International Multicenter Multicohort Open-label Phase II Trial Aiming to Define Optimal Methods for Predicting Response/Resistance to Antibody-drug Conjugates in Patients With Solid Tumors Treated According to Current Standard Indications.
概览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- UNICANCER
- 入组人数
- 400
- 试验地点
- 1
- 主要终点
- Biomarkers of resistance to ADC
概览
简要总结
International study that will evaluate the association of prespecified biomarkers with resistance to Antibody-drug conjugates (ADCs), a type of targeted cancer treatment currently used in clinical practice for treating different tumor types.
详细描述
Over the past five years, antibody-drug conjugates (ADCs) have dramatically improved survival in solid and hematologic malignancies. Among 14 ADCs approved worldwide, nine are now available in Europe, and over 370 others are in clinical development. This expanding landscape indicates that ADCs could soon replace conventional chemotherapy across multiple tumor types. Given this rapid evolution, clinicians will need to select the most suitable ADC for each patient, considering tumor biology, microenvironment (TME) and patient-specific factors. Yet, despite remarkable efficacy, resistance to ADCs eventually arises. Understanding resistance mechanisms is therefore essential to guide therapeutic sequencing and optimize next-generation ADCs.
ADCs are complex molecules combining an antibody, a linker, and a cytotoxic payload. Their activity depends on factors such as antigen expression, internalization, linker stability, and payload sensitivity. Resistance can result from altered vascular perfusion, antigen downregulation, defective internalization or trafficking, impaired linker cleavage, drug efflux, or payload target modifications. These multifactorial processes differ from those driving resistance to traditional chemotherapies. Existing preclinical and clinical tools (Patient-Derived Xenograft(PDX)/Cell-line-Derived Xenograft (CDX) models, standard imaging, Immunohistochemistry (IHC), genomic profiling) fail to capture this complexity or predict ADC efficacy and resistance. Furthermore, ADCs often cause significant toxicities-on-target or off-target-affecting the ocular surface, skin, lungs, and peripheral nerves. Patient factors such as age, comorbidities, and weight influence these events. Understanding the determinants of toxicity is critical to maintain quality of life and treatment adherence.
The OASIS program aims to identify predictive biomarkers of ADC response and toxicity to enable personalized ADC selection and toxicity prevention. This multicenter study will integrate advanced technologies-digital pathology, liquid biopsy, and Patient-derived organoids (PDOs)-to generate comprehensive biological and clinical data. Using these datasets, a multimodal machine-learning model (OASIS Multiparametric Score) will be developed to predict both efficacy and key toxicities of ADCs. The project will prospectively include patients receiving ADCs in standard practice, with longitudinal tumor and blood sampling to investigate biomarkers of resistance and toxicity. In parallel, preclinical models derived from patient tumors will explore resistance mechanisms and screen ADC sensitivity.
A retrospective cohort of patients previously treated with ADCs will first be analyzed to prioritize biomarker candidates based on published data and prior findings. From this, five binary biomarkers will be selected for the primary objective. Combined with prospective data, this retrospective work will expand the translational biobank and support the construction of the OASIS score.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients must have signed a written informed consent form prior to any trial specific procedures;
- •Patients must be ≥18 years old;
- •Histologically confirmed or radiologically documented unresectable locally advanced or metastatic cancer (Breast, Urothelial, Non small Cell Lung or Gastric) with an indication to receive an Antibody-Drug Conjugate (ADC) approved or accessible through an early access program;
- •Patients must have at least 2 tumor lesions (primary tumor can be included): at least one measurable tumor lesion for tumor evaluation according to response evaluation criteria in solid tumors (RECIST) V1.1 and at least one tumor lesion other than bone and brain for biopsy;
- •Patients must have a metastatic or locally advanced tumor site easily accessible to biopsy (with exception of bone and brain metastasis) and must have agreed to perform pretreatment and post-treatment biopsies; an archival pre-treatment biopsy may be used if it was collected within one month of enrolment, if no anticancer therapy was administered after the biopsy and if sufficient material is available for research;
- •Life expectancy must be ≥12 weeks according to the discretion of the investigator;
- •ECOG performance status ≤ 2;
- •Patients must have adequate hematologic and organ function, compatible with ADC administration, as per drug-specific recommendations;
- •Women of childbearing potential and male patient must agree to use adequate contraception for the duration of trial participation and up to 7 months after completing treatment for women and up to 4 months for men;
- •Patients must be affiliated to a social security system (or equivalent);
排除标准
- •Patients treated with an antibody drug conjugate in a curative setting;
- •Patients who did not consent to sample use;
- •Presence of another progressive pathology with short-term life-threatening prognosis;
- •Patients undergoing concurrent treatment for a malignancy or hematologic disorder distinct from the indication for which the ADC is being administered.
- •Patients with inadequate washout period prior to Cycle 1 Day 1, defined as:
- •Whole brain radiation therapy \<14 days or stereotactic brain radiation therapy \<7 days.
- •Any cytotoxic chemotherapy, investigational agents or other anticancer drug(s) (including another ADC) from a previous cancer treatment regimen or clinical study (other than epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI)), \<14 days or 5 half-lives, whichever is longer.
- •Immune checkpoint inhibitor therapy \<21 days.
- •Hormonal therapy \<21 days.
- •Major surgery (excluding placement of vascular access) \<28 days.
结局指标
主要结局
Biomarkers of resistance to ADC
时间窗: Through study completion, an average of 3 years
Resistance is defined by differences in the frequency (higher or lower) of molecular aberrations detected between paired baseline samples and progression samples (i.e., samples collected at the time of disease progression under ADC treatment)
次要结局
- Additional biomarkers of resistance characterised by histology(Through study completion, an average of 3 years)
- Biomarkers of ADC outcome(From first day of cycle 1 (each cycle is 21 to 28 days) to date of death from any cause, assessed up to 60 months)
- Biomarkers of resistance to ADC(From first day of cycle 1 (each cycle is 21 to 28 days) to date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months)
- Expression of ADC target measured on CTC and within tumor tissue(Through study completion, an average of 3 years)
- Patients' reported outcomes (PROs)(Through study completion, an average of 3 years)
- Treatment cost(Through study completion, an average of 3 years)
- ADC-related specific toxicities(Through study completion, an average of 3 years)