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

4132 General Poster Session (Board #52C), Mon, 8:00 AM-12:00 PM
Final results of a phase Ib study of tivozanib and FOLFOX6 in patients (pts)
with advanced gastrointestinal (GI) tumors. Presenting Author: Ferry
Eskens, Erasmus University Medical Center, Daniel den Hoed Cancer
Center, Rotterdam, Netherlands
Background: Tivozanib is a potent, selective, oral small-molecule tyrosine
kinase inhibitor of vascular endothelial growth factor receptors 1, 2 and 3
with a long half-life. A Phase I study found tivozanib’s maximum tolerated
dose (MTD) to be 1.5 mg/d and responses were observed in pts with
colorectal cancer (CRC) and other tumors. Tivozanib has shown additive
anti-tumor activity with 5-fluorouracil in a preclinical breast tumor model.
FOLFOX6 is a standard chemotherapy for GI cancers. This open-label,
Phase Ib study (NCT00660153) sought to determine the MTD, doselimiting
toxicities (DLTs), pharmacokinetics (PK), and anti-tumor activity
of escalating doses of tivozanib combined with a modified (m) FOLFOX6
regimen (85 mg/kg2 oxaliplatin) in pts with advanced GI tumors. Methods:
Tivozanib was administered once daily in 4-week cycles (3 weeks on, 1
week off) with mFOLFOX6 administered on Days 1 and 15 of each cycle.
Pts also received a single dose of tivozanib on day -5 for PK analysis. Pts
were allowed to continue tivozanib following discontinuation of mFOL-
FOX6. Results: Twenty two pts (14:8 male:female; median age 58 years;
91% Caucasian) received tivozanib 0.5 mg (n�9), 1.0 mg (n�3), or 1.5
mg (n�10) and mFOLFOX6. Pts received a median of 5.2 (range 0.0 to
25.1) months of treatment. DLTs were observed in 2 pts on tivozanib 0.5
mg (reversible Grade [Gr] 3 diarrhea and Gr 3/4 transaminase elevations)
and in 2 pts on tivozanib 1.5 mg (Gr 3 seizure and reversible Gr 3 vertigo).
Other Gr 3/4 drug-related adverse events (AEs) included neutropenia,
fatigue, and hypertension (n�2 each). Eight pts discontinued treatment
due to AEs. The MTD for tivozanib with mFOLFOX6 was 1.5 mg. The
disease control rate was 63% (�1% complete response, 27% partial
response, 36% stable disease). Preliminary PK data showed no interaction
between tivozanib and mFOLFOX6. Eight additional pts enrolled at the 1.5
mg dose level are currently being evaluated. Final results will be presented.
Conclusions: Tivozanib can be combined at its recommended dose of 1.5
mg/day with mFOLFOX6 for pts with advanced GI tumors. The combination
was tolerable and showed encouraging anti-tumor activity. A Phase II study
of this combination for mCRC is ongoing.
TPS4134 General Poster Session (Board #52E), Mon, 8:00 AM-12:00 PM
Dasatinib combined with gemcitabine (Gem) in patients (pts) with locally
advanced pancreatic adenocarcinoma (PaCa): Design of CA180-375, a
placebo-controlled, randomized, double-blind phase II trial. Presenting
Author: T.R. Jeffry Evans, Beatson West of Scotland Cancer Centre,
Glasgow, United Kingdom
Background: Dasatinib, a potent oral BCR-ABL and SRC family kinase
(SFK) inhibitor, is approved for first- and second-line therapy of Philadelphia
chromosome-positive chronic phase chronic myeloid leukemia (CML)
in pts with newly diagnosed CML or CML resistant/intolerant to prior
therapy. SRC expression and activity is upregulated in PaCa and correlates
with reduced survival in resected high-grade PaCa (Morton, Gastroenterology
2010) and resistance to Gem, a PaCa standard of care (Duxbury, J Am
Coll Surg 2004). In preclinical PaCa studies, inhibition of SFKs with
dasatinib reduces tumor cell proliferation, migration, and invasion; increases
apoptosis; sensitizes cells to Gem; and inhibits development of
metastases in vivo either alone or in combination with Gem (Duxbury, Clin
Cancer Res 2004; Duxbury, J Am Coll Surg 2004; Nagaraj, Mol Cancer
Ther 2010; Morton, op cit). Phase I clinical studies of dasatinib and Gem
therapy in PaCa have demonstrated feasibility and suggested efficacy of the
combination (Uronis, ASCO 2009, abstract e15506). Methods: This
double-blind phase II study tests whether addition of dasatinib to Gem is
tolerable and improves efficacy in pts with histologically/cytologically
confirmed unresectable locally advanced nonmetastatic PaCa. Eligible pts,
aged �18 years with Eastern Cooperative Oncology Group performance
status �1 and adequate organ function, are randomized 1:1 to Gem 1000
mg/m2 IV once weekly (Weeks 1–3 of a 4-week cycle) plus either dasatinib
100 mg once daily or matched placebo. Pts are treated until progression,
unacceptable toxicity, withdrawal of consent, or study termination. The
primary endpoint is OS, and secondary endpoints are progression-free
survival and safety. Exploratory endpoints include freedom from distant
metastases, measures of pain and fatigue, overall response rate, and
carbohydrate antigen 19-9. Final study analysis will be conducted after
135 deaths; all pts will be followed for survival. To date, 23/200 pts have
enrolled; estimated primary completion date is March 2013. ClinicalTrials.
gov identifier: NCT01395017.
