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

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

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

Study Overview

• Status: Recruiting
• Conditions: Metastatic HER2 Positive Gastroesophageal Junction Cancer
• Intervention / Treatment: Drug: cadonilimab; Drug: Trastuzumab; Drug: XELOX; Drug: Disitamab Vedotin; Drug: mFOLFOX6

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.

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Jieer Ying
• Study Contact Backup: Name: Jieer Ying, MD; Phone Number: 13858195803; Email: jieerying@aliyun.com

Study Locations

• China
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310022
      • Recruiting
      • Zhejiang Cancer Hospital
      • Contact: Jieer Ying, Doctor; Phone Number: 13858195803; Email: hzyingjieer@163.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

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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.

   Exclusion Criteria due to Concurrent Diseases or Comorbid Conditions:

10. Active or documented history of inflammatory bowel disease (such as Crohn's disease or ulcerative colitis).
11. 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.
12. 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.
13. Diagnosis of any malignancy other than gastric cancer within 5 years prior to entering the study.
14. Severe neurological or psychiatric disorders, including dementia, depression, and epilepsy.
15. Pregnant or breastfeeding women or individuals planning to conceive.

16. Presence of cardiovascular disease or cardiovascular risk factors.

    Drug Treatment-Related Exclusion Criteria:

17. Palliative radiotherapy for non-target lesions for symptom control is permitted, provided it was completed at least 2 weeks before the start of study treatment and any radiotherapy-induced adverse events have not resolved to ≤CTCAE Grade 1.
18. Prior treatment with immune checkpoint inhibitors, immune checkpoint agonists, immune cell therapies, or any other antibody-drug conjugates targeting tumor immune mechanisms.
19. Palliative local treatment for non-target lesions or systemic nonspecific immunomodulatory treatments (e.g., interleukins, interferons, thymosin) or traditional Chinese medicine/herbal remedies with antitumor indications within 2 weeks before the first dose.

20. Toxicities from prior anticancer therapy have not resolved to ≤CTCAE Grade 1, except for:

    1. Alopecia.
    2. Pigmentation changes.
    3. Peripheral neuropathy that has resolved to <CTCAE Grade 2.
    4. Late effects of radiotherapy that are unlikely to resolve, as judged by the investigator.

21. Requires systemic treatment with corticosteroids (>10 mg/day prednisone or equivalent) or other immunosuppressive drugs within 14 days before the first dose, except for:

    1. Inhalational, ophthalmic, topical corticosteroids or ≤10 mg/day prednisone or equivalent if no active autoimmune disease.
    2. Physiologic doses of systemic corticosteroids ≤10 mg/day prednisone or equivalent.
    3. Corticosteroids as premedication for infusion-related or allergic reactions (e.g., before CT scans).
22. Known history of severe hypersensitivity reactions to other monoclonal antibodies or known allergy or hypersensitivity to any of the study drugs or their components.

23. Known contraindications to oxaliplatin and capecitabine (Cohort 1); known contraindications to oxaliplatin, fluorouracil, and leucovorin (Cohorts 2 and 3).

    Exclusion Criteria for Special Immunological Status or Infections:

24. Active autoimmune disease requiring systemic therapy within 2 years before the start of study treatment, or an autoimmune disease that the investigator judges may recur or require treatment.
25. Known interstitial lung disease or non-infectious pneumonia that is currently symptomatic or required systemic corticosteroid treatment in the past, or that the investigator judges may impact the assessment or management of treatment-related toxicities.
26. Active infection, including infections requiring intravenous antibiotics or antifungal therapy within 2 weeks before dosing, fever of unknown cause during screening (CTCAE ≥ Grade 1, excluding fever due to tumor as judged by the investigator).
27. Subjects who are planned for or have undergone solid organ transplantation or allogeneic hematopoietic stem cell transplantation.
28. Active hepatitis B or active hepatitis C.
29. Known history of immunodeficiency or positive HIV test result.

30. Receipt of live vaccine within 28 days before the first dose, or plans to receive a live vaccine during the study.

    Other Exclusion Criteria:

31. Currently participating in another clinical study, unless it is observational, non-interventional, or in the follow-up phase of an interventional study.
32. Any condition that, in the investigator's judgment, may increase the risk of receiving the study drug or interfere with the evaluation of the study drug, the safety of the participant, or the interpretation of study results.
33. Participants who are not compliant with the requirements of this clinical trial or who have other factors that make them unsuitable for participation, as judged by the investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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)	Drug: cadonilimab; Cohort 1:10 mg/kg, iv, Q3W, D1; Cohort 2/3:6 mg/kg, iv, Q2W, D1; Other Names: AK104; Drug: Trastuzumab; loading dose 8 mg/kg, iv, Q3W, D1; maintenance dose 6 mg/kg, iv, Q3W, D1; Drug: XELOX; Oxaliplatin: 130 mg/m\(^2\), IV, D1; Capecitabine: 1000 mg/m\(^2\), oral (PO), twice daily, D1-14.
Experimental: 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) .	Drug: cadonilimab; Cohort 1:10 mg/kg, iv, Q3W, D1; Cohort 2/3:6 mg/kg, iv, Q2W, D1; Other Names: AK104; Drug: Disitamab Vedotin; 1.5、2.0、2.5mg/kg，IV，D1，Q2W; Other Names: RC48; Drug: mFOLFOX6; 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.
Experimental: 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) .	Drug: cadonilimab; Cohort 1:10 mg/kg, iv, Q3W, D1; Cohort 2/3:6 mg/kg, iv, Q2W, D1; Other Names: AK104; Drug: Disitamab Vedotin; 1.5、2.0、2.5mg/kg，IV，D1，Q2W; Other Names: RC48; Drug: mFOLFOX6; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease control rate (DCR)	Percentage of confirmed cases including complete remission (CR), partial remission (PR) and disease stability (SD) among patients with evaluable efficacy	up to 12 months
Progression-free survival (PFS)	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).	up to 24 months
Overall survival (OS)	The time interval between the start date of study drug and the date of death (any cause)	up to 3 years
Adverse Events	Number and percentage of participants with Adverse Events(any grade)	[up to 24 months after enrollment or study close]

Collaborators and Investigators

• Sponsor: Zhejiang Cancer Hospital
• Investigators: Principal Investigator: Jieer Ying, MD, Zhejiang Cancer Hospital

Study record dates

Study Major Dates

• Study Start (Actual): July 10, 2024
• Primary Completion (Estimated): August 10, 2026
• Study Completion (Estimated): December 30, 2027

Study Registration Dates

• First Submitted: October 16, 2024
• First Submitted That Met QC Criteria: October 17, 2024
• First Posted (Actual): October 21, 2024

Study Record Updates

• Last Update Posted (Actual): October 21, 2024
• Last Update Submitted That Met QC Criteria: October 17, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Immunoconjugates; Trastuzumab; Disitamab vedotin
• Other Study ID Numbers: AK104-IIT-C-M-0119

Drug and device information, study documents

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