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RO and Cd, as well as PD data for circulating angiogenic factors will be
presented.
Disclosure: All authors have declared no conflicts of interest.
449PD PHASE 1 DOSE-ESCALATION TRIAL OF THE
INVESTIGATIONAL HEDGEHOG (HH) PATHWAY INHIBITOR
TAK-441 IN PATIENTS WITH ADVANCED SOLID TUMORS
J.W. Goldman 1 , S.G. Eckhardt 2 , M. Borad 3 , M. Hidalgo 4 , D.P. Ryan 5 , A. Parikh 6 ,
S. Kuan 7 ,J.Yu 7 , S. Stewart 1 , L.S. Rosen 1
1 Hematology / Oncology, UCLA Medical Center, Santa Monica, CA, UNITED
STATES OF AMERICA, 2 Medical Oncology, University of Colorado School of
Medicine, Aurora, CO, UNITED STATES OF AMERICA, 3 Hematology / Oncology,
Mayo Clinic, Scottsdale, AZ, UNITED STATES OF AMERICA, 4 GIi Cancer Clinical
Research Unit, CNIO- Spanish National Cancer Center, Madrid, SPAIN,
5 Hematology / Oncology, Massachusetts General Hospital, Boston, MA, UNITED
STATES OF AMERICA, 6 General Medicine, Takeda Pharmaceuticals
International, Inc., Deerfield, IL, UNITED STATES OF AMERICA, 7 Clinical
Pharmacology, Millennium Pharmaceuticals, Inc., Cambridge, MA, UNITED
STATES OF AMERICA
Background: Dysregulation of the Hh pathway is a principal event in the
carcinogenesis of multiple tumor types, including basal cell carcinoma. TAK-441 is
an investigational, orally-available inhibitor of the G protein-coupled receptor
Smoothened, a component of the Hh signalling cascade.
Methods: This study (NCT01204073) was designed to determine safety, maximum
tolerated dose (MTD) and maximum feasible dose (MFD) in patients with advanced
solid tumors. Cycles consisted of 3 weeks continuous dosing, with a single-dose cycle
1 lead-in, followed by 7 d pharmacokinetics (PK). Dose escalation (DE) proceeded in
a modified 3 + 3 fashion. Radiographic tumor assessments were performed after
cycles 2, 4, and every 4 cycles thereafter.
Results: Thirty-two patients were enrolled in the DE phase, median age 59 y (range
28–82), and treated with doses from 50–1600 mg daily. TAK-441 concentrations
were quantifiable in plasma after the starting 50 mg dose, with total exposure
increasing dose-proportionally to 800 mg. Maximum plasma concentration typically
was reached 3 h post-dose. The median terminal disposition half-life was 15 h (range
6–35 h). DLTs of Gr 3 fatigue and muscle spasms were observed in 1 pt at the 1600
mg dose. Six subjects discontinued due to an adverse event (AE) including a patient
who suffered a fatal cerebral hemorrhage in cycle 4 related to 50 mg TAK-441. Most
common treatment-emergent AEs were muscle spasms (44%), dysguesia (41%),
nausea (41%), fatigue (38%) and constipation (28%). The MFD is 1600 mg and the
MTD has not been reached. Four patients remained on trial for >10 cycles, and 3
patients continue on treatment. Response and PK/PD data will be presented.
Conclusions: TAK-441 was well-tolerated up to an MFD of 1600 mg taken once
daily. A dose expansion cohort has been initiated at 800 mg in patients with
untreated basal cell carcinoma.
Disclosure: S.G. Eckhardt: Consultancy, Research funding and Speakers Bureau/
Advisory Committee for Millennium/Takeda. S. Kuan: Employment with Millennium
Pharmaceuticals, Inc. J. Yu: Employment and consultancy for Millennium. L.S. Rosen:
Research support from Millennium. All other authors have declared no conflicts of interest.
450PD A PHASE IB COMBINATION STUDY OF RO4929097 (RO), A
GAMMA-SECRETASE INHIBITOR, AND TEMSIROLIMUS
(TEM) IN PATIENTS (PTS) WITH ADVANCED SOLID TUMORS
I. Diaz-Padilla 1 , S.J. Hotte 2 , S.P. Ivy 3 , A.M. Oza 1 , H.W. Hirte 2 , A.R.A. Razak 1 ,
E.X. Chen 1 , I. Brana Garcia 1 , L. Siu 1 , P. Bedard 1
1 Dept. of Medical Oncology and Hematology, Princess Margaret Hospital,
Toronto, ON, CANADA, 2 Medical Oncology, Juravinski Cancer Centre, Hamilton,
ON, CANADA, 3 Cancer Therapy Evaluation Program, National Cancer Institute,
Bethesda, MD, UNITED STATES OF AMERICA
Background: The notch signalling pathway has a critical role in regulating cellular
differentiation, proliferation, and apoptosis. RO is a potent and selective gamma-secretase
inhibitor with antitumor activity in animal models. Pre-clinical experiments indicate that
the PI3K/AKT/mTOR pathway may mediate resistance to gamma secretase inhibitors,
providing a rationale for combination therapy with RO and TEM.
Methods: A phase Ib dose-escalation study with a 3 + 3 design was conducted.
Three dose levels (DLs) were planned. Objectives were to determine the
recommended phase II dose (RP2D), safety, pharmacokinetics (PK) and
pharmacodynamics (PD) of the combination. Eligible pts received once daily oral
RO on a 3 day on/4 day off schedule every week (QW), and intravenous QW
TEM. Initial doses were 10 mg RO and 25 mg TEM. Cycles were every 21 days,
except for cycle 1, which was 28 days. Treatment-related dose-limiting toxicities
(DLTs) were evaluated during cycle 1.
