Iparomlimab and Tuvonralimab With Lenvatinib, Radiotherapy, and HAIC for Hepatocellular Carcinoma With Portal Vein Tumor Thrombus

Phase 2RecruitingNCT07776080

Union Hospital, Tongji Medical College, Huazhong University of Science and Technology35 enrolled

Overview

The purpose of this study is to learn how well a combination of iparomlimab and tuvonralimab (QL1706), lenvatinib, radiotherapy, and hepatic arterial infusion chemotherapy (HAIC) works and how safe it is for people with hepatocellular carcinoma (HCC) that has grown into the portal vein, forming a portal vein tumor thrombus (PVTT). Participants will receive iparomlimab and tuvonralimab together with lenvatinib, radiotherapy directed at the portal vein tumor thrombus, and HAIC, which delivers chemotherapy directly through the hepatic artery. Researchers will evaluate how long the cancer remains controlled without getting worse, how much the tumors shrink, how long participants survive, and whether the treatment makes surgery possible for some participants. Treatment-related side effects will also be assessed. The study will also explore whether features in tumor tissue and blood are associated with treatment response and may help identify patients who are more likely to benefit from this treatment strategy.

This is a prospective, single-center, single-arm Phase II study designed to evaluate the efficacy and safety of a multimodal first-line treatment strategy consisting of iparomlimab and tuvonralimab (QL1706), lenvatinib, radiotherapy, and hepatic arterial infusion chemotherapy (HAIC) in patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT). A total of 35 participants are planned to be enrolled. Treatment will be administered according to the following sequence. Iparomlimab and tuvonralimab (QL1706) will be administered intravenously at a dose of 7.5 mg/kg on Day 1 of each 3-week cycle, with each infusion given over 30-60 minutes. Lenvatinib will be administered orally once daily at 8 mg for participants weighing \<60 kg and 12 mg for those weighing ≥60 kg. PVTT-directed external beam radiotherapy will be initiated within 7 days after the first administration of QL1706. The radiation target will include the PVTT. Gross tumor volume will be delineated based on the venous or delayed phase of contrast-enhanced imaging. A planning target volume margin of approximately 5-15 mm will be added according to the protocol. Stereotactic body radiotherapy will be delivered at a total dose of 18-40 Gy, with a dose of 3-6 Gy per fraction. HAIC will be initiated in combination with the second cycle of QL1706. Lenvatinib will be withheld for 3 days before HAIC and for 7 days after HAIC. The interruption period may be extended at the investigator's discretion according to the participant's clinical condition and laboratory findings. HAIC will be performed using a FOLFOX-based regimen through a catheter selectively placed in the main tumor-feeding hepatic artery. Oxaliplatin will be administered at 85 mg/m² by hepatic arterial infusion over 3 hours, followed by leucovorin calcium at 200 mg/m² over 3-5 hours. Fluorouracil will then be administered at 400 mg/m² by hepatic arterial injection, followed by 2400 mg/m² as a continuous hepatic arterial infusion over 46 hours. HAIC will be repeated every 3 weeks for up to 4 cycles, with the number of cycles adjusted according to the participant's clinical condition. QL1706 and lenvatinib will be continued for up to 2 years or until disease progression, unacceptable toxicity, or another protocol-defined reason for treatment discontinuation. Tumor response will be assessed every 2 treatment cycles, corresponding to approximately every 6 weeks, according to modified Response Evaluation Criteria in Solid Tumors (mRECIST). Participants who achieve sufficient tumor regression will be reviewed by a multidisciplinary team, and those considered suitable for curative resection may undergo conversion surgery. The primary objective of the study is to evaluate progression-free survival. Secondary assessments include objective response rate, disease control rate, duration of response, overall survival, conversion-to-surgery rate, pathological complete response in participants undergoing surgery, and treatment safety.

Interventions

Iparomlimab and Tuvonralimab (QL1706)DRUG

Iparomlimab and tuvonralimab (QL1706) will be administered intravenously at 7.5 mg/kg on Day 1 of each 3-week cycle. Each infusion will be administered over 30-60 minutes. Treatment will continue for up to 2 years or until disease progression, unacceptable toxicity, or another protocol-defined reason for discontinuation.

LenvatinibDRUG

Lenvatinib will be administered orally once daily at 8 mg for participants weighing \<60 kg and 12 mg for participants weighing ≥60 kg. During HAIC treatment, lenvatinib will be withheld for 3 days before HAIC and for 7 days after HAIC. The interruption period may be extended at the investigator's discretion based on the participant's clinical condition and laboratory findings. Lenvatinib will continue for up to 2 years or until disease progression, unacceptable toxicity, or another protocol-defined reason for discontinuation.

