Ipilimumab and Nivolumab With SBRT in Locally Advanced Hepatocellular Cancer

Официальное название

Pilot Study of Ipilimumab and Nivolumab With Response-adapted Stereotactic Body Radiotherapy Followed by Definitive Resection for Patients With Locally Advanced Hepatocellular Cancer

Обзор

Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths globally, with Native Hawaiian and Pacific Islander (NHPI) populations experiencing significantly higher mortality rates compared to other groups in Hawaii. This disparity is influenced by factors such as higher prevalence of chronic hepatitis B, non-alcoholic fatty liver disease, limited access to early detection, and delayed diagnoses. NHPI patients are also underrepresented in clinical trials, limiting the relevance of treatment advances for this population. The standard treatment for HCC is surgical resection; however, many NHPI patients present with unresectable disease. Recent advances with immune checkpoint inhibitors (ICIs), such as nivolumab and ipilimumab, have shown promise in treating advanced HCC and improving survival in previously untreatable cases. Additionally, stereotactic body radiotherapy (SBRT) has been shown to enhance survival and local control when combined with systemic therapies like ICIs. However, without surgery, outcomes remain suboptimal, with response rates for ICIs alone at 20-30%, and combination ICI-SBRT treatment showing slightly better results but still a high risk of progression. Despite improvements in HCC treatment, significant gaps remain in managing borderline resectable disease, especially in NHPI patients. This study aims to evaluate the safety and efficacy of combining ICIs and SBRT with curative surgery for patients with borderline resectable HCC, focusing on NHPI populations. The study will also explore the use of biomarkers such as cell-free DNA (cfDNA), CD8+ T-cell infiltration, and serum cytokine markers to guide personalized treatment strategies. Preliminary findings suggest that this multimodal approach may improve outcomes and enable surgical resection for patients previously considered inoperable. This study seeks to address the unmet need for effective treatment strategies in borderline resectable HCC and to improve survival outcomes for underserved NHPI populations.

Вмешательства

• Препарат Ipilimumab and Nivolumab
  Immunotherapy combination (Ipilimumab and Nivolumab) targeting CTLA-4 and PD-1 pathways to enhance immune response.
• Лучевая терапия Stereotactic Body Radiotherapy (SBRT)
  High-dose radiation therapy delivered in 3-5 fractions for local control of tumors in combination with immunotherapy. Radiation dosages are based on the RTOG 1112 trial guidelines to minimize normal tissue exposure.

Первичные конечные точки

• Feasibility of Treatment Regimen [Срок оценки: From treatment initiation to surgery completion (up to 12 months)]
• R0 Resection Rate [Срок оценки: From treatment initiation to surgery (up to 12 weeks)]

Вторичные конечные точки (4)

• Objective Response Rate (ORR) [Срок оценки: From the date of treatment initiation until the date of best documented response, assessed up to 36 months.]
• Pathologic Complete Response (pCR) and Disease-Free Survival (DFS) [Срок оценки: From the date of treatment initiation until disease recurrence or progression, assessed up to 36 months.]
• Overall Survival (OS) [Срок оценки: From the date of treatment initiation until death, assessed up to 36 months.]
• Toxicity Evaluation [Срок оценки: From the start of treatment to the time of surgery, assessed up to 12 months.]

Критерии участия

Main Criteria for Inclusion/Exclusion

• Inclusion Criteria:

• Histologically or cytologically confirmed hepatocellular cancer
• Locally advanced/borderline resectable HCC as defined by:

• Solitary tumor >5 cm, OR
• Unilobar multifocal disease either with >3 tumors or one tumor >3 cm, OR
• Bilobar disease with adequate future liver remnant, still technically resectable, OR
• High risk disease features (tumor >3 cm with macrovascular invasion or tumor >3 cm with AFP>400).
• No extrahepatic spread, no nodal disease, no bilateral left and right branch portal vein involvement, no hepatic vein / IVC involvement. Unilateral hepatic vein involvement is not exclusionary.
• Measurable disease per RECIST 1.1 as determined by the investigator
• Age ≥ 18 years old on the day of consent
• ECOG performance status ≤1 (Appendix XX)
• Adequate organ and marrow function, as defined below. Criteria "a," "b," "c," and "f" cannot be met with transfusions, infusions, or growth factor support administered within 14 days of starting the first dose.

