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This is a prospective, open-label, single-arm phase II study designed to evaluate the efficacy and safety of FOLFOX-based hepatic arterial infusion chemotherapy (HAIC) in combination with donafenib and pucotenlimab as first-line treatment in patients with unresectable intrahepatic cholangiocarcinoma.
Eligible patients will receive FOLFOX-HAIC administered every three weeks together with oral donafenib and intravenous pucotenlimab. Tumor response will be assessed according to RECIST v1.1. The primary objective of the study is to determine the objective response rate, and secondary objectives include progression-free survival, overall survival, disease control rate, and safety.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| FOLFOX-HAIC + Donafenib + Pucotenlimab | Experimental | Participants receive combination therapy in 21-day cycles: HAIC (FOLFOX): Hepatic Arterial Infusion Chemotherapy administered on Day 1 via a port-catheter system: Oxaliplatin: 85 mg/m^2 intra-arterial infusion (2 hours). Leucovorin: 400 mg/m^2 intra-arterial infusion (2 hours). Fluorouracil: 400 mg/m^2 bolus intra-arterial injection, followed by 2400 mg/m^2 continuous intra-arterial infusion over 46 hours. Pucotenlimab: 200 mg administered via intravenous (IV) infusion on Day 1. Donafenib: 0.2 g (200 mg) administered orally, twice daily (BID), continuously throughout the cycle. Treatment continues until disease progression, unacceptable toxicity, or withdrawal of consent. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| hepatic arterial infusion chemotherapy (HAIC) | Procedure | This intervention consists of a combination regimen including hepatic arterial infusion chemotherapy, targeted therapy, and immunotherapy for the treatment of unresectable intrahepatic cholangiocarcinoma. Hepatic arterial infusion chemotherapy is delivered through an implanted hepatic arterial catheter using a FOLFOX-based regimen, allowing high local drug concentrations within the liver while reducing systemic exposure. Donafenib, an oral multikinase inhibitor with anti-angiogenic activity, is administered continuously during treatment. Pucotenlimab, a programmed cell death protein-1 inhibitor, is administered by intravenous infusion to enhance antitumor immune responses. The combination is intended to achieve synergistic antitumor effects through regional cytotoxic chemotherapy, inhibition of tumor angiogenesis, and immune checkpoint blockade. Safety and antitumor activity of the regimen will be evaluated throughout the study period. |
| Measure | Description | Time Frame |
|---|---|---|
| Objective Response Rate (ORR) | The ORR is defined as the percentage of participants who achieve a confirmed Complete Response (CR) or Partial Response (PR). Efficacy will be evaluated by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. | From baseline until disease progression or loss of clinical benefit, assessed approximately every 6 to 9 weeks, up to 2 years. |
| Measure | Description | Time Frame |
|---|---|---|
| Progression-Free Survival (PFS) | Defined as the time from the first date of study treatment to the date of first documented disease progression per RECIST v1.1 or death from any cause, whichever occurs first. | From baseline up to approximately 2 years. |
| Overall Survival (OS) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Zhongguo Zhou, PhD | Contact | 020-87343115 | zhouzhg@sysucc.org.cn |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Sun Yat-san University Cancer Center | Guangzhou | Guangdong | 510080 | China |
Individual participant data (IPD) will be made available upon request after publication of the study results.
