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Here we report emerging data from the first clinical study of MLN8237 in
combination with docetaxel in pts with solid tumors or CRPC.
Methods: Pts aged ≥18 y with ≤3 prior myelosuppressive chemotherapy regimens
who were candidates for docetaxel received MLN8237 BID (days 1–5 or1–7) in 3 + 3
dosing cohorts plus docetaxel on day 1 in 21-d cycles. Primary objectives were safety/
tolerability and to determine a recommended phase 2 dose/schedule (RP2D);
secondary objectives were pharmacokinetics (PK) and antitumor activity (RECIST
v1.1 and/or PSA response by PCWG2).
Results: 22 pts in 5 dose cohorts received a median of 5 cycles (range 1–17); 9 pts
remain on therapy. Median age was 63 y (36–87), 82% were male, and 14 had CRPC.
8 pts reported dose-limiting toxicities including G4 neutropenia >7 days (n = 5) and
G3/4 febrile neutropenia (n = 3). MTD has not yet been reached. 21 pts reported
drug-related AEs; G ≥ 3 in 20 pts, including neutropenia (86%), leukopenia (27%),
and febrile neutropenia (23%). 11 pts had serious AEs and 3 discontinued due to
AEs. There were 2 on-study deaths (due to disease progression). Steady-state systemic
exposure of MLN8237 increased in an approx. dose proportional manner over 10–
30 mg BID when administered with docetaxel 75 mg/m (n = 18). There was no
consistent effect of MLN8237 dose on docetaxel exposure (n = 19). Of 20
response-evaluable pts, 3 with CRPC achieved PR plus a >50% decrease in PSA and
7 had stable disease including 3 pts who also had a >50% decrease in PSA; 1 pt with
bladder cancer had a PR.
Conclusions: Myelosuppressive G ≥ 3 AEs were common, but 10 of 22 pts remained
on study for ≥6 cycles. PK data from the expansion cohort are pending to support
definitive conclusions regarding drug-drug interaction between docetaxel and
MLN8237. Emerging data suggest this combination may have preliminary antitumor
activity in pts with solid tumors/CRPC. Dose escalation/modification is ongoing to
determine RP2D.
Disclosure: N.M. Hahn: Research Support to institution: Merck, Dendreon, Sanofi,
Millennium, Exelexis, Novartis, Bristol-Myers Squibb, Celgene Consultant: Sanofi,
Celgene Speakers Bureau Honoraria: Sanofi, Janssen Biotech, C. Higano: Amgen,
Bayer, Dendreon, GTx, MPI, AZ, Pfizer, Cell Ther., Centocor, Perceptive Inform.,
Sanofi, TEVA, BMS, Aragon, Cell Genesys, Exelixis, Genentech, GSK, ImClone,
OncoGenex, Mediv., Clin. Care Ops, Curatio, Medscape, RBC Capital Mkts Corp.,
Cougar, Endo, X. Zhou: Employment (Millennium Pharmaceuticals, Inc.), B. Zhang:
Employment: Millennium Pharmaceuticals, Inc., E.J. Leonard: Employment
(Millennium Pharmaceuticals, Inc.) Ownership interest (Millennium
Pharmaceuticals, Inc.), E. Benaim: Employment (Millennium Pharmaceuticals, Inc.).
All other authors have declared no conflicts of interest.
