Trial Title:
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
NCT ID:
NCT05994001
Condition:
Biliary Tract Cancer
Candonilimab
Claudin 18.2
Conditions: Official terms:
Biliary Tract Neoplasms
Antibodies, Bispecific
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Intervention model description:
Each cycle of the first phase was defined as cardonilizumab (6mg/kg,Q2W) combined with
different concentrations of 1.6mg/kg or 1.8mg/kg LM-302 (Q2W), 14 days as a course of
treatment, and the combined dose (RP2D) of LM-302 during combination therapy was
determined according to the 3+3 design.
In the second phase, Claudin18.2 expression was positive, and the positive population was
randomly assigned to trial group 1, trial group 2, and trial group 3.
Group 1:6 mg/kg cardonilizumab, 14 days for 1 course. Group 2:1.8mg /mg LM-302 was
treated for 1 course for 14 days. 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.
Primary purpose:
Treatment
Masking:
Single (Participant)
Masking description:
Each cycle of the first phase was defined as cardonilizumab (6mg/kg,Q2W) combined with
different concentrations of 1.6mg/kg or 1.8mg/kg LM-302 (Q2W), 14 days as a course of
treatment, and the combined dose (RP2D) of LM-302 during combination therapy was
determined according to the 3+3 design.
In the second phase, Claudin18.2 expression was positive, and the positive population was
randomly assigned to trial group 1, trial group 2, and trial group 3.
Group 1:6 mg/kg cardonilizumab, 14 days for 1 course. Group 2:1.8mg /mg LM-302 was
treated for 1 course for 14 days. 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.
Intervention:
Intervention type:
Drug
Intervention name:
cardonilizumab
Description:
cardonilizumab:PD1 and CTLA-4 bispecific antibody
Arm group label:
Group 1
Arm group label:
Group 3
Other name:
PD1 and CTLA-4 bispecific antibody
Intervention type:
Drug
Intervention name:
LM-302
Description:
LM-302 :ClAUDIN 18.2-ADC
Arm group label:
Group 2
Arm group label:
Group 3
Other name:
ClAUDIN 18.2-ADC
Summary:
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.
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.
Criteria for eligibility:
Criteria:
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.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Zhongshan hospital, Fudan University
Address:
City:
Shanghai
Country:
China
Status:
Recruiting
Contact:
Last name:
Guo-Ming Shi, MD
Phone:
+8613916969578
Email:
shi.guoming@zs-hospital.sh.cn
Contact backup:
Last name:
Xiao-Yong Huang, MD
Phone:
+8615021519215
Email:
huang.xiaoyong@zs-hospital.sh.cn
Start date:
August 1, 2023
Completion date:
August 1, 2026
Lead sponsor:
Agency:
Shanghai Zhongshan Hospital
Agency class:
Other
Source:
Shanghai Zhongshan Hospital
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05994001
