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

TPS4694 General Poster Session (Board #16E), Sun, 8:00 AM-12:00 PM
A phase I/IIa study of the safety and efficacy of radium-223 chloride
(Ra-223) with docetaxel (D) for castration-resistant prostate cancer (CRPC)
patients with bone metastases. Presenting Author: Michael J. Morris,
Memorial Sloan-Kettering Cancer Center, New York, NY
Background: Ra-223is a first-in-class alpha-pharmaceutical that targets
bone metastases (mets) with high energy alpha-particles of short range (�
100 �m). In the ALSYMPCA trial, Ra-223 plus best standard of care (BSC)
significantly improved OS vs placebo plus BSC in CRPC patients (pts) with
bone mets (Parker et al. ECCO/ESMO 2011), and was shown to have an
excellent safety profile. Since D is an approved chemotherapy with
demonstrated survival benefit for pts progressing after castrating hormone
therapy, it is logical to explore combining Ra-223 plus D in pts with CRPC
and bone mets. This study is being conducted in the Prostate Cancer
Clinical Trials Consortium with an aim to establish the safe dose of Ra-223
and D when used in combination in pts with bone mets with CRPC.
Methods: This ongoing phase I/IIa trial (NCT01106352) is enrolling pts
with bone mets from CRPC intended for treatment with D. D naïve pts are
preferred, although up to 10 previous infusions of D are acceptable if D was
well tolerated and the patient is in good condition and fulfills all eligibility
criteria at study entry. Phase I dose-escalation study: minimum of 9 pts
(max. 18 pts) will be included if no dose limiting toxicity (DLT) is observed.
Dose escalation will follow a ‘3�3’ design, with no intra-patient dose
escalation or overlapping of cohorts permitted. Ra-223 doses are 25 or 50
kBq/kg, with number of Ra-223 injections (inj) (2, 4, 5, or 10) and interval
between inj (3 or 6 wks) varying by escalation schema; D doses are 60 or 75
mg/m2 q3wk. DLT will be assessed when 6 wks post-inj safety data are
available after 1st Ra-223 �D inj. Phase IIa open-label expanded safety
study: pts will be randomized 2:1 to the recommended dose of Ra-223 to
be used with D or to treatment with D alone (approx. 42 pts will be
included). Primary endpoint is to assess safety of combining Ra-223 with
D. Exploratory efficacy endpoints for the open-label expanded safety
portion of the study include change in disease-related biomarkers, time to
1st radiological or clinical progression, CTC and pain assessment. Enrollment
in dose-escalation portion of the study is complete; expanded safety
cohort to begin enrolling in March 2012.
TPS4696^ General Poster Session (Board #16G), Sun, 8:00 AM-12:00 PM
First-line use of cabazitaxel in chemotherapy-naive patients with metastatic
castration-resistant prostate cancer (mCRPC): A three-arm study in
comparison with docetaxel. Presenting Author: Stephane Oudard, Georges
Pompidou European Hospital, Paris, France
Background: Docetaxel (D) in combination with prednisone (P) as first-line
(1L) chemotherapy in patients (pts) with mCRPC is the current standard of
care. However, treatment is not curative and D-resistant disease typically
develops. Cabazitaxel (Cbz) is a novel taxane active in D-sensitive and
-resistant tumor models. Clinical activity of Cbz plus P (CbzP) was
demonstrated in the Phase III TROPIC study in mCRPC pts previously
treated with a D-containing regimen; CbzP showed a significant overall
survival (OS) benefit vs mitoxantrone plus prednisone (median OS 15.1 vs
12.7 months; HR 0.70; P � 0.0001). Therefore, it is of interest to
determine if CbzP provides an OS advantage vs DP in 1L mCRPC pts.
Methods: The phase III FIRSTANA study (NCT01308567) is a randomized,
open-label, multinational trial in 1L mCRPC pts, designed to compare the
efficacy of Cbz 25 mg/m² IV Q3W (Arm A) and Cbz 20 mg/m² IV Q3W (Arm
B) vs D 75 mg/m2 IV Q3W (Arm C). P 10 mg PO QD is to be given
concomitantly. Pts are stratified by ECOG PS (0–1 vs 2), measurable
disease (yes/no) and region (depending on availability of Cbz as 2L). Pts
with ECOG PS � 2, histologically/cytologically confirmed metastatic
prostate adenocarcinoma, with no prior chemotherapy and with disease
progression following medical or surgical castration are eligible. The
primary endpoint is OS. Secondary endpoints include progression-free
survival (PFS) (PCWG2 criteria), radiologic PFS, tumor response in measurable
disease (RECIST 1.1), PSA response and PSA PFS, pain response and
pain PFS, time to occurrence of any skeletal-related events, safety profile
and health-related quality of life. Cbz pharmacokinetics and pharmacogenomics
will be assessed in pt subgroups. Pts will be treated until
progression, unacceptable toxicity or pt request. Planned enrollment is
1,170 pts; study size was calculated to achieve 90% power for OS. Study
start was in May 2011; at January 2012, 219 pts were enrolled. The first
DMC meeting recommended continuing the study without change.
