Y90 Radioembolization as Neoadjuvant Therapy for Potentially Resectable Patients With Colorectal Liver Metastases: Immune Markers Evaluation, Impact on Circulating Tumor DNA and Personalized Dosimetry Approach
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 发起方
- 入组人数
- 30
- 试验地点
- 5
- 主要终点
- Monitoring for adverse events related to the procedure.
研究概览
简要总结
This is a observational, prospective, single arm, proof of concept study to assess safety, feasibility, and potential efficacy of combining Yttrium-90 transarterial radioembolization(TARE) with standard systemic therapy in clinical practice for potentially resectable patients with colorectal liver metastases (CRLM). Alternatively, resectability will also be evaluated. The investigators hypothesize that by applying this approach, higher local control and resection rates can be achieved (typically below 13% for patients who are initially deemed unresectable). Additionally, this treatment option is expected to help delay or reduce the need for (a switch in) systemic treatment and eventually improve survival in patients with liver metastases that are not resectable. All studies reporting the results of TARE at ablative doses are retrospective cohort studies or cases series. Prospective data is needed to expand the indications and reimbursement of radioembolization.
Other objectives of the study are:
- To calculate the resection rate in patients undergoing the combined approach.
- To evaluate immune markers in peripheral blood and resected metastases.
- To formulate the first concept of an algorithm, enable to deliver personalized AI assisted dosimetry.
- To assess potential role of circulating tumor DNA (ctDNA) in evaluation of patient prognosis and follow up.
- To determine the grade of necrosis at the time of resection and correlate with the absorbed dose.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
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
- •Histologically confirmed primary adenocarcinoma of the colon or rectum
- •Potentially resectable colorectal liver metastases, with limiting factors for resection including:
- •Insufficient future liver remnant.
- •Unfavorable tumor location (e.g. involvement of a major vessel and/or bile duct)/ large size and/ or number of lesions, which limit resection with R0 margins and requires downsizing of the metastases
- •No or limited extrahepatic metastatic disease (limited extrahepatic disease should be amenable to eradicate with locoregional therapies as per multidisciplinary discussion of surgeons, radiation oncologists and interventional radiologists)
- •Patient should match standard 90Y radioembolization inclusion criteria:
- •Signed informed consent;
- •Age ≥ 18 years;
- •Eastern Cooperative Oncology Group (ECOG) performance status 0-1;
- •Life expectancy of ≥ 3 months;
- •Measurable target tumors in the liver according to RECIST 1.1
- •Laboratory parameters: eGFR >45/mL/min/1.73 m2; albumin > 3.0 g/dl, normal bilirubin (unless Gilbert syndrome); aminotransferase (ALAT/ASAT) <3.0 ULN
排除标准
- •Life expectancy ≤3 months
- •Patient initially eligible for surgery or thermal ablation of the liver metastases
- •Progressive extra-hepatic disease
- •Active extra-hepatic disease that cannot be treated
- •Life-threatening extra-hepatic disease (i.e. dialysis, unresolved diarrhea, serious unresolved infections (HIV, HBV, HCV etc.))
- •Uncorrectable coagulopathy
- •Contraindication for angiography or MRI
- •Significant toxicities due to prior cancer therapy that have not resolved before the initiation of the study; if the investigator determines that the continuing complication will compromise the safe treatment of the patient
- •Any surgical contraindication
- •Expected difficulties for safe execution of TARE based on pretreatment Tc99m-MAA imaging, including;
- •Flow to extra-hepatic vessels not correctable by reposition of catheter or embolization Uncorrectable estimated dose to the lungs >30Gy in a single administration or >50Gy cumulatively
- •Uncorrectable estimated dose to the untreated liver of >70Gy
- •Estimated average dose to the viable tumor volume <200Gy
- •Prior liver radiotherapy
- •Severe portal hypertension
- •Second primary malignancy within the past 5 years, other that adequately treated non-melanoma skin cancer, carcinoma in situ of any organ or second primary colorectal cancer
- •Unresectable primary tumor in situ;
- •Other serious comorbidity or any other condition, that renders patients unsuitable for the study treatment
- •Pregnancy, lactation or refusal to use adequate contraceptive measures
- •History of allergic reaction to any components of the treatment that cannot be medically corrected.
结局指标
主要结局
Monitoring for adverse events related to the procedure.
