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.

• HCC patients who are appropriate candidates for local ablation therapy (local ablation group)

• Sorafenib + RFA vs placebo + RFA• Primary endpoint: TTR, survival

Sub-study 1

Phase II Study: Composed of 3 Substudies

• 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 2

• 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

Sub-study 3

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

Local ablation arm

Off study due to • Systemic mets• BCLC 0, BCLC D

Gd-EOB-DTPAMRI

SCREENING MICRO-TX SYSTEMIC-TX

Sorafenib

Sorafenib

Sorafenib

Placebo

CE-MSCT

Palliative arm

RE

RFA

• Check in-/exclusion criteria

• Informed consent

Assignment to study arm

RANDOMIZATION

RANDOMIZATION

Recruitment for study:

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, Y90-microspheres, 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.