Metastatic HER2 Positive Gastroesophageal Junction Cancer
Conditions
Brief summary
This trial is An open-label, multicohort, multicenter clinical study aimed at evaluating the efficacy and safety of the cadonilimab combination regimen in the treatment of advanced HER-2 positive gastric/gastroesophageal junction tumors
Detailed description
This is a phase Ⅰ/Ⅱ clinicaltrial. Phase I aims to determine the maximum tolerated dose (MTD) or, if the MTD is not reached, the maximum administered dose (MAD) of AK104 in combination with RC48 (disitamab vedotin) as first-line treatment for unresectable locally advanced or metastatic GC/GEJ cancer, as well as the recommended phase II dose (RP2D). Phase II aims to evaluate the efficacy and safety of AK104 in combination with trastuzumab and chemotherapy as first-line treatment for HER2-positive, unresectable locally advanced or metastatic GC/GEJ cancer; as well as the efficacy and safety of AK104 in combination with RC48 (disitamab vedotin) and chemotherapy as first-line treatment for HER2-expressing, unresectable locally advanced or metastatic GC/GEJ cancer.
Interventions
DRUGcadonilimab
Cohort 1:10 mg/kg, iv, Q3W, D1; Cohort 2/3:6 mg/kg, iv, Q2W, D1
DRUGTrastuzumab
loading dose 8 mg/kg, iv, Q3W, D1; maintenance dose 6 mg/kg, iv, Q3W, D1
DRUGXELOX
Oxaliplatin: 130 mg/m\\(\^2\\), IV, D1; Capecitabine: 1000 mg/m\\(\^2\\), oral (PO), twice daily, D1-14.
DRUGDisitamab Vedotin
1.5、2.0、2.5mg/kg，IV，D1，Q2W
DRUGmFOLFOX6
Oxaliplatin 85 mg/m\\(\^2\\), IV, d1; Leucovorin (folinic acid) 400 mg/m\\(\^2\\), IV, d1; 5-FU 400 mg/m\\(\^2\\), IV, d1, followed by 2400 mg/m\\(\^2\\), continuous intravenous infusion over 46 hours.
Sponsors
Zhejiang Cancer Hospital
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
\- 1.Sign the informed consent form. 2. ≥18 years and ≤75 years . 3.Histologically confirmed unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma (tumor center located within 5 cm proximally or distally from the esophagogastric junction according to the Siewert classification system). 4.Confirmed PD-L1 expression status (accepts PD-L1 expression test results confirmed by the investigator). 5.HER2 expression (accepts HER2 expression test results confirmed by the investigator): * Cohort 1 and Cohort 2: HER2-positive defined as IHC 3+, or IHC 2+ and ISH or FISH positive. ISH positivity is defined as a HER2 gene copy number to CEP17 copy number ratio ≥2.0; if the ratio is \<2.0 but the HER2 gene copy number \>6, it is also considered ISH positive. * Cohort 3: HER2 low expression, defined as IHC 1+ or IHC 2+ but ISH or FISH negative. 6.No prior systemic anti-tumor therapy. 7.With at least one measurable lesion (RECIST 1.1 criteria) in the subject . 8.Expected survival ≥ 3 months. 9.ECOG 0/1. 10.Adequate organ function is determined by the following criteria: 1. Hematological (no transfusions or growth factor support allowed within 7 days before the first dose):Absolute neutrophil count (ANC) ≥ 1.5 × 10\^9/L (1,500/mm³); Platelet count ≥ 100 × 10\^9/L (100,000/mm³);Hemoglobin ≥ 90 g/L or ≥ 5.6 mmol/L. 2. Liver:Serum albumin ≥ 28 g/L (no albumin infusions allowed within 14 days before the first dose);Total bilirubin (TBil) ≤ 1.5 × ULN; for subjects with liver metastases or evidence/suspicion of Gilbert's disease, TBil ≤ 3 × ULN; Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN; for subjects with liver metastases, AST and ALT ≤ 5 × ULN. 3. Renal:Serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance (CrCl) ≥ 50 mL/min (calculated using the Cockcroft-Gault formula);Urinalysis: urine protein \< 2+; if urine protein ≥ 2+, then 24-hour urine protein ≤ 1 g. 4. Coagulation:International normalized ratio (INR) ≤ 1.5 × ULNActivated partial thromboplastin time (aPTT) ≤ 1.5 × ULN;Prothrombin time (PT) ≤ 1.5 × ULN. 5. Cardiac function:New York Heart Association (NYHA) class \< III;Left ventricular ejection fraction (LVEF) ≥ 50%. 11.For premenopausal women, a negative serum pregnancy test must be confirmed within 7 days before the first dose, and they must agree to use effective contraception during the study drug administration period and for 120 days after the last dose. 12.Compliance with the trial schedule and follow-up procedures
Exclusion criteria
1. Known squamous cell carcinoma, undifferentiated carcinoma, or other histological types of gastric cancer, or adenocarcinoma mixed with other histological types. 2. Patients with gastric cancer without HER2 expression. 3. Known active or untreated brain metastases, leptomeningeal metastases, spinal cord compression, or leptomeningeal disease. 4. History of gastrointestinal perforation or fistula within 6 months before the first dose. Eligible if the perforation or fistula has been surgically repaired and the investigator judges the condition to be resolved or stable. 5. Active diverticulitis, abdominal abscess, or gastrointestinal obstruction. 6. Inability to swallow, malabsorption syndrome, or uncontrolled nausea, vomiting, diarrhea, or other significant gastrointestinal conditions that affect drug intake and absorption. 7. Clinically significant bleeding events or clear predisposition to bleeding within 1 month before the first dose, such as gastrointestinal bleeding, bleeding gastric ulcers (with active bleeding signs on endoscopy), or vasculitis. 8. Symptomatic moderate to severe ascites requiring therapeutic paracentesis (exceptions include asymptomatic ascites detected only on imaging). Uncontrolled or moderate to large pleural effusions, pericardial effusions. 9. Signs or symptoms of unacceptable worsening of primary disease during screening, as judged by the investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| DLT | 28 days after the first dose | Within 28 days after the first dose, adverse reactions related to Vicinium, including Grade 4 or higher hematologic toxicities or Grade 3 or higher non-hematologic toxicities (excluding alopecia), as graded by NCI CTCAE v5.0 |
| Objective response rate(ORR) | up to 12 months | The number of cases in which tumor size is reduced to PR or CR / the total number of evaluable cases (%) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease control rate (DCR) | up to 12 months | Percentage of confirmed cases including complete remission (CR), partial remission (PR) and disease stability (SD) among patients with evaluable efficacy |
| Progression-free survival (PFS) | up to 24 months | Refers to the date from the date of admission to the date of the first progression of disease or death of any cause, using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). |
| Overall survival (OS) | up to 3 years | The time interval between the start date of study drug and the date of death (any cause) |
| Adverse Events | [up to 24 months after enrollment or study close] | Number and percentage of participants with Adverse Events(any grade) |
Countries
China
Contacts
Primary ContactJieer Ying, MD
Backup ContactJieer Ying
Outcome results
None listed