Assessing Iparomlimab and Tuvonralimab in Recurrent or Metastatic MSI-H/dMMR Gastric Cancer

Official title

A Randomized, Controlled, Multi-centers, Non Inferiority Phase II Clinical Study Comparing Iparomlimab and Tuvonralimab With Standard Chemotherapy Combined With PD-1/PD-L1 Monoclonal Antibody as First-line Treatment for MSI-H/dMMR Recurrent/Metastatic Gastric Cancer

Overview

A randomized controlled phase II study exploring first-line treatment options for recurrent/metastatic MSI-H gastric cancer

Detailed description

This is a randomized controlled, non-inferiority design phase II study in the first-line treatment of recurrent/metastatic MSI-H gastric cancer, using iparomlimab and tuvonralimab and standard first-line chemotherapy combined with PD-1/PD-L1 antibody in two cohorts, respectively,

Interventions

• Drug Iparomlimab and Tuvonralimab
  Iparomlimab and tuvonralimab for experimental arm
• Drug First line chemotherapy plus PD-1/PD-L1 antibody
  standard first-line chemotherapy（FOLFOX/XELOX/SOX）combined with PD-1/PD-L1 antibody for control arm

Primary outcome measures

• Antitumor efficacy-Objective response rate (ORR) [Time frame: 2 years]

Secondary outcome measures (5)

• Antitumor efficacy-Progression-free survival (PFS) [Time frame: 2 years]
• Antitumor efficacy-Overall survival (OS) [Time frame: 2 yeas]
• Treatment related AEs [Time frame: 2 years]
• Antitumor efficacy-Duration of response (DOR) [Time frame: 2 years]
• Antitumor efficacy-Time to response (TTR) [Time frame: 2 years]

Eligibility criteria

Inclusion criteria

1\. Voluntarily willing to participate in the study and sign the written informed consent form 2. Age ≥18 years male or female . 3. Expected survival time ≥ 3 months 4. Patients with unresectable locally advanced, recurrent, or metastatic gastric/gastroesophageal junction adenocarcinoma diagnosed by histological or cytological examination: 5. Confirmed by PCR or next-generation sequencing(NGS) as microsatellite instability-high(MSI-H) . Patients with mismatch repair defecient identified by immunohistochemistry need to undergo PCR/NGS verification as MSI-H before treatment 6. Patients should not receive systematic anti-tumor treatment before, and for those who have received induction chemotherapy, concurrent radiochemotherapy, or neoadjuvant/adjuvant chemotherapy for curative purposes, the recurrence time must be at least 6 months from the end of the last treatment; 7. Agree to provide archived tumor tissue specimens or fresh tissue samples of primary or metastatic lesions within 3 years; If the patinet is unable to provide tumor tissue samples, they can be enrolled after evaluation by the researcher, provided that they meet other inclusion and exclusion criteria; 8. Patients must have at least one measurable lesion defined by RECIST 1.1. 9. European Cooperative Oncology Group (ECOG) ≤1 10. No severe cardiac dysfunction, left ventricular ejection fraction ≥ 50%; 11. Patients must meet the following criteria at screening and before preconditioning (baseline). If any laboratory test result is abnormal referring to the following criteria,

• Hematology: neutrophils (NE) ≥1.5×109 per liter, , platelets (PLT) ≥100×109per liter and hemoglobin (Hb) ≥8.0 g/dL.
• Blood chemistry: creatinine clearance ≥50 mL/min, Creatinine (Cr) ≤ 1.5 × ULN, alanine aminotransferase (ALT) ≤2.5×ULN（Gilbert syndrome or liver metastasis subjects ≤ 5 × ULN）, aspartate aminotransferase (AST) ≤2.5×ULN（Gilbert syndrome or liver metastasis subjects ≤ 5 × ULN）, total bilirubin (TB) ≤1.5×ULN（Gilbert syndrome or liver metastasis subjects ≤ 3 × ULN）,
• International normalized ratio (INR) ≤ 1.5, and activated partial thromboplastin time (APTT) ≤ 1.5 × ULN; 12. Urinary protein ≤ 2+or < 1000mg/24h; 13. Women of childbearing potential must have negative serum pregnancy test result at screening and before preconditioning and agree to use an effective and reliable contraceptive method for at least 1 year after the last study treatment. Te acceptable methods include bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusion; any approved oral, injection or implantation of hormone; or barrier contraceptive method: condoms containing spermicidal .

Exclusion criteria

• Pregnant or lactating women.
• Previous use of PD-1/PD-L1 monoclonal antibodies, CTLA-4 monoclonal antibodies, or monoclonal and bispecific drugs containing the aforementioned targets;
• Existence of any active autoimmune disease or history of autoimmune disease (such as but not limited to: autoimmune hepatitis, interstitial pneumonia, enteritis, vasculitis, nephritis; asthma in which subjects require bronchodilators for medical intervention cannot be included); However, the following diseases are allowed to be included: vitiligo, psoriasis, alopecia without systemic treatment, well controlled type I diabetes, hypothyroidism with normal thyroid function after replacement treatment;
• Patients who require immunosuppressive therapy, systemic or absorbable local hormone therapy to achieve immunosuppressive goals (calculated as prednisone, dose>10mg/day or other therapeutic hormones) and continue to use it within 2 weeks of the first administration;
• Patients with uncontrolled pleural effusion, pericardial effusion, or ascites that require repeated drainage;
• Patients with uncontrollable symptoms of brain metastasis, spinal cord compression, malignant meningitis, or brain or pia mater diseases detected by CT or MRI examination during screening within 4 weeks before the first administration
• Patients who have received non systematic anti-tumor therapy within 3 weeks prior to the start of treatment, including but not limited to surgery, radiation therapy, interventional therapy, and anti-tumor traditional Chinese medicine treatment (based on the indications in the Chinese medicine instructions, and may also be enrolled after a 2-week washout period). Patients whose adverse events caused by previous treatment (excluding hair loss) have not recovered to ≤ CTCAE grade 2 are not within the above range;
• Patients with any severe and/or uncontrolled illnesses, including:

1\) Patients with poor blood pressure control (systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 90 mmHg) 2) Patients who experience unstable angina, myocardial infarction, ≥ grade 2 congestive heart failure, or arrhythmia requiring treatment within 6 months of initial administration (including QTc ≥ 480ms); 3) Active or uncontrolled severe infection (≥ CTCAE grade 2 infection); 4) A history of clinically significant liver disease, including viral hepatitis, known as a carrier of hepatitis B virus (HBV), must exclude active HBV infection, i.e. HBV DNA positive (>2000 IU/mL); Known hepatitis C virus infection (HCV) and HCV RNA positivity (>1 × 103 copies/mL), or other decompensated liver diseases or chronic hepatitis requiring antiviral therapy; 5) HIV test positive 6) Poor control of diabetes (fasting blood glucose ≥ CTCAE level 2); 9. Patients who have experienced severe infections (CTCAE>grade 2) within the first 4 weeks of randomization, such as severe pneumonia, bacteremia, sepsis, tuberculosis, etc; Indications of pulmonary infection or active pulmonary inflammation within the first 2 weeks of randomization; 10. Patients with a history of allergies to recombinant humanized antibodies who are allergic to any excipient components of the drug; 11. History of autologous or allogeneic stem cell transplantation; 12. Patients with a history of serious neurological or psychiatric disorders, including but not limited to: dementia, depression, epileptic seizures, bipolar disorder, etc; 13. Patients diagnosed as active malignant tumor within the first 3 years of randomization, except for the following cases: radical skin basal cell carcinoma, skin squamous cell carcinoma, superficial bladder cancer, cervical carcinoma in situ, breast carcinoma in situ and/or radical resection of carcinoma in situ, which the researchers think can be included; 14. Patients who plan to receive live vaccines within 28 days prior to randomization; 15. Researchers evaluate situations where participation in this clinical trial is inappropriate due to complications or other reasons.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 10 centers

• The Fourth Hospital of Hebei Medical University — Shijiazhuang
• Harbin Medical University Cancer Hospital — Harbin
• The First Affiliated Hospital of Zhengzhou University — Zhengzhou
• Jiangsu Provincial People's Hospital — Nanjing
• The First Affiliated Hospital of Xi'an Jiao Tong University） — Xi'an
• The Affiliated Hospital of Qingdao University — Qingdao
• Shanxi Cancer Hospital — Taiyuan
• West China Hospital, Sichuan University — Chengdu
• … and 2 more centers

Identifiers

NCT: NCT07127822 · PUCH MSI-H GC 1st

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