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

4115 General Poster Session (Board #50B), Mon, 8:00 AM-12:00 PM
Efficacy, safety, tolerability, and PK of the HDAC inhibitor resminostat in
sorafenib-refractory hepatocellular carcinoma (HCC): Phase II SHELTER
study. Presenting Author: Michael Bitzer, Medical University Clinic, Eberhard-Karls-University,
Tuebingen, Germany
Background: Resminostat (R), an oral HDAC inhibitor, was studied in the
SHELTER trial evaluating safety, PK and efficacy in HCC patients (pts)
refractory to sorafenib (S). R was explored as monotherapy and within a
novel resensitization approach to overcome tolerance to S by the combination
of both drugs. Methods: Pts with advanced HCC (BCLC B/C) were
included in a multi-center, two-arm trial. Radiologic progression under S
firstline therapy had to be confirmed by central review (RECIST) prior to
study entry. A dose escalation of R (range 200 to 600 mg) combined with S
(400 or 800 mg) was performed. Arm A investigated the drug combination
(R�S), Arm B the monotherapy of R (600 mg). Primary objective was the
progression-free survival rate (PFSR) after 12 weeks (w). Secondary
objectives included safety, tolerability, tumor response, PFS, TTP, OS and
the analyses of PK and biomarkers (BM), incl. AFP, VEGF, HDAC enzyme
inhibition, histone acetylation and gene expressions in peripheral blood.
Results: 50 pts were enrolled, dose escalation determined 600 mg R and
400 mg S for Arm A. Clinical activity results of 15 evaluable pts from
combination treatment revealing a PFSR of 66.6% after 12 w, not all
patients in Arm B already reached the 12 w staging. Most frequent AE were
CTC grade 1-2 GI complaints (nausea, vomiting) and skin disorders (rash,
pruritus, HFSR). Grade 3-4 toxicity (SAE reports) consisted mainly of
non-hematological events mostly related to tumor disease. Plasma concentrations
of both drugs correlated with administered doses and were in the
expected range without obvious influence of preexisting liver disease. BM
investigations revealed effective target modulation by R in both arms.
Conclusions: The primary study objective was achieved for both treatment
arms. R demonstrated a favorable PK, safety and tolerability profile, even in
combination with S and despite preexisting liver disease, includig cirrhosis.
The observed clinical activity emphazises the resensitizing activity of R by
an epigenetic mode-of-action to overcome tolerance to S and warrants
further development, in particular for combination therapy in both, first and
second line HCC treatment.
4118 General Poster Session (Board #50E), Mon, 8:00 AM-12:00 PM
Updated results from a phase III trial of sunitinib versus placebo in patients
with progressive, unresectable, well-differentiated pancreatic neuroendocrine
tumor (NET). Presenting Author: Aaron Vinik, EVMS Strelitz Diabetes
Research Center and Neuroendocrine Unit, Norfolk, VA
Background: In a double-blind phase III trial, sunitinib (Sutent; SU)
improved progression-free survival (PFS) vs placebo (PBO; 11.4 vs 5.5
mos; HR: 0.42, 95% CI: 0.26–0.66; P�0.0001) and was well tolerated in
patients (pts) with unresectable, well-differentiated pancreatic NET that
had progressed �12 mos before baseline. Initial overall survival (OS)
revealed a benefit for SU vs PBO, although median OS had not been
reached. We now report PFS assessed by blinded independent central
review (BICR) and updated OS. Methods: Pts were randomized 1:1 to SU
37.5 mg or PBO on a continuous daily dosing schedule, each with best
supportive care. The primary endpoint was investigator-assessed PFS; OS
was a secondary endpoint to be evaluated every 2 yrs for 5 yrs, or until 95%
of pts had died. Additionally, BICR was performed retrospectively; baseline
and on-study CT/MRI scans were evaluated by a 2-reader, 2-time-point
lock, followed by a sequential locked-read, batch-mode paradigm by
blinded, third-party radiologists. Results: 171 pts were randomized (SU,
n�86; PBO, n�85) from Jun 2007 to Apr 2009. The trial ended when an
independent data monitoring committee noted efficacy favoring SU and
more serious AEs and deaths with PBO. The study was unblinded at
closure; pts were offered open-label SU and followed for survival. Median
PFS by BICR was 12.6 mos (SU) vs 5.8 mos (PBO) (HR: 0.32, 95% CI:
0.18–0.55; P�0.00001). At study closure, there were 9 and 21 deaths in
the SU and PBO arms (HR: 0.41, 95% CI: 0.19–0.89; P�0.02). By Apr
2011 (2 yrs additional follow-up) a total of 87 deaths occurred (51%),
median OS was estimated at 33.0 mos in the SU arm, and 26.7 mos in the
PBO arm (HR: 0.71, 95% CI: 0.47–1.09; P�0.11 [Table]). 69% of pts
crossed over to SU on progression. Conclusions: BICR confirmed investigator
assessment of PFS and demonstrated a 6.8-mo improvement in median
PFS with SU. Updated OS favors SU, although this result is non-significant
for reasons that may include crossover of treatment and limited statistical
power.
2-yr OS update, Apr 2011
Deaths, n
Censored, n
Median OS (95% CI), mos
SU
n�86
40
46
33.0 (25.6–NR)
HR (95% CI) 0.71 (0.47–1.09)
P 0.11
Gastrointestinal (Noncolorectal) Cancer
PBO
n�85
47
38
26.7 (16.4–35.3)
267s
4117 General Poster Session (Board #50D), Mon, 8:00 AM-12:00 PM
Safety and efficacy of MET inhibitor tivantinib (ARQ 197) combined with
sorafenib in patients (pts) with hepatocellular carcinoma (HCC) from a
phase I study. Presenting Author: Robert E. Martell, Tufts Medical Center
Cancer Center, Boston, MA
Background: The multikinase inhibitor sorafenib is standard of care for pts
with advanced HCC. Tivantinib, an oral, selective MET inhibitor, demonstrated
synergistic antitumor activity when combined with sorafenib in
several tumor models. The phase 1 dose-escalation study assessed the
safety profile of tivantinib plus sorafenib in pts with advanced solid tumors.
Methods: Endpoints were safety, the recommended phase 2 dose (RP2D) of
tivantinib plus sorafenib, and antitumor activity. Dose escalation previously
established the RP2D as tivantinib 360 mg twice daily (BID) plus sorafenib
400 mg BID. Extension cohorts enrolled � 20 pts each with HCC or other
tumors. Patients were treated until disease progression or unacceptable
toxicity. After a safety review in HCC pts in other studies and a report of
febrile neutropenia in this study, the tivantinib dose for newly enrolled pts
was reduced to 240 mg BID. Results: 20 pts with HCC (mean age, 62 yr;
Child-Pugh [CP] A [n � 14], or CP B [n � 6]) were treated at the RP2D (n �
10) or at the reduced tivantinib dose plus sorafenib (n � 10). 10 pts
received � 1 previous systemic anticancer treatment (median, 0.5; range,
0-3). The most common adverse events (� 25%) were rash (40%),
palmar-plantar erythrodysesthesia syndrome (35%), fatigue and diarrhea
(30% each), and nausea and anorexia (25% each). Neutropenia was
reported in 2 pts. Best response was 1 complete response (CR), 1 partial
response (PR), and 12 stable disease (SD). Overall response rate and
disease control rate were 10% and 70%, respectively. Median progressionfree
survival (mPFS) was 3.5 mo (95% CI, 2.8-11.1 mo). Among 8 pts
previously treated with vascular endothelial growth factor (VEGF) inhibitors
(6 sorafenib; 1 sunitinib; 1 sorafenib plus sunitinib), best response was 1
CR, 1 PR, and 3 SD, and mPFS was 15.9 mo (95% CI, 1.6-15.9 mo). 2 pts
are still on study. Conclusions: The combination of tivantinib (360 mg BID)
plus sorafenib (240 mg BID) was well tolerated. Preliminary evidence of
antitumor activity indicates that combined inhibition of MET and angiogenic
signals may have therapeutic potential in this setting, including pts
pretreated with VEGF inhibitors.
4119 General Poster Session (Board #50F), Mon, 8:00 AM-12:00 PM
PAZONET: Results of a phase II trial of pazopanib as a sequencing
treatment in progressive metastatic neuroendocrine tumors (NETs) patients
(pts), on behalf of the Spanish task force for NETs (GETNE)—
NCT01280201. Presenting Author: Enrique Grande Pulido, Hospital
Ramon y Cajal, Madrid, Spain
Background: Pazopanib is an oral tyrosine kinase inhibitor of the VEGFR,
PDGFR and KIT that has demonstrated clinical activity in NETs. The aims
of our study were to assess efficacy, safety and potential predictive
biomarkers of pazopanib in pts with NETs who had previously failed to at
least one antiangiogenic or mTOR inhibitor treatment. Methods: Pts
presented locally-advanced or metastatic gastrointestinal or pancreatic
NET disease documented as progressive. Pazopanib 800 mg was given
daily until disease progression (DP) or unacceptable toxicity. Primary
endpoint was Clinical Benefit Rate (CBR) defined as Complete Response
plus Partial Response (PR) plus Stable Disease (SD) at 6 months by
RECIST-V-1.0. Optimal two-stage Simon design was utilized with H1 and
H0 set at 70 % and 50 % respectively, Kaplan-Meier estimates waere used
for the analysis of time-to-event variables: 95% CI. Results: 33 pts were
evaluable for response per protocol. 54.5% males, mean age 60.7�10.3
years. At 6 months, 2 pts had PR (6%), 26 SD (79%), and 5 DP (15%),
thus the CBR was 85%. By subgroups, CBR was 100% in pts with no
previous targeted therapy (7 pts), 89% in pts with previous mTOR
inhibitors (9 pts), 83% in pts with previous antiangiogenics (12 pts), and
60% in pts with previous antiangiogenics and mTOR inhibitors (5 pts). The
sum of the longest diameter of target lesions had a decrease over 10% in
22% of pts (29% without previous biological treatment, 22% mTOR
without prior multitarget, 18% prior multitarget without mTor, and 20%
with previous multitarget and mTOR. Median PFS was only reached in the
subgroup of pts (26 pts) with previously treated with antiangiogenics and
mTOR inhibitors (20.6 weeks, 95% CI, 10.4-30.8). Most frequent toxicities,
any grade: asthenia (75%), diarrhoea (63%), nausea (42%). Translational
studies on angiogenesis and inmunohistochemistry biomarkers and
CTCs are ongoing. Conclusions: Pazopanib at 800 mg daily has promising
activity in advanced NET regardless of previous treatment with other
targeted therapies. This trial may introduce the concept of treatment
sequencing with novel targeted agents in NETs.
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