N-3C01 Monotherapy and Combination With PD-(L)1 Inhibitors in Advanced Solid Tumors

A Phase I/II Clinical Study Evaluating the Safety, Tolerability, and Efficacy of N-3C01 as Monotherapy and in Combination With PD-(L)1 Monoclonal Antibody in Patients With Advanced Malignant Solid Tumors

This Phase I/II study evaluates the safety, tolerability, and efficacy of N-3C01 administered subcutaneously, both as monotherapy and in combination with a PD-(L)1 monoclonal antibody, in patients with advanced solid tumors. Phase I involves dose escalation for both monotherapy and combination therapy, while Phase II includes cohort expansion for the combination therapy.

This is a Phase I/II clinical study designed to evaluate the safety, tolerability, and efficacy of N-3C01 administered subcutaneously, both as monotherapy and in combination with a PD-(L)1 monoclonal antibody, in patients with advanced solid tumors. Phase I consists of dose escalation of N-3C01 as monotherapy and in combination with PD-(L)1 antibody, while Phase II involves cohort expansion of the combination therapy.

The Phase I study employs an escalation design. Participants will receive N-3C01 either as monotherapy or in combination with a fixed dose of PD-(L)1 monoclonal antibody. The study will assess safety, tolerability, and pharmacokinetics across different dose levels and dosing schedules to determine the maximum tolerated dose and the recommended Phase II dose (RP2D).

A Safety Review Committee (SRC), comprising the Investigator, Sponsor representative, and Medical Monitor, will oversee safety evaluations. The SRC will review dose-limiting toxicity data and provide recommendations on dose escalation, de-escalation, expansion, or study discontinuation and RP2D. In Phase II, eligible participants will receive N-3C01 at the RP2D in combination with a fixed dose of PD-(L)1 monoclonal antibody.

Inclusion Criteria:

1. Willingness to voluntarily participate in the study and provide written informed consent.

2. Age 18 to 75 years (inclusive) at the time of signing the informed consent form, regardless of gender.

3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 (refer to Appendix 1).

4. Estimated life expectancy of ≥3 months.

5. Disease criteria:

   • Phase I: Patients with histologically or cytologically confirmed advanced, metastatic, or unresectable solid tumors who have progressed following standard systemic therapy, have no available standard treatment options, are intolerant to standard therapies, or are deemed unsuitable for standard treatment by the Investigator.
   • Phase II:
   • Cohort 1: Advanced non-small cell lung cancer (NSCLC) with progression after immune checkpoint inhibitor therapy (as monotherapy or in combination with chemotherapy).
   • Cohort 2: Advanced melanoma with progression following chemotherapy and/or immune checkpoint inhibitor therapy.
   • Other cohorts: Tumor types such as colorectal cancer, renal cell carcinoma, head and neck squamous cell carcinoma, etc., that have progressed after chemotherapy and/or immune checkpoint inhibitor therapy and are considered potentially responsive by the Investigator.

6. Presence of at least one measurable lesion per RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1 (except for participants enrolled in the monotherapy dose-escalation phase).

7. Adequate organ function.

8. Use of effective contraception during the treatment period and for at least 3 months after the last dose.

Exclusion Criteria:

1. Presence of unstable central nervous system (CNS) metastases or concurrent primary intracranial tumors requiring treatment. Participants may be eligible if CNS disease is asymptomatic, radiologically stable for at least 4 weeks prior to the first dose, and does not require corticosteroids or anticonvulsant therapy.

2. History of two or more primary malignancies, except for adequately treated and controlled malignancies such as cervical carcinoma in situ, breast carcinoma in situ, basal cell or squamous cell carcinoma of the skin, and papillary thyroid carcinoma, with no evidence of recurrence within the past 2 years.

3. Uncontrolled tumor-related pain. Participants requiring analgesics must be on a stable pain management regimen at study entry.

4. Uncontrolled pleural effusion, pericardial effusion, or ascites. Participants may be eligible if drainage is not required or if fluid accumulation remains stable for at least 3 days following drainage.

5. Presence of significant pulmonary conditions, including idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or active pneumonitis at screening. Participants with prior radiation-induced pneumonitis (fibrotic changes confined to the radiation field) may be included.

6. History of autoimmune disease, except for conditions that are well-controlled, including type 1 diabetes mellitus, hypothyroidism managed with hormone replacement, and dermatologic conditions not requiring systemic therapy (e.g., eczema, psoriasis, vitiligo, alopecia), as well as well-controlled celiac disease.

7. Receipt of systemic corticosteroids within 1 week prior to the first dose or other systemic immunosuppressive therapies within 2 weeks (e.g., cyclophosphamide, azathioprine, methotrexate, thalidomide), except for physiologic replacement doses of prednisone ≤10 mg/day (or equivalent).

8. History of clinically significant cardiovascular disease, including but not limited to:

   Congestive heart failure (New York Heart Association [NYHA] class >2) Unstable angina Myocardial infarction within 3 months prior to the first study dose Clinically significant supraventricular or ventricular arrhythmias requiring treatment or intervention

9. History of clinically significant bleeding within 3 months prior to the first study dose. Participants with significant hemoptysis (i.e., coughing bright red blood of ≥2.5 mL per episode) within 1 month prior to the first dose are not eligible.

10. History of arterial or venous thrombotic events within 6 months prior to the first study dose, including but not limited to cerebrovascular accident, deep vein thrombosis, or pulmonary embolism.

11. Evidence of active tuberculosis (TB), as indicated by medical history or imaging (e.g., CT scan) within 1 year prior to enrollment, or a history of untreated active tuberculosis (TB) more than 1 year prior to screening.

12. Severe infection within 4 weeks prior to the first study dose (e.g., bacteremia requiring hospitalization, severe pneumonia), or active infection requiring systemic antimicrobial therapy of CTCAE(Common Terminology Criteria for Adverse Events ) v6.0 Grade ≥2 within 2 weeks prior to dosing.

13. Known history of immunodeficiency.

14. Active viral or infectious diseases requiring treatment, including:

15. Hepatitis B (HBsAg or HBeAg positive with Hepatitis C Virus (HBV) deoxyribonucleic acid (DNA) greater than or equal to 500 International Units per milliliter)

16. Hepatitis C (positive Hepatitis C Virus (HCV) antibody with detectable Hepatitis C Virus (HCV) ribonucleic acid (RNA))

17. human immunodeficiency virus (HIV) infection

18. Syphilis (positive serology with confirmatory Rapid Plasma Reagin (RPR)/TRUST test)

19. Toxicities from prior anti-cancer therapy that have not resolved to baseline or ≤Grade 1 (per Common Terminology Criteria for Adverse Events (CTCAE) v6.0), except for adverse events that are not clinically significant (e.g., alopecia), as determined by the Investigator.

20. Receipt of any anti-tumor therapy-including surgery, chemotherapy, radiotherapy, immunotherapy, biologic therapy, hormonal therapy, traditional Chinese medicine, or investigational agents-within 4 weeks prior to the first study dose or within 5 half-lives of the respective drug (whichever is longer). Palliative radiotherapy for bone metastases within 2 weeks prior to the first dose is also not permitted.