Genitourinary Cancer
325s
TPS4695 General Poster Session (Board #16F), Sun, 8:00 AM-12:00 PM
A randomized, open-label, phase II study of MDV3100 alone or in
combination with leuprolide and dutasteride as neoadjuvant therapy to
prostatectomy in intermediate and high-risk prostate cancer. Presenting
Author: Robert B. Montgomery, University of Washington School of
Medicine, Seattle, WA
Background: MDV3100 is a potent androgen receptor (AR) signaling
inhibitor (ARSI) that inhibits AR signaling via three mechanisms: inhibition
of androgen binding to AR, inhibition of AR nuclear translocation, and
inhibition of nuclear AR-DNA binding. In vivo, MDV3100 induces significant
prostate cancer apoptosis, an effect not seen with anti-androgens. To
date, the use of neoadjuvant androgen deprivation therapy has not led to an
improvement in time to PSA progression (Soloway 2002; Aus 2002). While
serum androgens may be suppressed using luteinizing hormone-releasing
hormone agonists, intratumoral levels of androgens remain, driving continued
AR signaling and prostate cancer survival. More effective inhibition of
AR signaling may improve local and systemic disease control. Methods:
MDV3100-07 will assess the effect of 6 mos of neoadjuvant AR blockade
with AR inhibition alone (MDV3100) or in combination with maximal
suppression of androgens (MDV3100 �leuprolide [L] � dutasteride [D]).
Eligible patients will have treatment-naive localized prostate cancer and be
candidates for radical prostatectomy. Patients must have either PSA � 10
ng/mL or Gleason score � 7(4� 3) with �3 cores containing tumor.
Patients with evidence of metastatic/nodal disease are excluded. All
patients receive MDV3100 (160 mg/d PO); those randomized to
MDV3100�L�D therapy also receive L (22.5mg IM q3m) and D (0.5
mg/day PO). Serum/tumor androgen levels will be serially assessed. Tissue
from the diagnostic and prostatectomy specimens will be evaluated for
androgen levels, AR signaling profiles, and selected markers of apoptosis
and mitotic indices. The primary efficacy endpoint is pathological complete
response (pCR) rate at time of radical prostatectomy. For each arm, the
percent of patients who achieve a pCR will be compared to the percent pCR
in patients treated with neoadjuvant leuprolide, estimated to be 5% in a
mixed low-to-intermediate risk population. Target Accrual: 40 pts will be
randomized 1:1 to MDV3100 or MDV3100�L�D therapy. Keywords:
MDV3100, prostate cancer, androgen receptor, anti-androgen, Phase 2,
neoadjuvant.
TPS4697 General Poster Session (Board #16H), Sun, 8:00 AM-12:00 PM
A phase II study of the androgen signaling inhibitor ARN-509 in patients
with castration-resistant prostate cancer (CRPC). Presenting Author: Dana
E. Rathkopf, Sidney Kimmel Center for Prostate and Urologic Cancers,
Memorial Sloan-Kettering Cancer Center, New York, NY
Background: ARN-509 is a novel small molecule androgen signaling
inhibitor that impairs AR nuclear translocation and binding to DNA,
inhibiting tumor growth and promoting apoptosis, with no partial agonist
activity. Preclinical data suggests that the maximal therapeutic index of
ARN-509 can be achieved at low steady state plasma levels with minimal
toxicity (Clegg et al, 2012). Enrollment in the Phase 1 dose escalation
study of ARN-509 in patients with progressive CRPC with and without prior
chemotherapy was completed in January 2012. The recommended Phase 2
dose of 240 mg was determined based on safety, PSA kinetics, and
pharmacokinetic and pharmacodynamic analysis (Rathkopf et al, GU
ASCO, 2012). Methods: The primary objective of this Phase 2 study is to
determine the PSA response at 12 weeks according to Prostate Cancer
Working Group 2 (PCWG2) Criteria (Scher et al, 2008). Three expansion
cohorts will enroll a total of 80-90 patients for treatment with 240 mg
continuous oral ARN-509 daily. These cohorts include: 1) non-metastatic
treatment-naïve CRPC (50 patients); 2) chemotherapy-naïve metastatic
(m) CRPC (20 patients); and 3) chemotherapy-naïve, post abiraterone
mCRPC (10-20 patients). The effect of food on the PK of ARN-509 and the
effect of ARN-509 on ventricular repolarization will also be evaluated.
Phase 2 enrollment is ongoing. DOD/PCF PCCTC trial sponsored by Aragon
Pharmaceuticals. NCT01171898.
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