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Sorafenib and Micro-therapy Guided by Primovist Enhanced MRI in Patients With Inoperable Liver Cancer (SORAMIC)

29 mai 2019 mis à jour par: Jens Ricke, University of Magdeburg

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.

Aperçu de l'étude

Statut

Complété

Les conditions

Intervention / Traitement

Type d'étude

Interventionnel

Inscription (Réel)

529

Phase

  • Phase 2

Contacts et emplacements

Cette section fournit les coordonnées de ceux qui mènent l'étude et des informations sur le lieu où cette étude est menée.

Lieux d'étude

  • Allemagne
      • Magdeburg, Allemagne, 39120
        • University of Magdeburg

Critères de participation

Les chercheurs recherchent des personnes qui correspondent à une certaine description, appelée critères d'éligibilité. Certains exemples de ces critères sont l'état de santé général d'une personne ou des traitements antérieurs.

Critère d'éligibilité

Âges éligibles pour étudier

18 ans à 85 ans (Adulte, Adulte plus âgé)

Accepte les volontaires sains

Non

Sexes éligibles pour l'étude

Tout

La description

Inclusion Criteria

  1. Age: 18-85 years
  2. Diagnosis of hepatocellular carcinoma

  3. If primary diagnosis of HCC: diagnosis based on the following criteria:

    1. cyto-histological criteria, OR
    2. radiological criteria: Focal lesion >1 cm with arterial hypervascularization in 2 coincident imaging techniques (CT, MRI, or US), OR
    3. combined criteria: one imaging technique showing a focal lesion 1-2 cm with arterial hypervascularization AND AFP levels >400 ng/mL, OR
    4. combined criteria: one imaging technique showing a focal lesion >2 cm with arterial hypervascularization AND AFP levels >200 ng/mL
  4. If extrahepatic metastases: liver-dominant disease
  5. Stage BCLC A, B, or C
  6. 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)
  7. Willing to comply with all study procedures
  8. Has voluntarily given written informed consent

Exclusion Criteria

  1. 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)
  2. If male, not using adequate birth control measures

  3. 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
  4. Life expectancy <16 weeks or medically unstable
  5. 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)
  6. Patients with known GFR <30 mL/min/1.73m2
  7. 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)
  8. Uncontrolled infections at the time of microtherapy
  9. 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)
  10. Uncontrolled ascites
  11. Tumor load of the whole liver >70%
  12. 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)
  13. Prior resection of the papilla of Vater (e.g., Whipple procedure) or bile duct stent across the papilla
  14. 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
  15. Uncontrolled hypertension
  16. 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).
  17. History of GI bleeding within 30 days before inclusion into this study
  18. History of esophageal varices bleeding which has not been controlled by effective therapy and/or therapy to prevent bleeding recurrence
  19. Previous malignancy other than carcinoma in situ of the skin or the cervix uteri within 5 years prior to inclusion
  20. History of organ transplant (including prior liver transplantation)
  21. HIV, congenital immune defect, any immunosuppressive therapy for autoimmune disease (rheumatoid arthritis) or inflammatory bowel disease
  22. Mental conditions rendering the subject incapable to understand the nature, scope, and consequences of the trial
  23. Close affiliation with the investigational site; e.g. first-degree relative of the investigator
  24. Participating in another therapeutic clinical trial or has completed study participation in another therapeutic clinical trial within 30 days of enrolment into this trial
  25. Having been previously enrolled in this clinical trial

Plan d'étude

Cette section fournit des détails sur le plan d'étude, y compris la façon dont l'étude est conçue et ce que l'étude mesure.

Comment l'étude est-elle conçue ?

Détails de conception

  • Objectif principal: Traitement
  • Répartition: Randomisé
  • Modèle interventionnel: Affectation parallèle
  • Masquage: Double

Armes et Interventions

Groupe de participants / Bras
Intervention / Traitement
Autre: 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.
Procédure: RFA

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.

Autres noms:
  • Sorafenib (Nexavar 200 mg film-coated tablets),marketing authorization no.:EU/1/06/342/001
Comparateur actif: 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.
Procédure: Radioembolization (SIRT)

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.

Autres noms:
  • Sorafenib (Nexavar)
  • SIR Spheres Microspheres

Que mesure l'étude ?

Principaux critères de jugement

Mesure des résultats
Description de la mesure
Délai
time to recurrence
Délai: 13-18 months (average time to recurrence)
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.
13-18 months (average time to recurrence)
overall survival
Délai: 10-15 months (average survival)

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)
Primovist®-enhanced MRI is non-inferior or superior compared with contrast-enhanced multislice CT
Délai: 3 years

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

Mesures de résultats secondaires

Mesure des résultats
Description de la mesure
Délai
quality of life
Délai: 3 years
assess health-related quality of life via ECOG questionnaire
3 years
safety of RFA
Délai: 3 years
To assess the safety of the combination of RFA + sorafenib in comparison to RFA + placebo
3 years
safety of SIR Spheres
Délai: 3 years
To assess the safety of the combination of SIR-Spheres therapy and sorafenib in comparison to sorafenib alone.
3 years

Collaborateurs et enquêteurs

C'est ici que vous trouverez les personnes et les organisations impliquées dans cette étude.

Parrainer

University of Magdeburg

Collaborateurs

Bayer
Sirtex Medical

Les enquêteurs

  • Directeur d'études: Jens Ricke, Prof. Dr., University Hospital Munich
  • Directeur d'études: Peter Malfertheiner, Prof. Dr., University of Magdeburg

Publications et liens utiles

La personne responsable de la saisie des informations sur l'étude fournit volontairement ces publications. Il peut s'agir de tout ce qui concerne l'étude.

Publications générales

Dates d'enregistrement des études

Ces dates suivent la progression des dossiers d'étude et des soumissions de résultats sommaires à ClinicalTrials.gov. Les dossiers d'étude et les résultats rapportés sont examinés par la Bibliothèque nationale de médecine (NLM) pour s'assurer qu'ils répondent à des normes de contrôle de qualité spécifiques avant d'être publiés sur le site Web public.

Dates principales de l'étude

Début de l'étude (Réel)

1 décembre 2010

Achèvement primaire (Réel)

25 janvier 2018

Achèvement de l'étude (Réel)

31 décembre 2018

Dates d'inscription aux études

Première soumission

17 mai 2010

Première soumission répondant aux critères de contrôle qualité

19 mai 2010

Première publication (Estimation)

20 mai 2010

Mises à jour des dossiers d'étude

Dernière mise à jour publiée (Réel)

31 mai 2019

Dernière mise à jour soumise répondant aux critères de contrôle qualité

29 mai 2019

Dernière vérification

1 mai 2019

Plus d'information

Termes liés à cette étude

Mots clés

Termes MeSH pertinents supplémentaires

Autres numéros d'identification d'étude

  • EudraCT No. 2009-012576-27

Ces informations ont été extraites directement du site Web clinicaltrials.gov sans aucune modification. Si vous avez des demandes de modification, de suppression ou de mise à jour des détails de votre étude, veuillez contacter register@clinicaltrials.gov. Dès qu'un changement est mis en œuvre sur clinicaltrials.gov, il sera également mis à jour automatiquement sur notre site Web .

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