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

198s Developmental Therapeutics—Experimental Therapeutics
3100 General Poster Session (Board #20B), Mon, 8:00 AM-12:00 PM
A phase I study of S-222611 an oral reversible dual inhibitor of EGFR and
HER2, in patients with solid tumors. Presenting Author: Richard D. Baird,
University of Cambridge, Department of Oncology, Cambridge, United
Kingdom
Background: S-222611 is a novel oral, potent, reversible tyrosine kinase
inhibitor with antiproliferative activity in human tumor cell lines expressing
EGFR and/or HER2 in vitro and in mouse xenograft models. We conducted
the first study in patients (pts) with solid tumors expressing EGFR or HER2.
Methods: Daily oral doses of S-222611 were escalated in successive
cohorts from 100 mg to a maximum 1600 mg, using a 3 � 3 design. Full
plasma pharmacokinetic (PK) profiles were obtained in all pts for 7 days
after a single dose on Day 1 and for 24 h following 21 days of once daily
dosing (Cycle 1). Trough PK samples were drawn weekly during the first 3
weeks of daily dosing. A CT scan was performed at baseline and every 8
weeks post-dose to assess response (RECIST). Results: Of 23 treated pts
(16 male) aged 24-77y, 19 completed Cycle 1. One dose-limiting toxicity
(DLT) has been seen to date, a rash at 1200 mg, which resolved on
interruption and dose reduction. Other adverse events related to drug,
diarrhea, rash, and nausea, were mild (grade 1 or 2) but more frequent at
higher doses. Tumor responses have been seen over a wide range of doses.
One complete clinical response was observed at 1200 mg in a pt with
HER2 positive breast carcinoma previously treated with lapatinib and
trastuzumab. Two pts showed confirmed partial responses (one with EGFR
positive renal cell carcinoma at 200 mg daily and one with EGFR and HER2
positive esophageal carcinoma at 400 mg daily); 2 pts showed unconfirmed
partial responses and 3 pts (with vaginal, gastric and pancreatic adenoCa)
showed stable disease for �6 months (mo); 2 pts have been treated for
�12 mo. Plasma Cmax, AUC and steady state concentrations increased with
dose up to 1200 mg, exceeding those eliciting maximal responses in mice.
The plasma t½ is �24 h. Conclusions: S-222611 was generally tolerated
well in doses up to 1200 mg, with only one DLT; rash, diarrhea and nausea
have been readily manageable. PK data support once daily dosing to
achieve highly effective concentrations. A substantial proportion of patients
with HER2 or EGFR expressing tumors have shown partial responses
or stable disease (�6 mo) and one patient has shown a complete clinical
response.
3103 General Poster Session (Board #20E), Mon, 8:00 AM-12:00 PM
A phase I study of selumetinib (AZD6244/ARRY-142866) in combination
with cetuximab (cet) in refractory solid tumors and KRAS mutant colorectal
cancer (CRC). Presenting Author: Dustin A. Deming, University of Wisconsin
Carbone Cancer Center, Madison, WI
Background: KRAS mutations have been recognized as clinically important
predictors of resistance to EGFR-directed therapies in CRC. Oncogenic
activation of the RAS/RAF/MEK/ERK signaling cascade mediates proliferation
independent of growth factor receptor signaling. We hypothesized that
targeting MEK with selumetinib could overcome resistance to cet in KRAS
mutant CRC. A phase I study (NCT01287130) was undertaken to determine
the tolerability, and pharmacokinetic profiles of the combination of
selumetinib and cet, with an expanded cohort in KRAS mutant CRC at the
MTD dose to evaluate preliminary anti-tumor activity. Methods: In the dose
escalation portion, patients (pts) with advanced solid tumors received fixed
dose cet with escalating doses of selumetinib in cohorts of 3-6 pts. In the
expansion cohort, 14 pts with KRAS mutant CRC were enrolled at the MTD
level. Results: 15 pts (9 M, 6 F), average age of 60 (41-73) years were
treated at 3 dose levels in the dose escalation cohort and 14 pts were
treated in the expansion cohort. Pts had the following tumor types: CRC
73%, NSCLC 13%, and H&N 13%, and had received a median of 4 (1-8)
prior lines of therapy. 33% (only CRC) had prior EGFR-directed therapies.
ECOG PS 0 (40%), 1 (53%), 2 (7%). 13 of 15 pts were evaluable for
tolerability and response. One DLT for grade 4 hypomagnesemia occurred,
and no other grade 4 toxicities were seen. Grade 3 (20%) toxicities
included; rash, hyponatremia, and headache. The most common cycle 1
grade 1 and 2 adverse events included acneiform rash (100%), fatigue
(54%), nausea/vomiting, (54%), diarrhea (54%), dry skin (46%), fever
(23%), and hypomagnesemia (15%). Most pts (60%) required no dose
modifications. The MTD was established at selumetinib 75 mg PO BID and
cet 250 mg/m2 weekly following a 400 mg/m2load. Best response included
2 PR in pts with CRC and SD in 4 pts (1 SCC of the tonsil, 1 NSCLC, and 2
CRC). Conclusions: The combination of selumetinib and cet is well
tolerated, and preliminary anti-tumor activity was observed in multiple pts.
Results of the KRAS mutant CRC expansion cohort will be presented.
3101 General Poster Session (Board #20C), Mon, 8:00 AM-12:00 PM
A phase I study of the gamma-secretase inhibitor RO4929097 and
capecitabine in refractory solid tumors. Presenting Author: Noelle K.