• Hemoglobin ≥9 g/dL
• Absolute neutrophil count ≥1000/μL
• Platelet count ≥90,000/μL
• Total bilirubin (TBL) <2.0 mg/dL
• ASTandALT≤5×ULN
• Albumin≥2.8g/dL
• International normalized ratio(INR)≤2xULN
• Calculated creatinine clearance ≥ 40 mL/minute as determined by Cockcroft-Gault (using actual body weight) or 24-hour urine creatinine clearance
• Exclusion Criteria:

• Prior systemic therapy for hepatocellular carcinoma
• Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 28 days of the first dose of study drug(s).
• Ascites that requires ongoing paracentesis, within 6 weeks prior to the first scheduled dose, to control symptoms.
• Active or prior documented GI variceal bleed or history of upper GI bleeding, ulcers, or esophageal varices with bleeding within 60 days prior to registration; adequate endoscopic therapy according to institutional standards is required for patients with history of esophageal variceal bleeding or assessed as high risk for esophageal variceal by the treating investigator.
• Hepatic encephalopathy within 12 months of trial registration
• Patient currently exhibits symptomatic or uncontrolled hypertension defined as diastolic blood pressure >90 mmHg or systolic blood pressure >140 mmHg.
• Prior external beam radiation therapy to the liver, prior yttrium-90 radioembolization
• HBV viral load >100 IU/mL, ongoing corticosteroid therapy >10 mg prednisone daily, and active autoimmune disease requiring systemic therapy in the past 2 years.
• Direct tumor extension into stomach, duodenum, small or large bowel
• Active or untreated central nervous system (CNS) and leptomeningeal metastases
• History of another primary malignancy except for:

• Malignancy treated with curative intentand with no known active disease ≥ 5years before the first dose of study drug(s) and of low potential risk for recurrence
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
• Adequately treated carcinoma in situ without evidence of disease
• Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
• Active infection including tuberculosis (TB) (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), or human immunodeficiency virus (positive human HIV 1/2 antibodies).

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

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 2 центра

• The Queen's Medical Center — Honolulu
• University of Hawai'i Cancer Center — Honolulu

Публикации

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• Duffy AG, Ulahannan SV, Makorova-Rusher O, Rahma O, Wedemeyer H, Pratt D, Davis JL, Hughes MS, Heller T, ElGindi M, Uppala A, Korangy F, Kleiner DE, Figg WD, Venzon D, Steinberg SM, Venkatesan AM, Krishnasamy V, Abi-Jaoudeh N, Levy E, Wood BJ, Greten TF. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. J Hepatol. 2017 Mar;66(3):545-551. doi: 10.1016/j.j PMID 27816492
• Yau T, Kang YK, Kim TY, El-Khoueiry AB, Santoro A, Sangro B, Melero I, Kudo M, Hou MM, Matilla A, Tovoli F, Knox JJ, Ruth He A, El-Rayes BF, Acosta-Rivera M, Lim HY, Neely J, Shen Y, Wisniewski T, Anderson J, Hsu C. Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial. JAMA PMID 33001135
• Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, Verslype C, Zagonel V, Fartoux L, Vogel A, Sarker D, Verset G, Chan SL, Knox J, Daniele B, Webber AL, Ebbinghaus SW, Ma J, Siegel AB, Cheng AL, Kudo M; KEYNOTE-224 investigators. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. La PMID 29875066
• Li Z, Liu J, Zhang B, Yue J, Shi X, Cui K, Liu Z, Chang Z, Sun Z, Li M, Yang Y, Ma Z, Li L, Zhang C, Sun P, Zhong J, Zhao L. Neoadjuvant tislelizumab plus stereotactic body radiotherapy and adjuvant tislelizumab in early-stage resectable hepatocellular carcinoma: the Notable-HCC phase 1b trial. Nat Commun. 2024 Apr 16;15(1):3260. doi: 10.1038/s41467-024-47420-3. PMID 38627377
• Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Kudo M, Breder V, Merle P, Kaseb AO, Li D, Verret W, Xu DZ, Hernandez S, Liu J, Huang C, Mulla S, Wang Y, Lim HY, Zhu AX, Cheng AL; IMbrave150 Investigators. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020 May 14;382(20):1894-1905. doi: 10.1056/NEJMoa1915745. PMID 32402160
• Juloori A, Katipally RR, Lemons JM, Singh AK, Iyer R, Robbins JR, George B, Hall WA, Pitroda SP, Arif F, Fung J, Pillai A, Liao CY, Sharma M, Liauw SL. Phase 1 Randomized Trial of Stereotactic Body Radiation Therapy Followed by Nivolumab plus Ipilimumab or Nivolumab Alone in Advanced/Unresectable Hepatocellular Carcinoma. Int J Radiat Oncol Biol Phys. 2023 Jan 1;115(1):202-213. doi: 10.1016/j.ijro PMID 36108891
• Luke JJ, Onderdonk BE, Bhave SR, Karrison T, Lemons JM, Chang P, Zha Y, Carll T, Krausz T, Huang L, Martinez C, Janisch LA, Hseu RD, Moroney JW, Patel JD, Khodarev NN, Salama JK, Ott PA, Fleming GF, Gajewski TF, Weichselbaum RR, Pitroda SP, Chmura SJ. Improved Survival Associated with Local Tumor Response Following Multisite Radiotherapy and Pembrolizumab: Secondary Analysis of a Phase I Trial. Cl PMID 33028595

Идентификаторы

NCT: NCT07075120 · ACOBA-2024-1

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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