Advanced Solid Tumor Cancer, Breast Cancer, CNS Disease, Triple-Negative Breast Cancer (TNBC)
Conditions
Keywords
Tislelizumab, Bevacizumab, Capecitabine, Breast Cancer, Advanced Solid Tumour Cancer, CNS disease, Triple-Negative Breast Cancer (TNBC)
Brief summary
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.
Interventions
DRUGTislelizumab + 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
Sponsors
National University Hospital, Singapore
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
No
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. * Patients must have received at least one prior line of standard systemic therapy for locally advanced/unresectable or metastatic disease, OR be ineligible for, intolerant of, or have declined standard-of-care therapy, with the specific reason documented in the source records. * 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
Design outcomes
Primary
| 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
| 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 |
Countries
Singapore
Contacts
CONTACTSoo Chin Lee
PRINCIPAL_INVESTIGATORSoo Chin Lee
National University Hospital, Singapore
Outcome results
None listed