A Phase II, Single-Arm, Prospective Trial on the Efficacy and Safety of QL1706 Combination Regimen as Second-Line Therapy for Targeted-Immunotherapy-Resistant Hepatocellular Carcinoma

NCT07138885 | Active Not Recruiting Phase 2 DMC

• 1 other identifier: DRIVE-II
• Study Type: interventional
• Target: 62
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this prospective Phase II clinical trial is to evaluate the efficacy and safety of QL1706-based combination therapy in patients with hepatocellular carcinoma (HCC) who have failed prior targeted-immunotherapy (e.g., anti-PD-1/PD-L1 + antiangiogenic therapy). The main question is: Can the combination of localized-regional therapy (e.g., HAIC/TACE) and systemic dual immunotherapy (QL1706) overcome resistance and improve outcomes in second-line HCC treatment? Participants will:

1. 1.Receive QL1706 (a dual immune checkpoint inhibitor) combined with either:
2. 2.Undergo regular imaging (e.g., MRI/CT) and biomarker assessments for efficacy monitoring.
3. 3.Be evaluated for adverse events (AEs) and quality of life.

Conditions

Hepatocellular Carcinoma (HCC); Second Line Treatment

Keywords

Second line treatment; Hepatocellular Carcinoma (HCC); Immunotherapy resistance

Outcome Measures

Primary Outcomes (1)

• Objective response rate (ORR) by RECIST 1.1

  ORR is defined as the percentage of participants who have best overall response (BOR) of complete response (CR) or partial response (PR) at the time of data cutoff as assessed by RECIST 1.1.

  From date of first dose of study drug until disease progression (up to approximately 3 years)

Secondary Outcomes (10)

• Objective response rate (ORR) by mRECIST

  From date of first dose of study drug until disease progression (up to approximately 3 years)

• The disease control rate (DCR)

  From date of first dose of study drug until disease progression, stable disease (up to approximately 3 years)

• The time to response (TTR)

  From date of first dose of study drug to the date of first documentation of CR or PR (up to approximately 3 years)

• Duration of response (DOR) by RECIST 1.1 and mRECIST

  From the first documentation of CR or PR to the first date of documentation of disease progression or death whichever occurs first (up to approximately 3 years)

• The progression-free survival time (PFS)

  From date of first dose of study drug to the date of first documentation of disease progression or death (up to approximately 3 years)

Study Arms (2)

HAI-FOLFOX + bevacizumab + QL1706

EXPERIMENTAL

To evaluate the objective response rate (ORR) of HAI-FOLFOX + bevacizumab + QL1706 in patients with intermediate-advanced hepatocellular carcinoma (HCC) who developed resistance or recurrence after prior treatment with surgical resection/ablation/TACE combined with TKIs and/or PD-(L)1 inhibitors.

Procedure: HAI-FOLFOX + bevacizumab + QL1706

TACE + bevacizumab + QL1706 + TAS-102

EXPERIMENTAL

To evaluate the objective response rate (ORR) of TACE + bevacizumab + TAS-102 + QL1706 in patients with intermediate-advanced HCC who developed resistance or recurrence after prior HAI-FOLFOX combined with TKIs and/or PD-(L)1 inhibitors.

Procedure: TACE + bevacizumab + TAS-102 + QL1706

Interventions

HAI-FOLFOX + bevacizumab + QL1706 PROCEDURE

Arm 1: HAI-FOLFOX Administration (Day 1 of Each Cycle) Super-selective insertion the arterial catheter into the tumor-feeding artery, then infusion: Oxaliplatin: 85 mg/m², Leucovorin: 400 mg/m², 5-FU: 2500 mg/m² Administer bevacizumab (7.5 mg/kg; total dose capped at 300 mg or 400 mg) via arterial infusion. Then QL1706 (5 mg/kg, IV infusion, Q3W). Treatment Schedule: Repeat HAI-FOLFOX + arterial bevacizumab every 3 weeks (max 6 cycles), followed by QL1706 maintenance (Q3W).

Also known as: HAI-FOLFOX, bevacizumab, QL1706

HAI-FOLFOX + bevacizumab + QL1706

TACE + bevacizumab + TAS-102 + QL1706 PROCEDURE

Arm 2: On-Demand TACE (Lipiodol: ≤10 mL, mixed with platinum + doxorubicin agent, each ≤50 mg) to form an emulsion. Repeat TACE until TACE resistance develops (typically \~4 sessions). Administer bevacizumab (7.5 mg/kg; total dose capped at 300 mg or 400 mg) via intra-arterial route. After first TACE, begin TAS-102 (15 mg/m² po BID) once liver function recovers to acceptable levels. Then QL1706 (5 mg/kg, IV infusion, Q3W).

