Retrospective registration

A Multicenter, Open-Label Phase II Clinical Study Evaluating the Safety, Tolerability, and Efficacy of SHR2554 Tablets in Combination with Other Antitumor Therapies in Patients with Locally Advanced Unresectable or Metastatic Gastric or Gastro-oesophageal Junction Adenocarcinoma

A Multicenter, Open-Label Phase II Clinical Study Evaluating the Safety, Tolerability, and Efficacy of SHR2554 Tablets in Combination with Other Antitumor Therapies in Patients with Locally Advanced Unresectable or Metastatic Gastric or Gastro-oesophageal Junction Adenocarcinoma

Shuyao Liang 

Yanqiao Zhang 

No. 7, Kunlunshan Road, Economic and Technological Development Zone, Lianyungang City, Jiangsu Province

150 Haping Road, Nangang District, Harbin City, Heilongjiang Province

Shanghai Hengrui Pharmaceutical Co., Ltd.

Harbin Medical University Cancer Hospital

Yes

Ethics Committee of Harbin Medical University Cancer Hospital

Lingyu Xie

150 Haping Road, Nangang District, Harbin City, Heilongjiang Province

Harbin Medical University Cancer Hospital

150 Haping Road, Nangang District, Harbin City, Heilongjiang Province

Shanghai Hengrui Pharmaceutical Co., Ltd.

Advanced or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma

Interventional study

2

Single arm 

1. Primary Objective: (1) To evaluate the safety, tolerability, and objective response rate (ORR) of SHR2554 tablets in combination with other antitumor therapies in subjects with advanced GC/GEJC; 2. Secondary Objectives: (1) To evaluate other efficacy endpoints of SHR2554 tablets in combination with other antitumor therapies in subjects with advanced GC/GEJC; (2) To assess the pharmacokinetic (PK) characteristics of SHR2554 and/or SHR-A1811, SHR-A1904 in subjects with advanced GC/GEJC;(3) To evaluate the immunogenicity of SHR-A1811 and SHR-A1904 in subjects with advanced GC/GEJC; 3. Exploratory Objectives: (1) To evaluate the correlation between biomarkers and efficacy.

