Tislelizumab in Combination With Bevacizumab and Capecitabine in Advanced Solid Tumors With Evaluation in Immunotherapy-Resistant and Central Nervous System Disease (TIBEC)

Phase Ib/II Study of Tislelizumab in Combination With Bevacizumab and Capecitabine in Advanced Solid Tumors With Evaluation in Immunotherapy-Resistant and Central Nervous System Disease (TIBEC)

This study is designed to establish the safety of the combination of PD-1 inhibitor tislelizumab, an anti-angiogenic agent bevacizumab and a chemotherapeutic agent capecitabine, in a phase Ib setting and to evaluate preliminary efficacy in selected expansion cohorts, including PD-L1-negative metastatic triple negative breast cancer (TNBC) and patients with active CNS disease. A sequential approach to cohort expansion will allow further evaluation in hormone receptor positive (HR+), HER2 negative (HER2-) disease if a signal of activity is observed in PD-L1 negative TNBC.

Study Overview

• Status: Not yet recruiting
• Conditions: Breast Cancer; CNS Disease; Advanced Solid Tumor Cancer; Triple-Negative Breast Cancer (TNBC)
• Intervention / Treatment: Drug: Tislelizumab + Bevacizumab + Capecitabine

• Study Type: Interventional
• Enrollment (Estimated): 154
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Soo Chin Lee; Phone Number: +6567724621; Email: soo_chin_lee@nuhs.edu.sg

Study Locations

• Singapore
  • Singapore, Singapore
    • National University Cancer Institute, Singapore, National University Health System
    • Contact: Soo Chin Lee; Phone Number: +6567724621; Email: soo_chin_lee@nuhs.edu.sg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Patients are eligible for enrolment if they meet all applicable general inclusion criteria and, where relevant, the cohort-specific inclusion criteria.

1. General Inclusion Criteria

   • Age 21 years or older at the time of informed consent.
   • Histologically or cytologically confirmed advanced or metastatic solid tumor.
   • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
   • Estimated life expectancy of at least 12 weeks.
   • At least one evaluable (measurable or non-measurable) lesion as defined by RECIST version 1.1, unless otherwise specified for a disease-specific cohort.
   • Recovery to Grade 1 or baseline from acute toxicities of prior anti-cancer therapy, except for alopecia, vitiligo, or other toxicities deemed not clinically significant by the investigator.

   • Adequate organ and marrow function within 14 days prior to first dose of study treatment, defined as follows:

     1. Absolute neutrophil count ≥1.5 × 10^9/L
     2. Platelet count ≥100 × 10^9/L
     3. Haemoglobin ≥9.0 g/dL
     4. Total bilirubin <1.5 × upper limit of normal, except in patients with known Gilbert's syndrome, in whom total bilirubin up to 3.0 × upper limit of normal is permitted provided direct bilirubin is within normal limits
     5. AST and ALT <2.5 × upper limit of normal, or <5 × upper limit of normal in the presence of liver metastases
     6. Calculated creatinine clearance ≥50 mL/min (calculated using the Cockcroft-Gault formula)
     7. Urine protein dipstick <2+, or if urine dipstick is 2+ or greater, 24-hour urine protein <1 g per 24 hours
   • Adequately controlled blood pressure (systolic <150mmHg, diastolic <100mmHg) with or without anti-hypertensive medication.
   • Able to swallow and retain oral medication.
   • Able to understand and willing to sign written informed consent.
   • Willing and able to comply with study visits, treatment plan, laboratory tests, imaging, and other protocol-required procedures.
   • Prior exposure to immune checkpoint inhibitors, anti-angiogenic therapy, or fluoropyrimidines is permitted, unless prohibited by cohort-specific criteria.