Also known as: bevacizumab, TAS-102, QL1706, TACE

TACE + bevacizumab + QL1706 + TAS-102

Eligibility Criteria

• Age: 18 Days - 65 Days
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Voluntary Participation, Willingly signs the written informed consent form.
• Aged 18-65 years (inclusive), any gender.
• Histologically, cytologically, or clinically confirmed hepatocellular carcinoma (HCC) with disease progression after first-line targeted therapy combined with immunotherapy, or intolerable to first-line targeted-immunotherapy combination treatment.
• No prior exposure to VEGF monoclonal antibodies, CTLA-4 inhibitors, or bispecific antibodies. For arm 1: No prior treatment with oxaliplatin or fluorouracil-based drugs.
• Liver Function: Child-Pugh class A or class B (score ≤7), with no history of hepatic encephalopathy.
• Performance Status: ECOG PS score 0 or 1.
• Life Expectancy ≥12 weeks.
• Measurable Lesion: ≥1 measurable target lesion per RECIST v1.1 (not previously irradiated/localized; lesions in prior treatment areas are acceptable if progression is confirmed).
• Preserved organ \& bone marrow function (within 7 days before treatment; no blood products/growth factors within 14 days prior):
• Neutrophil count (ANC) ≥1.5×10⁹/L
• Platelets ≥75×10⁹/L
• Hemoglobin ≥90 g/L
• Albumin ≥28 g/L
• ALT/AST/Alkaline phosphatase (AKP) ≤3×ULN
• Total bilirubin (TBIL) ≤2×ULN

You may not qualify if:

• Histologically/cytologically confirmed fibrolamellar HCC, sarcomatoid HCC, cholangiocarcinoma, or mixed hepatocellular-cholangiocarcinoma.
• Other active malignancies within 5 years prior to enrollment, except cured localized tumors (e.g., basal cell carcinoma, squamous cell skin cancer, superficial bladder cancer, in situ prostate/cervical/breast cancer).
• History of or planned liver transplantation.
• Clinically significant ascites requiring therapeutic paracentesis, uncontrolled pleural/pericardial effusion (asymptomatic minimal ascites on imaging allowed).
• Known CNS metastases or leptomeningeal disease.
• Tumor thrombus involving both main portal vein and superior mesenteric vein, or portal vein and inferior vena cava.
• High-risk variceal bleeding:
• Esophageal/gastric variceal bleeding within 6 months
• High-grade varices on endoscopy within 3 months
• Portal hypertension with bleeding risk (splenomegaly, active ulcers, occult blood+, or endoscopic "red signs").
• Life-threatening hemorrhage within 3 months requiring transfusion/surgery/medical intervention.
• Significant bleeding risk:
• Hemoptysis/tumor bleeding within 2 weeks
• Thromboembolism within 6 months
• Therapeutic anticoagulation (except prophylactic LMWH) within 2 weeks

Sponsors & Collaborators

• Sun Yat-sen University: lead
• Qilu Pharmaceutical Co., Ltd.: collaborator

Study Sites (1)

Sun Yat-sen University Cancer Center

Guangzhou, Guangdong, 510060, China

Location

MeSH Terms

Conditions

Carcinoma, Hepatocellular

Interventions

Bevacizumab; trifluridine tipiracil drug combination

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Pei-Hong Wu, Professor

  Sun Yat-Sen University Cancer Center

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor, Associate Chief Physician

Model Details: Arm 1: To evaluate the objective response rate (ORR) of HAI-FOLFOX + bevacizumab + QL1706 (iparomlimab and tuvonralimab, PD-1/CTLA-4 dual inhibitor) in patients with intermediate-advanced hepatocellular carcinoma (HCC) who developed resistance or recurrence after prior treatment with surgical resection/ablation/TACE combined with TKIs and/or PD-(L)1 inhibitors. Arm 2: To evaluate the objective response rate (ORR) of TACE + bevacizumab + TAS-102 + QL1706 in patients with intermediate-advanced HCC who developed resistance or recurrence after prior HAI-FOLFOX combined with TKIs and/or PD-(L)1 inhibitors.

Study Record Dates

• First Submitted: August 17, 2025
• First Posted: August 24, 2025
• Study Start: August 1, 2025
• Primary Completion (Estimated): July 31, 2027
• Study Completion (Estimated): July 31, 2028
• Last Updated: April 29, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR
• Time Frame: Beginning 3 months and ending 1 years after the publication of results.
• Access Criteria: Data will be shared with qualified researchers who: 1. Submit a scientifically valid research proposal with defined objectives and statistical analysis plans 2. Require individual participant data (IPD) to address research questions not covered in the original publication 3. Provide institutional ethics approval for the proposed secondary analysis 4. Sign a Data Use Agreement (DUA) committing to: * Protect participant confidentiality * Not attempt to re-identify participants * Not transfer data to third parties * Destroy data after analysis completion

Locations

CN (1)