GB268 Monotherapy or Combination Therapy for Locally Advanced/Metastatic Breast Cancer (Phase Ib/Ⅱ)

The Phase Ib part of the study will primarily assess the safety and tolerability of GB268 in combination therapies, including dose-limiting toxicities (DLTs). The Phase II part will primarily evaluate the preliminary anti-tumor activity of GB268 as monotherapy and in various combination regimens in corresponding breast cancer populations.

Cohort-Specific Requirements:

Cohort A: Histologically confirmed locally advanced unresectable or metastatic Triple-Negative Breast Cancer [TNBC]; no prior systemic therapy for advanced disease; prior adjuvant/neoadjuvant taxane allowed if recurrence ≥6 months after last taxane dose; no prior Trop-2 Antibody-Drug Conjugate [ADC].

Cohort B: Histologically confirmed locally advanced unresectable or metastatic TNBC; no prior systemic therapy for advanced disease; prior adjuvant/neoadjuvant taxane allowed if recurrence ≥12 months after last taxane dose.

Cohort E: Histologically confirmed locally advanced unresectable or metastatic HR+/HER2- breast cancer; disease progression after ≥1 line of endocrine therapy (aromatase inhibitor and/or fulvestrant) and CDK4/6i in advanced setting; received ≥1 line of systemic chemotherapy in advanced setting; no prior Trop-2 ADC.

Cohort F: Histologically confirmed locally advanced unresectable or metastatic HR+/HER2- breast cancer; disease progression after ≥1 line of endocrine therapy and CDK4/6i with primary or secondary endocrine resistance; prior adjuvant/neoadjuvant taxane allowed if recurrence ≥12 months after last taxane dose.

Cohort G: Histologically confirmed locally advanced unresectable or metastatic HR+/HER2- breast cancer; prior CDK4/6i and endocrine therapy in any setting; received a TROP2 or HER2 ADC in advanced setting.

Inclusion criteria

• Age ≥ 18 years, male or female.
• Histologically confirmed locally advanced unresectable or metastatic breast cancer (Triple-Negative Breast Cancer [TNBC] or Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative [HR+/HER2-]).
• At least one measurable lesion per Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST v1.1].
• No prior treatment with any immune checkpoint inhibitor (e.g., anti-Programmed Death-1 [PD-1], anti-Programmed Death-Ligand 1 [PD-L1], anti-Cytotoxic T-Lymphocyte-Associated Protein 4 [CTLA-4]) or Programmed Death-1/Vascular Endothelial Growth Factor [PD-1/VEGF] bispecific antibody, except for adjuvant therapy if relapse occurred ≥12 months after discontinuation.
• Assessed by the investigator as suitable for the assigned combination therapy.
• Eastern Cooperative Oncology Group [ECOG] performance status 0 or 1.
• Life expectancy ≥ 3 months.
• Adequate organ function (within 14 days before first dose, without transfusion or Granulocyte Colony-Stimulating Factor [G-CSF] support): Hemoglobin ≥ 9 g/dL, Absolute Neutrophil Count [ANC] ≥ 1.5×10^9/L, Platelets ≥ 100×10^9/L; Aspartate Aminotransferase [AST] and Alanine Aminotransferase [ALT] ≤ 3×Upper Limit of Normal [ULN] (≤5×ULN if liver metastases); Alkaline Phosphatase [ALP] ≤ 2.5×ULN (≤5×ULN if bone or liver metastases); Total Bilirubin ≤ 1.5×ULN (≤3×ULN for Gilbert's Syndrome); Serum Creatinine ≤ 1.5×ULN or Creatinine Clearance ≥ 50 mL/min (Cockcroft-Gault formula); Urine protein dipstick ≤ 1+ (if ≥2+, 24-hour urine protein quantification < 1 g); Coagulation function: International Normalized Ratio [INR] or activated Partial Thromboplastin Time [aPTT] ≤ 1.5×ULN (for patients not on anticoagulation therapy).
• Provide a Formalin-Fixed Paraffin-Embedded [FFPE] tumor tissue sample for biomarker testing.
• Effective contraception for fertile participants.

Exclusion criteria

• Prior anti-cancer therapy within specified washout periods.
• Systemic immunosuppressive therapy within 2 weeks before first dose.
• Major surgery or significant traumatic injury within 4 weeks before first dose.
• Unresolved toxicity from prior therapy > Grade 1 (except alopecia or Grade ≤2 hypothyroidism stable on hormone replacement).
• Prior immune-related adverse events [irAEs] ≥ Grade 3 leading to treatment discontinuation.
• Active Central Nervous System [CNS] metastases (except stable asymptomatic lesions).
• History of other malignancies within 3 years (except cured non-melanoma skin cancer or carcinoma in situ).
• Uncontrolled pleural effusion or ascites requiring repeated drainage.
• Clinically significant cardiovascular disease (e.g., myocardial infarction, unstable angina, stroke within 6 months; QTcF prolongation; New York Heart Association [NYHA] Class II-IV heart failure; pericarditis/myocarditis).
• History of Interstitial Lung Disease [ILD] or non-infectious pneumonitis requiring steroids.
• Active or history of autoimmune disease requiring systemic treatment in the past 2 years.
• History of inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis, or chronic diarrhea).
• History of hypertensive crisis or hypertensive encephalopathy.
• Severe coagulation disorders or significant bleeding risk (e.g., severe vascular disease, hemoptysis, intracranial/spinal hemorrhage, tumor invading major vessels).
• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess.
• Active infection requiring systemic anti-infective therapy within 2 weeks; severe infection within 4 weeks.
• Uncontrolled intercurrent illness (e.g., poorly controlled hypertension or Type 2 diabetes mellitus).
• Known active tuberculosis [TB].
• Positive for Hepatitis B Virus [HBV] surface antigen [HBsAg] or core antibody [HBcAb] with HBV-Deoxyribonucleic Acid [DNA] > 500 IU/mL; or positive Hepatitis C Virus [HCV] antibody with HCV-Ribonucleic Acid [RNA] above the lower limit of quantification.
• Known primary immunodeficiency or positive Human Immunodeficiency Virus [HIV] antibody.
• History of solid organ or hematopoietic stem cell transplantation (except corneal transplant).
• Pregnant or breastfeeding women.
• Known hypersensitivity to GB268 or its excipients; history of severe hypersensitivity to other monoclonal antibodies.
• Any other condition that would make the participant unsuitable for the study.
• History of severe hypersensitivity to other drugs in the combination regimen.