A Clinical Study Evaluating the Safety and Efficacy of Ivonescimab as Second-line Treatment in Patients With Advanced Hepatocellular Carcinoma (ANTHELA)

Inclusion Criteria:

1. Participant, or legal representative (if applicable), must be capable of understanding the purpose of the Study and have signed written informed consent form (ICF) prior to beginning specific protocol procedures.
2. Female or male participants ≥ 18 years of age at the time of signing ICF.
3. Locally advanced or metastatic unresectable HCC: BCLC intermediate (B) (BCLC-B patients should not be amenable to locoregional therapies (TACE/TARE)) or advanced (C) stage, ineligible for curative options (e.g. resection, transplant, or ablation).
4. Histological or cytological confirmation of HCC or non-invasive clinical diagnosis of HCC as per American Association for the Study of Liver Diseases (AASLD) criteria in cirrhotic participants.
5. At least 1 measurable lesion according to RECIST v.1.1.
6. Disease progression as defined by RECIST 1.1 following prior dual immune checkpoint blockade for HCC with durvalumab-tremelimumab or nivolumab-ipilimumab. A wash out period of at least 28 days or 5 half-lives, whichever is shorter, from last cycle must be completed for eligibility in this Study.
7. Participant has adequate bone marrow, liver, and renal function.
8. Participants diagnosed with HBV infection-defined by the presence of hepatitis B surface antigen (HBsAg), detectable HBV DNA, or hepatitis B core antibodies (anti-HBc Ab)-and meeting eligibility criteria must receive at least 14 days of antiviral treatment according to institutional guidelines to achieve sufficient viral suppression (HBV DNA ≤2000 IU/mL) before enrollment. Note: Individuals who are HBV-positive must continue antiviral therapy throughout the Study and for six months following the final dose of the Study drug.
9. Participants with HCV infection must have a confirmed diagnosis at enrollment, indicated by detectable HCV RNA or anti-HCV antibodies. Management of HCV will follow local institutional protocols.
10. Resolution of all acute toxic effects of prior anticancer therapy to grade ≤ 1 as determined by the US National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 6.0 (v.6.0) (except for alopecia or other toxicities not considered a safety risk for the participant at investigator's discretion).
11. ECOG performance status of 0-1.
12. Child-Pugh Score class A or B7.
13. Minimum life expectancy of ≥ 12 weeks at screening.
14. Women of childbearing potential who are sexually active with a non-sterilized male partner must have a negative serum pregnancy test within 14 days before Study treatment initiation. In addition, they must agree to use one highly effective method of birth control from the time of screening until at least 3 months after the last dose of Study treatments. Female participants must refrain from egg cell donation and breastfeeding during this same period.
15. Male participants who are sexually active with a female partner of childbearing potential must be surgically sterile or using an acceptable method of contraception from the time of screening until at least 3 months after the last administration of the Study drug. Male participants must not donate or bank sperm during this same period.
16. Participant must be accessible for treatment and follow-up.

Exclusion Criteria:

1. Participation in another clinical trial, interventional or observational, until the Study's safety visit.

   Note: participation in retrospective studies or data analysis is allowed.

2. Treatment with approved or investigational anti-cancer therapy within 14 days prior to initiation of Study drug.

3. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.

4. Has previously been treated with anti-VEGF therapies in the palliative setting. Such treatment is allowed if given for another malignancy or as a neoadjuvant/adjuvant therapy followed by resection with curative intent.

5. Diagnosis of immunodeficiency or participant is receiving chronic systemic steroid therapy (in doses exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of Study interventions. The use of physiologic doses of corticosteroids may be approved after consultation with the Medical Monitor.

6. Active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Prior immune-related AEs on prior treatment that required systemic corticoids.

7. History of bleeding events within 3 months prior to initial treatment.

8. Presence of clinically significant ascites requiring non-pharmacological intervention such as large-volume paracentesis, transjugular intrahepatic portosystemic shunt (TIPS), or other invasive procedures in the last 14 days before inclusion.

9. Non-healing wound, non-healing ulcer, or non-healing bone fracture.

10. Known active uncontrolled or symptomatic central nervous system (CNS) metastases and/or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or progressive growth.

11. Have a concurrent malignancy or malignancy within 3 years of Study enrollment with the exception of carcinoma in situ of the cervix, basal cell carcinoma or squamous cell carcinoma of the skin that has been previously treated with curative intent. For other cancers considered to have a low risk of recurrence, discussion with the Sponsor's Medical Monitor is required. Prior diagnosis of HCC is not considered an exclusion criterion.

12. Known allergy or hypersensitivity reaction to ivonescimab or its incorporated substances.

13. Palliative radiotherapy with a limited field of radiation within 2 weeks or with wide field of radiation or to more than 30% of the bone marrow within 4 weeks prior to start of Study treatment.

14. Major surgical procedure or significant traumatic injury within 28 days before the first dose of Study treatment or anticipation of need for major surgery within the course of the Study treatment.

15. Has an active cardiac disease or a history of cardiac dysfunction or conduction abnormalities.

16. Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (e.g., pulmonary emboli within three months of the Study enrolment, severe asthma, severe chronic obstructive pulmonary disease [COPD], restrictive lung disease, pleural effusion, post COVID-19 pulmonary fibrosis, etc.), and any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement (e.g., rheumatoid arthritis, Sjogren's syndrome, sarcoidosis, etc.), or prior pneumonectomy.

17. Has a history of non-infectious clinically relevant interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening and that according to investigator could represent a safety issue for treatment with ivonescimab.

18. Pregnant or lactating women or participants not willing to apply highly effective contraception as defined in the protocol.

19. Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the participant's safe participation in and completion of the Study.

20. Concurrent infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) and/or HBV.

21. Has active primary immunodeficiency virus (HIV) infection. Participants with undetectable viral load, T CD4+ > 500 cells/uL and receiving triple antiviral therapy are eligible.

22. Other uncontrolled infection at the time of enrollment.

23. Receipt of live or attenuated vaccine within 30 days prior to the first dose of ivonescimab.

24. A history of uncontrolled seizures, CNS disorders, or serious and/or unstable pre-existing psychiatric disability judged by the investigator to be clinically significant and adversely affecting compliance to Study drug or interfering with participant's safety.

25. Known substance abuse or any other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgement, contraindicate participation in the Study.

26. Inability or unwillingness to comply with the requirements of the protocol in the opinion of the investigator.