A Study Investigating the Efficacy and Safety of LBL-007 Plus Tislelizumab in Combination With Bevacizumab Plus Fluoropyrimidine Versus Bevacizumab Plus Fluoropyrimidine in Participants With Unresectable or Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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This is a Phase 1b/2 study to investigate the efficacy and safety of LBL-007 plus Tislelizumab when administered in combination with bevacizumab plus fluoropyrimidine to participants with colorectal cancer.

Official Title
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A Phase 1b/2, Randomized, Open-Label Study Investigating the Efficacy and Safety of LBL-007 Plus Tislelizumab in Combination With Bevacizumab Plus Fluoropyrimidine Versus Bevacizumab Plus Fluoropyrimidine as Maintenance Therapy in Patients With Unresectable or Metastatic Microsatellite Stable/Mismatch Repair Proficient Colorectal Cancer

Conditions
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Unresectable or Metastatic Microsatellite Stable/Mismatch Repair Proficient Colorectal Cancer

Intervention / Treatment
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* Drug: LBL-007
* Drug: LBL-007
* Drug: LBL-007
* Drug: Tislelizumab
* Drug: Tislelizumab
* Drug: Bevacizumab biosimilar
* Drug: Bevacizumab biosimilar
* Drug: Capecitabine
* Drug: 5-Fluorouracil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must have measurable disease as defined per RECIST version 1.1 Has a histologically confirmed colorectal adenocarcinoma with metastatic or unresectable disease (Stage IV as defined by American Joint Committee on Cancer [AJCC] 8th edition) No prior systemic therapy for colorectal cancer (CRC) in the metastatic setting except for the induction treatment of first-line therapy. Note: Local regional treatment performed during induction systemic treatment is allowed Participants who have completed the first-line induction treatment, with an overall response of stable disease or better Exclusion Criteria: Participants whose disease has become resectable at the investigator's discretion during or after induction treatment are not eligible Induction treatment initiated less than 6 months from completion of any prior neoadjuvant or adjuvant chemotherapy or radiotherapy which occurred later Participants who have been treated with anti-epidermal growth factor receptor (EGFR) antibody in the induction treatment Any prior therapy targeting T-cell stimulation or checkpoint pathways Participants with B-raf proto-oncogene, serine/threonine kinase (BRAF)V600E mutations Have locally or centrally confirmed microsatellite instability-high (MSI-H) by polymerase chain reaction (PCR) method or dMMR by immunohistochemistry (IHC) method Note: Other protocol defined criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b: Cohort-1: LBL-007 + tislelizumab + bevacizumab + capecitabine<br>LBL-007 + tislelizumab + bevacizumab + capecitabine | Drug: LBL-007<br>* Low dose intravenously (IV) once every 3 weeks.<br>Drug: Tislelizumab<br>* Low dose IV once every 3 weeks<br>* Other names: BGB-A-317;Drug: Bevacizumab biosimilar<br>* 7.5 mg/kg IV every 3 weeks<br>Drug: Capecitabine<br>* 850 milligrams per square meter (mg/m^2) twice daily orally for 2 weeks, followed by a one-week treatment break every 3 weeks<br>|
| Experimental: Phase 1b: Cohort 1a: LBL-007 + tislelizumab + bevacizumab + capecitabine<br>LBL-007 + tislelizumab + bevacizumab + capecitabine | Drug: LBL-007<br>* Medium dose IV once every 3 weeks<br>Drug: Tislelizumab<br>* Low dose IV once every 3 weeks<br>* Other names: BGB-A-317;Drug: Bevacizumab biosimilar<br>* 7.5 mg/kg IV every 3 weeks<br>Drug: Capecitabine<br>* 850 milligrams per square meter (mg/m^2) twice daily orally for 2 weeks, followed by a one-week treatment break every 3 weeks<br>|
| Experimental: Phase 1b: Cohort 2: LBL-007 + tislelizumab + bevacizumab + fluoropyrimidine<br>LBL-007 + tislelizumab (low dose every 3 weeks or high dose every 4 weeks) + bevacizumab (7.5 mg/kg once every 2 weeks or 5 mg/kg once every 3 weeks)+ fluoropyrimidine (5-FU or capecitabine) | Drug: LBL-007<br>* High dose IV once every 2 or 3 weeks<br>Drug: Tislelizumab<br>* Low dose IV once every 3 weeks<br>* Other names: BGB-A-317;Drug: Tislelizumab<br>* High dose IV once every 4 weeks<br>* Other names: BGB-A-317;Drug: Bevacizumab biosimilar<br>* 7.5 mg/kg IV every 3 weeks<br>Drug: Bevacizumab biosimilar<br>* 5 mg/kg IV once every 2 weeks<br>Drug: Capecitabine<br>* 850 milligrams per square meter (mg/m^2) twice daily orally for 2 weeks, followed by a one-week treatment break every 3 weeks<br>Drug: 5-Fluorouracil<br>* 1600 to 2400 mg/m^2 IV every 2 weeks<br>|
