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Annals of Oncology
440O RESULTS OF A FIRST-IN-HUMAN PHASE I STUDY OF THE
ALK INHIBITOR LDK378 IN ADVANCED SOLID TUMORS
A.T. Shaw 1 , D.R. Camidge 2 , E. Felip 3 , S. Sharma 4 , D.S.W. Tan 5 , D. Kim 6 ,
T. De Pas 7 , J.F. Vansteenkiste 8 , A. Santoro 9 , G. Liu 10 , M. Goldwasser 11 ,
D. Dai 12 , A.L. Boral 13 , R. Mehra 14
1 Medicine, Harvard Medical School, Boston, MA, UNITED STATES OF
AMERICA, 2 School of Medicine, University of Colorado, Denver, CO, UNITED
STATES OF AMERICA, 3 Oncology, Vall d’Hebron University Hospital, Barcelona,
SPAIN, 4 Center for Investigational Therapeutics, Huntsman Cancer Institute, Salt
Lake City, UT, UNITED STATES OF AMERICA, 5 Department of Medical
Oncology, National Cancer Center, Singapore, SINGAPORE, 6 Department of
Internal Medicine, Seoul National University Hospital, Seoul, KOREA, 7 Medical
Oncology Unit of Respiratory Tract and Sarcomas, Istituto Europeo di Oncologia,
Milano, ITALY, 8 Respiratory Oncology Unit (pulmonology), University Hospital
Gasthuisberg, Leuven, BELGIUM, 9 Department of Medical Oncology and
Hematology, Istituto Clinico Humanitas, Rozzano, ITALY, 10 Ontario Cancer
Institute, Princess Margeret Hospital, Toronto, ON, CANADA, 11 Novartis
Institutes for BioMedical Research, Novartis Pharmaceuticals, Cambridge, MA,
UNITED STATES OF AMERICA, 12 Oncology Clinical Pharmacology, Novartis
Pharmaceuticals, East Hanover, NJ, UNITED STATES OF AMERICA, 13 Clinical
Research, Novartis Institutes for Biomedical Research, Inc, Cambridge, MA,
UNITED STATES OF AMERICA, 14 Department of Developmental Therapeutics,
Fox Chase Cancer Center, Philadelphia, PA, UNITED STATES OF AMERICA
Background: Translocations of the anaplastic lymphoma kinase (ALK) gene occur in
3–8% of NSCLC. LDK378 is a novel, potent small molecule ALK inhibitor that produces
tumor regressions in ALK-driven (ALK+) NSCLC xenografts. A Phase 1 study is being
conducted with the primary objective of determining the MTD and safety profile in
patients (pts) with ALK+ cancers. Other objectives are to assess safety, PK, and
antitumor activity in pts with ALK+ NSCLC, either previously untreated with ALK
inhibitors, or relapsed following ALK inhibitor treatment, and other ALK+ cancers.
Methods: LDK378 was administered orally once-daily on a continuous 21-day
schedule, in adult pts with advanced malignancies harboring a genetic alteration in
ALK who progressed on standard therapy or for whom there was no effective
therapy. Dose escalation was guided by a Bayesian logistic regression model to
determine the MTD, and started at 50 mg/day.
Results: As of 25 April2012, 56 pts (primary site: lung 50 pts [37 with prior crizotinib];
breast 4 pts; other 2 pts; median age 53 (22–76) years; 88% ECOG PS 0/1) had received
LDK378 at doses of 50–750 mg/day. Of 47 pts evaluable for response (per investigator),
there were 24 (51%) responses. All responses were in ALK+ NSCLC (FISH positive in
≥15% of tumor cells). In 26 pts with NSCLC who had progressed following crizotinib and
were treated at ≥400 mg/day there were 21 (81%) responses. Dose limiting toxicities (DLTs)
have occurred in 2/14 pts at 400 mg/day, 2/9 pts at 600 mg/day, and 1/9 pts at 750 mg/day.
DLTs included diarrhea, vomiting, nausea, dehydration, and ALT elevation. The MTD was
750 mg/day. At the cutoff date, 36 (64%) pts remain on treatment. Discontinuations were
due to adverse events (AEs) in 1 (2%), and disease progression in 19 (34%) pts. The most
frequent AEs (all grades) were nausea 33 (59%), vomiting 30 (54%), and diarrhea 27 (48%)
pts. The most frequent Grade 3/4 AE was diarrhea (5 [9%] pts). Oral absorption of
LDK378 was rapid with a T max of 5–6 hours, and half-life was about 36 hours.
Conclusions: Daily oral LDK378 is well tolerated and the MTD was 750 mg/day.
Striking activity was seen in ALK+ NSCLC pts treated at doses ≥400mg, who had
previously progressed following crizotinib.
