Yttrium-90 Radioembolization Neoadjuvant Therapy With Immune Marker Profiling and Dosimetry for Potentially Resectable Patients With Colorectal Liver Metastases

Официальное название

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

Обзор

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.

Вмешательства

• Процедура Yttrium-90 Radioembolization with standard systemic therapy
  Yttrium-90 microspheres are administered through the hepatic artery which supplies blood to tumor tissue (the portal vein supplies blood to the normal hepatic tissue). The microspheres are trapped in the vasculature of the tumor due to arteriolar capillary blockage where they exert a local radiotherapeutic effect. In clinical use, the glass microspheres remain permanently trapped in the vasculature where the isotope decays to infinity leaving background radiation with no therapeutic value. This

Первичные конечные точки

• Monitoring for adverse events related to the procedure. [Срок оценки: From 90Y radioembolization (week 2-4) to the end of study at 30 weeks]
• Evaluate the safety related to the procedure by measuring changes in Liver function values in blood. [Срок оценки: From 90Y radioembolization (week 2-4) to the end of study at 30 weeks]
• Evaluate the safety related to the procedure by measuring changes in Liver function values in blood. [Срок оценки: From 90Y radioembolization (week 2-4) to the end of study at 30 weeks]
• Evaluate the safety related to the procedure by measuring changes in Liver function values in blood. [Срок оценки: From 90Y radioembolization (week 2-4) to the end of study at 30 weeks]
• Evaluate the safety related to the procedure by measuring changes in tumor markers in blood. [Срок оценки: From 90Y radioembolization (week 2-4) to the end of study at 30 weeks]
• Evaluate the quality of Life After Liver Resection Assessed by FACT-C (Version 4) Following 90Y Radioembolization [Срок оценки: From 90Y radioembolization (week 2-4) to the end of study at 30 weeks]
• Evaluate the efficacy of the procedure by tumor response rate assessed by means of RECIST 1.1 [Срок оценки: From week 0 to resection, progression or week 26-28]
• Evaluate the efficacy of the procedure: pathologic response assessment on the resected specimens. [Срок оценки: From week 0 to resection, progression or week 26-28]

Вторичные конечные точки (9)

• Resection rate in patients undergoing the combined approach [Срок оценки: week 18-20 and week 26-28]
• Cellular population quantification on peripheral blood samples: leukocytes, neutrophils, lymphocytes, monocytes, eosinophils and basophils. [Срок оценки: Week 0, 6, 8 and 16]
• Inflammatory interleukines IL-6, IL-10 and IFN-γ quantification: [Срок оценки: Week 0, 6, 8 and 16]
• Intratumoral T Cells Infiltration in biopsies and resected tumors. [Срок оценки: week 0, week 18/20 and week 26/28]
• PERSONALIZED AI ASSISTED DOSIMETRY evaluation [Срок оценки: week 0 to 26-28]
• ctDNA analysis: Identification of genetic alterations and circulating tumor DNA (ctDNA) monitoring through digital droplet PCR [Срок оценки: week 6, 8, 12, 16, 22 and 30]
• Macroscopic determination of the grade of necrosis [Срок оценки: week 18/20 and week 26/28.]
• Determination of the grade of necrosis: Microscopic study. [Срок оценки: week 18/20 and week 26/28.]
• Evaluation of Post-treatment liver damage: Microscopic study [Срок оценки: week 18/20 and week 26/28.]

Критерии участия

Критерии включения

• 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

Критерии исключения

• 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
• Ascites
• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

Испания · 5 центров

• Hospital Universitario de Navarra — Pamplona
• Hospital Provincial de Castellón — Castelló
• Hospital Universitario Virgen de las Nieves — Granada
• Hospital Universitario Ramón y Cajal — Madrid
• Hospital Universitario y Politécnico la Fe — Valencia

Публикации

• Alsultan AA, van Roekel C, Barentsz MW, Smits MLJ, Kunnen B, Koopman M, Braat AJAT, Bruijnen RCG, de Keizer B, Lam MGEH. Dose-Response and Dose-Toxicity Relationships for Glass 90Y Radioembolization in Patients with Liver Metastases from Colorectal Cancer. J Nucl Med. 2021 Nov;62(11):1616-1623. doi: 10.2967/jnumed.120.255745. Epub 2021 Mar 19. PMID 33741643
• Mulcahy MF, Mahvash A, Pracht M, Montazeri AH, Bandula S, Martin RCG 2nd, Herrmann K, Brown E, Zuckerman D, Wilson G, Kim TY, Weaver A, Ross P, Harris WP, Graham J, Mills J, Yubero Esteban A, Johnson MS, Sofocleous CT, Padia SA, Lewandowski RJ, Garin E, Sinclair P, Salem R; EPOCH Investigators. Radioembolization With Chemotherapy for Colorectal Liver Metastases: A Randomized, Open-Label, Internati PMID 34541864
• Torkian P, Haghshomar M, Farsad K, Wallace S, Golzarian J, Young SJ. Cancer Immunology: Impact of Radioembolization of Hepatocellular Carcinoma on Immune Response Modulation. AJR Am J Roentgenol. 2023 Jun;220(6):863-872. doi: 10.2214/AJR.22.28800. Epub 2023 Feb 8. PMID 36752368
• Garin E, Tselikas L, Guiu B, Chalaye J, Edeline J, de Baere T, Assenat E, Tacher V, Robert C, Terroir-Cassou-Mounat M, Mariano-Goulart D, Amaddeo G, Palard X, Hollebecque A, Kafrouni M, Regnault H, Boudjema K, Grimaldi S, Fourcade M, Kobeiter H, Vibert E, Le Sourd S, Piron L, Sommacale D, Laffont S, Campillo-Gimenez B, Rolland Y; DOSISPHERE-01 Study Group. Personalised versus standard dosimetry ap PMID 33166497
• Simmonds PC, Primrose JN, Colquitt JL, Garden OJ, Poston GJ, Rees M. Surgical resection of hepatic metastases from colorectal cancer: a systematic review of published studies. Br J Cancer. 2006 Apr 10;94(7):982-99. doi: 10.1038/sj.bjc.6603033. PMID 16538219
• De Greef K, Rolfo C, Russo A, Chapelle T, Bronte G, Passiglia F, Coelho A, Papadimitriou K, Peeters M. Multisciplinary management of patients with liver metastasis from colorectal cancer. World J Gastroenterol. 2016 Aug 28;22(32):7215-25. doi: 10.3748/wjg.v22.i32.7215. PMID 27621569

Идентификаторы

NCT: NCT07406126 · GIBI2^30- YRENE

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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