Results: 17 pts (data cut-off 26-Apr-2012) have been treated on three DLs. Number of
pts, DLTs and schedule are shown in Table 1. Demographics: M:F 6:11; median age: 60
yrs (range 28-84); ECOG 0/1:4/13. Pts received a median of 3 cycles (range 1-12). The
most common adverse events (AEs) related to the study drug combination included:
fatigue (82%; G3 6%), mucositis, (71%; G3 6%), neutropenia (59%; G3 12%), anemia
(59%;G30%),andhypertriglyceridemia(59%,G30%).TwoDLTs(G3rash,G3
mucositis) were observed in the same patient in DL1 prompting dose expansion. No
additional DLTs were observed. Of 15 patients evaluable for response, no objective
responses were observed. 11 pts (73%) had stable disease (SD) as their best response; with
3 pts (sarcoma, neuroendocrine, non-small cell lung cancer) on therapy for ≥6 cycles.
Conclusions: RO can be safely combined with TEM. The RP2D was established as
RO at 20 mg combined with 37.5 mg of TEM. PK and circulating angiogenic factors
analyses will be presented.
RO Dose
(mg)
TEM Dose
(mg)
No. of pts
treated
No. of pts
with DLT DLT
Dose Level
1 †
10 25 8 1 G3 rash, G3
mucositis
2 20 25 3 0
3 ∧
20 37.5 6 0
† 2 pts were not evaluable for DLT ∧ DL3 (RP2D) was expanded to 6 pts
Disclosure: All authors have declared no conflicts of interest.
Annals of Oncology
451P PHASE I AND PHARMACOKINETICS/PHARMACODYNAMICS
(PK/PD) STUDY OF MEK INHIBITOR, RO4987655, IN
JAPANESE PATIENTS WITH ADVANCED SOLID TUMORS
S. Nakamichi 1 , H. Nokihara 1 , N. Yamamoto 1 , Y. Tamura 1 , K. Honda 1 , H. Wakui 1 ,
Y. Yamada 2 , N. Yamazaki 3 , S. Suzuki 4 , T. Tamura 1
1 Division of Thoracic Oncology, National Cancer Center Hospital, Tokyo, JAPAN,
2 Division of Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo,
JAPAN, 3 Division of Dermatological Oncology, National Cancer Center Hospital,
Tokyo, JAPAN, 4 Division of Ophthalmic Oncology, National Cancer Center
Hospital, Tokyo, JAPAN
Background: RO4987655, an oral and selective inhibitor of MEK, is a key enzyme of
the MAPK signaling pathway. This was a phase I, non-randomized, open-label,
dose-escalation study in Japanese patients with advanced solid tumors. Primary
objectives were determination of maximum tolerated dose (MTD) based on
dose-limiting toxicities (DLTs), safety evaluation and PK analysis. Secondary
objectives were PD analysis and exploratory analysis of RO4987655’s anti-tumor
activity according to the RECIST 1.0 criteria.
Methods: Patients received an oral single dose of RO4987655 (1, 2, 4, 5, and 6.5 mg)
(Cycle 0) followed by continuous once daily dosing (QD, 1, 2, and 4 mg/day) then
twice daily dosing (4, 5, and 6.5 mg BID, total daily dose: 8, 10, and 13 mg/day) in
28-day cycles. A 3 + 3 dose-escalation design was used. Blood samples for PK analysis
were collected in Cycle 0 (Day 1, 2, and 3) and in Cycle 1 (Day 1, 8, 15, and 22). PD
was evaluated by pERK inhibition in peripheral blood mononuclear cells (PBMCs).
Results: As of March 2012, 25 patients were enrolled in 6 cohorts of 1, 2, 4, 8, 10,
and 13 mg/day. Four DLTs were observed in the 13 mg/day (n = 2) and 10 mg/day
(n = 2) cohorts, all of them reversible Grade 3 creatine phosphokinase (CPK)
elevation. MTD was defined as 8 mg/day. Most commonly related adverse events
(AEs) included dermatitis acneiform, CPK elevation, and eye disorders. Plasma
exposure of RO4987655 appeared to increase in a dose-proportional manner with a
plasma half-life (t1/2) of 14.0 to 24.4 hours. After multiple dose administration,
steady-state conditions were reached by Cycle 1 Day 8 (240 hours). The inhibitory
effects of RO4987655 on pERK in PBMCs increased in a dose-dependent manner.
Conclusions: The MTD of RO4987655 for Japanese patients was defined as 8 mg/
day. RO4987655 has a manageable safety profile with a favorable PK/PD correlation
in Japanese patients with advanced solid tumors.
Disclosure: S. Nakamichi: This phase I clinical trial is sponsored by Chugai
Pharmaceutical Co., Ltd. H. Nokihara: This phase I clinical trial is sponsored by
Chugai Pharmaceutical Co., Ltd. N. Yamamoto: This phase I clinical trial is
sponsored by Chugai Pharmaceutical Co., Ltd. Y. Tamura: This phase I clinical trial
is sponsored by Chugai Pharmaceutical Co., Ltd. K. Honda: This phase I clinical trial
is sponsored by Chugai Pharmaceutical Co., Ltd. H. Wakui: This phase I clinical trial
is sponsored by Chugai Pharmaceutical Co., Ltd. Y. Yamada: This phase I clinical
trial is sponsored by Chugai Pharmaceutical Co., Ltd. N. Yamazaki: This phase I
clinical trial is sponsored by Chugai Pharmaceutical Co., Ltd. S. Suzuki: This phase I
clinical trial is sponsored by Chugai Pharmaceutical Co., Ltd. T. Tamura: This phase
I clinical trial is sponsored by Chugai Pharmaceutical Co., Ltd.
ix156 | Abstracts Volume 23 | Supplement 9 | September 2012