| Experimental: Phase 2: Arm A and Arm D: LBL-007 + tislelizumab + bevacizumab + fluoropyrimidine<br>LBL-007 + tislelizumab (low dose every 3 weeks or high dose every 4 weeks) + bevacizumab (7.5 mg/kg once every 2 weeks or 5 mg/kg once every 3 weeks) + fluoropyrimidine (5-FU or capecitabine) | Drug: LBL-007<br>* High dose IV once every 2 or 3 weeks<br>Drug: Tislelizumab<br>* Low dose IV once every 3 weeks<br>* Other names: BGB-A-317;Drug: Tislelizumab<br>* High dose IV once every 4 weeks<br>* Other names: BGB-A-317;Drug: Bevacizumab biosimilar<br>* 7.5 mg/kg IV every 3 weeks<br>Drug: Bevacizumab biosimilar<br>* 5 mg/kg IV once every 2 weeks<br>Drug: Capecitabine<br>* 850 milligrams per square meter (mg/m^2) twice daily orally for 2 weeks, followed by a one-week treatment break every 3 weeks<br>Drug: 5-Fluorouracil<br>* 1600 to 2400 mg/m^2 IV every 2 weeks<br>|
| Experimental: Phase 2: Arm B: LBL-007 + bevacizumab + fluoropyrimidine<br>LBL-007 + bevacizumab (7.5 mg/kgonce every 2 weeks or 5 mg/kg once every 3 weeks) + fluoropyrimidine (5-FU or capecitabine) | Drug: LBL-007<br>* High dose IV once every 2 or 3 weeks<br>Drug: Bevacizumab biosimilar<br>* 7.5 mg/kg IV every 3 weeks<br>Drug: Bevacizumab biosimilar<br>* 5 mg/kg IV once every 2 weeks<br>Drug: Capecitabine<br>* 850 milligrams per square meter (mg/m^2) twice daily orally for 2 weeks, followed by a one-week treatment break every 3 weeks<br>Drug: 5-Fluorouracil<br>* 1600 to 2400 mg/m^2 IV every 2 weeks<br>|
| Other: Phase 2: Arm C and Arm E: bevacizumab + fluoropyrimidine<br>bevacizumab (7.5 mg/kg once every 2 weeks or 5 mg/kg once every 3 weeks) + fluoropyrimidine (5-FU or capecitabine) | Drug: Bevacizumab biosimilar<br>* 7.5 mg/kg IV every 3 weeks<br>Drug: Bevacizumab biosimilar<br>* 5 mg/kg IV once every 2 weeks<br>Drug: Capecitabine<br>* 850 milligrams per square meter (mg/m^2) twice daily orally for 2 weeks, followed by a one-week treatment break every 3 weeks<br>Drug: 5-Fluorouracil<br>* 1600 to 2400 mg/m^2 IV every 2 weeks<br>|
| Experimental: Phase 1b: Cohort 1b: LBL-007 + Tislelizumab + Bevacizumab + 5- Flurouracil (5-FU)<br>LBL-007 + Tislelizumab + Bevacizumab + 5- Flurouracil | Drug: LBL-007<br>* Medium dose IV once every 3 weeks<br>Drug: Tislelizumab<br>* High dose IV once every 4 weeks<br>* Other names: BGB-A-317;Drug: Bevacizumab biosimilar<br>* 5 mg/kg IV once every 2 weeks<br>Drug: 5-Fluorouracil<br>* 1600 to 2400 mg/m^2 IV every 2 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: Number of participants with Adverse events (AE) and Serious AEs (SAE) | AEs and SAE are characterized by type, frequency, severity (as graded by National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 [NCI-CTCAE v5.0]) | First Cycle of treatment (21 days) | 
| Phase 2: Progression Free Survival (PFS) as Assessed by The Investigator in PD-L1 Positive Arms A and C | PFS, as assessed by the investigator per RECIST v1.1 is defined as the time from the date of randomization to the date of first documentation of disease progression or death, whichever occurs first | Approximately 44 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2: Overall Survival (OS) as Assessed by The Investigator in PD-L1 Positive Arms A and C and PD-L1 Negative Arms D and E | OS is defined as the time from the date of randomization until the date of death from any cause. | Approximately 44 months | 
| Phase 2: PFS 2 as Assessed by The Investigator in PD-L1 Positive Arms A and C and PD-L1 Negative Arms D and E | PFS2 is defined as the time from the date of randomization to the date of documentation of disease progression in second-line treatment, or death, whichever occurs first | Approximately 44 months | 
| Phase 2: Objective Response rate (ORR) as Assessed by The Investigator in PD-L1 Positive Arms A and C and PD-L1 Negative Arms D and E | ORR is defined as the proportion of participants with a confirmed complete response (CR) or partial response (PR) from the time of randomization | Approximately 44 months | 