2. TNBC Cohort Inclusion Criteria

   • Histologically confirmed triple-negative breast cancer, defined as estrogen receptor <1%, progesterone receptor <1%, and HER2-negative according to current ASCO/CAP guidelines.
   • Metastatic or unresectable locally advanced disease not amenable to curative treatment.
   • PD-L1-negative disease, defined as combined positive score (CPS) <10 using an approved assay.
   • Candidate for first-line systemic therapy for metastatic disease.
   • Patients must have measurable or non-measurable but evaluable disease per RECIST v1.1.
   • Patients without measurable disease may be enrolled provided they have unequivocal non-measurable disease that can be adequately assessed or disease status on serial radiologic evaluations, in the opinion of the investigator.
   • Prior neoadjuvant or adjuvant chemotherapy is permitted.
   • Prior immune checkpoint inhibitor therapy in the neoadjuvant or adjuvant setting is permitted, provided it was completed at least 12 months prior to start of study treatment.
   • Prior capecitabine is permitted only in the adjuvant setting, provided it was completed at least 12 months prior to start of study treatment.
   • Patients with prior CNS disease are eligible only if CNS disease is clinically controlled, defined as asymptomatic or minimally symptomatic, does not require corticosteroids and does not require ongoing CNS-directed therapy.

3. CNS Cohort Inclusion Criteria

   • Histologically or cytologically confirmed advanced solid tumor.
   • Progressive brain metastases.
   • At least one measurable CNS lesion.
   • Leptomeningeal disease is allowed.
   • Patients receiving corticosteroids for management of CNS disease or CNS-related symptoms are eligible provided the corticosteroid dose is stable or decreasing for at least 7 days prior to first dose of study treatment.
   • Patients with driver mutations (e.g., EGFR-mutant or ALK-rearranged NSCLC, HER2+ metastatic breast cancer) must have received at least one prior line of matched systemic therapy, unless such therapy is contraindicated, not tolerated, unavailable, or the patient is otherwise unsuitable in the investigator's judgment.

4. HR-Positive/HER2-Negative Cohort Inclusion Criteria

   • Histologically confirmed hormone receptor-positive (defined as ER>1% or PR>1%), HER2-negative metastatic or unresectable locally advanced breast cancer not amenable to curative treatment.
   • Patients must have measurable or non-measurable but evaluable disease per RECIST v1.1.
   • Patients without measurable disease may be enrolled provided they have unequivocal non-measurable disease that can be adequately assessed or disease status on serial radiologic evaluations, in the opinion of the investigator.
   • Prior failure of at least one line of endocrine therapy in the advanced or metastatic setting, unless deemed endocrine-resistant in the opinion of the investigator.
   • Up to one prior line of palliative chemotherapy is permitted.
   • If prior capecitabine was given, it must not have been administered in the metastatic setting and must have been completed >12 months prior to study entry.
   • Any CNS disease must be clinically controlled, defined as asymptomatic or minimally symptomatic, must not require corticosteroids, and must not require ongoing CNS-directed therapy.

Exclusion Criteria:

Patients will be excluded if they meet any applicable general exclusion criterion or any relevant cohort-specific exclusion criterion.

1. General Exclusion Criteria

   • Treatment with an investigational agent within 14 days prior to first dose of study treatment.
   • Known hypersensitivity or contraindication to tislelizumab, bevacizumab, capecitabine, fluoropyrimidines, or any excipients of the study drugs.
   • Known clinically significant dihydropyrimidine dehydrogenase deficiency.
   • Uncontrolled or clinically unstable CNS disease, including poor performance status attributable to CNS disease, ongoing requirement for escalating corticosteroids, uncontrolled seizures, or rapid neurologic deterioration.
   • Clinically significant cardiovascular disease, including uncontrolled hypertension, unstable angina, clinically significant arrhythmia, myocardial infarction, or stroke that is of clinical concern in the opinion of the investigator.
   • Significant bleeding risk or recent clinically significant hemorrhage.
   • History of gastrointestinal perforation, fistula, or intra-abdominal abscess within 6 months prior to first dose, or other conditions conferring high risk in the opinion of the investigator.
   • Non-healing wound, active ulcer, or untreated fracture.
   • Active infection requiring systemic therapy.
   • Active autoimmune disease requiring systemic immunosuppressive treatment within the past 2 years, with exceptions such as replacement therapy or other conditions judged unlikely to recur.
   • Current use of systemic immunosuppressive medication, excluding physiologic corticosteroid replacement or other permitted low-dose steroids.
   • Active pneumonitis or interstitial lung disease requiring treatment, or other clinically significant pulmonary condition that, in the opinion of the investigator, would increase the risk of study treatment.
   • Other active malignancy requiring treatment or likely to interfere with assessment of study endpoints, in the opinion of the investigator.
   • Pregnancy or breastfeeding.
   • Any serious medical, psychiatric, or social condition that, in the opinion of the investigator, would compromise patient safety, interfere with study participation, or confound interpretation of study results.

