Nectin-4 PET to Predict Response to Nectin-4-Targeted Therapy in Advanced Breast Cancer
Nectin-4 PET to Predict Response to Nectin-4-Targeted Therapy in Advanced Breast Cancer
This is a prospective, single-arm, exploratory clinical trial that plans to enroll 40 patients with locally advanced or metastatic breast cancer who are expected to participate in a therapeutic clinical trial of a Nectin-4-targeted agent at our center and receive at least two treatment cycles. All participants must meet the eligibility criteria of the therapeutic clinical trial in which they intend to participate and provide separate written informed consent for this study. The Nectin-4-targeted agents used in the two clinical trials currently underway at our center are provided to participants free of charge.
All participants must undergo an ^18F-FDG PET/CT scan and a complimentary ^68Ga-FZ-NR-1 PET/CT scan (Nectin-4 PET) within 28 days before initiating treatment with a Nectin-4-targeted agent. After completing the baseline assessments, participants will begin treatment in accordance with the protocol of the therapeutic clinical trial of the Nectin-4-targeted agent in which they are enrolled and will be followed according to the requirements of the corresponding protocol until disease progression, unacceptable toxicity, or withdrawal from the study.
Participants will be encouraged to undergo an additional complimentary Nectin-4 PET/CT scan after completion of the first treatment cycle and within 7 days before administration of the second treatment cycle to assess early changes in target expression during treatment.
Peripheral blood samples will be collected at baseline, before the first dose of Cycle 3, and at disease progression. Participants will also be encouraged to undergo needle biopsy of a metastatic lesion at baseline and at disease progression to explore potential mechanisms of resistance and other relevant biomarkers.
All PET/CT images will be independently reviewed by two physicians from the Department of Nuclear Medicine at our center who have extensive experience in diagnostic imaging.
Inclusion Criteria:
- 1. **Age ≥18 years.**
2. **Histopathologically confirmed unresectable locally advanced or metastatic breast cancer.**
3. The participant must be confirmed during screening to meet all inclusion and exclusion criteria for at least one of the following therapeutic clinical trials involving a Nectin-4-targeted agent being conducted at this center and must have signed the corresponding informed consent form:
**Protocol BC-MUL-IIT-SHRA2102:** *A Study of the Efficacy and Safety of SHR-A2102 in Patients With HR-Positive/HER2-Negative Advanced Breast Cancer Following Failure of a CDK4/6 Inhibitor Combined With Endocrine Therapy*;
**Protocol SC-101-201:** *A Phase IIa Clinical Study Evaluating the Efficacy and Safety of SC-101 in Patients With Advanced Malignant Tumors Positive for NECTIN4 Gene Amplification.*
Note:** Summaries of the study designs and eligibility criteria for these two clinical trials are provided in Appendix 1.
4. **Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.**
5. Radiographic or objective evidence of disease progression during or after the most recent systemic therapy administered before initiation of the study treatment, or intolerance to toxicity associated with prior treatment.
6. **Life expectancy of ≥12 weeks at screening.**
7. At least one lesion that has not previously received radiotherapy and is accurately measurable at baseline by CT or MRI, with a longest diameter of ≥10 mm. For lymph nodes, the short-axis diameter must be ≥15 mm. For participants with bone-only disease, osteolytic or mixed osteolytic bone lesions evaluable by CT, MRI, or X-ray are acceptable.
8. **Left ventricular ejection fraction ≥50% within 28 days before randomization.**
9. Adequate organ and bone marrow function within 14 days before randomization. For all parameters listed below, the most recently obtained test results must meet the following eligibility criteria:
Hemoglobin ≥9 g/dL;
Absolute neutrophil count ≥1,500/mm³;
Platelet count ≥100,000/mm³;
At baseline, total bilirubin (TBL) ≤1.5 × the upper limit of normal (ULN) in the absence of liver metastases, or <3 × ULN in participants with Gilbert syndrome (unconjugated hyperbilirubinemia) or liver metastases;
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 × ULN, or <5 × ULN in participants with liver metastases;
Serum albumin ≥2.5 g/dL;
Creatinine clearance ≥30 mL/min, calculated using the Cockcroft-Gault formula;
International normalized ratio (INR) or prothrombin time (PT), and partial thromboplastin time or activated partial thromboplastin time (aPTT), ≤1.5 × ULN.
10. From screening throughout the study treatment period and for 7 months after the final dose of study treatment, female participants must not donate ova or retrieve ova for their own use. Breastfeeding must be avoided during this period. Participants wishing to preserve ova should consider doing so before randomization into this study.
Exclusion Criteria:
- 1. **Uncontrolled intercurrent illness**, including but not limited to ongoing or active infection; uncontrolled or clinically significant cardiovascular disease; severe chronic gastrointestinal disease associated with diarrhea; or psychiatric or social conditions that may limit compliance with study requirements, substantially increase the risk of adverse events (AEs), or impair the patient's ability to provide written informed consent.
2. **Uncontrolled or clinically significant cardiovascular disease**, including any of the following:
a. A history of myocardial infarction or symptomatic congestive heart failure (CHF; New York Heart Association [NYHA] Class II-IV) within 6 months before randomization. Patients with troponin levels above the upper limit of normal (ULN), as defined by the manufacturer, at screening but without symptoms suggestive of myocardial infarction must undergo cardiology consultation before randomization to rule out myocardial infarction; b. Uncontrolled hypertension; c. Uncontrolled and/or clinically significant cardiac arrhythmia.
3. **Uncontrolled infection** requiring intravenous antibiotics, antiviral agents, or antifungal agents.
4. **Spinal cord compression or clinically active central nervous system metastases**, defined as untreated and symptomatic disease or disease requiring corticosteroids or anticonvulsants to control associated symptoms. Patients with clinically inactive brain metastases may be enrolled. Patients who have received treatment for brain metastases may be included provided that they are asymptomatic, no longer require corticosteroids or anticonvulsants, and have recovered from the acute toxic effects of radiotherapy.
5. **Active primary immunodeficiency, known human immunodeficiency virus (HIV) infection, or active hepatitis B or hepatitis C infection.** Among patients who test positive for hepatitis C antibodies, only those with negative hepatitis C virus RNA by polymerase chain reaction are eligible for enrollment.
6. **Unresolved toxicity from prior anticancer therapy**, defined as toxicity that has not recovered to Grade ≤1 or baseline, except for alopecia.
Note:** Patients with chronic, stable Grade 2 toxicities that, in the investigator's judgment, are related to prior anticancer therapy may be enrolled, provided that the toxicity has not worsened to Grade ≥2 for at least 3 months before enrollment and can be managed with standard treatment. Examples include chemotherapy-induced neuropathy or fatigue and residual toxicities from prior immunotherapy, such as Grade 1 or 2 endocrine disorders.
7. **Female patients who are pregnant or breastfeeding, or patients planning to become pregnant.**
8. **Known history of severe hypersensitivity** to the active pharmaceutical ingredient, any inactive component of the drug formulation, or other monoclonal antibodies.
9. **History of another primary malignancy within the previous 3 years**, except for adequately resected non-melanoma skin cancer, cured carcinoma in situ, other cured solid tumors, or contralateral breast cancer.
10. **Substance abuse or any other medical condition**, such as a psychiatric disorder, that, in the investigator's judgment, may interfere with the patient's participation in the clinical study or with the evaluation of study results.