Sorafenib and Micro-therapy Guided by Primovist Enhanced MRI in Patients With Inoperable Liver Cancer (SORAMIC)
Evaluation of Sorafenib in Combination With Local Micro-therapy Guided by Gd-EOB-DTPA Enhanced MRI in Patients With Inoperable Hepatocellular Carcinoma
The purpose of this study is to evaluate Sorafenib and local microtherapy guided by Primovist enhanced MRI in patients with inoperable liver cancer (HCC).
Methodology:
Patients with a diagnosis of hepatocellular carcinoma will receive either:
- local ablation therapy of liver lesions by radiofrequency ablation followed by sorafenib or placebo (local ablation group), or
- radioembolization (SIRT) + sorafenib or sorafenib alone (palliative treatment group).
In each study group, patients will be randomized to one of the two treatment arms following a pre-defined randomization plan. Randomization will be on a 1:1 basis in the local ablation group and on the basis of 10 (sorafenib only) : 11 (SIRT + sorafenib) in the palliative treatment group.
Patients in the local ablation group will be followed at 2 months intervals for recurrence and overall survival, patients in the palliative treatment group will be followed for overall survival. Follow-up in each study group will end 24 months after inclusion of the last patient into the respective study group.
The assignment of patients to the local ablation or palliative study group will be based on the ablative potential of RFA (local ablation if ≤4 tumors, each ≤5 cm in size). Diagnostic imaging will be used to guide this decision. The assignment to the local ablation or the palliative treatment group will be made by the local investigator.
As a sub-study, all patients will undergo Primovist®-enhanced MRI in addition to contrast-enhanced CT before assignment to one treatment group. The goal of the sub-study is to assess the value of Primovist®-enhanced MRI to correctly stratify patients for a local ablation or palliative treatment strategy. Primovist®-enhanced MRI will be compared with contrast-enhanced multislice CT using a truth panel assessment as the standard of reference. In addition, Primovist-enhanced MRI and contrast-enhanced CT will be obtained during follow-up of patients in the local ablation group to assess its potential for detection of recurrence.
調査の概要
研究の種類
入学 (実際)
段階
- フェーズ2
連絡先と場所
研究場所
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Magdeburg、ドイツ、39120
- University of Magdeburg
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参加基準
適格基準
就学可能な年齢
健康ボランティアの受け入れ
受講資格のある性別
説明
Inclusion Criteria
- Age: 18-85 years
- Diagnosis of hepatocellular carcinoma
If primary diagnosis of HCC: diagnosis based on the following criteria:
- cyto-histological criteria, OR
- radiological criteria: Focal lesion >1 cm with arterial hypervascularization in 2 coincident imaging techniques (CT, MRI, or US), OR
- combined criteria: one imaging technique showing a focal lesion 1-2 cm with arterial hypervascularization AND AFP levels >400 ng/mL, OR
- combined criteria: one imaging technique showing a focal lesion >2 cm with arterial hypervascularization AND AFP levels >200 ng/mL
- If extrahepatic metastases: liver-dominant disease
- Stage BCLC A, B, or C
- Child-Pugh A, Child-Pugh B up to 7 points (in patients receiving anticoagulant therapy: Child-Pugh score up to 5 points; INR category not regarded for calculation of the Child-Pugh score)
- Willing to comply with all study procedures
- Has voluntarily given written informed consent
Exclusion Criteria
- If female, pregnant or breast feeding (females of child-bearing potential must use adequate contraception and must have a negative pregnancy test performed within 7 days prior to inclusion into this study)
- If male, not using adequate birth control measures
One or more of the following:
- Hemoglobin <10g/dL,
- WBC <2,500 cells/mm3,
- ANC <1,500 cells/mm3,
- platelets <50,000/mm3,
- ECOG performance status >2
- Life expectancy <16 weeks or medically unstable
- Extrahepatic metastases (except metastases to bone, lymph nodes, and adrenal glands which do not constitute an exclusion criterion), but, see Additional Criteria for the Local Ablation Group, below (Section 4.2 of the study protocol)
- Patients with known GFR <30 mL/min/1.73m2
