Sponsor Decision

This is an Open-label, Non-Randomized, Multi-center Phase 2 study of YH001 in Combination with Toripalimab，The study is designed to determine the safety ，tolerability and antitumor activity of YH001 in combination with Toripalimab in subjects with advanced NSCLC and HCC.

This study will include two cohorts of up to 40 subjects each treated with RP2D dose YH001 in combination with 240 mg Toripalimab to assess the antitumor activity and safety/tolerability.

According to Simon's two stage design, in the first stage, 9-10 subjects will be accrued. If there are ≤ 1 subjects achieving an objective response, the futility stop will be called. Enrollment will start for the second stage after Stage 1 data pass futility test. In the second stage, 17-19 subjects will be enrolled to have 27 subjects in total. If there are ≥ 5 subjects achieving an objective response, a stop could be called for meeting the primary objective.

In all cohorts, 4 mg/kg or other higher dose level of YH001 (not exceeding MTD) may be needed based on the safety data in the first stage.

• Cohort A: YH001 in combination with Toripalimab in subjects with advanced PD-L1 positive NSCLC as 1st line treatment;
• Cohort B: YH001 in combination with Toripalimab in subjects with previously systemically treated advanced HCC as 2nd line treatment;

Inclusion Criteria:

1. Male or female, aged ≥ 18 years；

2. Willing and able to provide signed and dated informed consent prior to any study-related procedures and willing and able to comply with all study procedures.

3. Target Population

   Cohort A:

   • Have histologically or cytologically confirmed diagnosis of NSCLC (squamous or non-squamous)
   • Recurrent or unresectable locally advanced (Stage IIIB) or metastatic (Stage IV);
   • Naïve to any systemic anti-cancer therapy
   • No EGFR mutation or ALK/ ROS1 gene rearrangement
   • PD-L1 positive (TPS≥1%) NSCLC

   Cohort B:

   • HCC diagnosis confirmed by or radiology, histology, or cytology;
   • Barcelona Clinic Liver Cancer (BCLC) Stage C or BCLC Stage B disease not amenable to locoregional therapy or refractory to locoregional therapy and not amenable to a curative treatment approach;
   • Child-Pugh A liver score within 7 days prior to first dose of study drug;
   • Documented objective radiographic progression during or after treatment with sorafenib/lenvatinib, or intolerant of sorafenib/lenvatinib; or documented objective radiographic progression during or after treatment with atezolizumab and bevacizumab, or intolerant of atezolizumab and bevacizumab.

4. At least 1 unidimensional measurable target lesion per RECIST v1.1

5. ECOG performance status score 0 or 1

6. Have life expectancy of at least 12 weeks based on investigator's judgement.

7. Adequate organ and bone marrow function:

8. Women of reproductive potential must have negative serum beta human chorionic gonadotropin (β -HCG) pregnancy test within 7 days of the fist dose of YH001.

9. Women of reproductive potential who are sexually active with a non-sterilized male must consistently use highly effective contraception/birth control between signing of the informed consent and 120 days after the last administration of the study drug.

Exclusion Criteria:

1. Treatment with any investigational drug within 4 weeks prior to the fist dose of study drug；

2. Prior anticancer therapy:

   • Cohort B: Subjects received sorafenib/lenvatinib within 14 days of first dose of study medication.
   • Prior palliative radiotherapy to bone metastases ≤ 2 weeks prior to the first dose of YH001 is acceptable.
   • It is unacceptable to have wash out less than 2 weeks for herbal therapy approved for anticancer.

3. Subjects with prior anti-CTLA-4 checkpoint inhibitors should be excluded.

4. Subjects with a history of ≥ Grade 3 immune-related adverse events resulted from previous immunotherapy or an AE of any grade that resulted in discontinuation of prior immunotherapy

5. History of (non-infectious) pneumonitis that required corticosteroids or current pneumonitis, or history of interstitial lung disease

6. Subjects requiring systemic treatment with corticosteroids (>10 mg/day prednisone or equivalent) or other immunosuppressive medications within 21 days before the planned first dose of study drug or has need to be treated while on trial

7. Allergic to YH001 and Toripalimab or any component of the study drug formulation.

8. Subjects with concomitant active autoimmune disease, history of autoimmune disease requiring systemic treatment, or history of autoimmune disease within the two years prior to study entry.

9. Primary central nervous system (CNS) malignancies or symptomatic CNS metastases.

10. Subjects with severe cardiovascular diseases, e.g. New York Heart Association (NYHA) Class III or IV heart failure, myocardial infection within 6 months prior to first dose of YH001, uncontrolled hypertension, unstable angina pectoris or unstable cardiac arrhythmia.

11. QTcF > 470 ms at baseline; no concomitant medications that would prolong the QT interval; no family history of long QT syndrome.

12. Viral infection:

    • Acute or Chronic active Hepatitis B (HBsAg positive and HBV DNA≥2000 IU/mL).
    • Chronic HCV infection (HCV antibody positive and HCV RNA detectable).
    • Human immunodeficiency virus (HIV) infection as well as COVID-19.

13. Subjects with active tuberculosis are excluded. Subjects who have received BCG vaccination may have a false positive PPD test. These subjects are eligible if they have a negative Interferon Gamma Release Assay (IGRA).

14. Clinically uncontrolled concurrent illnesses, including, but not limited to, active infection that requires systematic treatment, serious diabetes (fasting blood glucose > 250 mg/dl), psychiatric illness that would limit compliance with the study requirements and other serious medical illnesses requiring systemic therapies.

15. Continuance of toxicities due to prior radiotherapy or chemotherapy agents that have not recovered to ≤ Grade 1 per CTCAE v5.0

16. Failure to recover adequately, as judged by the investigator, from prior surgical procedures; the subjects have had major surgery within 28 days, or minor surgery within 2 weeks prior to the first dose of YH001.

17. Subjects received any live or attenuated vaccine within 28 days prior to the first dosing of study drug. For inactivated or attenuated COVID -19 vaccine, follow local guidelines.

18. Pregnant or breast-feeding females.

19. Any clinically significant abnormality in the laboratory

20. Subjects have another active invasive malignancy within 5 years

21. Cohort B:

    • History of esophageal or gastric variceal bleeding within the last 6 months, or current active gastrointestinal bleeding;
    • Large tumor lesion in liver (≥60% liver volum), portal vein invasion at the main portal branch (Vp4), inferior vena cava, or cardiac involvement of HCC based on imaging;
    • Clinically diagnosed hepatic encephalopathy in the last 6 months