Phase I/II Clinical Study of the Combination of Disitamab Vedotin and Trastuzumab in the Treatment of HER2 Positive Gastric/Gastroesophageal Junction Tumors With Previous Systemic Therapy Failure
Overview
- Phase
- Phase 1
- Intervention
- Disitamab Vedotin(RC48) Plus Tratuzumab
- Conditions
- HER2-positive Gastric Cancer
- Sponsor
- Zhejiang Cancer Hospital
- Enrollment
- 35
- Locations
- 1
- Primary Endpoint
- Objective response rate(ORR)
- Status
- Recruiting
- Last Updated
- last year
Overview
Brief Summary
This trial is a single center, single arm, open label clinical study aimed at evaluating the efficacy and safety of the combination therapy of Disitamab Vedotin and trastuzumab in the treatment of advanced HER-2 positive gastric/gastroesophageal junction tumors
Detailed Description
In a specific tumor area, the absorption of antibodies is driven by its blood vessels or permeable surface, while the microscopic distribution depends on the number of binding sites available for the specific antibody. Due to the much faster binding rate of antibodies to their targets than their diffusion rate, their penetration into tumor tissue is severely limited (such as binding site barriers). This will limit the drug's penetration into the tumor before the antibody reaches saturation dose. Due to the toxicity brought by the toxins carried by ADC itself (toxin shedding, non-specific endocytosis, or on target, off tumor toxicity), its dose will be relatively reduced compared to naked antibodies. By adding naked antibodies or directly reducing DAR, the dose of ADC can be increased to overcome the binding site barrier and improve the tumor penetration of antibody drugs. In theory, if the antibody dose is large enough, the antibody will reach all (accessible) binding points within the tumor and saturate both the interior and periphery of the tumor. In addition, in addition to ADC drugs, chemotherapy, immunotherapy, targeted therapy, and other options are also available for HER2 positive gastric cancer posterior line, but the efficacy is still unclear. Therefore, it is urgent to explore new treatment options to further improve the efficacy of this special population. Therefore, we designed this Phase I/II clinical trial to explore whether the combination of RC48 and naked anti trastuzumab currently on the market can improve efficacy.
Investigators
Ying Jieer
MD
Zhejiang Cancer Hospital
Eligibility Criteria
Inclusion Criteria
- •Sign the informed consent form; 2.18-75 years old (including 18 years old, excluding 75 years old), gender not limited;
- •The pathological histology confirmed by pathology is adenocarcinoma of the gastric/gastroesophageal junction;
- •HER2 positive tumor criteria (primary tumor or metastatic lesion, HER2 positive is defined as IHC 2+/FISH+(HER2: CEP17 ratio ≥ 2.0) or IHC (3+). Using the criteria for interpreting HER2 in gastric cancer
- •Recurrent or metastatic diseases that cannot be surgically treated, with at least one measurable lesion (RECIST 1.1 criteria) in the subject and an estimated survival time of at least 12 weeks;
- •ECOG score ranges from 0 to 1 points;
- •At least first-line systemic therapy has failed (regardless of whether it includes anti-HER2 monoclonal antibody therapy);
- •Having sufficient bone marrow, liver and kidney function:
- •Absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelets ≥ 90 × 109/L, or
- •hemoglobin ≥ 9g/dL;
- •ALT or AST levels without liver metastasis are less than 2.5 times the upper limit of the normal range; When liver metastasis occurs, ALT or AST is less than 5 times the upper limit of the normal range; Serum bilirubin is 1.5 times lower than the upper limit of the normal reference range;
Exclusion Criteria
- •Known to be allergic to the received therapeutic drugs or excipients;
- •Baseline LVEF\<50% (measured by echocardiography or MUGA);
- •Previously received treatment with anti-HER2 ADC drugs;
- •Individuals who have undergone systemic immunotherapy, biologic therapy, or participated in any clinical drug trials within the past 2 weeks;
- •Those who have undergone surgery within 3 weeks before the start of the experimental treatment and have not fully recovered;
- •Patients with uncontrolled central nervous system (CNS) metastases or epilepsy requiring medication treatment;
- •Serious systemic diseases. Such as infected or uncontrolled diabetes;
- •Suffering from other malignant tumors within 5 years, except for non melanoma skin cancer and cervical carcinoma in situ;
- •Clinically symptomatic active coronary heart disease, cardiomyopathy, or congestive heart failure, NYHA III-IV; uncontrolled hypertension (systolic blood pressure\>180 mmHg or diastolic blood pressure\>100 mmHg), clinically symptomatic heart valve disease, or high-risk arrhythmia;
- •Patients receiving long-term or high-dose corticosteroid treatment (inhaled steroids or short-term oral steroids are allowed to resist vomiting or promote appetite)
Arms & Interventions
Phase Ⅰ/Ⅱ： Disitamab Vedotin(RC48) Plus Tratuzumab
Dose exploration： Disitamab Vedotin（RC48）: 2.5mg/kg，ivgtt，D1, every 2 weeks for a treatment cycle. Tratuzumab:"3+3"Design，1mg/kg Q2W，2.5mg/kg Q2W，4mg/kg Q2W Dose expansion： Disitamab Vedotin（RC48）: 2.5mg/kg，ivgtt，D1, every 2 weeks for a treatment cycle. Tratuzumab: RP2D
Intervention: Disitamab Vedotin(RC48) Plus Tratuzumab
Outcomes
Primary Outcomes
Objective response rate(ORR)
Time Frame: 12 months
he number of cases in which tumor size is reduced to PR or CR / the total number of evaluable cases (%)
Secondary Outcomes
- Progression-free survival (PFS)(up to 12 months)
- Disease control rate (DCR)(up to 12 months)
- Overall survival (OS)(up to 36 months)
- Incidence of Treatment-Emergent 3/4 Adverse Events(up to 12 months after enrollment or study close)