Cadonilimab Combination Regimen as First-line Treatment for HER2-expressing GC/GEJ Patients

NCT06650332 | Recruiting Phase 1

• 1 other identifier: AK104-IIT-C-M-0119
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 1

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

Conditions

Metastatic HER2 Positive Gastroesophageal Junction Cancer

Outcome Measures

Primary Outcomes (2)

• DLT

  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

  28 days after the first dose

• Objective response rate(ORR)

  The number of cases in which tumor size is reduced to PR or CR / the total number of evaluable cases (%)

  up to 12 months

Secondary Outcomes (4)

• 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]

Study Arms (3)

Cohort 1:AK104+trastuzumab+chemo

EXPERIMENTAL

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)

Drug: cadonilimab; Drug: Trastuzumab; Drug: XELOX

Cohort 2:HER2-positive,AK104+RC48+chemo

EXPERIMENTAL

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) .

Drug: cadonilimab; Drug: Disitamab Vedotin; Drug: mFOLFOX6

Cohort 3:HER2-expressing,AK104+RC48+chemo

EXPERIMENTAL

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) .

Drug: cadonilimab; Drug: Disitamab Vedotin; Drug: mFOLFOX6

Interventions

cadonilimab DRUG

Cohort 1:10 mg/kg, iv, Q3W, D1; Cohort 2/3:6 mg/kg, iv, Q2W, D1

Also known as: AK104

Cohort 1:AK104+trastuzumab+chemo; Cohort 2:HER2-positive,AK104+RC48+chemo; Cohort 3:HER2-expressing,AK104+RC48+chemo

Trastuzumab DRUG

loading dose 8 mg/kg, iv, Q3W, D1; maintenance dose 6 mg/kg, iv, Q3W, D1

Cohort 1:AK104+trastuzumab+chemo

XELOX DRUG

Oxaliplatin: 130 mg/m\\(\^2\\), IV, D1; Capecitabine: 1000 mg/m\\(\^2\\), oral (PO), twice daily, D1-14.

Cohort 1:AK104+trastuzumab+chemo

Disitamab Vedotin DRUG

1.5、2.0、2.5mg/kg，IV，D1，Q2W

Also known as: RC48

Cohort 2:HER2-positive,AK104+RC48+chemo; Cohort 3:HER2-expressing,AK104+RC48+chemo

mFOLFOX6 DRUG

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.

Cohort 2:HER2-positive,AK104+RC48+chemo; Cohort 3:HER2-expressing,AK104+RC48+chemo

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).
• Confirmed PD-L1 expression status (accepts PD-L1 expression test results confirmed by the investigator).
• 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.
• 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:
• 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.
• 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.
• Coagulation:International normalized ratio (INR) ≤ 1.5 × ULNActivated partial thromboplastin time (aPTT) ≤ 1.5 × ULN;Prothrombin time (PT) ≤ 1.5 × ULN.
• Cardiac function:New York Heart Association (NYHA) class \< III;Left ventricular ejection fraction (LVEF) ≥ 50%.
• 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.
• Compliance with the trial schedule and follow-up procedures

You may not qualify if:

• 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.
• Active or documented history of inflammatory bowel disease (such as Crohn's disease or ulcerative colitis).
• Major surgery within 4 weeks before the start of study treatment that has not fully recovered, or anticipated need for major surgery during the study period.
• Uncontrolled systemic diseases, including but not limited to diabetes, hypertension, pulmonary fibrosis, acute lung disease, interstitial lung disease, decompensated cirrhosis, nephrotic syndrome, angina pectoris, severe arrhythmias, uncontrolled metabolic disorders, severe active peptic ulcer disease or gastritis.
• Diagnosis of any malignancy other than gastric cancer within 5 years prior to entering the study.
• Severe neurological or psychiatric disorders, including dementia, depression, and epilepsy.
• Pregnant or breastfeeding women or individuals planning to conceive.

Sponsors & Collaborators

• Zhejiang Cancer Hospital: lead

Study Sites (1)

Zhejiang Cancer Hospital

Hangzhou, Zhejiang, 310022, China

RECRUITING

MeSH Terms

Interventions

Trastuzumab; XELOX; disitamab vedotin

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Jieer Ying, MD

  Zhejiang Cancer Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jieer Ying, MD

CONTACT

13858195803; jieerying@aliyun.com

Jieer Ying

CONTACT

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Chief physician

Study Record Dates

• First Submitted: October 16, 2024
• First Posted: October 21, 2024
• Study Start: July 10, 2024
• Primary Completion (Estimated): August 10, 2026
• Study Completion (Estimated): December 30, 2027
• Last Updated: October 21, 2024

Record last verified: 2024-10

Locations

CN (1)