Annual Meeting Proceedings Part 1 - American Society of Clinical ...

TPS4148 General Poster Session (Board #54C), Mon, 8:00 AM-12:00 PM
Sorafenib in combination with local microtherapy guided by gadolinium-
EOB-DTPA enhanced MRI in patients with inoperable hepatocellular
carcinoma (HCC) (SORAMIC). Presenting Author: Jens Ricke, Otto-von-
Guericke-University Magdeburg, Magdeburg, Germany
Background: HCC is a leading cause of cancer-related mortality in both men
and women. It represents the fifth most common cancer worldwide with an
increasing incidence. For the individual patient 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 principal prognostic factors. The clinical management
of HCC requires a comprehensive, multidisciplinary approach. In early HCC
curative treatment can be achieved by local ablation, resection or liver
transplantation. In intermediate stages patients (pts) are offered locoregional
treatment with palliative intent (transarterial chemoembolisation
(TACE), Yttrium-90-radioembolisation (SIRT)). In advanced disease systemic
therapy with sorafenib (sor) has the potential to prolong survival of
pts and is standard of care in pts with preserved liver function. Studies on
the combined use of locoregional and systemic therapy with their potential
of a beneficial synergism are few and conducted in a small number of pts.
Methods: This phase II-study is composed of three substudies with the
following primary objectives: 1. In pts in whom local ablation is appropriate
to determine if sor in combination with RFA prolongs the time-torecurrence
in comparison with RFA plus placebo. Primary endpoint (PEP):
time to recurrence, n � 290 pts 2. In pts in whom RFA is not appropriate
(palliative treatment group) to determine if the combination of SIRT and sor
improves the overall survival in comparison to sor alone. PEP: overall
survival, n � 375 pts 3. To confirm in a 2-step procedure that Gd-EOB-
DTPA enhanced MRI is non-inferior or superior compared with contrastenhanced
multislice CT for stratification of pts to a palliative or a local
ablation treatment strategy. PEP: correct stratification of pts to a palliative
versus local ablation treatment strategy; n � 830 pts The trial has started
in December 2010 as a multinational and multicentric study. 90 pts have
been enrolled until January 31st 2012 with 51 pts randomized in the
palliative arm and 14 pts treated in the curative arm.
TPS4150 General Poster Session (Board #54E), Mon, 8:00 AM-12:00 PM
TACE 2: A randomized placebo-controlled, double-blinded, phase III trial
evaluating sorafenib in combination with transarterial chemoembolisation
(TACE) in patients with unresectable hepatocellular carcinoma (HCC).
Presenting Author: Tim Meyer, University College London, London, United
Kingdom
Background: TACE is regarded as the standard of care for patients with
intermediate stage HCC (BCLC B), while sorafenib (S) is the current
standard for advanced disease (BCLC C). The combination of S with TACE
for intermediate disease is rational since sorafenib inhibits the action of
VEGF which may be induced by tumour hypoxia following TACE, and S also
has direct anti-tumour effect. The combination has been shown to be safe
in and active in phase I and II studies. Phase III trials are now required to
determine whether TACE � S is superior to TACE alone in terms of survival.
Methods: We are conducting a double blind multicentre trial to determine if
the addition of S to TACE is superior to TACE alone. This is a UK NCRI trial
sponsored by University College London (UCL) (EudraCT 2008-005073-
36). Patients with intermediate stage HCC are randomised 1:1 to continuous
S (400mg BD) or placebo (P). Key inclusion criteria include unresectable
HCC confined to the liver, patent main portal vein, ECOG PS �1 and Child
Pugh A liver score. After randomisation patients commence study drug and
TACE is performed at 2-5 weeks using drug eluting beads loaded with
150mg doxorubicin (Biocompatibles UK Ltd) according to a standard
protocol. Further TACE is performed at the discretion of the investigator
based on radiological response and patient tolerance. The primary outcome
measure is progression free survival and central, external, real time
radiology review is required to confirm progression. Secondary outcome
measures are overall survival, time to progression, toxicity, disease control,
quality of life and number of TACE procedures performed in 12 months.
The target recruitment is 412 in order to detect a hazard ratio of 0.72 using
a 2-sided level of significance of ��0.05 with 85% power. The trial was
reviewed by the IDMC after the presentation of the SPACE trial (Lencioni et
al J Clin Oncol 30, 2012). The IDMC concurred with the conclusion of the
SPACE investigators that the combination is tolerated and results required
confirmation in a phase III trial. Thus recruitment into the TACE2 trial will
continue as planned.
Gastrointestinal (Noncolorectal) Cancer
275s
TPS4149 General Poster Session (Board #54D), Mon, 8:00 AM-12:00 PM
Randomized phase II trial of TACE plus everolimus as first-line therapy in
localized unresectable hepatocellular carcinoma (HCC): The TRACER trial.
