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Annals of Oncology
advanced HCC, tivantinib monotherapy improved time to progression by 56%.
However, in that study at the standard phase 2 dose of 360 mg twice daily (BID),
tivantinib exposure was increased, and the absolute incidence of severe neutropenia
increased approximately 6% compared to pts with solid tumors from previous
studies. An exposure-response analysis was conducted to explore the relationship
between neutropenia and tivantinib pharmacokinetics (PK).
Methods: Tivantinib plasma concentration and incidence of grade ≥ 2 neutropenia
were pooled from phase 1/1b and 2 studies. A population PK model (NONMEM
v.7.1.0) was used to predict tivantinib exposure in HCC. The relationship between
tivantinib exposure and neutropenia was evaluated by logistic regression analysis
(S plus v8.0).
Results: Data were available from 289 cancer pts, including 73 pts with HCC and
mild-to-moderate hepatic impairment. Cases of grade ≥ 3 (n = 28) and grade ≥ 2
(n = 40) neutropenia were included in the analysis. Based on the population PK
analysis, tivantinib clearance was reduced approximately 67% in HCC pts, resulting
in approximately 3 times higher exposure compared with other cancer pts. There was
a significant (P < .001) relationship between tivantinib exposure and incidence of
grade ≥ 2/3 neutropenia. By reducing the tivantinib starting dose from 360 to 240 mg
BID, the incidence of grade ≥ 3 neutropenia is modeled to decrease from 28% to 16%
in HCC pts. Further reduction in the risk of neutropenia (∼6%) was achieved with
intensive clinical monitoring and an aggressive dose-reduction schema.
Conclusions: Based on the current analysis, the increased incidence of neutropenia
in HCC pts compared to pts with other solid tumors resulted from increased
tivantinib exposure due to hepatic impairment. Consistent with the model, the risk of
neutropenia was successfully managed in HCC pts by implementing dose reduction
and tighter clinical monitoring without compromising efficacy.
Disclosure: H. Zahir: H Zahir is an employee of Daiichi Sankyo, Inc. H. Kastrissios:
H Kastrissios is an employee of Pharsight Corporation and was retained by Daiichi
Sankyo to provide scientific consulting services on tivantinib. M. Jansen: M Jansen is
an employee of Daiichi Sankyo, Inc. R. Savage: R Savage is currently an employee of
ArQule. I participate in the ESPP employee stock purchase plan and receive stock
options as part of my compensation package as an employee of ArQule.
G. Abbadessa: G Abbadessa is an employee of ArQule, Inc. and owns Arqule stock
options. F. Chai: F Chai is an employee of ArQule, Inc., the sponsor of the studies.
F Chai holds ArQule stock. B. Schwartz: B Schwartz is currently an employee (Chief
Medical officer) of ArQule and own stock in the company. R. Miller: R Miller is a
full time employee of Daiichi Sankyo Pharma Development. T. Tokui: T Tokui is an
employee of Daiichi Sankyo Co., Ltd. All other authors have declared no conflicts of
interest.
739P PHASE 1 EXPERIENCE OF TIVANTINIB IN PATIENTS WITH
HEPATOCELLULAR CARCINOMA (HCC) OR BILIARY TRACT
CANCER (BTC)
F. Chai 1 , G. Abbadessa 2 , R. Savage 3 , H. Zahir 4 , Y. Chen 2 , M. Lamar 5 ,
J. Kazakin 6 , D. Ferrari 2 , R. von Roemeling 7 , B. Schwartz 2
1 Medical Administration, ArQule, Inc., Woburn, MA, UNITED STATES OF
AMERICA, 2 Clinical Development, ArQule, Inc., Woburn, MA, UNITED STATES
OF AMERICA, 3 Preclinical Development and Clinical Pharmacology, ArQule, Inc.,
Woburn, MA, UNITED STATES OF AMERICA, 4 Clinical Pharmacology, Daiichi
Sankyo, Inc., Edison, NJ, UNITED STATES OF AMERICA, 5 Clinical Operations,
ArQule, Inc., Woburn, MA, UNITED STATES OF AMERICA, 6 Arqule, Inc., ArQule,
Inc., Woburn, MA, UNITED STATES OF AMERICA, 7 Clinical Development
Oncology, Daiichi Sankyo Pharma Development, Edison, MA, UNITED STATES
OF AMERICA
Background: Tivantinib is a selective MET inhibitor that is extensively metabolized
by the liver. Since 2006, > 700 cancer patients (pts) have been treated with tivantinib.