- PT-INR/PTT >1.5 times the upper limit of normal (patients on anticoagulation therapy will be allowed to participate provided that no prior evidence exists of an underlying abnormality in anticoagulation)
- Uncontrolled infections at the time of microtherapy
- Child-Pugh score >7 points; in patients receiving anticoagulant therapy: Child-Pugh score >5 points (INR category not regarded for calculation of the Child-Pugh score)
- Uncontrolled ascites
- Tumor load of the whole liver >70%
- Contraindications for study medications according to product labeling or procedures (sorafenib, Primovist®, x-ray contrast agents, SIR-Spheres®, RFA, MWA, MRI, CT) incl. any contraindication to the transarterial interventional procedure (e.g., allergy against x-ray contrast agents, uncontrolled hyperthyroidism)
- Prior resection of the papilla of Vater (e.g., Whipple procedure) or bile duct stent across the papilla
- Significant cardiovascular disease; e.g., myocardial infarction within 6 months of inclusion, chronic heart failure (New York Heart Association class III or IV), unstable coronary artery disease
- Uncontrolled hypertension
- Thrombotic or embolic events including transient ischemic attacks within the past 6 months (tumor-related portal vein thrombosis allowed in the palliative part of the trial).
- History of GI bleeding within 30 days before inclusion into this study
- History of esophageal varices bleeding which has not been controlled by effective therapy and/or therapy to prevent bleeding recurrence
- Previous malignancy other than carcinoma in situ of the skin or the cervix uteri within 5 years prior to inclusion
- History of organ transplant (including prior liver transplantation)
- HIV, congenital immune defect, any immunosuppressive therapy for autoimmune disease (rheumatoid arthritis) or inflammatory bowel disease
- Mental conditions rendering the subject incapable to understand the nature, scope, and consequences of the trial
- Close affiliation with the investigational site; e.g. first-degree relative of the investigator
- Participating in another therapeutic clinical trial or has completed study participation in another therapeutic clinical trial within 30 days of enrolment into this trial
- Having been previously enrolled in this clinical trial
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：ランダム化
- 介入モデル：並列代入
- マスキング：ダブル
武器と介入
参加者グループ / アーム |
介入・治療 |
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他の：local ablation group
Local ablation group: Potentially curative treatment of early HCC includes surgical resection and local ablation (RFA, PEI, BT).
Recurrence rates after such approaches are reported to amount to 50% at 3 years and 70% at 5 years.
Tumor recurrence may be either due to de novo development of new primary tumors or due to intrahepatic (unrecognized) metastases.
Prevention of recurrence after local ablation is an important strategy to improve overall survival.
So far, adjuvant chemoembolization and chemotherapy have not proven to be effective in preventing recurrences.
There is, however, a strong rationale to assume that sorafenib will be of value in the adjuvant treatment of HCC as sorafenib has a dual mechanism of action (inhibition of tumor proliferation and antiangiogenesis) and has proven efficacy in HCC.
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A max.of 2 percutaneous RFA sessions is permitted per patient with a max.of 2 liver lesions treated in each RFA session. Randomization to sorafenib or placebo is performed after completion of RFA. Percutaneous RFA is to be performed according to the manufacturer's instructions and following as far as possible routine procedures of the participating hospital. Typically, RFA will be performed under conscious sedation, general anesthesia is permitted. After local anesthesia of the site of puncture, the applicator is positioned in the center of the lesion using ultrasound-, CT- or MR-guidance. The success of ablation is to be controlled directly after RFA using ultrasound, contrast-enhanced CT, or MR imaging. If for any reason RFA is deemed incomplete within the immediate follow-up (up to 2 weeks after the initial ablation), RFA is to be repeated once (in this case, the total (max.) number of RFA sessions will be three). The study procedure guide will contain further instructions for RFA.