Disclosure: A.T. Shaw: I have a consultant/advisory role for Pfizer, Novartis, Chugar,
Ariad, and Daiichi. D.R. Camidge: I have a compensated consultant/advisory role
with Novartis Pharmacuticals Inc. S. Sharma: I have a compensated consultant/
advisory role for Novartis (LEAD Summit). I have received honoraria for Novartis
LEAD Summit. I have received research funding from Novartis (Phase Ib clinical
trial). D.S.W. Tan: I have received research funding from Novartis. M. Goldwasser:
Employment or leadership position to disclose: Associate Director Biostatistics:
Novartis Pharmaceuticals. D. Dai: Employment or leadership position to disclose.
Clinical Pharmacology Expert: Novartis Pharmaceuticals; Stock ownership: Myself;
Novartis Pharmaceuticals. A.L. Boral: I am an employee of Novartis Institutes for
Biomedical Sciences (Executive Director). I have stock ownership (Novartis). All
other authors have declared no conflicts of interest.
441O A PHASE I/II STUDY OF ALK INHIBITOR CH5424802 IN
PATIENTS WITH ALK-POSITIVE NSCLC; SAFETY AND
EFFICACY INTERIM RESULTS OF THE PHASE II PORTION
M. Nishio1 , K. Kiura2 , K. Nakagawa3 , T. Seto4 , A. Inoue5 , M. Maemondo6 ,
T. Hida7 , M. Harada8 , H. Yoshioka9 , T. Tamura10 1
Thracic Oncology Center, Cancer Institute Hospital of JFCR, Tokyo, JAPAN,
2
Department of Respiratory Medicine, Okayama University Hospital, Okayama,
JAPAN, 3 Medical Oncology, Kinki University School of Medicine, Osaka, JAPAN,
4
Thoracic Oncology, National Kyushu Cancer Center, Fukuoka, JAPAN,
5
Department of Respiratory Medicine, Tohoku University, Sendai, JAPAN,
6
Department of Respiratory Medicine, Miyagi Cancer Center, Natori, JAPAN,
7 8
Thoracic Oncology, Aichi Cancer Center, Nagoya, JAPAN, Respiratory Medicine,
National Hospital Organization Hokkaido Cancer Center, Sapporo, JAPAN,
9 10
Respiratory, Kurashiki Central Hospital, Kurashiki, JAPAN, Division of Internal
Medicine and Thoracic Oncology, National Cancer Center Hospital, Tokyo, JAPAN
Background: Anaplastic lymphoma kinase (ALK) is a tyrosine kinase constitutively
activated following chromosomal gene translocation in a subset of non-small cell
lung cancer (NSCLC). CH5424802, an oral ALK inhibitor, was well tolerated with
promising efficacy in patients (pts) with ALK-positive NSCLC in the phase I portion
(ASCO 2012). Here we report the interim results of the ongoing phase II portion.
Methods: The primary objective of the phase II portion was to investigate the efficacy
and safety at the recommended dose (RD) determined in the phase I portion. Pts with
ALK-positive NSCLC, measurable disease, and no prior ALK inhibitor therapy were
treated with CH5424802 at 300 mg bid until progressive disease or intolerable toxicity.
Results: As of March 23, 2012, 34 pts have been enrolled: median age; 46 years, M/F;
16/18, ECOG PS 0/1; 17/17, never-smoker; 62%, number of prior chemotherapy 1/2/
3/ > 4; 18/6/0/10. Among the first 15 pts, the response rate was 73.3% with 1 CR and
10 PRs. Main treatment-related adverse events (AEs) among the 34 pts were AST
increased (7 pts), ALT increased (6), neutropenia (5), rash (4), nausea (4), myalgia
(3), dysgeusia (3), constipation (3), blood CPK increased (3), blood bilirubin
increased (3), and blood ALP increased (3), which were mostly Grade 1 except for
neutropenia. Grade 3 treatment-related AEs were two cases of neutropenia. For
treatment-related eye disorders which are frequent in crizotinib, only one Grade 1
case (vision blurred) was observed. No treatment-related AEs led to dose reduction.
At the time of submission, 30 pts are on study (range 1 - 8 months).
Conclusion: CH5424802 demonstrated clinically meaningful antitumor activity with
well tolerated toxicity profile. A phase I/II study in ALK-positive NSCLC pts
previously treated with or without crizotinib is ongoing in the US.
Disclosure: M. Nishio: Corporate-sponsored research:Chugai pharmaceutical Co.,
Ltd., Pfizer. K. Kiura: Corporate-sponsored research:Chugai pharmaceutical Co., Ltd.,
Pfizer. K. Nakagawa: Corporate-sponsored research:Chugai pharmaceutical Co., Ltd.,
Pfizer. T. Seto: Corporate-sponsored research:Chugai pharmaceutical Co., Ltd., Pfizer.