Herein we summarize safety, pharmacokinetic (PK), and efficacy data for pts with
HCC or BTC treated with tivantinib in phase 1 clinical trials.
Methods: Adverse events (AEs) were assessed using Common Terminology Criteria
for Adverse Events (CTCAE) version 3.0. Tumor responses were assessed via
Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. PK parameters
were calculated using blood samples collected on day 1 and on day 2 or day 15 of
cycle 1.
Results: 53 pts (median age, 63 y) with HCC (n = 42; 79%), cholangiocarcinoma
(n = 10; 19%), or gallbladder adenocarcinoma (n = 1; 2%) were included. Of these, 23
pts (43%) received tivantinib monotherapy, and 30 pts (57%) received tivantinib in
combination with sorafenib (n = 20; 38%), gemcitabine (n = 8; 15%), or erlotinib
(n = 2; 4%). Starting tivantinib BID doses were < 240 mg in 3 (6%), 240 mg in 11
(21%), and 360 mg in 39 (74%) pts. Common treatment-emergent AEs (≥ 15% of
pts) were fatigue and anemia (45% each); diarrhea (40%); neutropenia and anorexia
(38% each); asthenia (30%); thrombocytopenia, peripheral edema, pyrexia, and
nausea (25% each); hyperbilirubinemia (23%); vomiting and alopecia (21% each);
rash (19%); leukopenia (17%); and palmar-plantar erythrodysesthesia syndrome,
dyspnea, and ascites (15% each). Tivantinib PK analysis indicated peak plasma levels
2 h after oral administration (range, 1-6 h). Tivantinib exposure was higher in pts
with HCC vs pts with BTC (12,385 vs 5,992 ng·h/mL). Best responses were complete
response in 1 pt (2%), partial response in 2 pts (4%), and stable disease (SD) in 30
pts (57%). Response rate and disease control rate were 6% and 62%, respectively.
Conclusions: Tivantinib demonstrated a manageable safety profile and was well
tolerated at doses up to 360 mg BID in pts with BTC and up to 240 mg BID in pts
with HCC. Only pts with HCC had increased exposure, presumably due to
disease-specific hepatic impairment. Encouraging clinical activity (primarily SD) was
observed in this pt population.
Disclosure: F. Chai: F Chai is an employee of ArQule, Inc., the sponsor of the
studies and holds ArQule stock. G. Abbadessa: G Abbadessa is an employee of
ArQule, Inc. and owns ArQule stock options. R. Savage: R Savage is currently an
employee of ArQule and participates in the ESPP employee stock purchase plan and
receives stock options as part of his compensation package as an employee of
ArQule. H. Zahir: H Zahir is an employee of Daiichi Sankyo, Inc. Y. Chen: Y Chen
is an ArQule employee and own ArQule stocks. M. Lamar: M Lamar is an employee
of ArQule, Inc. J. Kazakin: J Kazakin is an employee of ArQule, Inc. and has
ArQule’s stock options. D. Ferrari: D Ferrari is an ArQule Inc. employee and
currently owns ArQule stock. R. von Roemeling: R von Roemeling is an employee of
Daiichi Sankyo Pharma Development. B. Schwartz: B Schwartz is currently an
employee of ArQule Inc. and own stock in the company.