2. TNBC Cohort Exclusion Criteria

   • Prior systemic therapy for metastatic TNBC.
   • Prior capecitabine in the metastatic setting.
   • Progressive CNS disease. Patients with progressive CNS disease should be enrolled into the CNS cohort instead.

3. CNS Cohort Exclusion Criteria

   • Severely symptomatic or clinically unstable CNS disease, including rapid neurologic deterioration, uncontrolled seizures, or requirement for rapidly escalating corticosteroids.
   • CNS disease requiring immediate neurosurgical intervention or urgent radiation therapy, in the opinion of the investigator.
   • Stereotactic radiosurgery (SRS) including gamma knife, within 7 days before the first dose of study treatment.
   • Whole brain radiotherapy (WBRT) within 21 days before the first dose of study treatment.
   • Use of checkpoint inhibitor, bevacizumab, and/or capecitabine within 6 months before the first dose of study treatment.

4. HR-Positive/HER2-Negative Cohort Exclusion Criteria

   • More than one prior line of palliative chemotherapy.
   • Progressive CNS disease. Patients with progressive CNS disease should be enrolled into the CNS cohort instead.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase Ib: Dose-Finding / Safety Confirmation; Patients with advanced solid tumors will be enrolled into a standard 3+3 design. Dose escalation will proceed using two predefined dose levels (DL1 and DL-1). There will be no dose reductions permitted for either tislelizumab or bevacizumab; dose modifications, if required, will apply only to capecitabine in accordance with protocol-defined guidelines. If the DL-1 dose level is not tolerated, further dose de-escalation is not pre-specified. In such a scenario, a formal review will be undertaken in consultation with the Study's Scientific Committee to determine the appropriate next steps, including consideration of additional dose reduction strategies or discontinuation of further dose exploration for the combination.	Drug: Tislelizumab + Bevacizumab + Capecitabine; Phase Ib Dose Levels Dose Level DL1 (Starting Dose); Tislelizumab: 200 mg IV Day 1 q3w; Bevacizumab: 7.5 mg/kg IV Day 1 q3w; Capecitabine: 1000 mg/m² PO BID Days 1-14 q3w DL-1 (De-escalation); Tislelizumab: 200 mg IV Day 1 q3w; Bevacizumab: 7.5 mg/kg IV Day 1 q3w; Capecitabine: 800 mg/m² PO BID Days 1-14 q3w
Experimental: Phase II: Multi-Cohort Expansion - PD-L1 negative TNBC cohort	Drug: Tislelizumab + Bevacizumab + Capecitabine; Phase Ib Dose Levels Dose Level DL1 (Starting Dose); Tislelizumab: 200 mg IV Day 1 q3w; Bevacizumab: 7.5 mg/kg IV Day 1 q3w; Capecitabine: 1000 mg/m² PO BID Days 1-14 q3w DL-1 (De-escalation); Tislelizumab: 200 mg IV Day 1 q3w; Bevacizumab: 7.5 mg/kg IV Day 1 q3w; Capecitabine: 800 mg/m² PO BID Days 1-14 q3w
Experimental: Phase II: Multi-Cohort Expansion - Active CNS disease cohort	Drug: Tislelizumab + Bevacizumab + Capecitabine; Phase Ib Dose Levels Dose Level DL1 (Starting Dose); Tislelizumab: 200 mg IV Day 1 q3w; Bevacizumab: 7.5 mg/kg IV Day 1 q3w; Capecitabine: 1000 mg/m² PO BID Days 1-14 q3w DL-1 (De-escalation); Tislelizumab: 200 mg IV Day 1 q3w; Bevacizumab: 7.5 mg/kg IV Day 1 q3w; Capecitabine: 800 mg/m² PO BID Days 1-14 q3w
Experimental: Phase II: Multi-Cohort Expansion - HR+/HER2- MBC cohort	Drug: Tislelizumab + Bevacizumab + Capecitabine; Phase Ib Dose Levels Dose Level DL1 (Starting Dose); Tislelizumab: 200 mg IV Day 1 q3w; Bevacizumab: 7.5 mg/kg IV Day 1 q3w; Capecitabine: 1000 mg/m² PO BID Days 1-14 q3w DL-1 (De-escalation); Tislelizumab: 200 mg IV Day 1 q3w; Bevacizumab: 7.5 mg/kg IV Day 1 q3w; Capecitabine: 800 mg/m² PO BID Days 1-14 q3w