A. Inoue: Corporate-sponsored research:Chugai pharmaceutical Co., Ltd., Pfizer. M.
Maemondo: Corporate-sponsored research:Chugai pharmaceutical Co., Ltd. T. Hida:
Corporate-sponsored research:Chugai pharmaceutical Co., Ltd., Pfizer. M. Harada:
Corporate-sponsored research:Chugai pharmaceutical Co., Ltd., Pfizer. H. Yoshioka:
Corporate-sponsored research:Chugai pharmaceutical Co., Ltd. T. Tamura:
Corporate-sponsored research:Chugai pharmaceutical Co., Ltd.
442O PI3K KINASE INHIBITOR GSK2126458 (GSK458): CLINICAL
ACTIVITY IN SELECT PATIENT (PT) POPULATIONS DEFINED
BY PREDICTIVE MARKERS (STUDY P3K112826)
P. Munster 1 , R. van der Noll 2 , E. Voest 3 , J. Specht 4 , T.L. Werner 5 , E.C. Dees 6 ,
A.R. Tan 7 , A. Daud 8 , J. Schellens 9 , M.P. Lolkema 3 , M. Griffin 4 , N. Agarwal 10 ,
G.S. Falchook 11 , J.F. Kleha 12 , M. Durante 13 , D.A. Smith 12 , L. Adams 12 ,
J. Greshock 12 , S.R. Morris 12 , R. Kurzrock 11
1 Medicine, Division of Hem/Onc, University of California, San Francisco,
San Francisco, CA, USA, 2 Department of Pharmacology, The Netherlands
Cancer Institute, Amsterdam, NETHERLANDS, 3 Department of Medical
Oncology, University Medical Center Utrecht, Utrecht, NETHERLANDS,
4 University of Washington Division of Medical Oncology, Fred Hutchinson Cancer
Research Center, Seattle, WA, UNITED STATES OF AMERICA, 5 Department of
Internal Medicine, Oncology Division, University of Utah School of Medicine, Salt
Lake City, UT, UNITED STATES OF AMERICA, 6 Developmental Therapeutics
Working Group, UNC Lineberger Cancer Comprehensive Cancer Center, Chapel
Hill, NC, UNITED STATES OF AMERICA, 7 Breast Medical Oncology and Phase I
Program, The Cancer Institute of New Jersey, New Brunswick, NJ, UNITED
STATES OF AMERICA, 8 Melanoma Program, University of California,
San Francisco, San Francisco, CA, UNITED STATES OF AMERICA, 9 Department
of Pharmacology, The Netherlands Cancer Institute, Amsterdam,
NETHERLANDS, 10 Hunstman Cancer Institute, University of Utah, Salt Lake City,
UT, UNITED STATES OF AMERICA, 11 Department of Investigational Cancer
Therapeutics, UT MD Anderson Cancer Center, Houston, TX, UNITED STATES
OF AMERICA, 12 Research and Development, Oncology, GlaxoSmithKline,
Research Triangle Park, NC, UNITED STATES OF AMERICA, 13 Research and
Development, Oncology, GlaxoSmithKline, Collegeville, PA, UNITED STATES OF
AMERICA
Background: GSK458 is an oral, potent inhibitor of PI3K (α, β, γ, δ), mTORC1, and
mTORC2. Cell lines with activation of the PI3K pathway are more likely to be
sensitive to GSK458.
Methods: Pts with advanced solid tumors received GSK458 until disease progression
or intolerable toxicity. Dose escalation with once (QD) and twice daily dosing (BID)
was explored. Pharmacodynamics (PD) (tumor biopsies and FDG–PET) in unselected
populations, and clinical activity in specific populations (PIK3CA-mutant and wild-type
[WT]) bladder cancer, renal cell carcinoma, PIK3CA-mutant metastatic breast cancer,
and KRAS-WT metastatic endometrial cancer) were evaluated.
Results: 170 pts (49% female; mean age 57 [22-85] yrs) received doses ranging from
0.1 to 3 mg, the MTD for both QD and BID was 2.5 mg. The median (range) time
above the target plasma concentration (20 ng/mL) was longer in BID versus QD
dosing: 21hour (h) (14.8-24; n = 6) versus 8h (0-23.9; n = 18), respectively. Dose
limiting toxicities were Grade 3 diarrhea. Most frequent (≥ 20%) drug related adverse
events were diarrhea (28%), fatigue (24%) and nausea (23%). A dose response
relationship between GSK458 plasma concentrations and increases in serum insulin
levels was observed. 13 paired pre/post-dose tumor biopsies showed inconsistent
changes in pAKT/total AKT, Ki67 and phospho-histone-H3. 9 pts had pre/post-dose
FDG-PET; one pt had a mean SUV value decrease by ≥30% post-dose although none
had responses per RECIST. Objective responses were seen in bladder cancer (1/3
PIK3CA mutant and 2/15 wild-type) and renal cell (2/23: 1 CR duration 25+ months,
Volume 23 | Supplement 9 | September 2012 doi:10.1093/annonc/mds395 | ix153