| Phase 2: Duration of response (DOR) as Assessed by The Investigator in PD-L1 Positive Arms A and C and PD-L1 Negative arms D and E | DOR is defined as the time from the first confirmed objective response after randomization until the first documentation of disease progression or death, whichever comes first | Approximately 44 months | 
| Phase 2: Progression Free Survival (PFS) as Assessed by The Investigator in PD-L1 Negative Arms D and E | PFS, as assessed by the investigator per RECIST v1.1 is defined as the time from the date of randomization to the date of first documentation of disease progression or death, whichever occurs first | Approximately 44 months | 
| Phase 2: Progression Free Survival (PFS) as Assessed by The Investigator in Arms A + D and Arms C + E Regardless of PD-L1 Expression | PFS, as assessed by the investigator per RECIST v1.1 is defined as the time from the date of randomization to the date of first documentation of disease progression or death, whichever occurs first | Approximately 44 months | 
| Phase 2: Overall Survival (OS) as Assessed by The Investigator in Arms A + D and Arms C + E Regardless of PD-L1 Expression | OS is defined as the time from the date of randomization until the date of death from any cause. | Approximately 44 months | 
| Phase 2: PFS 2 as Assessed by The Investigator in Arms A + D and Arms C + E Regardless of PD-L1 Expression | PFS, as assessed by the investigator per RECIST v1.1 is defined as the time from the date of randomization to the date of first documentation of disease progression or death, whichever occurs first | Approximately 44 months | 
| Phase 2: Objective Response rate (ORR) as Assessed by The Investigator in Arms A + D and Arms C + E Regardless of PD-L1 Expression | ORR is defined as the proportion of participants with a confirmed complete response (CR) or partial response (PR) from the time of randomization | Approximately 44 months | 
| Phase 2: DOR as Assessed by The Investigator in Arms A + D and Arms C + E Regardless of PD-L1 Expression | DOR is defined as the time from the first confirmed objective response after randomization until the first documentation of disease progression or death, whichever comes first | Approximately 44 months | 
| Phase 2 : Number of participants with Adverse events (AE) and Serious AEs (SAE) | AEs and SAE are characterized by type, frequency, severity as graded by NCI-CTCAE v5.0 | Up to last dose + 30 days (Approximately 44 months) | 
| Phase 1b: Maximum Concentration (Cmax) of LBL-007 |  | Cycle 1 Day 1 (C1D1) Predose, End of Infusion (EOI) 6 hours (h), C1D2, C1D4, C1D8, and C1D15, C2 to C25 D1 Predose and EOI (each cycle 21 days) | 
| Phase 1b: Time to achieve Maximum Concentration (Tmax) of LBL-007 |  | Cycle 1 Day 1 (C1D1) Predose, End of Infusion (EOI) 6 hours (h), C1D2, C1D4, C1D8, and C1D15, C2 to C25 D1 Predose and EOI (each cycle 21 days) | 
| Phase 1b: Area Under the Concentration Curve from Day 0 to Day 21(AUC 0-21) |  | Cycle 1 Day 1 (C1D1) Predose, End of Infusion (EOI) 6 hours (h), C1D2, C1D4, C1D8, and C1D15, C2 to C25 D1 Predose and EOI (each cycle 21 days) | 
| Phase 1b: Mean Half Life (t1/2) of LBL-007 |  | Cycle 1 Day 1 (C1D1) Predose, End of Infusion (EOI) 6 hours (h), C1D2, C1D4, C1D8, and C1D15, C2 to C25 D1 Predose and EOI (each cycle 21 days) | 
| Phase 1b: Clearance (CL) of LBL-007 |  | Cycle 1 Day 1 (C1D1) Predose, End of Infusion (EOI) 6 hours (h), C1D2, C1D4, C1D8, and C1D15, C2 to C25 D1 Predose and EOI (each cycle 21 days) | 
| Phase 1b: Apparent Volume of Distribution (Vz) of LBL-007 |  | Cycle 1 Day 1 (C1D1) Predose, End of Infusion (EOI) 6 hours (h), C1D2, C1D4, C1D8, and C1D15, C2 to C25 D1 Predose and EOI (each cycle 21 days) | 
| Phase 2: Cmax of LBL-007, Tislelizumab, and Bevacizumab |  | Up to approximately 27 months (predose at cycle 1,2,5,9,17, safety follow-up (each cycle 21 days)) | 
| Phase 2: Cmin of LBL-007, Tislelizumab, and Bevacizumab |  | Cycle 1 Day 1 (C1D1) Predose, End of Infusion (EOI) 6 hours (h), C1D2, C1D4, C1D8, and C1D15, C2 to C25 D1 Predose and EOI (each cycle 21 days) | 
| Number of Participants with anti-drug antibodies (ADAs) to Tislelizumab, and Bevacizumab in Arm A, Arm B and Arm D |  | Up to approximately 27 months (predose at cycle 1,2,5,9,17, safety follow-up, and EOI at cycle 1 and 5 (each cycle 21 days)) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Colorectal Cancer, Microsatellite Stable, Mismatch Repair Proficient, Maintenance Therapy