Overview

The safety, tolerability, and determination of the maximum tolerated dose (MTD) of the combination therapy were first evaluated for IAH0968 in combination with or without the CAPEOX regimen in unsystematically treated subjects with HER2-expressing advanced/metastatic colorectal or gastric cancers (including adenocarcinomas of the gastro-esophageal junction) or HER2-hypo-expressing advanced/metastatic solid tumors. The efficacy of IAH0968 in combination with the CAPEOX regimen versus trastuzumab in combination with the CAPEOX regimen in subjects with HER2-positive advanced/metastatic gastric cancer, including gastro-esophageal junction adenocarcinoma, was then assessed by progression-free survival (PFS) according to the Research and Evaluation Criteria for the Evaluation of Efficacy in Solid Tumors (RECIST) 1.1.

Eligibility

Inclusion Criteria:

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1. Age 18~75 years old (including critical mass), gender is not limited. 2) Phase II cohort 1 and III only: patients with locally advanced or metastatic gastric cancer (including adenocarcinoma of the gastro-esophageal junction) diagnosed by histopathology, unsuitable for radical surgical resection or localized treatment, and who have not received systemic antitumor therapy (including systemic chemotherapy, molecularly-targeted drug therapy, biologic therapy, and other investigational therapeutic agents) for GC (except for adjuvant chemotherapy for >6 months), and who have demonstrated disease progression; and patients who have been diagnosed by immunohistochemistry (IHC) staining and/or fluorescence in situ hybridization (FISH). and demonstrated disease progression excepted); HER2 positivity (IHC 3+, or IHC 2+ and FISH +) demonstrated by immunohistochemical (IHC) staining and/or fluorescence in situ hybridization (FISH).
2. Phase II Cohort 2 only: Have histologically or cytologically confirmed advanced malignant solid tumors that have failed standard treatment, or for which no standard treatment options are available, or for which standard treatment is not applicable at this stage; and are HER2 underexpressed (IHC 2+ and FISH-, or IHC 1+) as evidenced by immunohistochemistry (IHC) staining and/or fluorescence in situ hybridization (FISH).
3. Phase II Cohort 3 only: with locally advanced or metastatic gastric cancer (including gastro-oesophageal junction adenocarcinoma) or colorectal cancer diagnosed by histopathology, unsuitable for radical surgical resection or localized treatment, with no prior systemic (including systemic chemotherapy, molecularly-targeted drug therapy, biologic therapy, and other investigational therapeutic agents) antitumor therapy (having received adjuvant chemotherapy for >6 months with evidence of disease progression), patients with wild-type KRAS, NRAS, and BRAF genes (mCRC only); and HER2 low expression (IHC 2+ and FISH-, or IHC 1+) demonstrated by immunohistochemical (IHC) staining and/or fluorescence in situ hybridization (FISH).
4. At least 1 measurable lesion according to RECIST 1.1 criteria (tumor lesions located in the area of prior radiotherapy or other localized regional treatment sites are generally not considered measurable lesions unless the lesion shows definite progression or persists after three months of radiotherapy).
5. Eastern Cooperative Oncology Group (ECOG) physical status score of 0 to 1. 7) Have an expected survival of ≥ 3 months. 8) Adequate organ function:
   • Hematologic system (no transfusion or hematopoietic stimulating factor therapy within 14 days): absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelet count (PLT) ≥ 90 × 109/L, hemoglobin (HGB) ≥ 90 g/L; Liver function: total bilirubin (TBIL) ≤ 1.5 times the upper limit of normal (ULN), except Gilbert's syndrome; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 times the ULN, liver metastasis or hepatocellular carcinoma patients need to AST and ALT ≤ 5.0 times the ULN and total bilirubin ≤ 3.0 times the ULN; Renal function: serum creatinine (Cr) ≤1.5 times ULN; if creatinine >1.5 times ULN, creatinine clearance (Ccr) ≥50 mL/min (calculated according to Cockcroft-Gault formula);

     ④ Coagulation function: International Normalized Ratio (INR) ≤ 1.5 times ULN for prothrombinogen, Activated Partial Thromboplastin Time (APTT) ≤ 1.5 times ULN, or INR and APTT ≤ 2.5 times ULN for patients with liver metastasis or hepatocellular carcinoma.

     9) Eligible patients (male and female) of childbearing potential must agree

     to use a reliable method of contraception (hormonal or barrier method or abstinence) with their partner for the duration of the trial and for at least 6 months after the last dose; female patients of childbearing potential must have a negative serum pregnancy test within 7 days prior to the first dose of study drug.

     10) Subjects must give informed consent for this study prior to the trial and

     voluntarily sign a written informed consent form.

Exclusion Criteria:

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1. Phase II Cohort 2 only: received antitumor therapy such as chemotherapy, radiotherapy, biologic therapy, endocrine therapy, immunotherapy, etc. within 4 weeks prior to the first use of study drug, except for the following:
   • Nitrosourea or mitomycin C within 6 weeks prior to first use of study drug;

     ② Oral fluorouracil analogs and small molecule targeted drugs for 2 weeks prior to the first use of the study drug or within 5 half-lives of the drug (whichever is longer);

     ③ Within 2 weeks prior to first use of the study drug for proprietary Chinese medicines with antitumor indications.

     2) Received other unlisted clinical investigational drug or therapy within 4

     weeks prior to first use of the study drug.

     3) Adverse effects of prior antineoplastic therapy have not returned to NCI

     CTCAE 5.0 grade rating of ≤ grade 1 or relevant provisions of the enrollment criteria (except for toxicities judged by the investigator to pose no safety risk, such as alopecia, grade 2 peripheral neurotoxicity, and hypothyroidism stabilized by hormone replacement therapy).

     4) Known hypersensitivity to any antibody-based drug (NCI CTCAE 5.0 grade

     rating ≥ 3) or hypersensitivity to the study drug and the active ingredient or inactive excipients of the CAPEOX regimen.

     5) Diagnosed defective mismatch repair (dMMR) or high microsatellite

     instability (MSI-H) solid tumor (except unknown MSI/MMR status).

     6) Major surgical procedure (excluding puncture biopsy), major trauma within

     4 weeks prior to first use of study drug, or need for elective surgery during the trial.

     7) Received systemic glucocorticosteroids (prednisone > 10 mg/day or

     equivalent) within 14 days prior to the first dose of study drug, except for the following: treatment with topical, ocular, intra-articular, intranasal, and inhaled glucocorticosteroids; and short-term prophylactic glucocorticosteroids (e.g., for prevention of allergy to contrast media).

     8) Other immunosuppressive therapy within 28 days or 5 half-lives (whichever

     is longer) prior to first use of study drug.

     9) Use of immunomodulatory drugs within 14 days prior to first use of study

     drug.

     10) Use of any live vaccine within 4 weeks prior to the first dose of study

     drug.

     11) Previous allogeneic hematopoietic stem cell transplantation or organ

     transplantation.

     12) Parenchymal brain metastases or meningeal metastases with clinical

     symptoms.

     13) Have an active infection that currently requires intravenous

     anti-infective therapy.

     14) Have a history of immunodeficiency, including a positive antibody test for

     human immunodeficiency virus (HIV).

     15) Have active hepatitis B (HBsAg positive and HBV-DNA positive or greater

     than the upper limit of normal) and active hepatitis C (hepatitis C virus antibody positive and HCV RNA positive or greater than the upper limit of normal).

     16) Have severe and uncontrollable lung disease (severe infectious pneumonia,

     interstitial lung disease, etc.).

     17) Have a history of severe cardiovascular disease, including but not limited

     to

   • Having severe cardiac rhythm or conduction abnormalities, such as ventricular

     arrhythmias requiring clinical intervention, degree II-III atrioventricular block;

     • Mean QT interval (QTcF) corrected by the Fridericia method > 470 ms;

       ③ Acute coronary syndrome, congestive heart failure, aortic coarctation, stroke, or other grade 3 or higher cardiovascular event within 6 months prior to the first dose;

       ④ Presence of New York Heart Association (NYHA) Cardiac Function Class ≥ Grade II heart failure or left ventricular ejection fraction (LVEF) < 50%, or other structural heart disease judged by the investigator to be of high risk;

       ⑤ Clinically uncontrolled hypertension. 18) Active, or previous autoimmune disease with potential for relapse (e.g., systemic lupus erythematosus, rheumatoid arthritis, vasculitis, etc.), except for clinically stable autoimmune thyroid disease, type I diabetes mellitus, vitiligo, cured atopic dermatitis in children, and psoriasis that does not require systemic therapy (within the past 2 years).

       19) Presence of other malignancies within 5 years prior to the start of

       study dosing, except: malignancies for which cure can be expected with treatment (including, but not limited to, adequately treated thyroid cancer, cervical carcinoma in situ, basal or squamous cell skin cancer, or ductal carcinoma in situ of the breast treated by radical surgery).

       20) Presence of clinically uncontrollable third interstitial fluid that,

       in the judgment of the Investigator, makes enrollment inappropriate.

       21) Known alcohol or drug dependence. 22) Have a mental disorder or poor

       compliance. 23) Pregnant or lactating females. 24) In the opinion of the investigator, the subject has a history of other serious systemic disease or is otherwise unsuitable for enrollment in this clinical study.