Perioperative zanidatamab combined with chemotherapy in HER2-positive locally advanced operable gastroesophageal adenocarcinoma (GEA): a Phase 1b/2a single-arm trial
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- UZ Leuven
- 入组人数
- 29
- 试验地点
- 4
- 主要终点
- Safety Incidence of qualifying safety events during the neoadjuvant period (first four cycles) in Phase 1b population as decision base for continuation of FLOT All other safety outcomes (including overall toxicity in Phases 1b and 2a) will be summarized descriptively.
研究概览
简要总结
To evaluate the safety and determine feasibility of the combination zanidatamab + FLOT (Phase 1b - safety run-in)
To evaluate the improvement of the pathological complete response rate (pCR) (total population)
入排标准
- 年龄范围
- 18 years 至 65+ years（65+ Years, 18-64 Years）
- 接受健康志愿者
- 否
入选标准
- •Voluntary written informed consent of the participant or their legally authorized representative has been obtained prior to any screening procedures
- •Hematologic function as follows: Absolute neutrophil count (ANC) ≥ 2.0 × 109/L. Platelet count ≥ 100 × 109/L. Subjects must not have required platelet transfusions or received thrombopoietic growth factor support within 30 days prior to randomization. Hemoglobin ≥ 8 g/dL. Subjects with chronic anemia that is supported by intermittent red blood cell (RBC) transfusions are eligible.
- •The cardiac ejection fraction (LVEF), as determined by echocardiography must be at least 50 %
- •At least 18 years of age at the time of signing the Informed Consent Form (ICF)
- •Use of highly effective methods of birth control for male and female patients defined as those that, alone or in combination, result in low failure rate (i.e., less than 1% per year) when used consistently and correctly; such as implants, injectables, combined oral contraceptives, some IUDs, true sexual abstinence (i.e. refraining from heterosexual intercourse) or commitment to a vasectomised partner for the entire period of risk associated with the Trial treatment(s).
- •WHO-ECOG performance status 0 – 1
- •Histologically proven gastroesophageal (esophageal, gastroesophageal junction or gastric) operable adenocarcinoma HER2-positive: HER2 IHC 3+ or IHC 2+/ISH+
- •Localized disease (resectable) fit for perioperative treatment including surgery (assessed by MDT)1,2,3
- •Fit for receiving chemotherapy backbone treatment
- •Adequate hepatic function, as defined by both: Aspartate aminotransferase (AST) ≤ 2.5 × upper limit of normal (ULN), and alanine aminotransferase (ALT) ≤ 2.5 × ULN. Total bilirubin ≤ 1.5 × the ULN or ≤ 2.5 × ULN for subjects with Gilbert’s disease.
- •Adequate renal function, as defined by estimated glomerular filtration rate (GFR) > 50 mL/min per local institutional standard method.
排除标准
- •Prior chemotherapy, immunotherapy, targeted therapy or radiation.
- •For the Phase 2a part (patients receiving tislelizumab: Active autoimmune diseases or history of autoimmune diseases that may relapse with the following exceptions: Controlled Type 1 diabetes. Hypothyroidism (provided it is managed with hormone replacement therapy only). Controlled celiac disease. Skin diseases not requiring systemic treatment (e.g., vitiligo, psoriasis, alopecia). Any other disease that is not expected to recur in the absence of external triggering factors.
- •Squamous cell cancer of the esophagus
- •Metastatic/unresectable gastroesophageal cancer
- •Known hypersensitivity to the active substances zanidatamab or to any of the excipients [Polysorbate 20 (E432), disodium succinate, succinic acid (E363), sucrose].
- •Known DPD deficiency
- •Patients with active infection requiring systemic treatment, known human immunodeficiency virus infection, or positive test for hepatitis B surface antigen (HbsAg)5 or hepatitis C virus (HCV)
- •Participants who test positive for HCV antibodies are eligible if HCV RNA is undetectable. Additionally, serious infections within 4 weeks prior to the first dose, including but not limited to infectious complications, bacteremia, severe pneumonia treated with IV antibiotics for ≥2 weeks; active infections with therapeutic IV antibiotics within 2 weeks prior to the first dose or oral antibiotics within 1 week prior to the first dose. Participants who are receiving or have received prophylactic antibiotics (e.g., prophylaxis against urinary infections) are allowed.
- •History of significant cardiac disease including history of myocardial infarction or unstable angina within 6 months prior to initiating treatment and ventricular arrhythmia requiring therapy, uncontrolled hypertension, or symptomatic congestive heart failure.
- •Previous malignancy within the last 5 years, with the exception of adequately treated cervical carcinoma in situ, localized non-melanoma skin cancer, or other curatively treated cancer not needing chemotherapy/immunotherapy and without impact on the patient's overall prognosis (expected OS> 5 years) according to the judgment of the investigator.
- •Participation in an interventional Trial with an investigational medicinal product (IMP) or device.
结局指标
主要结局
Safety Incidence of qualifying safety events during the neoadjuvant period (first four cycles) in Phase 1b population as decision base for continuation of FLOT All other safety outcomes (including overall toxicity in Phases 1b and 2a) will be summarized descriptively.
Safety Incidence of qualifying safety events during the neoadjuvant period (first four cycles) in Phase 1b population as decision base for continuation of FLOT All other safety outcomes (including overall toxicity in Phases 1b and 2a) will be summarized descriptively.
pCR improvement to 30% or higher in the 29 patients treated. The primary pCR analysis will be conducted in the overall treated population (N=29), acknowledging that chemotherapy backbone may differ due to the Phase 1b safety-triggered selection. Backbone regimen and exposure will be summarized, and a sensitivity analysis will descriptively report pCR by backbone (no formal hypothesis testing). The contribution of tislelizumab will be explored in the subset of patients receiving it.
pCR improvement to 30% or higher in the 29 patients treated. The primary pCR analysis will be conducted in the overall treated population (N=29), acknowledging that chemotherapy backbone may differ due to the Phase 1b safety-triggered selection. Backbone regimen and exposure will be summarized, and a sensitivity analysis will descriptively report pCR by backbone (no formal hypothesis testing). The contribution of tislelizumab will be explored in the subset of patients receiving it.
次要结局
- EFS defined as the time from the first dose of IMP on study until the date of occurrence of any of the following events: Disease progression (per Response Evaluation Criteria in Solid Tumours [RECIST] 1.1) Clinical progression Failure to achieve complete resection Relapse Appearance of a new primary cancer Death from any cause Patients in whom no “event” is recorded at the time of discontinuation for other causes and starting a subsequent line of treatment will be censored for EFS
- OS defined as the time from the first dose of IMP on study until death from any cause. Patients starting a subsequent line of treatment after study discontinuation will not be censored for survival at the start of this subsequent treatment. Subjects who are still alive at the time of final data cut-off date will be censored at the last day known to be alive.
研究者
Filip Van Herpe
Scientific
UZ Leuven