A Phase I Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of Disitamab Vedotin Combined With RC98 in the Treatment of Subjects With HER2-expressing Locally Advanced or Metastatic Gastric Cancer (Including AEG).
Overview
- Phase
- Phase 1
- Intervention
- RC48-ADC
- Conditions
- Gastric Cancer
- Sponsor
- RemeGen Co., Ltd.
- Enrollment
- 24
- Locations
- 1
- Primary Endpoint
- Dose limiting toxicity (DLT)
- Status
- Recruiting
- Last Updated
- 2 years ago
Overview
Brief Summary
This is a single-center, open-label, dose-escalation phase I clinical study.This study aimed to evaluate the safety, tolerability, pharmacokinetics and preliminary clinical efficacy of RC48-ADC combined with RC98 in subjects with advanced gastric cancer.Which will provide a reference basis for dose confirmation in subsequent clinical studies.
Detailed Description
The dose escalation phase will enroll subjects with HER2-expressing locally advanced or metastatic gastric cancer, including gastroesophageal junction adenocarcinoma. HER2 expression is defined as follows (meets one of the following): • HER2 IHC3+, 2+, 1+; (Subjects with HER2 immunohistochemistry (IHC) results of IHC1+, IHC 2+, and IHC 3+, previous test results (confirmed by the investigator) or research center test results are acceptable; The dose-escalation phase preset doses for this combination therapy are as follows: RC48-ADC: 2.5mg/kg Q2W; RC98 increasing dose: 5.0mg/kg Q2W, 10.0mg/kg Q2W, 15.0mg/kg Q2W. The dose escalation phase of the combination therapy adopts the Bayesian optimal interval (BOIN) design method: the fixed dose of RC48-ADC is 2.5 mg/kg, and the dose of RC98 is escalated, and the initial incremental dose of RC98 is 5.0 mg/kg. MTD has a target toxicity rate of 0.3 and a maximum sample size of 24. The subjects will be enrolled in units of 3, with a maximum of 12 subjects in each dose group; the 28 days after the first dose will be used as the observation window of DLT to make decisions such as dose increase and decrease. If the DLT criteria were not met within 28 days after the first dose, dose escalation was not continued to observe DLT and MTD. After the dose escalation period is over, the investigator decides the recommended phase 2 dose (RP2D) based on the available safety, tolerability, PK, and efficacy information. After completing the dose-limiting toxicity (DLT) evaluation, the subject can continue to receive the original dose of study drug treatment (but not more than the currently ongoing escalating dose or the maximum tolerated dose under the condition that the investigator judges that there may be benefits) ), subjects received treatment until intolerable toxicity, disease progression, or termination of the study by the sponsor.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Voluntarily agree to participate in the research and sign the informed consent;
- •Age 18-70 (including 18 and 70);
- •Expected survival period ≥ 12 weeks;
- •ECOG performance status of 0 or 1 within 3 days before the first dose of study treatment;
- •Patients with metastatic or unresectable locally advanced or metastatic gastric cancer (including gastroesophageal junction adenocarcinoma) confirmed by histology or cytology with disease progression after standard treatment or intolerant to standard treatment;
- •Female subjects should be surgically sterilized, postmenopausal patients, or agree to use at least one medically approved contraceptive measure (such as an intrauterine device, contraceptives) during the study treatment period and within 6 months after the end of the study treatment period. pills or condoms), must have a negative blood pregnancy test within 7 days prior to study enrollment, and must be non-nursing. Male subjects should agree to use at least one medically approved contraceptive method during the study treatment period and within 6 months after the end of the study treatment period;
- •Able to understand trial requirements, willing and able to comply with trial and follow-up procedures.
- •Adequate organ and bone marrow hematopoiesis
- •Bone marrow function:
- •Hemoglobin≥90g/L;
Exclusion Criteria
- •The study drug has been used within 4 weeks before the start of the study drug;
- •Major surgery has been performed within 4 weeks before the start of the study drug and the patient has not fully recovered;
- •Have been vaccinated with live vaccines within 4 weeks before the start of the study drug or plan to receive any vaccines during the study period (except for the new coronavirus vaccine);
- •Arterial/venous thrombotic events, such as cerebrovascular accident (including temporary ischemic attack), deep vein thrombosis and pulmonary embolism, occurred within 6 months before the study drug;
- •Major cardiovascular disease (NYHA grade 3 or 4 heart failure, second-degree or higher heart block, myocardial infarction within the past 12 months, unstable arrhythmia or unstable angina pectoris, cerebral infarction within 6 months infarction, etc.);
- •Active autoimmune disease requiring systemic treatment (such as the use of immunomodulatory drugs, corticosteroids or immunosuppressants) within 2 years before the start of study administration, allowing related replacement therapy (such as thyroxine, insulin, or renal or Physiological corticosteroid replacement therapy for pituitary insufficiency);
- •Subjects who need to receive glucocorticoid (prednisone\>10 mg/day or other similar drugs at an equivalent dose) or other immunosuppressive therapy due to certain conditions within 14 days before the start of the study drug;
- •Suffering from uncontrolled systemic diseases, including diabetes, hypertension, pulmonary fibrosis, acute lung disease, interstitial lung disease, liver cirrhosis, etc.;
- •Suffering from active infection requiring systemic treatment;
- •History of active tuberculosis;
Arms & Interventions
RC48 combind with RC98
Intervention: RC48-ADC
RC48 combind with RC98
Intervention: RC98
Outcomes
Primary Outcomes
Dose limiting toxicity (DLT)
Time Frame: 28 days after first treatment
In the DLT evaluation window (observation period 1-28 days after the first administration), according to the NCI-CTCAE v5.0 grading standard, the investigator or the sponsor believes that toxic reaction which are reasonably related to RC48 and/or RC98 treatment
The incidence and severity of adverse events (AE)
Time Frame: From the day of ICF sign to 28 days after the day of the last treatment
Adverse events was assessed by investigator(s) according to NCI-CTCAE v5.0
Secondary Outcomes
- AUC of RC98(24 months)
- Cmax of RC48(24 months)
- AUC of RC48(24 months)
- Cmax of RC98(24 months)
- AUC of MMAE(24 months)
- Progression-free survival(24 months)
- Cmax of MMAE(24 months)
- Immunogenicity of RC48(24 months)
- Immunogenicity of RC98(24 months)
- Objective response rate (ORR)(24 months)
- Duration of Remission (DOR)(24 months)
- Disease Control Rate(DCR)(24 months)