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Phase Ib: Number and percentage of participants with treatment-related adverse events as assessed by CTCAE v5.0	2 years
Phase Ib: Phase II recommended dose of capecitabine in combination with tislelizumab and bevacizumab	2 years
Phase II TNBC Cohort: 12-month progression-free survival rate with tislelizumab, bevacizumab and capecitabine	12 months
Phase II CNS Cohort: Intracranial objective response rate with tislelizumab, bevacizumab and capecitabine	2 years
Phase II HR-positive/HER2-negative Cohort (if activated): 12-month progression-free survival rate with tislelizumab, bevacizumab, and capecitabine.	12 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Phase Ib: Incidence and severity of adverse events (AEs), including serious adverse events (SAEs) and immune-related adverse events (irAEs)	2 years
Phase II (TNBC, HR+/HER2- MBC): Objective response rate (ORR)	2 years
Phase II (TNBC, HR+/HER2- MBC): Disease control rate (DCR)	2 years
Phase II (TNBC, HR+/HER2- MBC): Duration of response (DoR)	2 years
Phase II (TNBC, HR+/HER2- MBC): Median progression-free survival (PFS)	2 years
Phase II (TNBC, HR+/HER2- MBC): Overall survival (OS)	2 years
Phase II CNS Cohort: Intracranial progression-free survival (iPFS)	2 years
Phase II CNS Cohort: Objective response rate (ORR) in extracranial sites	2 years
Phase II CNS Cohort: Disease control rate (DCR) in extracranial sites	2 years
Phase II CNS Cohort: Median progression-free survival (PFS) in extracranial sites	2 years
Phase II CNS Cohort: Overall survival (OS)	2 years

Other Outcome Measures

Outcome Measure	Time Frame
All Phases and Cohorts: Association between tumor genetic biomarkers and treatment response (ORR, DCR, PFS)	2 years
All Phases and Cohorts: Association between tumor immunohistochemistry biomarkers and treatment response (ORR, DCR, PFS)	2 years
All Phases and Cohorts: Association between plasma protein biomarkers and treatment response (ORR, DCR, PFS)	2 years
All Phases and Cohorts: Association between circulating tumor DNA (ctDNA) levels and treatment response (ORR, DCR, PFS)	2 years
All Phases and Cohorts: Association between germline pharmacogenetics and treatment response (ORR, DCR, PFS)	2 years

Collaborators and Investigators

• Sponsor: National University Hospital, Singapore
• Investigators: Principal Investigator: Soo Chin Lee, National University Hospital, Singapore

Publications and helpful links

General Publications

• Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012 Jun 28;366(26):2443-54. doi: 10.1056/NEJMoa1200690. Epub 2012 Jun 2.
• Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012 Jun 28;366(26):2455-65. doi: 10.1056/NEJMoa1200694. Epub 2012 Jun 2.

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2026
• Primary Completion (Estimated): August 1, 2028
• Study Completion (Estimated): August 1, 2028

Study Registration Dates

• First Submitted: June 2, 2026
• First Submitted That Met QC Criteria: June 26, 2026
• First Posted (Actual): July 2, 2026

Study Record Updates

• Last Update Posted (Actual): July 2, 2026
• Last Update Submitted That Met QC Criteria: June 26, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Breast Cancer; Capecitabine; Bevacizumab; Tislelizumab; Triple-Negative Breast Cancer (TNBC); CNS disease; Advanced Solid Tumour Cancer
• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Breast Neoplasms; Triple Negative Breast Neoplasms; Central Nervous System Diseases; Amino Acids, Peptides, and Proteins; Proteins; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Nucleosides; Uracil; Pyrimidinones; Deoxyribonucleosides; Fluorouracil; Capecitabine; Bevacizumab; tislelizumab
• Other Study ID Numbers: BR01/01/26; 2026-0764 (Other Identifier: ECOS)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No