Transcript Exclusion Criteria

Evaluation of Sorafenib
in Combination With Local
Microtherapy Guided
by Gadolinium-EOB-DTPA Enhanced MRI in Patients
With Inoperable Hepatocellular Carcinoma
(SORAMIC)
J Ricke, K Schuette, IW Graziadei,
A Jakob, C Verslype, B Sangro,
J Walecki, HJ Klumpen, B Peynircioglu,
S Yalcin, C Bartolozzi, H Amthauer,
P Malfertheiner
Background
Hepatocellular carcinoma (HCC) is the fifth most common cancer
worldwide with an increasing incidence rate and is a leading cause of
cancer-related mortality in both men and women
Tumor stage at diagnosis (number and size of nodules, presence or
absence of vascular invasion, presence or absence of extrahepatic
spread), liver function and general health status are the most important
prognostic factors for the individual patient
Treatment strategy in early HCC aims at the local removal of the tumor and
represents a potentially curative treatment option (resection, liver
transplantation or local ablation using PEI or RFA. In intermediate and
advanced stages of HCC, patients receive treatment with palliative
intent (TACE, SIRT, or systemic therapy with sorafenib)
Studies with the combined use of locoregional and systemic therapy with
their potential of a beneficial synergism are few and conducted in a
small number of patients
PEI=percutaneous ethanol injection; RFA=radiofrequency ablation; SIRT=yttrium-90-radioembolisation;
TACE=transarterial chemoembolization.
Adapted from Ricke J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Phase II Study:
Composed of 3 Substudies
Sub-study 1
• HCC patients who are appropriate candidates for local ablation therapy
(local ablation group)
• Sorafenib + RFA vs placebo + RFA
• Primary endpoint: TTR, survival
Sub-study 2
• HCC patients who are not appropriate candidates for local ablation
therapy (palliative treatment group)
• Sorafenib + yttrium-90-microspheres (SIRT) vs sorafenib alone
• Primary endpoint: OS
Sub-study 3
• Primary endpoint: To confirm in a 2-step procedure that Gd-EOB-DTPA
enhanced MRI is noninferior (first step) or superior (second step)
compared with contrast-enhanced multislice CT for stratification of
patients to a palliative or a local ablation treatment strategy
CT=computed tomography; Gd-EOB-DTPA=gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid;
MRI=magnetic resonance imaging; OS=overall survival; TTR=time to recurrence.
Adapted from Ricke J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Study Design
SCREENING
MICRO-TX
SYSTEMIC-TX
Local ablation arm
Sorafenib
CE-MSCT
RFA
Recruitment for
study:
• Check in/exclusion criteria
• Informed consent
RANDOMIZATION
Assignment
to study arm
Placebo
Palliative arm
Sorafenib
Gd-EOBDTPA
MRI
RANDOMIZATION
Off study due to
• Systemic mets
• BCLC 0, BCLC D
RE
Sorafenib
BCLC=Barcelona Clinic Liver Cancer; CE-MSCT=contrast-enhanced multislice computed tomography;
mets=metastases; Tx=therapy.
Adapted from Ricke J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Inclusion Criteria (All Substudies)
Male or female, age 18-85 years
Diagnosis of hepatocellular carcinoma
If primary diagnosis of HCC: diagnosis based on the following criteria:
 Cytohistological 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 OR
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 scores 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
AFP=alfafeto protein; INR=international normalized ratio; US=ultrasound.