RadiotherapyRADIATION

External beam radiotherapy directed at the portal vein tumor thrombus (PVTT) will be initiated within 7 days after the first administration of QL1706. The radiation target will include the PVTT. Gross tumor volume will be delineated based on the venous or delayed phase of contrast-enhanced imaging, and a planning target volume margin of approximately 5-15 mm will be applied according to the protocol. SBRT will be delivered at a total dose of 18-40 Gy with 3-6 Gy per fraction.

hepatic arterial infusion chemotherapy (HAIC)PROCEDURE

HAIC will be initiated during Cycle 2 of systemic therapy. Using a modified Seldinger technique, a catheter will be selectively placed in the main tumor-feeding hepatic artery for administration of FOLFOX chemotherapy. HAIC will be repeated every 3 weeks for up to 4 cycles, with the number of cycles adjusted according to the participant's clinical condition

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Age ≥18 and ≤75 years at the time of signing informed consent. 2. Histologically or clinically confirmed hepatocellular carcinoma (HCC) according to the 2024 Chinese Guidelines for the Diagnosis and Treatment of Primary Liver Cancer. 3. Radiologically confirmed portal vein tumor thrombus (PVTT), classified as Cheng type I-IV. 4. No prior systemic or local treatment directed at PVTT, including targeted therapy, immunotherapy, or systemic chemotherapy. 5. Child-Pugh class A or B with a Child-Pugh score ≤7. 6. Considered unsuitable for curative surgery or liver transplantation after multidisciplinary evaluation, but suitable for radiotherapy. 7. Adequate organ function, including: WBC ≥3.0 × 10⁹/L; PLT ≥50 × 10⁹/L; hemoglobin ≥80 g/L; ALT ≤5 × ULN; AST ≤5 × ULN; total bilirubin ≤3 × ULN; albumin ≥28 g/L; and creatinine clearance ≥80 mL/min. 8. At least one measurable lesion according to mRECIST. 9. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. 10. Life expectancy \>3 months. 11. No history of abdominal radiotherapy. 12. Women of childbearing potential must use effective contraception beginning at least 1 month before screening and throughout the study until the protocol-specified period after study completion. 13. Willing and able to comply with study follow-up until death, study completion, or study termination. Exclusion Criteria: 1. ECOG performance status ≥2. 2. Child-Pugh score ≥8. 3. Severe dysfunction of major organs, including the heart, liver, or kidneys. 4. Prior targeted therapy, immunotherapy, radiotherapy, systemic chemotherapy, or other anticancer treatment. 5. Known hypersensitivity or allergic reaction to any component of the study treatment. 6. History of organ transplantation or autologous/allogeneic stem cell transplantation. 7. Currently receiving chronic systemic immunotherapy or hormonal therapy other than physiologic replacement therapy. 8. Any unstable systemic disease, including active infection; uncontrolled severe hypertension; unstable angina; new-onset angina within the previous 3 months; congestive heart failure of NYHA class II or higher; myocardial infarction within the previous 6 months; severe cardiac arrhythmia requiring medication; gastrointestinal bleeding within the previous 1 month; or active bleeding tendency. 9. Concurrent other malignancy that has not been cured, except carcinoma in situ at another site. 10. Any disease, metabolic disorder, physical examination finding, or laboratory abnormality that, in the investigator's judgment, suggests a contraindication to the study treatment or a high risk of treatment-related complications. 11. Evidence of acute or active hepatitis B or hepatitis C infection, including HBV-DNA \>2,000 IU/mL or HCV-RNA \>1,000 copies/mL. 12. Pregnancy or breastfeeding. 13. Any other unfavorable medical or psychiatric condition that, in the investigator's judgment, may affect protocol compliance or evaluation of study endpoints and makes the participant unsuitable for the study. 14. Lack of legal capacity or limited legal capacity. 15. Other contraindications to radiotherapy or targeted/immunotherapy. 16. Any participant considered unsuitable for enrollment by the investigator.

Outcomes

Primary Outcomes

Progression-Free Survival (PFS)

Progression-free survival is defined as the time from the first administration of study treatment to the first documented radiographic disease progression, as assessed by the investigator according to mRECIST, or death from any cause, whichever occurs first.

Time frame: From first administration of study treatment to radiographic disease progression or death from any cause, whichever occurs first, up to 24 months

Secondary Outcomes

Objective Response Rate (ORR)

ORR is defined as the proportion of participants who achieve a confirmed complete response (CR) or partial response (PR), as assessed by the investigator according to mRECIST.

Time frame: From first administration of study treatment to disease progression or the last tumor assessment, up to 24 months

Overall Survival (OS)

Overall survival is defined as the time from the first administration of study treatment to death from any cause.

Time frame: From first administration of study treatment to death from any cause, up to 24 months

Incidence and Severity of Adverse Events

The incidence and severity of adverse events will be assessed and graded according to NCI CTCAE version 5.0.

Time frame: From informed consent through 30 days after the last administration of study treatment