Candonilimab in Combination With LM-302 for Claudin 18.2 Positive-advanced Biliary Tract Cancer After Failure of Standard of Chemotherapy and PD1/PD-L1 Antibody

Two Stage, Multi-center Trial of Candonilimab in Combination With LM-302 for Treatment of Patients With Claudin 18.2 Positive-advanced Biliary Tract Cancer After Failure of Standard of Chemotherapy and PD1/PD-L1 Antibody

In this clinical study, we will evaluate the efficacy and safety of cardonilimumab (PD1 monoclonal antibody and CTLA-4 monoclonal antibody bisspecific antibodies) and LM-302 (Claudin18.2-ADC) in Claudin18.2-positive advanced BTC patients who have progressed after SOC and PD1/PD-L1 monoclonal antibody treatment.

Study Overview

• Status: Active, not recruiting
• Conditions: Biliary Tract Cancer; Candonilimab; Claudin 18.2
• Intervention / Treatment: Drug: cardonilizumab; Drug: LM-302

Detailed Description

The prognosis for unresectable and metastatic biliary malignancies (BTC) is extremely poor, with a median overall survival of only about 1 year for advanced biliary tumors treated with gemcitabine and cisplatin or combined with duvaliumab (PD-L1) as recommended by NCCN guidelines. At present, the NCCN guidelines recommend that the posterior line treatment of advanced BTC, such as FOLFOX, has a very limited effect, with an objective response rate of only about 5% and a median survival time of only about 6 months. There is an urgent need to develop new therapeutic methods to improve patient survival. Chronic inflammation caused by viral infection and bile duct stones are the most common potential risk factors for BTC, and immune system abnormalities play a key role in the occurrence and development of BTC. BTC, including intrahepatic cholangiocarcinoma (iCCA), showed abnormal expression of immune checkpoint molecules PD-L1 and CTLA-4 and obvious heterogeneity. Therefore, immunotherapy is of great value. TOPAZ-1 and KENOTE-966 studies both showed the value of PD-L1/PD1 monoclonal antibody in the treatment of advanced BTC. There is currently a lack of treatment options for progression after treatment with standard chemotherapy (SOC) combined with PD-L1/PD1 monoclonal antibodies. CTLA-4 inhibitors combined with PD-1/PD-L1 inhibitors have shown significantly enhanced clinical effects. Clinical studies on treating CTLA-4 inhibitors combined with PD-1/PD-L1 inhibitors have been carried out in several solid tumors. Although significant therapeutic effects have been achieved, adverse reactions (AEs) that cannot be ignored limit the benefit of patients. Claudin18.2 is a newly discovered tumor therapeutic target. Multiple clinical studies have shown that Claudin18.2 monoclonal antibody, Claudin18.2-ADC, and Cart-Claudin18.2 have good ORR in Claudin18.2-positive gastric cancer. At present, no independent research data on advanced BTC has been reported.

In this clinical study, we will evaluate the efficacy and safety of cardonilimumab (PD1 monoclonal antibody and CTLA-4 monoclonal antibody bispecific antibodies) and LM-302 (Claudin18.2-ADC) in Claudin18.2-positive advanced BTC patients who have progressed after SOC and PD1/PD-L1 monoclonal antibody treatment.

• Study Type: Interventional
• Enrollment (Actual): 78
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• China
  • Shanghai, China
    • Zhongshan Hospital, Fudan University

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Advanced BTC that is not resectable or metastatic or recurred after surgery, histologically confirmed, and sufficient tissue specimens are provided for PD-L1, CTLA-4, Claudin18.2 immunohistochemistry and exon sequencing. Claudin18.2 expression is not required at the first stage. In the second stage, Claudin18.2-positive patients were required to be enrolled (≥40% immunohistochemical expression of Claudin18.2 was considered positive, <40% was considered negative, and two independent pathologists made the judgment. If there was any discrepancy, the third pathologist was asked to make the judgment together).
2. Failure of standard chemotherapy (gemcitabine or platinum or fluorouracil) and PD1/PD-L1 for advanced BTC due to disease progression or toxicity;
3. Measurable lesions;
4. For patients with a prior history of hepatic chemoembolization, radiofrequency ablation/intervention, or radiotherapy, measurable lesions outside the chemoembolization or radiotherapy area or measurable progression lesions at the chemoembolization or radiotherapy site must be present;
5. ECOG physical state ≤ 2;
6. Life expectancy > 3 months;
7. Adequate renal function: creatinine (Cr) ≤ 1.5 × upper limit of normal (ULN) or glomerular filtration rate (GFR) ≥ 60mL/min/ 1.73m2;
8. Adequate liver function: bilirubin ≤ 1.5 × ULN and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN;
9. Adequate bone marrow reserve: absolute value of neutrophil (ANC) > 1500/mcl, platelets (Plts) > 75,000/mcl, hemoglobin (Hgb) ≥ 9.0g/dl;
10. Prothrombin time/activated partial thromboplastin time (PT/PTT) <1.5 × ULN;
11. Age ≥18 years old, male or female;
12. Participants with a prior history or persistent hepatitis C virus (HCV) infection will be eligible to participate in the study. Participants receiving antiviral therapy must complete treatment at least 1 month before the start of the study intervention. For HCV subjects who have not received or have not completed antiviral therapy, treatment should be initiated only after liver function has remained stable for at least 3 months during the study intervention.