时间窗: From 90Y radioembolization (week 2-4) to the end of study at 30 weeks
Evaluate the safety of combining neoadjuvant ablative dose 90Y radioembolization with standard systemic therapy in patients with CRLM. Safety assessments will include monitoring for adverse events related to the procedure.
Evaluate the safety related to the procedure by measuring changes in Liver function values in blood.
时间窗: From 90Y radioembolization (week 2-4) to the end of study at 30 weeks
To evaluate hepatic safety after neoadjuvant ablative-dose Yttrium-90 radioembolization combined with standard systemic therapy in patients with CRLM changes in laboratory biomarkers will be compared with baseline values and subsequent assessments. Biomarkers and Units of Measure: \- Liver Function Markers: Bilirubin (mg/dL), Albumin (g/dL), Aspartate Aminotransferase (AST) (U/L), Alanine Aminotransferase (ALT) (U/L), Gamma-Glutamyl Transferase (GGT) (U/L), Alkaline Phosphatase (FA) (U/L), Cholinesterase (ChE) (U/L), Lactate Dehydrogenase (LDH) (U/L)
Evaluate the safety related to the procedure by measuring changes in tumor markers in blood.
时间窗: From 90Y radioembolization (week 2-4) to the end of study at 30 weeks
Evaluate the safety of combining neoadjuvant ablative dose 90Y radioembolization with standard systemic therapy in patients with CRLM by assessing tumor markers in blood: Carcinoembryonic antigen (CEA) and CA 19-9.
Evaluate the quality of Life After Liver Resection Assessed by FACT-C (Version 4) Following 90Y Radioembolization
时间窗: From 90Y radioembolization (week 2-4) to the end of study at 30 weeks
Evaluate the safety of combining neoadjuvant ablative dose 90Y radioembolization with standard systemic therapy in patients with CRLM. Safety assessments will include assessing overall well-being of the patients focus on quality of life after liver resection. Outcome Measure: Change in Functional Assessment of Cancer Therapy-Colorectal (FACT-C, Version 4) total score from baseline to 30 weeks. The FACT-C (Version 4) total score and each subscale will be analyzed as independent measures to evaluate longitudinal changes in overall well-being and postoperative recovery after liver resection, characterizing treatment-related safety and tolerability. Quality-of-Life Instrument: Functional Assessment of Cancer Therapy-Colorectal (FACT-C, Version 4): Total score and subscale scores (Physical Well-Being, Social/Family Well-Being, Emotional Well-Being, Functional Well-Being, and Colorectal Cancer Subscale), reported according to standard scoring guidelines.
Evaluate the efficacy of the procedure by tumor response rate assessed by means of RECIST 1.1
时间窗: From week 0 to resection, progression or week 26-28
Efficacy assessments will include tumor response rate assessed by means of RECIST 1.1. Baseline efficacy imaging scans will be conducted during the screening phase. Efficacy assessment scans will follow standard-of-care clinical management guidelines, occurring every 8 weeks (with a variance of +/- 1 week) post-inclusion until resection or until progression.
Evaluate the efficacy of the procedure: pathologic response assessment on the resected specimens.
时间窗: From week 0 to resection, progression or week 26-28
Efficacy assessments will include tumor response rate assessed by means of RECIST 1.1. It will be of capital interest the pathologic response assessment on the resected specimens.
次要结局
- Resection rate in patients undergoing the combined approach(week 18-20 and week 26-28)
- Cellular population quantification on peripheral blood samples: leukocytes, neutrophils, lymphocytes, monocytes, eosinophils and basophils.(Week 0, 6, 8 and 16)
- Inflammatory interleukines IL-6, IL-10 and IFN-γ quantification:(Week 0, 6, 8 and 16)
- Intratumoral T Cells Infiltration in biopsies and resected tumors.(week 0, week 18/20 and week 26/28)
- PERSONALIZED AI ASSISTED DOSIMETRY evaluation(week 0 to 26-28)
- ctDNA analysis: Identification of genetic alterations and circulating tumor DNA (ctDNA) monitoring through digital droplet PCR(week 6, 8, 12, 16, 22 and 30)
- Macroscopic determination of the grade of necrosis(week 18/20 and week 26/28.)
- Determination of the grade of necrosis: Microscopic study.(week 18/20 and week 26/28.)
- Evaluation of Post-treatment liver damage: Microscopic study(week 18/20 and week 26/28.)
研究者
Fernando Gómez Muñoz
Principal Investigator, MD, PhD
Instituto de Investigacion Sanitaria La Fe