1. Age 18-75 years (inclusive) at the time of signing the informed consent; no gender restriction; 2. Requirements for tumor diagnosis and prior antitumor treatments vary according to different study parts and cohorts: (1) For enrollment in Part A cohort: histologically confirmed locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma, with documented disease progression or intolerance confirmed by the investigator or medical history after prior treatment with trastuzumab-containing regimens or approved trastuzumab biosimilar regimens; (2) For enrollment in Part B cohort: histologically confirmed locally advanced unresectable or metastatic gastric/gastroesophageal junction adenocarcinoma; either treatment-naive or after prior adequate standard therapy (including fluoropyrimidine- and/or platinum-containing regimens) with documented disease progression or intolerance confirmed by the investigator or medical history; (3) For enrollment in Part C and Part D cohorts: histologically confirmed locally advanced unresectable or metastatic gastric/gastroesophageal junction adenocarcinoma; after prior adequate standard therapy (including fluoropyrimidine- and/or platinum-containing regimens) with documented disease progression or intolerance confirmed by the investigator or medical history; (4) For neoadjuvant/adjuvant therapy, if disease progression occurs during treatment or within 6 months after stopping treatment, it should be considered as first-line treatment failure; 3. For different study cohorts, the biomarker requirements are as follows: (1) Subjects enrolled in Part A must have tumors with high HER2 expression, defined as IHC3 or IHC2 with ISH+; (2) Subjects enrolled in Part B must have tumors positive for Claudin 18.2; Claudin 18.2 positivity is defined as >=1% of tumor cells in the tumor tissue expressing Claudin 18.2 >=1; (3) Subjects enrolled in Part C and Part B must have tumors with HER2 medium/low/negative expression, defined as IHC2 with ISH-, IHC1, or 0; 4. According to RECIST v1.1, there must be at least one measurable tumor lesion (brain metastases or lesions in hollow organs such as the esophagus and stomach cannot be counted as measurable); for subjects with only one measurable lesion who have previously received radiotherapy, the lesion must be outside the prior radiotherapy field or show documented progression post-radiotherapy; 5. Subjects must provide formalin-fixed, paraffin-embedded tumor tissue blocks or unstained tumor specimens (see the Laboratory Manual for details) for enrollment or retrospective testing of HER-2, Claudin 18.2, or PD-L1 expression levels; 6. ECOG performance status of 0 or 1; 7. Expected survival >=12 weeks; 8. Baseline assessment of vital organ function meets the following criteria (no use of any blood components or growth factors for corrective treatment within 14 days prior to screening visit inspections): (1) Absolute neutrophil count (ANC) >= 1.5 × 10^9/L (1,500/mm^3); (2) Hemoglobin (Hgb) >= 9.0 g/dL (90 g/L); (3) Platelet count (PLT) >= 100 × 10^9/L (100,000/mm^3); (4) Albumin >= 3.0 g/dL; (5) Serum total bilirubin <= 1.5 times the upper limit of normal (ULN) (<= 2 × ULN if liver metastasis is present); (6) Prothrombin time and activated partial thromboplastin time <= 1.5 × ULN; (7) ALT and/or AST <= 3 × ULN (<= 5 × ULN if liver metastasis is present); (8) Serum creatinine <= 1.5 × ULN and creatinine clearance >= 50 mL/min (calculated using the standard Cockcroft-Gault formula); if urinalysis indicates proteinuria, 24-hour urine protein must be confirmed <= 2.0 g; male QTcF <= 450 msec, female QTcF <= 470 msec (based on the mean of three 12-lead ECG assessments); (9) Left ventricular ejection fraction (LVEF) >= 50%; 9. Female subjects of reproductive potential must agree to use highly effective contraception and refrain from donating eggs from the time of signing the informed consent form until 8 months after the last administration of the study drug, must have negative serum or urine pregnancy tests within 7 days before dosing and during the study, and must not be breastfeeding; male subjects with female partners of reproductive potential must agree to use highly effective contraception and refrain from sperm donation from the time of signing the informed consent form until 8 months after the last administration of the study drug; 10. Subjects must be capable of giving informed consent, have signed an IRB/EC-approved informed consent form with the date indicated, and be willing and able to comply with the treatment schedule visits, examinations, and other procedural requirements.