13. Hepatitis B controlled subjects are eligible to participate in the study as long as they meet the following criteria:

    Subjects with chronic hepatitis B virus (HBV) infection (defined as hepatitis B surface antigen [HBsAg] positive and/or detectable HBV DNA) must have a HBV viral load of less than 2000 IU/ml prior to first dosing of the study intervention or a 10-fold reduction in HBV viral load with antiviral therapy. Subjects treated with active HBV with a viral load below 2000 IU/ml should receive antiviral therapy throughout the study intervention.

14. Subjects who are clinically cured of HBV infection (defined as HBsAg negative and anti-HBC positive) and whose HBV viral load is not detectable at screening should have their HBV viral load checked every 8 weeks and should be treated for HBV if the viral load exceeds 2000 IU/ml. Antiviral therapy after completion of the study intervention should follow local guidelines.

Exclusion Criteria:

• 1) Previous treatment with checkpoint inhibitor CTLA-4 monoclonal antibody, targeting Claudin18.2; 2) Major surgery or radiotherapy or intervention or ablation within 4 weeks before enrollment; 3) Active, known, or suspected autoimmune disease; 4) Congestive heart failure or symptomatic coronary artery disease within 3 months prior to enrollment; 5) Cerebrovascular accident occurred within the past 6 months; 6) Clinically significant bleeding, bleeding event, or thromboembolic disease within 6 months; 7) History of intestinal perforation; 8) Have a history of (non-infectious) pneumonia requiring steroid treatment or currently have pneumonia; 9) Known history of human immunodeficiency virus (HIV) infection; 10) A history of severely impaired lung function or interstitial lung disease; 11) Concurrent malignancies (other than adequately treated non-melanoma skin cancer, superficial transitional cell carcinoma of the bladder and cervical carcinoma in situ [CIS]) or any currently active malignancies have been diagnosed within the last 5 years; 12) Past or current evidence indicates any condition, treatment, or laboratory abnormality that may confuse the study results, interfere with the subject's participation throughout the study, or the investigator determines that participation in the study is not in the subject's best interest.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 2; 1.8mg /mg LM-302 was treated for 1 course for 14 days.	Drug: LM-302; LM-302 :ClAUDIN 18.2-ADC; Other Names: ClAUDIN 18.2-ADC
Experimental: Group 3; 6 mg/kg cardonilizumab for 14 days was a course of treatment; RP2D LM-302 is 1 course of treatment for 14 days	Drug: cardonilizumab; cardonilizumab:PD1 and CTLA-4 bispecific antibody; Other Names: PD1 and CTLA-4 bispecific antibody; Drug: LM-302; LM-302 :ClAUDIN 18.2-ADC; Other Names: ClAUDIN 18.2-ADC
Experimental: Group 1; 6 mg/kg cardonilizumab, 14 days for 1 course. Group 1 (6 mg/kg cadoniliamab) was closed due to no PR or CR achieved in 11 enrolled patients.	Drug: cardonilizumab; cardonilizumab:PD1 and CTLA-4 bispecific antibody; Other Names: PD1 and CTLA-4 bispecific antibody

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ORR(Phase II)	Objective response rate (ORR) in patients with Claudin18.2-positive treated with cardonillizumab combined with LM302 (RECIST 1.1)(Phase II)	24months
Incidence of Treatment-Emergent Adverse Events(Phase I)	Safety of cardonilizumab in combination with different doses of LM-302 in patients with advanced BTC	24months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
OS	Overall survival	24months
DOR	duration of overall response	24months
DCR	disease control rate	24months

Collaborators and Investigators

• Sponsor: Shanghai Zhongshan Hospital
• Investigators: Principal Investigator: Jia Fan, MD, Fudan University

Publications and helpful links

General Publications

• Kelley RK, Ueno M, Yoo C, Finn RS, Furuse J, Ren Z, Yau T, Klumpen HJ, Chan SL, Ozaka M, Verslype C, Bouattour M, Park JO, Barajas O, Pelzer U, Valle JW, Yu L, Malhotra U, Siegel AB, Edeline J, Vogel A; KEYNOTE-966 Investigators. Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023 Jun 3;401(10391):1853-1865. doi: 10.1016/S0140-6736(23)00727-4. Epub 2023 Apr 16.
• Oh DY, Lee KH, Lee DW, Yoon J, Kim TY, Bang JH, Nam AR, Oh KS, Kim JM, Lee Y, Guthrie V, McCoon P, Li W, Wu S, Zhang Q, Rebelatto MC, Kim JW. Gemcitabine and cisplatin plus durvalumab with or without tremelimumab in chemotherapy-naive patients with advanced biliary tract cancer: an open-label, single-centre, phase 2 study. Lancet Gastroenterol Hepatol. 2022 Jun;7(6):522-532. doi: 10.1016/S2468-1253(22)00043-7. Epub 2022 Mar 9.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2023
• Primary Completion (Estimated): May 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: July 21, 2023
• First Submitted That Met QC Criteria: August 12, 2023
• First Posted (Actual): August 16, 2023

Study Record Updates

• Last Update Posted (Actual): February 18, 2026
• Last Update Submitted That Met QC Criteria: February 13, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Biliary Tract Diseases; Biliary Tract Neoplasms; Physiological Effects of Drugs; Immunologic Factors; Antibodies, Bispecific
• Other Study ID Numbers: ZSAB-Calm

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