740P PHASE I STUDY OF NINTEDANIB (BIBF 1120) IN EUROPEAN
PATIENTS WITH ADVANCED HEPATOCELLULAR CARCINOMA
D. Palmer 1 , A.B. Loembé 2 , M. Studeny 2 , J. Hocke 3 ,T.Meyer 4
1 Liverpool Cancer Research Uk Centre, University of Liverpool, Liverpool,
UNITED KINGDOM, 2 Oncology, Boehringer Ingelheim RCV GmbH & Co KG,
Vienna, AUSTRIA, 3 Oncology, Boehringer Ingelheim Pharma GmbH & Co.KG,
Biberach an der Riss, GERMANY, 4 UCL Cancer Institute, University College
London, London, UNITED KINGDOM
Background: Caucasian and Asian patients (pts) with hepatocellular carcinoma
(HCC) tolerate anticancer drugs differently. This open-label, multicentre, phase I/
randomised phase II study (NCT01004003; phase II in progress) evaluated the
efficacy, safety and pharmacokinetics of nintedanib (a triple angiokinase inhibitor
targeting VEGFRs, PDGFRs and FGFRs) versus sorafenib in pts with advanced HCC
from Europe. Initial phase I results are reported.
Methods: Pts (ECOG performance status ≤2, Child-Pugh [CP] score ≤7) with
histologically/cytologically confirmed HCC and no prior systemic therapy were
enrolled in the phase I trial and stratified into two groups: (I) AST and ALT ≤2 x
upper limit of normal (ULN), and CP 5–6; (II) AST or ALT >2 to ≤5 x ULN, or CP
7. Utilising a 3 + 3 design, cohorts received oral nintedanib continuously in 28-day
courses, starting at 50mg bid (group II) or 100mg bid (group I) and escalating up to
200mg bid in 50mg bid intervals. Therapy was continued until no clinical benefit or
undue toxicity. The phase I primary endpoint was the maximum tolerated dose
(MTD) of nintedanib in Course 1.
Results: A total of 28 pts (71% Caucasian) have been treated: 13 in group I (median
[range] days: 345 [2–757]; 100/150/200mg bid, n = 6/3/4) and 15 in group II (median
[range] days: 74 [17–428]; 50/100/150/200mg bid, n = 3/4/4/4). No dose-limiting
toxicities (DLTs) were seen in group I or II during Course 1 at doses up to 200mg
bid, which was the MTD of nintedanib. After the dose-escalation phase and
determination of MTD, seven pts reported DLTs at various dose levels (CTCAE
Grade [G]3 bilirubin increase, G3 AST increase, G4 amylase increase, G3
hypertension/ALP increase, G3 amylase increase, G5 multi-organ failure, G3
bilirubin increase). The most frequent adverse events (AEs) in both groups, by
system organ class, were gastrointestinal (89%) and general/administration site (39%)
disorders. Class-related AEs (any grade) were uncommon (hypertension [n = 2], rash
[n = 3]). Hepatic enzyme data will be presented.
Conclusions: Nintedanib has an acceptable safety profile in pts with advanced HCC
at the same dose used in other cancers (200 mg bid).
Disclosure: D. Palmer: Daniel Palmer: research funding from Boehringer Ingelheim.
A.B. Loembé: Arsene-Bienvenu Loembé: employee of Boehringer Ingelheim. M.
Studeny: Matus Studeny: employee of Boehringer Ingelheim. J. Hocke: Julia Hocke:
employee of Boehringer Ingelheim. T. Meyer: Tim Meyer: research funding from
Boehringer Ingelheim
741P VALIDATION OF PROGNOSTIC VALUE OF AJCC 7TH STAGING
SYSTEM IN PATIENTS WITH RESECTED HEPATOCELLULAR
CARCINOMA (HCC)
S.F. Ang1 ,H.Li2 , S. Choo1 , I.B. Tan1 , M.H. Tan1 , H.C. Toh1 1
Medical Onocology, National Cancer Center Singapore, SINGAPORE,
2
Department of Clinical Research, Singapore General Hospital, Singapore,
SINGAPORE
Background: Accurate cancer staging is essential to determine prognosis and
appropriate treatment. The American Joint Committee on Cancer (AJCC) Staging
Manual 7th edition for HCC released in 2010 subdivided stage III HCC to IIIA
(multiple tumors of which any are greater than five centimeters, but lack major
vessel invasion, T3A) and IIIB (invasion of major vessels, T3B). Both were previously
classified as stage IIIA in the AJCC 6th. T4N0M0 and patients with node-positive
disease (N1) are upstaged to stage IIIC and IVA respectively. The aim of our study is
Volume 23 | Supplement 9 | September 2012 doi:10.1093/annonc/mds398 | ix245