Clinical Study of CVL006 Combination With 9MW2821

Phase Ib/II Clinical Study of CVL006 Combination With 9MW2821 in Advanced Solid Tumors

This study is a multi-center, open-label, dose-escalation and dose-optimized phase I/II clinical trial. Objective: To determine the safety, tolerability, PK characteristics and preliminary efficacy data of CVL006 combined with 9MW821 patients with advanced solid tumors.

In this Phase Ib study, dose escalation of CVLL006 combined with 9MW2821 (at a fixed dose) will be conducted using a 3+3 design:

Initially, 3 study participants will be enrolled into the starting dose level for DLT observation.

If no DLT occurs in all 3 participants after completion of the DLT observation period, dose escalation to the next dose level may proceed.

If 1 out of the 3 participants experiences a DLT, an additional 3 participants will be enrolled.

If no DLT is observed in the additional 3 participants, dose escalation to the next dose level may proceed.

If a DLT occurs in any of the additional 3 participants, dose escalation will be terminated.

If ≥2 out of the initial 3 participants experience DLTs, dose escalation will be terminated immediately.

Under normal circumstances, each study participant will receive study drug from only one dose level, and intra-individual dose escalation is not permitted.

The addition of new dosing schedules and dose levels will be determined through discussion between the investigator and the sponsor, based on available study data including safety, tolerability, pharmacokinetic (PK), and efficacy profiles.

If a participant fails to complete the DLT observation period for reasons other than DLT (including but not limited to withdrawal from the study during the DLT observation period), a replacement participant may be enrolled.

Inclusion Criteria:

• Age: 18-75 years old (inclusive), no restriction on gender.
• Patients with histologically or cytologically confirmed advanced solid tumors. Cohort A: Squamous cell carcinoma of the head and neck; the primary tumor must arise from the oral cavity, oropharynx, hypopharynx or larynx, excluding nasopharyngeal tumors, salivary gland tumors and/or parotid gland tumors.
• For Phase Ib participants: Advanced solid tumors with failure of prior standard therapy. For Phase II part, Cohort A: Recurrent or metastatic disease not curable by local therapy. Participants must have no prior systemic therapy, unless the prior systemic therapy was completed more than 6 months ago as adjuvant or neoadjuvant treatment. Participants who received prior PD-1/PD-L1 inhibitors in curative therapy are eligible if at least 12 months have elapsed since the last dose of anti-PD-L1 agent. Cohort B: No prior systemic therapy for locally advanced or metastatic disease. For patients who received adjuvant/neoadjuvant therapy or curative chemoradiotherapy, disease progression within 6 months after the last treatment is regarded as first-line setting.
• For Phase II: PD-L1 Combined Positive Score (CPS) ≥ 1 confirmed by local or central immunohistochemistry (IHC). If no PD-L1 testing result is available, participants shall submit archived or fresh tumor tissue samples during screening for central laboratory testing of programmed death ligand-1 (PD-L1) and Nectin4. The central PD-L1 testing result must be obtained prior to enrollment. Participants with known PD-L1 results confirming CPS ≥ 1 shall submit archived or fresh tissue samples for exploratory analysis within 5 days after enrollment.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS): 0-1.
• Estimated survival time ≥ 3 months.
• At least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST 1.1).
• Adequate bone marrow and organ function (no blood components and/or hematopoietic growth factors administered within 14 days prior to the initiation of study treatment):

Hemoglobin (HB) ≥ 90 g/L; Absolute Neutrophil Count (ANC) ≥ 1.5×10⁹/L; Platelet (PLT) ≥ 90×10⁹/L; Total bilirubin < 1.5×ULN (for participants with confirmed Gilbert's syndrome, total bilirubin ≤ 3×ULN); Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3×ULN; Serum creatinine ≤ 1.5×ULN or creatinine clearance ≥ 60 mL/min (calculated by the Cockcroft-Gault formula); nternational Normalized Ratio (INR) and activated partial thromboplastin time (APTT) ≤ 1.5×ULN;

• Urinalysis protein ≤ 1+; or if urine protein ≥ 2+, 24-hour urine protein < 1 g.
• Females of childbearing potential must agree to abstain from heterosexual intercourse or use highly effective contraceptive methods from the signing of informed consent until at least 6 months after the last dose of study drug. Serum HCG test must be negative within 7 days prior to study treatment initiation, and participants must be non-lactating. (A positive serum pregnancy test requires exclusion of pregnancy, and enrollment can only be confirmed after discussion with the sponsor.)
• Male patients with female partners of childbearing potential must agree to abstain from intercourse or use highly effective contraceptive methods from the signing of informed consent until at least 6 months after the last dose of study drug. Male participants must also agree not to donate sperm during the same period.
• Participants voluntarily join the study, sign the informed consent form, and have good treatment compliance.

