Clinical trial NCT06572319: Disitamab Vedotin Plus Trastuzumab in Patients With HER2 Positive GC/GEJ Patiens
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: HER2-positive Gastric Cancer
HER2-positive Gastroesophageal Junction Adenocarcinoma
Keywords: HER-2
ADC
Disitamab Vedotin
trastuzumab
Lead sponsor: Zhejiang Cancer Hospital
Sponsor class: OTHER
First posted: 2024-08-27
Enrollment: 35
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

1. Sign the informed consent form; 2.18-75 years old (including 18 years old, excluding 75 years old), gender not limited; 3. The pathological histology confirmed by pathology is adenocarcinoma of the gastric/gastroesophageal junction; 4. 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 5. 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; 6. ECOG score ranges from 0 to 1 points; 7. At least first-line systemic therapy has failed (regardless of whether it includes anti-HER2 monoclonal antibody therapy); 8. 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;
* Serum creatinine is lower than 1.5 times the upper limit of the normal reference range or creatinine clearance rate is ≥ 40ml/min; 9. Women of childbearing age and their spouses are willing to use effective contraceptive methods within the last 7 months of treatment.

Exclusion Criteria:

1. Known to be allergic to the received therapeutic drugs or excipients;
2. Baseline LVEF\<50% (measured by echocardiography or MUGA);
3. Previously received treatment with anti-HER2 ADC drugs;
4. Individuals who have undergone systemic immunotherapy, biologic therapy, or participated in any clinical drug trials within the past 2 weeks;
5. Those who have undergone surgery within 3 weeks before the start of the experimental treatment and have not fully recovered;
6. Patients with uncontrolled central nervous system (CNS) metastases or epilepsy requiring medication treatment;
7. Serious systemic diseases. Such as infected or uncontrolled diabetes;
8. Suffering from other malignant tumors within 5 years, except for non melanoma skin cancer and cervical carcinoma in situ;
9. 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;
10. Patients receiving long-term or high-dose corticosteroid treatment (inhaled steroids or short-term oral steroids are allowed to resist vomiting or promote appetite)
11. Individuals without legal capacity, those whose medical or ethical reasons affect the continuation of research;
12. Pregnant and lactating female patients, or those who wish to become pregnant during treatment;
13. Uncontrolled pleural and peritoneal effusion;
14. There is a persistent infection of\>level 2 (CTC-AE 4.0); Wounds, ulcers, or fractures that cannot heal, or patients with a history of organ transplantation;
15. There are unresolved toxicity levels\>1 caused by any previous treatment/procedure (CTC-AE 4.0, excluding hair loss, anemia, and hypothyroidism);
16. After comprehensive assessment of the patient's condition by the researchers, it is deemed that they are not suitable to participate in this study;
17. Simultaneously participating in another clinical study.

Primary outcomes:
measure: Objective response rate(ORR)
timeFrame: 12 months
Secondary outcomes:
measure: Overall survival (OS)
timeFrame: up to 36 months
measure: Progression-free survival (PFS)
timeFrame: up to 12 months
measure: Disease control rate (DCR)
timeFrame: up to 12 months
measure: Incidence of Treatment-Emergent 3/4 Adverse Events
timeFrame: up to 12 months after enrollment or study close
Other outcomes:
Locations:
city: Hangzhou
country: China
facility: Zhejiang Cancer Hospital
state: Zhejiang
Study officials:
affiliation: Zhejiang Cancer Hospital
name: Jieer Ying, M.D.
role: PRINCIPAL_INVESTIGATOR
References: