An Open-label, Multicohort Phase I/II Study of the Cadonilimab (AK104) Combination Regimen as First-line Treatment for HER2-expressing, Unresectable Locally Advanced or Metastatic Gastric (G) or Gastroesophageal Junction (GEJ) Cancer
Overview
- Phase
- Phase 1
- Intervention
- cadonilimab
- Conditions
- Metastatic HER2 Positive Gastroesophageal Junction Cancer
- Sponsor
- Zhejiang Cancer Hospital
- Enrollment
- 90
- Locations
- 1
- Primary Endpoint
- DLT
- Status
- Recruiting
- Last Updated
- last year
Overview
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.
Investigators
Ying Jieer
Chief physician
Zhejiang Cancer Hospital
Eligibility Criteria
Inclusion Criteria
- •1.Sign the informed consent form.
- •≥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/
- •10.Adequate organ function is determined by the following criteria:
- •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.
- •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.
Exclusion Criteria
- •Known squamous cell carcinoma, undifferentiated carcinoma, or other histological types of gastric cancer, or adenocarcinoma mixed with other histological types.
- •Patients with gastric cancer without HER2 expression.
- •Known active or untreated brain metastases, leptomeningeal metastases, spinal cord compression, or leptomeningeal disease.
- •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.
- •Active diverticulitis, abdominal abscess, or gastrointestinal obstruction.
- •Inability to swallow, malabsorption syndrome, or uncontrolled nausea, vomiting, diarrhea, or other significant gastrointestinal conditions that affect drug intake and absorption.
- •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.
- •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.
- •Signs or symptoms of unacceptable worsening of primary disease during screening, as judged by the investigator.
- •Exclusion Criteria due to Concurrent Diseases or Comorbid Conditions:
Arms & Interventions
Cohort 1:AK104+trastuzumab+chemo
AK104 (10 mg/kg, iv, Q3W, D1) in combination with trastuzumab (loading dose 8 mg/kg, iv, Q3W, D1; maintenance dose 6 mg/kg, iv, Q3W, D1) and chemotherapy (XELOX)
Intervention: cadonilimab
Cohort 1:AK104+trastuzumab+chemo
AK104 (10 mg/kg, iv, Q3W, D1) in combination with trastuzumab (loading dose 8 mg/kg, iv, Q3W, D1; maintenance dose 6 mg/kg, iv, Q3W, D1) and chemotherapy (XELOX)
Intervention: Trastuzumab
Cohort 1:AK104+trastuzumab+chemo
AK104 (10 mg/kg, iv, Q3W, D1) in combination with trastuzumab (loading dose 8 mg/kg, iv, Q3W, D1; maintenance dose 6 mg/kg, iv, Q3W, D1) and chemotherapy (XELOX)
Intervention: XELOX
Cohort 2:HER2-positive,AK104+RC48+chemo
Phase Ⅰ: AK104:6mg/kg，iv，Q2W，D1 RC48:"3+3" design,1.5mg/kg、2.0mg/kg、2.5mg/kg chemotherapy:XELOX Phase Ⅱ:AK104 (6 mg/kg, iv, Q2W, D1) in combination with RC48 (recommended Phase I dose, iv, Q2W, D1) and chemotherapy (mFOLFOX6); PS:The chemotherapy treatment cycles will be determined by the investigator based on the participant's tolerability,and the maintenance treatment is AK104 in combination with RC48 and fluorouracil (5-FU) .
Intervention: cadonilimab
Cohort 2:HER2-positive,AK104+RC48+chemo
Phase Ⅰ: AK104:6mg/kg，iv，Q2W，D1 RC48:"3+3" design,1.5mg/kg、2.0mg/kg、2.5mg/kg chemotherapy:XELOX Phase Ⅱ:AK104 (6 mg/kg, iv, Q2W, D1) in combination with RC48 (recommended Phase I dose, iv, Q2W, D1) and chemotherapy (mFOLFOX6); PS:The chemotherapy treatment cycles will be determined by the investigator based on the participant's tolerability,and the maintenance treatment is AK104 in combination with RC48 and fluorouracil (5-FU) .
Intervention: Disitamab Vedotin
Cohort 2:HER2-positive,AK104+RC48+chemo
Phase Ⅰ: AK104:6mg/kg，iv，Q2W，D1 RC48:"3+3" design,1.5mg/kg、2.0mg/kg、2.5mg/kg chemotherapy:XELOX Phase Ⅱ:AK104 (6 mg/kg, iv, Q2W, D1) in combination with RC48 (recommended Phase I dose, iv, Q2W, D1) and chemotherapy (mFOLFOX6); PS:The chemotherapy treatment cycles will be determined by the investigator based on the participant's tolerability,and the maintenance treatment is AK104 in combination with RC48 and fluorouracil (5-FU) .
Intervention: mFOLFOX6
Cohort 3:HER2-expressing,AK104+RC48+chemo
AK104:6mg/kg，iv，Q2W，D1 RC48:"3+3" design,1.5mg/kg、2.0mg/kg、2.5mg/kg chemotherapy:XELOX Phase Ⅱ:AK104 (6 mg/kg, iv, Q2W, D1) in combination with RC48 (recommended Phase I dose, iv, Q2W, D1) and chemotherapy (mFOLFOX6) PS:The chemotherapy treatment cycles will be determined by the investigator based on the participant's tolerability,and the maintenance treatment is AK104 in combination with RC48 and fluorouracil (5-FU) .
Intervention: cadonilimab
Cohort 3:HER2-expressing,AK104+RC48+chemo
AK104:6mg/kg，iv，Q2W，D1 RC48:"3+3" design,1.5mg/kg、2.0mg/kg、2.5mg/kg chemotherapy:XELOX Phase Ⅱ:AK104 (6 mg/kg, iv, Q2W, D1) in combination with RC48 (recommended Phase I dose, iv, Q2W, D1) and chemotherapy (mFOLFOX6) PS:The chemotherapy treatment cycles will be determined by the investigator based on the participant's tolerability,and the maintenance treatment is AK104 in combination with RC48 and fluorouracil (5-FU) .
Intervention: Disitamab Vedotin
Cohort 3:HER2-expressing,AK104+RC48+chemo
AK104:6mg/kg，iv，Q2W，D1 RC48:"3+3" design,1.5mg/kg、2.0mg/kg、2.5mg/kg chemotherapy:XELOX Phase Ⅱ:AK104 (6 mg/kg, iv, Q2W, D1) in combination with RC48 (recommended Phase I dose, iv, Q2W, D1) and chemotherapy (mFOLFOX6) PS:The chemotherapy treatment cycles will be determined by the investigator based on the participant's tolerability,and the maintenance treatment is AK104 in combination with RC48 and fluorouracil (5-FU) .
Intervention: mFOLFOX6
Outcomes
Primary Outcomes
DLT
Time Frame: 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)
Time Frame: 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 Outcomes
- Progression-free survival (PFS)(up to 24 months)
- Disease control rate (DCR)(up to 12 months)
- Overall survival (OS)(up to 3 years)
- Adverse Events([up to 24 months after enrollment or study close])