1. Presence of difficulty swallowing or other factors affecting the oral use of SHR2554; 2. Presence of untreated or active central nervous system (CNS) tumor metastases, history of leptomeningeal metastases, or current leptomeningeal metastases, or: (1) If CNS metastases are limited to the supratentorial and/or cerebellar regions (i.e., no metastases in the midbrain, pons, medulla, or spinal cord) and have received adequate local treatment (surgery or radiotherapy), with no progression observed in imaging examinations from the completion of local treatment to enrollment, and the participant's neurological symptoms have been stable for at least 2 weeks prior to the first dose without the need for steroid therapy, they can participate in the study (except for the prostate cancer cohort); (2) For asymptomatic participants with a single CNS metastasis, if the metastasis is limited to the supratentorial and/or cerebellar regions (i.e., no metastases in the midbrain, pons, medulla, or spinal cord), no corticosteroid treatment is needed, and the brain metastasis lesion diameter is <=1 cm, they can participate in the study; 3. Participants with other malignancies within five years prior to the first use of the study drug are excluded, unless it is skin basal cell carcinoma, superficial bladder cancer, skin squamous cell carcinoma, cervical carcinoma in situ, localized prostate cancer, ductal carcinoma in situ after radical surgery, or papillary thyroid carcinoma after radical surgery, which have achieved complete remission for at least 2 years prior to screening and do not require—or are not expected to require—other treatment during the study; 4. Spinal cord compression not curatively treated by surgery and/or radiotherapy is ineligible. Treated participants with clinical evidence showing symptom relief for >=1 week prior to the first dose can be enrolled; 5. Presence of poorly controlled tumor-related pain; (1) Participants requiring analgesics can be enrolled if they have a stable analgesic regimen prior to the first dose; (2) Participants with clinically symptomatic lesions suitable for palliative radiotherapy (e.g., bone pain from bone metastases or metastases invading nerves) can be enrolled if treatment is completed and stable for at least 14 days prior to the first dose; (3) For metastatic lesions without clinical symptoms, if further progression may cause functional impairment or refractory pain (e.g., epidural metastases without showing spinal cord compression), participants can be enrolled if such treatment is completed prior to the first dose; 6. Has received any of the following treatments:Plans to receive any other antitumor therapy during this trial; (1) Previously received treatment with compounds of the same mechanism (EZH2 inhibitors); (2) Received other investigational drugs or therapies within 4 weeks prior to the first dose in this study; received chemotherapy, radiotherapy, biological therapy, targeted therapy, or immunotherapy within 4 weeks prior to the first dose in this study (nitrosoureas or mitomycin C within 6 weeks prior to the first dose; oral fluoropyrimidines and small molecule targeted agents within 2 weeks prior to the first dose); palliative radiotherapy or local therapy within 2 weeks prior to the first dose; antitumor traditional Chinese medicine within 1 week prior to the first dose; (3) Underwent any major surgery other than diagnostic or biopsy procedures within 28 days prior to the first dose; underwent minor traumatic procedures (biopsy, bronchoscopy, and closed thoracic drainage) within 7 days prior to the first dose; (4) For Part A and Part B cohorts: previously received antibody-drug conjugates (ADC) with a topoisomerase I inhibitor payload; (5) For the Part A cohort: previously received anti-HER2 antibody-drug conjugate therapy;(6) For the Part B cohort: previously received anti-Claudin18.2 antibody-drug conjugate therapy; 7. Adverse events (AEs) caused by prior antitumor treatments have not recovered to CTCAE v5.0 grade <=1 (except for grade 2 alopecia, hypothyroidism controlled by hormone replacement therapy, and well-controlled diabetes with insulin, or other toxicities deemed safely manageable by the investigator); 8. Subjects with a history of interstitial pneumonia/non-infectious pneumonia requiring hormone therapy, those currently known or suspected to have interstitial pneumonia/non-infectious pneumonia, or those meeting any of the following conditions will not be included in this study: (1) Subjects known or suspected to have interstitial pneumonia; those with a prior history of clinically significant lung disease, or with moderate to severe lung disease within 3 months before initial dosing that could interfere with drug-related pulmonary toxicity assessment or management, including but not limited to idiopathic pulmonary fibrosis, organizing pneumonia/bronchiolitis obliterans, pulmonary embolism, severe asthma, severe COPD, obstructive/restrictive lung disease, etc.; (2) Any pulmonary-involved autoimmune, connective tissue, or inflammatory diseases, such as rheumatoid arthritis, Sj?gren's syndrome, sarcoidosis, etc.; 9. Subjects who develop pleural effusion, ascites, or pericardial effusion requiring intervention within 2 weeks before initial dosing, or moderate to severe effusion that requires repeated