Trial Title:
Cadonilimab Combination Regimen as First-line Treatment for HER2-expressing GC/GEJ Patients
NCT ID:
NCT06650332
Condition:
Metastatic HER2 Positive Gastroesophageal Junction Cancer
Conditions: Official terms:
Trastuzumab
Disitamab vedotin
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
cadonilimab
Description:
Cohort 1:10 mg/kg, iv, Q3W, D1; Cohort 2/3:6 mg/kg, iv, Q2W, D1
Arm group label:
Cohort 1:AK104+trastuzumab+chemo
Arm group label:
Cohort 2:HER2-positive,AK104+RC48+chemo
Arm group label:
Cohort 3:HER2-expressing,AK104+RC48+chemo
Other name:
AK104
Intervention type:
Drug
Intervention name:
Trastuzumab
Description:
loading dose 8 mg/kg, iv, Q3W, D1; maintenance dose 6 mg/kg, iv, Q3W, D1
Arm group label:
Cohort 1:AK104+trastuzumab+chemo
Intervention type:
Drug
Intervention name:
XELOX
Description:
Oxaliplatin: 130 mg/m\(^2\), IV, D1; Capecitabine: 1000 mg/m\(^2\), oral (PO), twice
daily, D1-14.
Arm group label:
Cohort 1:AK104+trastuzumab+chemo
Intervention type:
Drug
Intervention name:
Disitamab Vedotin
Description:
1.5、2.0、2.5mg/kg，IV，D1，Q2W
Arm group label:
Cohort 2:HER2-positive,AK104+RC48+chemo
Arm group label:
Cohort 3:HER2-expressing,AK104+RC48+chemo
Other name:
RC48
Intervention type:
Drug
Intervention name:
mFOLFOX6
Description:
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.
Arm group label:
Cohort 2:HER2-positive,AK104+RC48+chemo
Arm group label:
Cohort 3:HER2-expressing,AK104+RC48+chemo
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.
Criteria for eligibility:
Criteria:
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.
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 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.
Gender:
All
Minimum age:
18 Years
Maximum age:
75 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Zhejiang Cancer Hospital
Address:
City:
Hangzhou
Zip:
310022
Country:
China
Status:
Recruiting
Contact:
Last name:
Jieer Ying, Doctor
Phone:
13858195803
Email:
hzyingjieer@163.com
Start date:
July 10, 2024
Completion date:
December 30, 2027
Lead sponsor:
Agency:
Zhejiang Cancer Hospital
Agency class:
Other
Source:
Zhejiang Cancer Hospital
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06650332
