THIO and Cadonilimab in Resectable Hepatocellular Carcinoma

A Phase Ib Open-label, Randomized Trial Evaluating Neoadjuvant Ateganosine and Cadonilimab in Resectable Hepatocellular Carcinoma

The goal of this clinical study is to find out if cadonilimab or ateganosine plus cadonilimab is effective and safe in treating resectable hepatocellular carcinoma (HCC).

Study Overview

• Status: Not yet recruiting
• Conditions: Resectable Hepatocellular Carcinoma
• Intervention / Treatment: Drug: ateganosine; Drug: Cadonilimab

Detailed Description

In this study, ateganosine (also know as THIO, 6-thio-dG, 6-thio-2'-deoxyguanosine) and cadonilimab are given via intravenous infusion. The participant will be randomly assigned to receive cadonilimab alone, ateganosine alone, or ateganosine and cadonilimab.

For this study, a cycle is defined as 21 calendar days during which drugs are administered.

If the participant is randomized to the cadonilimab alone arm, infusions will be given on the first day of every 21-day cycle. The participant will receive 2 doses of cadonilimab and then be evaluated for surgery.

If the participant is randomized to be treated with ateganosine alone, infusions of ateganosine will be given on days 1 to 3 of every 21-day cycle for 3 cycles and then the participant will be evaluated for surgery.

If the participant is randomized to be treated with ateganosine and cadonilimab, infusions of ateganosine will be given on days 1 to 3 of every 21-day cycle for 3 cycles. Infusions of cadonilimab will be given on day 5 of every 21-day cycle for 2 cycles. After receiving 3 cycles of ateganosine and 2 cycles of cadonilimab, the participant will be evaluated for surgery.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Carrie Manwaring; Phone Number: 214-648-7097; Email: carrie.manwaring@utsouthwestern.edu

Study Locations

• United States
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
      • Principal Investigator: David Hsieh, MD
      • Contact: Carrie Manwaring; Phone Number: 214-648-7097; Email: carrie.manwaring@utsouthwestern.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Diagnosis of HCC confirmed by histology or according to the American Association for the Study of Liver Disease (AASLD) criteria

   a. Availability of tumor tissue samples prior to the first day of study treatment is required for all patients.

2. HCC that is amenable to R0 resection with curative intent as determined by treating surgical/medical oncologists in consultation with the principal investigator. Subject must be a suitable candidate for surgery based on evaluations by the treating surgeon/oncologist.
3. Measurable disease according to RECIST 1.1
4. No prior anti-PD (Programmed death)-1/L1 therapies for any indication
5. Age ≥18
6. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1
7. Child Pugh A

8. Adequate organ and marrow function as defined below:

   1. ANC (absolute neutrophil count) ≥ 1.5 x 109/L (does not apply to patients with benign ethnic neutropenia)
   2. Platelets ≥ 75 x 109/L without transfusion
   3. Hemoglobin ≥ 9 g/dL without transfusion within 2 weeks of screening
   4. ALT (Alanine Aminotransferase) ≤ 3 2 x ULN (Upper Limit of Normal)
   5. Bilirubin ≤ 3 x ULN
   6. Creatinine clearance ≥ 50 mL/min calculated by the Cockcroft-Gault formula using actual body weight
9. All etiologies of chronic liver disease including but not limited to Hepatis C Virus (HCV) or Hepatis B Virus (HBV) infection. HCV and HBV infection status does not preclude eligibility as long as patients meet all other eligibility criteria but must be known prior to starting treatment. Patients with HBV must be on anti-viral therapy prior to the first day of investigational drug treatment. Patients with HCV may include active or resolved infection.

10. All men, as well as women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 3 months following the last dose of ateganosine or 4 months following the last dose of cadonilimab. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

    A female of child-bearing potential is any woman (regardless of sexual orientation, marital status, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:

    • Has not undergone a hysterectomy or bilateral oophorectomy; or
    • Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).
11. Ability to understand and the willingness to sign a written informed consent.
12. Willing and able to comply with the requirements and restrictions in this protocol.

Exclusion Criteria:

1. Presence of extrahepatic extension of disease
2. Prior locoregional therapy to target lesions is not allowed. History of curative locoregional therapy is allowed provided the following are met: 1) previously treated tumor is not viable without evidence of residual disease for at least 12 months, and 2) patient has not received local therapy in the past 12 months.
3. Known fibrolamellar HCC or combined HCC-cholangiocarcinoma histology
4. History of hepatic encephalopathy
5. Severe ascites requiring paracentesis in the past 3 months
6. Subjects may not be receiving any other investigational agents for the treatment of the cancer under study
7. Prior significant bleeding event in the past 3 months that may pose a surgical risk
8. History of trauma or major surgery within 28 days prior to the first dose of study drug administration. (Tumor biopsy or placement of central venous access catheter (eg, port or similar) is not considered a major surgical procedure)

9. Underlying medical conditions that, in the investigator's opinion, will make the administration of study drugs hazardous, including but not limited to:

   1. Autoimmune interstitial lung disease (lymphangitic spread of cancer is not disqualifying or stable/chronic lung disease that is not likely to be autoimmune in nature and progressive),
   2. Active viral, bacterial, or fungal infections requiring parenteral treatment within 14 days of the initiation of study drugs,
   3. Clinically significant cardiovascular disease,
   4. A condition that may obscure the interpretation of toxicity determination or AEs,
   5. History of prior bone marrow and/or solid-organ transplantation
10. Hypersensitivity to IV contrast; not suitable for pre-medication

11. Any active autoimmune disease or a documented history of autoimmune disease or syndrome that required systemic treatment in the past year (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs), with the following exceptions:

    1. Autoimmune diseases with only dermatologic involvement such as eczema, vitiligo, lichen chronicus, or resolved childhood asthma/atopy which involves less than 10% of the body surface area and symptoms are well controlled on topical treatments without recent exacerbations requiring other therapies
    2. Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for thyroid, adrenal or pituitary insufficiency) is not considered a form of systemic treatment
    3. Participants with asthma who require intermittent use of bronchodilators, inhaled corticosteroids, or local corticosteroid injections will not be excluded from this study
12. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg/day prednisone equivalent) or other immunosuppressive medications within 14 days of study administration. Inhaled or topical steroids and adrenal replacement doses ≤10 mg/day prednisone equivalents are permitted in the absence of autoimmune disease.
13. Prior malignancy that required systemic treatment within the previous 2 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix, breast, or prostate cancer. Patients with a cancer history with a low risk of recurrence or progression may be enrolled as determined by the principal investigator.
14. Prisoners or subjects who are involuntarily incarcerated
15. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after contraception and until the termination of gestation, confirmed by a positive hCG (Human chorionic gonadotropin) laboratory test
16. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
17. Evidence of bleeding diathesis or significant coagulopathy
18. Current use of full dose anticoagulant use which cannot be temporarily discontinued for surgery
19. Receipt of live vaccinations within 30 days of first treatment day

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A: Ateganocine + Cadonilimab; Ateganosine: 60 mg/day (180 mg/cycle) IV over 30 minutes±5 minutes Cadonilimab: 10 mg/kg IV over 60 minutes±5 minutes	Drug: ateganosine; ateganosine: 180 mg IV D1, D2, D3 of 21-day cycle; Other Names: THIO, 6-thio-dG, 6-thio-2'-deoxyguanosine; Drug: Cadonilimab; cadonilimab: 10 mg/kg IV D5 of 21-day cycle; Other Names: AK104 (or AK-104)
Experimental: Arm B: Ateganocine; Ateganosine: 60 mg/day (180 mg/cycle) IV over 30 minutes±5 minutes	Drug: ateganosine; ateganosine: 180 mg IV D1, D2, D3 of 21-day cycle; Other Names: THIO, 6-thio-dG, 6-thio-2'-deoxyguanosine
Experimental: Arm C: Cadonilimab; Cadonilimab: 10 mg/kg IV over 60 minutes±5 minutes	Drug: Cadonilimab; cadonilimab: 10 mg/kg IV D5 of 21-day cycle; Other Names: AK104 (or AK-104)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of treatment-related delay of surgical resection >28 days from expected surgery date.	Safety is measured as the proportion of participants who experience a treatment-related delay in the planned surgical resection, defined as surgery occurring more than 28 days after the expected surgery date (day 5 of cycle 3 for all treatment arms)	28 days after the expected surgery date (day 5 of cycle 3 for all treatment arms)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathologic response of ateganosine plus cadonilimab	Response will be determined by pathology review of resection specimens and will be based on <30% residual viable tumor in the tumor bed at the time of surgery.	Day 1 of treatment up to surgery resection
Radiographic response after ateganosine plus cadonilimab	Radiographic response will be based on changes in only the largest diameter (unidimensional measurement) of the tumor lesions per the RECIST v1.1 criteria.	Baseline to between day 2-4 of the last cycle immediately prior to surgery
Survival outcomes after ateganosine plus cadonilimab	Overall survival (measured as time from the first dose of study treatment to death from any cause)	first dose of drug (whichever was last) up to 36 months until death, loss to follow-up, or until study termination by the Sponsor.
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]	Incidence of treatment emergent adverse events (AEs), immune-related AEs, and serious AEs (Grade ≥3 per Common Terminology Criteria for Adverse Events, CTCAE v5.0).	post last dose visit up to 3 years until death, loss to follow-up, or until study termination by the Sponsor.

Collaborators and Investigators

• Sponsor: University of Texas Southwestern Medical Center
• Collaborators: National Cancer Institute (NCI); Maia Biotechnology

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2026
• Primary Completion (Estimated): May 1, 2030
• Study Completion (Estimated): May 1, 2031

Study Registration Dates

• First Submitted: January 29, 2026
• First Submitted That Met QC Criteria: February 25, 2026
• First Posted (Actual): March 3, 2026

Study Record Updates

• Last Update Posted (Actual): March 3, 2026
• Last Update Submitted That Met QC Criteria: February 25, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: hepatocellular carcinoma; liver
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Liver Diseases; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular; alpha-2'-deoxythioguanosine
• Other Study ID Numbers: SCCC-12225; STU20251351

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No