drainage; imaging indicating the presence of large serous effusions; 10. Subjects with poorly controlled or severe cardiovascular or cerebrovascular diseases, including: (1) Severe cardiac rhythm or conduction abnormalities, such as clinically significant ventricular or supraventricular arrhythmias, third-degree atrioventricular block, etc.; (2) Myocardial infarction, unstable angina, acute coronary syndrome, congestive heart failure (New York Heart Association [NYHA] functional class >= II), aortic dissection, or other grade 3 or above cardiovascular or cerebrovascular events within 6 months prior to initial dosing; (3) Severe arterial or venous thrombotic events within 6 months prior to the initial study drug administration, such as cerebrovascular events (transient ischemic attack, stroke, cerebral hemorrhage), deep vein thrombosis, and pulmonary embolism, etc. 11. Untreated active hepatitis (active hepatitis B, defined as hepatitis B surface antigen [HBsAg] positive and HBV-DNA ≥2000 IU/ml; active hepatitis C, defined as hepatitis C virus antibody HCV-Ab positive and HCV-RNA above the lower limit of detection); 12. History of immunodeficiency, including HIV positive test, previous allogeneic hematopoietic stem cell transplantation, or organ transplantation; 13. Subjects who have experienced serious infections within 30 days before the first dose, including but not limited to infections requiring hospitalization, bacteremia, severe pneumonia, etc.; active infections treated with therapeutic intravenous or oral antibiotics within 2 weeks before the first dose (subjects receiving prophylactic antibiotics, such as for the prevention of urinary tract infections, may be included); subjects with active pulmonary tuberculosis within 1 year prior to enrollment, as determined by medical history or CT, or those with a history of active pulmonary tuberculosis more than 1 year ago without proper treatment; 14. Vaccination with a live attenuated vaccine within 30 days before the first dose; 15. Female subjects who are pregnant, breastfeeding, or planning to become pregnant during the study; 16. Known allergy to any component or excipient of SHR-2554, SHR-1316, SHR-A1904, SHR-1701, or SHR-A1811; or a history of severe allergic reactions to other monoclonal antibodies/fusion protein drugs; 17. Presence of other serious physical or mental illnesses or laboratory abnormalities that may increase the risk of participating in the study, interfere with study results, or are considered by the investigator as making the subject unsuitable for participation; 18. Subjects with active autoimmune diseases, diseases requiring systemic corticosteroid or immunosuppressive therapy, other acquired (HIV infection) or congenital immunodeficiency diseases, or a history of organ transplantation (including allogeneic bone marrow transplantation) are excluded, except for those with vitiligo or childhood asthma/allergies that have fully resolved and require no intervention in adulthood. Alternative therapies (e.g., thyroxine, insulin, or physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency) are not considered systemic therapy and can be included. Subjects who have previously experienced grade 3 or higher immune-related adverse events during treatment with immune checkpoint inhibitors are excluded (except for insulin-controlled diabetes or endocrine dysfunction that can be managed solely with hormone replacement therapy, who may be included); 19. Subjects who experienced gastrointestinal perforation and/or gastrointestinal fistula within 6 months prior to the first dose, or active gastrointestinal bleeding within 3 months prior to the first dose (including but not limited to hematemesis, hematochezia, melena, etc.), with endoscopic evidence of incomplete healing (excluding those with resolved symptoms after gastrectomy for gastric cancer-related bleeding/perforation), are excluded; 20. Subjects in cohorts involving SHR-1316 or SHR-1701 must also meet the following exclusion criteria: subjects previously treated with immune checkpoint inhibitors (including but not limited to PD-(L)1) may still be included in the study, except for those who experienced CTCAE grade 4 or persistent grade 3 immune-related adverse events lasting >= 28 days after prior immune checkpoint inhibitor therapy, who must be excluded; (1) Subjects who received systemic corticosteroids or other immunosuppressants (including but not limited to cyclophosphamide, azathioprine, methotrexate, thalidomide, etc.) within 14 days prior to the first study drug administration; (2) For subjects who received short-term systemic immunosuppressive therapy (e.g., corticosteroids for management or prevention of nausea, vomiting, or allergic reactions), the investigator and sponsor will discuss whether the subject can participate in the study and whether a washout period is needed before the first dose, as well as its duration; (3) Use of inhaled corticosteroids for chronic obstructive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for orthostatic hypotension, and low-dose corticosteroids (<= 10 mg/day of prednisone or equivalent) for adrenal insufficiency is permitted.

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The trial data were managed by the sponsor with the use of an electronic data capture (EDC) system.