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| Donafenib | Drug | This intervention consists of a combination regimen including hepatic arterial infusion chemotherapy, targeted therapy, and immunotherapy for the treatment of unresectable intrahepatic cholangiocarcinoma. Hepatic arterial infusion chemotherapy is delivered through an implanted hepatic arterial catheter using a FOLFOX-based regimen, allowing high local drug concentrations within the liver while reducing systemic exposure. Donafenib, an oral multikinase inhibitor with anti-angiogenic activity, is administered continuously during treatment. Pucotenlimab, a programmed cell death protein-1 inhibitor, is administered by intravenous infusion to enhance antitumor immune responses. The combination is intended to achieve synergistic antitumor effects through regional cytotoxic chemotherapy, inhibition of tumor angiogenesis, and immune checkpoint blockade. Safety and antitumor activity of the regimen will be evaluated throughout the study period. |
|
| Pucotenlimab | Drug | This intervention consists of a combination regimen including hepatic arterial infusion chemotherapy, targeted therapy, and immunotherapy for the treatment of unresectable intrahepatic cholangiocarcinoma. Hepatic arterial infusion chemotherapy is delivered through an implanted hepatic arterial catheter using a FOLFOX-based regimen, allowing high local drug concentrations within the liver while reducing systemic exposure. Donafenib, an oral multikinase inhibitor with anti-angiogenic activity, is administered continuously during treatment. Pucotenlimab, a programmed cell death protein-1 inhibitor, is administered by intravenous infusion to enhance antitumor immune responses. The combination is intended to achieve synergistic antitumor effects through regional cytotoxic chemotherapy, inhibition of tumor angiogenesis, and immune checkpoint blockade. Safety and antitumor activity of the regimen will be evaluated throughout the study period. |
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| FOLFOX (5-fluorouracil, Leucovorin, Oxaliplatin) | Drug | This intervention consists of a combination regimen including hepatic arterial infusion chemotherapy, targeted therapy, and immunotherapy for the treatment of unresectable intrahepatic cholangiocarcinoma. Hepatic arterial infusion chemotherapy is delivered through an implanted hepatic arterial catheter using a FOLFOX-based regimen, allowing high local drug concentrations within the liver while reducing systemic exposure. Donafenib, an oral multikinase inhibitor with anti-angiogenic activity, is administered continuously during treatment. Pucotenlimab, a programmed cell death protein-1 inhibitor, is administered by intravenous infusion to enhance antitumor immune responses. The combination is intended to achieve synergistic antitumor effects through regional cytotoxic chemotherapy, inhibition of tumor angiogenesis, and immune checkpoint blockade. Safety and antitumor activity of the regimen will be evaluated throughout the study period. |
|
Defined as the time from the first date of study treatment to the date of death from any cause. |
| From baseline up to approximately 3 years. |
| Disease Control Rate (DCR) | Defined as the percentage of participants who achieve a confirmed Complete Response (CR), Partial Response (PR), or Stable Disease (SD) maintained for a specified minimum duration, according to RECIST v1.1. | From baseline until disease progression, assessed approximately every 6 to 9 weeks, up to 2 years. |
| Duration of Response (DoR) | Defined as the time from the first documentation of objective response (CR or PR) to the first documentation of disease progression or death from any cause. | From date of first response up to approximately 2 years. |
| Safety (Adverse Events) | Number of participants with treatment-related adverse events as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. | From the first dose of study treatment through 30 days after the last dose. |
| Surgical Conversion Rate | The percentage of participants with initially unresectable disease who undergo successful surgical resection (R0 resection) following study treatment. | From baseline up to approximately 2 years. |
| ID | Term |
|---|---|
| D018281 | Cholangiocarcinoma |
| C562580 | Cirrhosis, Familial, with Pulmonary Hypertension |
| ID | Term |
|---|---|
| D000230 | Adenocarcinoma |
| D002277 | Carcinoma |
| D009375 | Neoplasms, Glandular and Epithelial |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
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| ID | Term |
|---|---|
| C000710249 | donafenib |
| C410216 | Folfox protocol |
| D005472 | Fluorouracil |
| D002955 | Leucovorin |
| D000077150 | Oxaliplatin |
| ID | Term |
|---|---|
| D014498 | Uracil |
| D011744 | Pyrimidinones |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D005575 | Formyltetrahydrofolates |
| D013763 | Tetrahydrofolates |
| D005492 | Folic Acid |
| D011622 | Pterins |
| D011621 | Pteridines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D003067 | Coenzymes |
| D045762 | Enzymes and Coenzymes |
| D056831 | Coordination Complexes |
| D009930 | Organic Chemicals |
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