Adapted from Ricke J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Additional Inclusion Criteria
(Local Ablation Group)
Maximum of 4 HCC lesions in the liver
No prior treatment of HCC
Maximum diameter of HCC lesions: 5 cm
(up to 4 lesions with a maximum diameter of 5 cm each
are allowed)
Adapted from Ricke J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Additional Inclusion Criteria
(Palliative Treatment Group)
Not eligible for TACE (at the discretion of the investigator; ie, diffuse
tumors, tumors larger than 5 cm)
Patients who have undergone prior hepatic treatments for HCC
(including resection, PEI, RFA, TAE, and TACE) are eligible for
inclusion in the study under the following conditions:
 Resection (segmentectomy, lobectomy), prior RFA and vascular interventions must
leave sufficient liver tissue to maintain hepatic functional reserve as indicated by the
general inclusion/exclusion criteria
 Prior TAE and TACE must have been conducted a minimum of 3 months prior to
evaluation for the current study, with sufficient hepatic vascular flow to permit
infusion of yttrium-90 microspheres
 For prior TAE/TACE procedures, there is sufficient hepatic vasculature to access
either preexisting lesion(s) that have revascularized, or there is sufficient collateral
flow to new lesions to permit the infusion of yttrium-90 microspheres
TAE=transarterial embolization.
Adapted from Ricke J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Exclusion Criteria (All Studies)
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 <10 g/dL
 WBC <2500 cells/mm3
 ANC <1500 cells/mm3
 Platelets <50000 cells/mm3
 ECOG performance status >2
Life expectancy <16 weeks
Extrahepatic metastases (except metastases to bone, lymph nodes, and
adrenal glands, which do not constitute an exclusion criterion)
ANC=absolute neutrophil count; ECOG=Eastern Cooperative Oncology Group.
Adapted from Ricke J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Exclusion Criteria (All Studies) (cont’d)
Patients with known GFR <30 mL/min/1.73 m2
PT-INR/PTT >1.5 times the upper limit of normal
Uncontrolled infections at the time of microtherapy
Child-Pugh >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 the study medications according to product labeling or
procedures (sorafenib, Gd-EOB-DTPA, X-ray contrast agents, Y90microspheres, RFA, MRI, CT) includes any contraindication to the
transarterial interventional procedure (eg, allergy against X-ray contrast
agents, uncontrolled hyperthyroidism)
GFR=glomerular filtration rate; PT-INR=prothrombin time-international normalized ratio; prothrombin
time-partial thromboplastin time.
Adapted from Ricke J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Exclusion Criteria (All Studies) (cont’d)
Prior resection of the papilla of Vater (eg, Whipple’s procedure) or bile duct
stent across the papilla
Significant cardiovascular disease (eg, 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
History of hemorrhage/bleeding events of Grade 3 or worse
Previous variceal bleeding within the past 3 months
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)
Adapted from Ricke J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Exclusion Criteria (All Studies) (cont’d)
HIV, congenital immune defect, any immunosuppressive therapy for
autoimmune disease (eg, 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; eg, 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
enrollment into this trial
Having been previously enrolled into this trial
HIV=human immunodeficiency virus.
Adapted from Ricke J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Additional Exclusion Criteria
(Local Ablation Group)
Patients in whom surgical resection is the most
appropriate treatment
Invasion of the portal vein main stem, or invasion of the
right/left portal vein (lobar level)
Extrahepatic metastases
Adapted from Ricke J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Additional Exclusion Criteria
(Palliative Treatment Group)
Bilirubin above 1.5 times the upper limit of the normal
range
Hepatopulmonary shunt leading to a lung dose
>30 gray
Any previous external beam radiation therapy to
the liver
Previous therapy with monoclonal antibodies
Adapted from Ricke J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Enrollment
This trial has already started with 16 out of 830 patients
enrolled until April 5, 2011, and will recruit in 41
European centers in 14 countries: Germany, Austria,
Switzerland, The Netherlands, Poland, Belgium, France,
Italy, Spain, Turkey, Serbia, Slovenia, Croatia, and Great
Britain
Adapted from Ricke J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Conclusions
Findings in the SORAMIC trial will provide insight into the
synergism of local microtherapy and systemic
treatment in patients with HCC
The complex trial design with 3 separate study sections
with their own primary endpoints will additionally define
the optimal imaging staging modality
SORAMIC=Sorafenib Micro-Therapy Guided by Primovist Enhanced MRI in Patients With Inoperable
Liver Cancer.
Adapted from Ricke J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.