922P A PHASE II STUDY OF SB939 IN PATIENTS (PTS) WITH
CASTRATION RESISTANT PROSTATE CANCER (CRPC)
B.J. Eigl1 , S. North2 , E. Winquist3 , J. Powers4 , J. Good5 , M. Sharma6 , J. Squire5 ,
M. Cox7 , E.A. Eisenhauer8 , K. Chi9 1 2
Oncology, Tom Baker Cancer Centre, Calgary, AB, CANADA, Oncology, Cross
Cancer Institute, Edmonton, AB, CANADA, 3 Medical Oncology, University of
Western Ontario London Regional Cancer Center, London, ON, CANADA,
4 5
Clinical Trials, NCIC Clinical Trials Group, Kingston, ON, CANADA, Pathology
and Molecular Medicine, Queens University, Kingston, ON, CANADA, 6 Urologic
Sciences, The Vancouver Prostate Centre, Vancouver, BC, CANADA, 7 Urologic
Sciences, University of British Columbia, Vancouver, BC, CANADA, 8 Clinical
Trials, Queen’s UniversityNCIC Clinical Trials Group, Kingston, ON, CANADA,
9
Oncology, Vancouver Cancer Centre, University of British Columbia, Vancouver,
BC, CANADA
Background: SB939 is a potent oral inhibitor of class 1, 2, and 4 histone deacetylases
(HDACs). These 3 HDAC classes are highly expressed in CRPC and associated with
poor clinical outcomes. HDAC inhibition abrogates androgen receptor signaling via
inactivation of HSP90, and may have particular relevance in prostate cancer with the
TMPRSS2-ERG (T2-E) fusion.
Methods: Pts with locally recurrent or metastatic CRPC received SB939 60mg every
other day 3 times per week x 3 weeks on a 28-day cycle. Primary endpoints were
PSA response rate (RR) (>50% decline from baseline for > 4 weeks) and
progression-free survival (PFS). Secondary endpoints included objective response rate
and duration; overall survival; circulating tumor cell (CTC) enumeration at baseline,
6 and 12 weeks; T2-E fusion analysis; correlative analysis of archival tissue; and
safety. In a 2-stage design, a planned maximum of 29 response evaluable patients
were to be enrolled.
Results: 32 pts were enrolled and have completed study treatment. Median age was
70; 88% of pts had received no prior chemotherapy; and ECOG performance status
was 0/1 in 44%/56%. Bone/lymph node/visceral metastases were present in 91%/75%/
12%. The median number of SB939 cycles administered was 3 (range 1-8). Adverse
events were generally grade 1-2, with 5 pts experiencing one or more grade 3 events
(fatigue (5), vomiting (1), dyspnea (1)). One pt died due to myocardial infarction. A
confirmed PSA response was noted in 2 pts (6%), lasting 3.0 and 9.4 mo. In 16 pts
with measurable disease, there were no objective responses, 7 pts had stable disease
lasting 1.6 to 8.0 months. CTC response (from ≥5 at baseline to 5 at 6 weeks correlated
with PSA progression. Correlative studies to evaluate T2-E from whole blood as well
as T2-E fusion and PTEN deletion status on archival tissue are ongoing.
Annals of Oncology
Conclusion: SB939 is tolerable at the dose/schedule given, but does not merit further
study as a single agent in CRPC based on PSA RR. Activity was observed in terms of
CTC declines however. Study of SB939 with cytotoxic or AR targeted therapies may
be warranted. Supported by grants from the Canadian Cancer Society and the
Ontario Institute for Cancer Research.
Disclosure: All authors have declared no conflicts of interest.
923P GTX-758, AN ORAL ERα AGONIST, INCREASES SEX
HORMONE BINDING GLOBULIN, REDUCES FREE T AND
DECREASES PSA IN PATIENTS WITH CASTRATION
RESISTANT PROSTATE CANCER
M.S. Steiner, R.P. Taylor, R.H. Getzenberg, M.A. Johnston, M. Hancock, J.
T. Dalton
Medical Affairs, GTx, Inc., Memphis, TN, UNITED STATES OF AMERICA
Introduction & objective: GTx-758 is an oral, selective estrogen receptor α agonist,
which induces sex hormone binding globulin (SHBG) and subsequently reduces free
testosterone (FT) to levels below that achieved with LHRH agonists. Such agonists
represent a distinct class of agents with the potential to impact men with advanced
prostate cancer. Herein we report the results of a proof of concept trial of GTx-758
in patients who developed castration resistant prostate cancer (CRPC) while on
androgen deprivation therapy (ADT).