Gastrointestinal (Noncolorectal) Cancer
271s
4133 General Poster Session (Board #52D), Mon, 8:00 AM-12:00 PM
Methylguanine DNA methyl transferase (MGMT) expression to predict
response to temozolomide (TMZ) in patients with digestive neuroendocrine
tumors (NETs). Presenting Author: Pascal Hammel, Beaujon, Paris, France
Background: TMZ is an orally given drug used in patients (pts) with NETs,
with encouraging results in pancreatic NETs in a recent study (Strosberg et
al, 2011). Higher treatment efficacy seems to be correlated to MGMT
tumor deficiency (Kulke et al, 2010). Aim-To assess MGMT expression in
digestive NETs and to correlate with the efficacy of TMZ-based therapies.
Methods: All pts with well differentiated, progressive, non resectable NETs
treated with TMZ-based chemotherapy were included. Treatment efficacy
was defined according to RECIST. Pts with progression or only stable
disease were considered as “non-responders”. Nuclear expression of
MGMT was assessed by immunohistochemistry on primary tumors or
metastases and graded according the product of the intensity of staining (0
to 3) and the rate of positive cells (%), leading to a score comprised
between 0 and 300. A score � 80 was defined as “high” staining. Results:
22 pts (age 59 years (36-81)) with pancreatic (14 pts), small bowel (5 pts)
or other (3 pts) NETs, grade 1 (5 pts) or 2 (17 pts) (WHO 2010
classification) were included. They received TMZ alone (19 pts) or
combined with capecitabine (3 pts) as first line (3 pts) or 2� line (19
pts).After a median of 6 cycles (3-16), objective response, stable disease
and progression rates were seen in 32 % (7 pts, all with pancreatic NETs),
41% (9 pts, 5 pancreatic) and 27% (6 pts, 4 small bowel), respectively.
Median (range) MGMT score was 10 (0-300). A “High” MGMT score was
seen in 36% of pts (small bowel 4, pancreas 3 pts) ; it was correlated with
primary tumor location (more frequent in small bowel NETs, p�0.02) and
predictive of the absence of response (p�0.02). A “Low “MGMT score
tended to be associated with objective response (p�0.06) whereas none of
the pts with “high” score had tumor response. Response rate in pts with
“low” MGMT score was 50%. Conclusions: MGMT deficiency is more
frequent in pancreatic than small bowel NETs. Patients with pancreatic
NET and low MGMT score are good candidates for TMZ, whereas those with
high score should be treated with other drug in first intention. In patients
with small bowel NET with most often high MGMT score, tumor stabilization
using TMZ seems to be rare.
TPS4135 General Poster Session (Board #52F), Mon, 8:00 AM-12:00 PM
A phase III, multicenter, randomized, double-blind, placebo-controlled
trial of ganitumab or placebo in combination with gemcitabine (G) as
first-line therapy for metastatic adenocarcinoma of the pancreas: The
GAMMA trial. Presenting Author: Charles S. Fuchs, Dana-Farber Cancer
Institute, Boston, MA
Background: Ganitumab (AMG 479) is an investigational, fully human,
monoclonal antibody inhibitor of the IGF1R. In a randomized phase II study
in patients with metastatic pancreatic cancer, addition of ganitumab 12
mg/kg every 2 weeks (Q2W) to G prolonged progression-free survival (PFS)
and overall survival (OS) (Kindler. Ann Onc. 2010;21:741P). Exposureefficacy
analysis showed that patients with higher ganitumab exposure
levels (AUCss at or above median) had longer PFS and OS (Lu. JCO.
2011;29:4049). Methods: In this phase III study, patients are randomized
2:2:1 to placebo � G, ganitumab 12 mg/kg � G, or ganitumab 20 mg/kg �
G. Patients receive ganitumab or placebo IV days (D) 1 and 15 and G 1000
mg/m2 IV D 1, 8, and 15 every 28 D. Patients receiving 20 mg/kg
ganitumab are expected to achieve ganitumab levels above the median in
phase 2. Key eligibility criteria: untreated metastatic adenocarcinoma of
the pancreas; ECOG score 0 or 1; � 18 years old; adequate organ function;
and fasting (or non-fasting) glucose � 160 mg/dL. The primary endpoint is
OS. A log-rank test stratified by ECOG, presence of liver metastases, and
geographic region will compare OS independently for each ganitumab arm
at an overall one-sided 2.5% significance level for declaring superiority of
ganitumab � G vs placebo � G. Key secondary endpoints include PFS,
objective response, safety, and patient-reported outcomes. An additional
objective is to define a subpopulation with improved OS based upon
baseline levels of circulating biomarkers. Enrollment began in April 2011.
As of January 23, 2012, 463 of 825 patients have been enrolled. The study
is overseen by an independent data monitoring committee. Status: open.
Supported by Amgen Inc. in collaboration with Takeda Global Research &
Development Center, Inc.; ClinicalTrials.gov: NCT01231347.
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