Presenting Author: Ronnie Tung Ping Poon, Department of Surgery,
University of Hong Kong, Hong Kong, China
Background: Transcatheter Arterial Chemoembolization (TACE) has shown
benefit in improving survival and is a widely used treatment for unresectable
HCC. However, TACE induces hypoxia leading to up-regulation of
HIF-1� and VEGF signaling, and tumor progression. Everolimus is an oral
inhibitor of mammalian target of rapamycin (mTOR) and its downstream
signaling including HIF-1�. Everolimus has also been shown to increase
chemosensitivity of HCC in preclinical study (Cancer Lett; 273(2):201-9).
Combining everolimus with TACE may delay tumor progression. TRACER
(Tace with Rad001 in Asian Centers for Evaluation and Research) aims to
evaluate the efficacy and safety of everolimus plus TACE in patients with
localised unresectable HCC. Methods: TRACER is a multinational, randomized,
double-blind, placebo-controlled phase II trial. Patients aged �18
years newly diagnosed with localized unresectable Child A HCC; ECOG PS
of �2; �1 unidimensional lesion measurable according to RECIST; and
adequate bone marrow, liver, and renal function. Exclusion criteria include
main portal vein invasion and/or extrahepatic spread; prior local or systemic
treatment for HCC, or contraindications to TACE. Eligible patients who have
successfully undergone the first TACE are randomized 1:1 to oral everolimus
7.5mg or matching placebo daily. TACE is repeated every 10 weeks or
so. A short everolimus dose interruption of 48 hours before and after each
TACE has been designed to allow recovery from complications of TACE. For
standardization, doxorubicin-eluting beads are being used in every TACE.
Patients shall exit the trial upon tumor progression, unacceptable toxicity,
death, or trial discontinuation. All endpoints will be assessed on an ITT
basis. The primary endpoint is time to progression base on Modified
RECIST Criteria. Secondary endpoints include objective response rate,
overall survival, and incidence of extrahepatic spread, safety and exploratory
biomarkers. An independent data monitoring committee has been
established to safeguard the trial subjects. Estimated total enrollment is
80, of which 12 subjects have been enrolled. (Clinical Trial Registry
Number: NCT01379521.)
TPS4151 General Poster Session (Board #54F), Mon, 8:00 AM-12:00 PM
A randomized phase III trial comparing sorafenib plus best supportive care
(BSC) versus BSC alone in Child-Pugh B patients (pts) with advanced
hepatocellular carcinoma (HCC): The BOOST study. Presenting Author:
Bruno Daniele, G. Rummo Hospital, Benevento, Italy
Background: The efficacy of sorafenib in pts with advanced HCC has been
demonstrated in two randomized phase III trials (Llovet JM, NEJM
2008;359:378; Cheng AL, Lancet Oncol 2009;10:25), both restricted to
pts with well-preserved liver function (Child-Pugh A). Child-Pugh B (CPB)
pts, that represent a relevant proportion of pts with advanced HCC in
clinical practice, were not eligible. Despite this limitation, the marketing
authorization of sorafenib by the main regulatory agencies was not
restricted to Child A pts. CPB pts are different in terms of prognosis, and
are potentially different in terms of balance between treatment efficacy and
toxicity. Large observational studies [Marrero JA, ASCO 2011 (abstr
4001)] are producing quite reassuring data about sorafenib tolerability in
CPB pts, but the real efficacy of the drug in this setting remains
substantially unknown, due to the lack of randomized trials. Methods:
BOOST (B Child HCC patients – Optimization Of Sorafenib Treatment) is a
randomized phase III trial comparing sorafenib � best supportive care
(BSC) vs. BSC alone in CPB pts with advanced HCC. Pts are eligible if older
than 18, with ECOG performance status 0-2. Pts assigned to experimental
arm receive sorafenib 400 mg twice daily, with dose reductions and
interruptions according to toxicity. Overall survival (OS) is the primary
endpoint. In order to demonstrate a Hazard Ratio of death 0.70 in favor of
sorafenib (2-month improvement in median OS, from 4.5 to 6.5 months),
with 80% power and � 0.05, 320 pts have to be randomized, 160 per arm.
The BOOST trial (ClinicalTrials.gov Identifier NCT01405573; Eudract
number 2009-013870-42) is approved by the Ethical Committee of the
National Cancer Institute, Napoli, Italy, as coordinating centre, and is
currently under evaluation by several other Institutions. BOOST is a
non-profit, academic trial. The trial has received a financial support by
Italian Ministry of Health (FARM84SA2X), although the support is not
enough to supply sorafenib to participating centers. BOOST is partially
supported by AIRC (grant IG2009-9316). The study is open to all
international Centers wishing to participate.
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