Methods: Men (n = 9) receiving ADT and developed CRPC, were enrolled in a Phase
II open label study to 2000 mg GTx-758 daily. Primary endpoint was the proportion
of subjects with a ≥ 50% reduction in prostate specific antigen (PSA) from Day
1. Secondary endpoints included serum FT and SHBG. SHBG, FT, and PSA were
assessed at, Days 1, 15, 30, 60, and 90 days.
Results: At enrollment (Day 1) values (n = 9) observed for PSA (38.7 ng/mL ± 52.8),
FT (0.89 pg/mL ± 0.70), and SHBG (53.4± 28.6 nmol/L). Data were available from 7
subjects with at least one on-study assessment for FT and SHBG. By Day 15, 75% (3/
7) and by Day 60, 100% (4/4) of patients had a ≥50% reduction in PSA. Mean
change in FT, at last observation, was -70.4% ± 16.7%. All subjects demonstrated
significant increases in SHBG at day 15 (251 ± 63.1 pmol/L) and end of study (266 ±
73.0 pmol/L), with a mean change at last observation of 429% ± 158%. Although
there were no venous thromboembolic events (VTEs) in this study, a separate study
of GTx-758 for primary ADT in men with advanced prostate cancer was stopped
prematurely due to an increased risk of VTEs, and consequently, this study was
halted as well.
Conclusions: GTx-758 is an oral selective ERα agonist that has demonstrated ability
to increase SHBG more than 4-fold and decrease FT in men with CRPC. Coupled
with the observation that 4/4 patients respond with a ≥50% reduction in PSA at day
30, these results suggest that progression of disease, and the need for increasingly
toxic therapies, may be delayed in this population. Significantly lower doses of
GTx-758 (100 – 600mg) have also been shown to increase SHBG with a more
favorable safety profile in previous Phase I and II GTx-758 studies. Lower doses of
GTx-758 are being evaluated in an ongoing Phase II trial in men with CRPC.
Disclosure: M.S. Steiner: CEO of GTx and own stock, R.P. Taylor: employee of GTx,
Inc. and own stock in GTx, Inc., R.H. Getzenberg: employee of GTx, Inc., M.A.
Johnston: employee of GTx and own stock, M. Hancock: employee of GTx, Inc. and
own stock in GTx, Inc., J.T. Dalton: employee of GTx, Inc. and own stock in
GTx, Inc.
924P ABIRATERONE IN PATIENTS WITH METASTATIC
CASTRATION-RESISTANT PROSTATE CANCER
PROGRESSING AFTER DOCETAXEL AND MDV3100: A
MULTICENTRE STUDY
D. Bianchini 1 , Y. Loriot 2 , E. Ileana 2 , S. Sandhu 1 , C. Pezaro 1 , L. Albiges 2 ,
G. Attard 1 , K. Fizazi 3 , J.S. de Bono 1 , C. Massard 3
1 Prostate Targeted Therapy Group/ DDU, Royal Marsden Hospital, Sutton,
UNITED KINGDOM, 2 Medical Oncology, Institut de Cancérologie Gustave
Roussy, Villejuif, FRANCE, 3 Department of Medical Oncology, Institute Gustave
Roussy, Villejuif, FRANCE
Background: Androgen receptor signalling remains critically important in metastatic
castration resistant prostate cancer (mCRPC) as confirmed by recent Phase III trials
showing a survival advantage for abiraterone acetate and MDV3100. These novel
inhibitors of androgen biosynthesis and androgen receptor function are anticipated
to be broadly utilized in the near future. The antitumor activity of abiraterone in
patients pre-treated with MDV3100 is as yet unknown.
Methods: We investigated the activity of abiraterone acetate in patients with mCRPC
who had progressed following treatment with docetaxel and MDV3100. Clinical
data were retrospectively analysed for prostate-specific antigen (PSA) response,
clinical benefit and progression-free survival (PFS). All patients received abiraterone
1000 mg/day plus prednisone 10mg/day.
Results: Thirty-nine patients [median age 70 years: range 52-84, median baseline
PSA 238 ng/mL range: 2-3000, metastatic sites: bone disease in 38 patients (97%),
ix304 | Abstracts Volume 23 | Supplement 9 | September 2012