他の名前：
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アクティブコンパレータ：palliative treatment group
Radioembolization has been reported to be effective in patients with unresectable HCC with preserved liver function from a number of trials. Successful downstaging of disease rendering patients eligible for potentially curative therapies, and even histologically confirmed complete responses of unresectable HCC, have repeatedly been reported providing the rationale to evaluate SIRT+sorafenib in comparison to sorafenib alone. The impact of cirrhosis as a concomitant disease in most patients with HCC is that it limits the ability of many patients to tolerate chemotherapy and is an independent cause of death in HCC patients. Thus, the historical difficulty in demonstrating an effect of therapy on survival in patients with advanced-stage, unresectable HCC (the majority). A new therapy that is effective in controlling hepatic disease, is less toxic than traditional chemotherapy, and improves the quality of life for patients in the advanced stages of HCC could represent an alternative. |
One SIRT prescription consists of the pre-treatment assessment followed by one or 2 treatment sessions The aim of pre-treatment assessment is to ensure delivery of the microspheres to the target. Evaluation includes a determination of the arterial location and any consequent necessity for coil-embolization of the gastroduodenal artery, right gastric artery and any other accessory arteries to prevent inadvertent administration of microspheres into the gastrointestinal tract or pancreas. In addition, parasitic extrahepatic supply should be coil-embolized. Patients in whom the shunt fraction indicates potential exposure to the lung to an absorbed radiation dose of more than 30 Gy should be excluded from treatment with SIR-Spheres. Patients who are randomized to receive SIRT but who are not regarded as eligible for SIRT after the pre-treatment assessment will be switched to the sorafenib only group within the palliative treatment arm.
他の名前：
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この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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time to recurrence
時間枠：13-18 months (average time to recurrence)
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In patients in whom local ablation therapy is appropriate, to determine if the sorafenib in combination with radiofrequency ablation (RFA) prolongs the time-to-recurrence (TTR) in comparison with RFA + placebo.
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13-18 months (average time to recurrence)
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overall survival
時間枠：10-15 months (average survival)
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In patients in whom RFA is NOT appropriate (palliative treatment group), to determine if the combination of yttrium-90 microspheres (SIRT) + sorafenib improves the overall survival (OS) in comparison to sorafenib alone. Interim analysis will be conducted after 60 and 180 deaths and a final analysis after 240 deaths. |
10-15 months (average survival)
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Primovist®-enhanced MRI is non-inferior or superior compared with contrast-enhanced multislice CT
時間枠：3 years
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To confirm in a 2-step procedure that Primovist®-enhanced MRI is non-inferior (first step) or superior (second step) compared with contrast-enhanced multislice CT for assignment of patients to a palliative vs. local ablation treatment strategy. The overall study is successful, if the primary objectives 1 OR 2 are met, AND Primovist-enhanced MRI is at least non-inferior to contrast-enhanced CT for treatment stratification. |
3 years
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二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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quality of life
時間枠：3 years
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assess health-related quality of life via ECOG questionnaire
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3 years
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safety of RFA
時間枠：3 years
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To assess the safety of the combination of RFA + sorafenib in comparison to RFA + placebo
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3 years
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safety of SIR Spheres
時間枠：3 years
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To assess the safety of the combination of SIR-Spheres therapy and sorafenib in comparison to sorafenib alone.
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3 years
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協力者と研究者
スポンサー
捜査官
- スタディディレクター：Jens Ricke, Prof. Dr.、University Hospital Munich
- スタディディレクター：Peter Malfertheiner, Prof. Dr.、University of Magdeburg
出版物と役立つリンク
研究記録日
主要日程の研究
研究開始 (実際)
一次修了 (実際)
研究の完了 (実際)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (見積もり)
学習記録の更新
投稿された最後の更新 (実際)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
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