LoConte, University of Wisconsin Carbone Cancer Center, Madison, WI
Background: RO4929097 is a oral inhibitor of gamma-secretase, which
results in Notch signaling inhibition. Prior work has demonstrated that
Notch-signaling inhibition enhances chemosensitivity of colon cancer
cells. This study sought to combine RO4929097 with capecitabine (cape)
and determine maximum tolerated dose (MTD), toxicities and efficacy.
Preclinical and prior phase I work demonstrated possible autoinduction of
RO4929097, so pharmacokinetic (PK) evaluation of RO4929097 and
cape was planned. Methods: Adult patients with refractory solid tumors
were eligible and received RO4929097 and cape at a fixed dose of 1000
mg/m2 BID with escalating doses of RO4929097 on a 21-day cycle
according to a 3�3 design. Cape was administered for 14 days and the
RO49029097 once daily, 3 days per week. RO4929097 plasma concentrations
were evaluated by LC/MS/MS on days 3 and 10 of cycle 1, and PK
parameters analyzed with WinNonLin version 5.2. Results: 4 dose levels
have been completed (20, 30, 45 and 68 mg); 18 of 19 patients are
evaluable for toxicity and PK data is available for 11 patients. One DLT has
been observed (intolerable grade 2 fatigue) at 68 mg. There have been 2
confirmed partial responses: fluoropyrimide-refractory colon cancer (for 12
cycles) and cervical cancer (for 6 cycles). The half-life, Cmax and AUC of
RO4929097 all significantly decreased on day 10 compared to day 3, with
an increase in clearance for all doses. The half-life was significantly shorter
in dose level 3 (p�0.0012) and dose level 4 (p�0.0126) compared to
dose level 1. Conclusions: RO4929097 plus cape was well tolerated.
Activity was seen in cervical and colon cancer. Autoinduction of RO4929097
was seen both with increasing cycle number and increasing dose. However,
all plasma concentrations of RO4929097 were above those needed for
Notch inhibition (1.9 ng/mL based on prior studies). Dose level 1 (cape
1000 mg/m2 BID and RO4929097 20 mg daily) is the recommended
phase II dose.
N�11
Ratio day 10/day 3
Mean (95% CI) P value
Half-life (hr) 0.62 (0.44 – 0.80) � 0.001
Cmax/dose 0.63 (0.44 – 0.82) � 0.001
AUC/dose 0.50 (0.12 – 2.57) 0.016
Vd (mL) 1.88 (1.19 – 2.57) � 0.001
Cl (mL/hr) 3.69 (2.13 – 5.25) � 0.001
3104 General Poster Session (Board #20F), Mon, 8:00 AM-12:00 PM
Phase I trial to assess the safety and pharmacokinetics of afatinib and
weekly vinorelbine in patients with advanced solid tumors. Presenting
Author: Antoine Hollebecque, Institut Gustave Roussy, Villejuif, France
Background: Afatinib (A) is an oral, irreversible ErbB Family Blocker with
activity in a wide range of tumor cell lines dependent on ErbB signaling.
Vinorelbine (VNR) interferes with tubulin polymerization and spindle
formation during metaphase. Additive or supra-additive activity of A or
EGFR TKI with VNR has been demonstrated in preclinical models. Methods:
This dose-escalation Phase I study established the safety profile, MTD and
PK of A with i.v. and p.o. VNR using a modified 3�3 design. Eligible
patients (pts) were �18 years with refractory advanced or metastatic
tumors, an ECOG PS 0–1, and adequate organ and bone marrow function.
VNR i.v. (25 mg/m2 )/oral (60 mg/m2 with escalation to 80 mg/m2 after 3
weeks) was administered weekly on Days 1, 8, 15 and 22 with escalating
oral daily doses of A 20 mg, 40 mg and 50 mg in 28-day treatment courses.
Results: The study treated 55 pts: 30 pts for MTD determination and 25 pts
in the PK expansion cohort (24 M/31 F), median age 54 years (range
34–72). 28/27 pts were included in the VNR i.v./p.o. cohorts, respectively.
Patients had NSCLC, breast, pancreatic (n�13/5/3), head and neck,
stomach or colorectal cancer (n�2 each group); 28 pts had other cancers.
At 20 mg A, no DLTs occurred in the VNR i.v./p.o. cohorts; whereas, at 50
mg A, 4/6 pts and 3/5 pts experienced DLTs. At 40 mg A and VNR i.v./p.o.,
1/6 pts included for MTD determination experienced DLT, as did 7/13 pts
and 2/12 pts in the VNR i.v./p.o. PK expansion cohorts, respectively. Main
DLTs were diarrhea and febrile neutropenia. Median treatment duration
(snapshot date 9 Dec 2011) across all dose groups was 80 days (range
10–687), with 98 and 58 days in the MTD cohorts of VNR i.v./p.o.,
respectively. Related AEs observed in most patients were diarrhea, asthenia,
nausea, vomiting, neutropenia, decreased appetite, mucositis and
rash. Five pts had a PR, confirmed in 2 pts. Preliminary PK analyses
suggest no drug–drug interaction between A and i.v. VNR. Conclusions:
Afatinib in combination with weekly i.v./p.o. VNR is tolerated, with
manageable, reversible, target-related side effects and promising signs of
clinical activity in heavily pretreated patients. The MTD for A for both
combinations is 40 mg daily.
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