A Phase I/IIa Study of SYS6041 in Patients With Advanced Solid Tumors

The trial consists of four stages: Phase I dose-escalation stage, as well as Phase IIa dose-reassignment stage, dose-expansion stage and cohort-expansion stage.

The dose-escalation stage includes a screening period (28 days), a treatment period (DLT observation period and subsequent treatment period), and a follow-up period (safety follow-up and survival follow-up). The first cycle (21 days) in which participants receive SYS6041 administration is defined as the DLT observation period.

Based on data obtained from the dose-escalation and dose-reassignment stages, two dose levels will be selected for randomized enrollment in the dose-expansion stage to further assess the efficacy, safety and pharmacokinetic (PK) profile of candidate doses and confirm the recommended Phase 2 dose (RP2D).

The cohort-expansion stage comprises a screening period (28 days), a treatment period and a follow-up period (safety follow-up and survival follow-up). Eligible screened participants will receive intravenous infusion of SYS6041 on Day 1 of each cycle, with each treatment cycle lasting 3 weeks. Treatment will be discontinued upon the first occurrence of progressive disease (PD), intolerable toxicity, withdrawal of informed consent, loss to follow-up, death, or any other conditions meeting the treatment discontinuation criteria.

Inclusion criteria

• Aged >= 18 years.
• The expected survival time is >=3 months.
• Eastern Cooperative Oncology Group (ECOG) 0~1.
• Willing to provide recent tumor tissue specimens for FRα testing.
• At least one measurable lesion as defined by RECIST Version 1.1.
• The organ function level and related laboratory indicators must meet requirement.
• Additional inclusion criteria for the dose-escalation stage: Histologically or cytologically confirmed unresectable locally advanced or metastatic ovarian cancer, endometrial cancer, NSCLC, or breast cancer with disease progression following standard therapy.
• Additional inclusion criteria for the expansion cohort stage: Radiological and/or pathological progression or intolerance to the most recent systemic anti-tumor therapy.
• Additional inclusion criteria for the expansion cohort stage: Histologically or cytologically confirmed advanced solid tumors, including ovarian cancer, endometrial cancer, or other FRα-positive solid tumors that have received at least one prior line of systemic therapy.
• Agree to use reliable and effective methods of contraception during the study treatment period and for at least 5 months (for male subjects) or 8 months (for female subjects) after the last study treatment.

Exclusion criteria

• Known severe allergic reaction to the study drug or any other components/excipients in the formulation.
• Untreated (including those identified at baseline screening) or unstable parenchymal brain metastases, spinal metastases or spinal cord compression, carcinomatous meningitis.
• History of other malignant tumors within 3 years, or concurrent active malignant tumors.
• Prior treatment with ADCs carrying topoisomerase I inhibitor payloads.
• Adverse reactions from prior anti-tumor therapies have not recovered to Grade ≤1 per CTCAE v5.0.
• Received immunotherapy, macromolecular targeted therapy or other anti-tumor biotherapy within 4 weeks prior to the first dose; or received endocrine therapy, cytotoxic chemotherapy, small-molecule targeted therapy within 2 weeks prior to the first dose; or received traditional Chinese medicinal preparations with anti-tumor indications within 2 weeks prior to the first dose.
• Patients who have undergone major organ surgery within 28 days prior to the first dose, or have planned systemic or local tumor resection during the study period.
• Patients who have received strong CYP3A4 inhibitors or strong CYP3A4 inducers systemically within 14 days prior to the first dose, or require continuous systemic administration of such agents during study treatment.
• Severe chronic or active infections requiring intravenous antibacterial, antifungal or antiviral therapy within 14 days prior to the first dose (including tuberculous infection, etc.).
• Subjects receiving long-term immunosuppressive therapy (e.g., cyclosporine) or daily systemic steroid therapy.
• Uncontrolled serous cavity effusions requiring frequent drainage or medical intervention within 7 days prior to the first dose.
• Presence of risk factors for intestinal obstruction or intestinal perforation.
• Grade ≥2 severe diarrhea per CTCAE within 7 days prior to the first dose.
• History of non-infectious lung disease/pneumonitis requiring steroid therapy, or current interstitial lung disease/pneumonitis, or suspected such diseases identified by imaging examinations during screening.
• History of severe cardiovascular diseases.
• Female subjects who are pregnant or breastfeeding.
• Any other circumstances that may interfere with the subject's participation in study procedures, compromise the subject's maximum benefit from study participation, or affect study results, in the Investigator's judgment.