Phase I Study of SYS6043 in Patients With Advanced/Metastatic Solid Tumors

Phase I Dose Escalation and Cohort Expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of SYS6043 in Patients With Advanced/Metastatic Solid Tumors

The goal of this clinical trial is to learn if investigational drug called SYS6043 works in adults with advanced or metastatic solid tumors that have spread or cannot be treated with standard therapies. The main goals of the study are to understand how safe SYS6043 is, what side effects it may cause, and what dose can be given safely. Researchers will also study how the drug moves through the body and whether the immune system reacts to it. In addition, the study will look for early signs that SYS6043 may help slow or shrink tumors and explore whether the amount of a tumor protein called B7-H3 is related to how well the treatment works.

Participants will:

• Provide written informed consent
• Undergo screening tests to ensure they are eligible for study treatment
• Attend all required study visits and receive SYS6043 by intravenous infusion once every 3 weeks (Q3W), with 21 days as one treatment cycle until the study doctor determines that study treatment should be stopped based on how well a participant is doing on treatment.
• Have safety follow-up (SFU), and long-term follow-up.
• Be followed until progression.

This is a multicenter, open-label, Phase I study of dose escalation, PK expansion, and cohort expansion, aiming to evaluate the safety, tolerability, PK characteristics, and preliminary anti-tumor efficacy of SYS6043 (a B7-H3-targeted antibody-drug conjugate) in patients with advanced/metastatic solid tumors. It includes three parts, namely dose escalation, PK expansion, and cohort expansion.

Phase Ia dose escalation is the first part (Part 1) of this study. The dose escalation is carried out using BOIN design, to evaluate the MTD/maximum administered dose (MAD) and the RP2D.

Phase Ia PK expansion (Part 2) will be conducted at 2-3 dose levels deemed acceptable (≤MTD) in terms of safety/tolerability as assessed by the SMC, to further evaluate the safety, tolerability, PK characteristics, and preliminary anti-tumor activity of SYS6043.

Phase Ib cohort expansion (Part 3) will further evaluate the safety and efficacy of SYS6043 at the selected RP2D dose (1-2 dose levels).

A safety monitoring committee (SMC) will be established for this study. The SMC will continuously review safety during the study period and make decisions on adjustments to dose escalation, addition of new dose groups, recommended doses, and recommended exploratory cohorts. For details, please refer to the SMC Charter.

Inclusion Criteria:

Major:

• Aged ≥18 years old (on the date of signing the ICF).
• Advanced/unresectable or metastatic solid tumors confirmed by histology or cytology, disease recurrence or progression during or after systemic standard of care, and should be intolerant of or have no available standard of care therapy.
• Have at least one measurable lesion, according to the Response Evaluation Criteria in Solid Tumors (RECIST V1.1). Participants with metastatic castration-resistant prostate cancer (mCRPC) who have only metastases to bone will be evaluated through discussion with the sponsor's medical monitor, before determining whether they can be enrolled.
• Expected life expectancy of ≥ 3 months.
• ECOG performance status of 0-1 and no worsening of the score within 28 days prior to enrollment.
• LVEF ≥ 50% as shown by ECHO or MUGA within 28 days prior to enrollment.

Exclusion Criteria:

Major:

• Prior B7-H3 targeted therapy.
• Previously received drug therapy with topoisomerase inhibitor antibody-drug conjugate (e.g., trastuzumab deruxtecan).
• Symptomatic congestive heart failure (CHF) (New York Heart Association [NYHA] Class II-IV) or a history of severe arrhythmia requiring treatment.
• History of myocardial infarction or unstable angina within 6 months prior to enrollment.
• Based on the results of three 12-lead electrocardiogram (ECG) examinations, the mean QT interval (QTcF) corrected by the Fridericia formula for both males and females is prolonged to >470 ms.
• Unable or unwilling to discontinue concomitant medications known to prolong the QT interval.
• History of interstitial lung disease (e.g., ILD/non-infectious pneumonia requiring glucocorticoid treatment in the past), or currently have interstitial lung disease, or are suspected to have such diseases through imaging examinations during screening.
• History of underlying lung disorders, including but not limited to pulmonary embolism within 3 months prior to the start of study treatment, severe asthma, severe COPD, restrictive pulmonary disease, and other clinically significant lung injuries or requiring supplemental oxygen.
• Any autoimmune diseases, connective tissue disorders, or inflammatory diseases involving the lungs recorded or suspected during screening (e.g., rheumatoid arthritis, Sjögren's syndrome, sarcoidosis, etc.).
• Presence of uncontrolled infection requiring intravenous injection of antibiotics, antiviral drugs, or antifungal drugs.
• Active and clinically significant bacterial, fungal, viral infection, or Hepatitis C infection at screening (HCV antibodies test positive and HCV-RNA levels higher than the lower limit of quantification or 1000 copies/mL (whichever is lower); HIV antibody positive or syphilis antibody positive (with confirmation)..
• HBsAg positive and HBV-DNA above the lower limit of quantification or 1,000 copies/mL (500 IU/mL) (whichever is lower). Liver tumor: For participants with liver metastases and HBV infection, HBV DNA must be <2000 IU/mL before the first dose. Participants who are HBsAg-positive and/or HBV DNA-positive should receive at least 2 weeks of anti-Hepatitis B virus treatment prior to the first dose and be willing to continue treatment during the study.
• Lactating women (women who are willing to temporarily discontinue breastfeeding will also be excluded), or women confirmed to be pregnant by pregnancy test within 7 days prior to enrollment.
• Presence of spinal cord compression or clinically active brain metastasis, and/or meningeal metastases, defined as untreated, symptomatic, or requiring corticosteroids or anticonvulsants.