83 Ratio |
Secondary
Observed Accumulation Ratio (Ro) for Cmax for Sitravatinib
Presented as geometric mean ratio and confidence interval, transformed from the difference of least square means and confidence interval of the least square differences in the logarithmic scale by exponentiation
Time frame: Predose and up to 24 hours post dose on C1D1 and C1D21; 21 days per cycle
Population: The Sitravatinib PK Analysis Set includes all participants who contributed at least 1 quantifiable PK sample for sitravatinib
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Sitravatinib + Tislelizumab | Observed Accumulation Ratio (Ro) for Cmax for Sitravatinib | 2.23 Ratio |
Secondary
Progression-free Survival (PFS)
PFS is defined as the time from the date of first dose to the date of first documentation of progressive disease or death, whichever comes first, as assessed by the investigator using RECIST v1.1. Efficacy was evaluated by cohort, as pre-specified in the statistical analysis plan.
Time frame: Up to approximately 4 years and 2 months
Population: The Safety Analysis Set for this endpoint is defined as all participants who received at least 1 dose of any study drug (any component of the combination therapy) and who met tumor type criteria per latest protocol amendment
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Sitravatinib + Tislelizumab | Progression-free Survival (PFS) | Cohort A: NSCLC | 4.2 Months |
| Sitravatinib + Tislelizumab | Progression-free Survival (PFS) | Cohort B: NSCLC | 7.0 Months |
| Sitravatinib + Tislelizumab | Progression-free Survival (PFS) | Cohort C: RCC | 15.9 Months |
| Sitravatinib + Tislelizumab | Progression-free Survival (PFS) | Cohort D: RCC | 2.7 Months |
| Sitravatinib + Tislelizumab | Progression-free Survival (PFS) | Cohort E: OC | 4.1 Months |
| Sitravatinib + Tislelizumab | Progression-free Survival (PFS) | Cohort F: NSCLC | 5.3 Months |
| Sitravatinib + Tislelizumab | Progression-free Survival (PFS) | Cohort G: Melanoma | 6.7 Months |
| Sitravatinib + Tislelizumab | Progression-free Survival (PFS) | Cohort H: NSCLC | 10.9 Months |
| Sitravatinib + Tislelizumab | Progression-free Survival (PFS) | Cohort I: NSCLC | 5.4 Months |
Secondary
Time to Maximum Plasma Concentration (Tmax) for Sitravatinib
Time frame: Predose and up to 24 hours post dose on C1D1 and C1D21; 21 days per cycle
Population: The Sitravatinib PK Analysis Set includes all participants who contributed at least 1 quantifiable PK sample for sitravatinib
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Sitravatinib + Tislelizumab | Time to Maximum Plasma Concentration (Tmax) for Sitravatinib | C1D1 | 6.09 Hours (h) |
| Sitravatinib + Tislelizumab | Time to Maximum Plasma Concentration (Tmax) for Sitravatinib | C1D21 | 6.08 Hours (h) |