Exclusion Criteria:

• 1. Participants with active central nervous system (CNS) metastases are excluded. Participants with previously treated CNS metastases are eligible only if all of the following criteria are met: The CNS metastases have been clinically stable for ≥ 6 weeks prior to screening; If steroid therapy is required for CNS metastases, participants are on a stable steroid dose equivalent to ≤ 20 mg/day prednisone for at least 2 weeks; Baseline imaging shows no evidence of new or enlarging brain metastases; Participants have no leptomeningeal disease.
• Participants with other malignant tumors within 5 years prior to the first dose of study drug, except adequately treated carcinoma in situ of the cervix, basal cell or squamous cell skin cancer, locally confined prostate cancer after radical resection, ductal carcinoma in situ after radical resection, and papillary thyroid carcinoma after radical resection.
• Participants with tumors judged by the Investigator to be prone to bleeding, including those with imaging evidence of tumor invasion into or encasement of major blood vessels on screening imaging.
• Participants with prior exposure to VEGF/PD-1 (PD-L1) bispecific antibodies or Nectin4-targeted therapy.
• Participants with severe cardiovascular and cerebrovascular diseases, including but not limited to:

Severe cardiac rhythm or conduction abnormalities within 6 months prior to the first study drug dose, such as ventricular arrhythmias requiring clinical intervention, second- or third-degree atrioventricular block; History of acute coronary syndrome, congestive heart failure (New York Heart Association [NYHA] functional class ≥ II), or aortic dissection within 6 months prior to the first dose; History of arteriovenous thromboembolic events within 6 months prior to the first dose, such as cerebrovascular accident (transient ischemic attack, cerebral hemorrhage, stroke), deep vein thrombosis and pulmonary embolism; Left ventricular ejection fraction (LVEF) < 50% within 28 days prior to the first dose; Mean QTcF interval averaged from 3 baseline 12-lead (or more) electrocardiograms at rest: QTcF > 470 ms (female) or QTcF > 450 ms (male).

• Participants with persistent clinically significant toxicities (≥ Grade 2, alopecia excluded) related to prior therapy (including systemic therapy, radiotherapy or surgery). Participants with persistent ≥ Grade 2 immune-related hypothyroidism or panhypopituitarism are excluded. Participants with persistent immune-related colitis, uveitis, myocarditis, pneumonitis, or other immune-related adverse events requiring high-dose steroid therapy (> 20 mg/day prednisone or equivalent) are excluded. Participants with well-controlled ≤ Grade 2 immune-related hypothyroidism or panhypopituitarism on stable hormone replacement therapy (if applicable) are eligible. Participants with ≥ Grade 2 sensory or motor neuropathy are excluded.
• Participants with active autoimmune diseases or a history of autoimmune diseases prone to recurrence (such as systemic lupus erythematosus, rheumatoid arthritis, vasculitis), excluding clinically stable autoimmune thyroid disease and type 1 diabetes mellitus.
• Participants who have undergone major surgery within 4 weeks prior to the first study drug dose; received radiotherapy, chemotherapy, biological agents, investigational drugs, and/or immunotherapy for antitumor purposes within 2 weeks prior to the first dose; or received traditional Chinese medicine with antitumor indications within 2 weeks prior to the first dose.
• Participants with a history of steroid-dependent (non-infectious) pneumonitis/interstitial lung disease or currently suffering from such diseases; history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonia; or evidence of active pneumonitis on chest CT during screening.
• Participants judged by the Investigator to have an expected survival of less than 3 months and/or rapidly progressive disease (e.g., tumor bleeding, uncontrolled tumor pain).
• Participants with a history of esophageal gastric varices, severe peptic ulcer, unhealed wounds, abdominal fistula, intra-abdominal abscess or acute gastrointestinal bleeding within 6 months prior to the first dose; history of gastrointestinal perforation and/or fistula, severe gastrointestinal obstruction (including incomplete intestinal obstruction requiring parenteral nutrition), or extensive intestinal resection (partial colectomy or extensive small bowel resection) within 6 months prior to the first dose.
• Participants with a history of immunodeficiency including positive HIV test; active hepatitis B infection (HBV DNA above the upper limit of normal of the local study center) or hepatitis C infection (anti-HCV positive and HCV RNA above the lower limit of quantification of the assay).
• Participants with active pulmonary tuberculosis infection within 1 year prior to enrollment confirmed by medical history or CT examination; or those with a history of active pulmonary tuberculosis infection more than 1 year ago without standard anti-tuberculosis treatment.
• Participants with a history of bleeding tendency or coagulation disorders and/or clinically significant bleeding symptoms or risks within 4 weeks prior to the first dose, including but not limited to:
• a. Gastrointestinal bleeding;
• b. Hemoptysis (coughing up ≥ 15 mL fresh blood or blood clots);
• c. Epistaxis;
• d. Receiving therapeutic anticoagulation prior to the first dose.
• Participants with a history of hypertensive crisis or hypertensive encephalopathy; persistent hypertension within 1 month prior to the first dose with systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg despite oral antihypertensive treatment.
• Participants with uncontrolled diabetes within 3 months prior to the first study treatment dose, defined as: Glycated hemoglobin (HbA1c) ≥ 8%; or HbA1c between 7% and < 8% accompanied by unexplained diabetes-related symptoms (polyuria or polydipsia).
• Participants with active or prior history of inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis or chronic diarrhea).
• Participants with a known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation.
• Participants who have received live attenuated vaccines within 30 days prior to the first dose or plan to receive live vaccines during the study period.
• Participants with known active keratitis or corneal ulcer are excluded; participants with superficial punctate keratitis under adequate treatment are allowed to be enrolled.
• Participants requiring use of strong inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) within 2 weeks prior to the first study dose and during the study period (concomitant use of strong CYP3A4 inhibitors or inducers is prohibited; representative drugs are listed in the appendix).
• Participants with any other conditions judged by the Investigator that may interfere with study results or lead to premature study termination, such as alcohol abuse, drug abuse, uncontrolled severe diseases (including psychiatric disorders) requiring combined medication, significantly abnormal laboratory parameters, family/social factors, or any other conditions that may compromise participant safety or affect study data collection.