The Borealis-2 Clinical Trial

The Borealis-2 Clinical Trial: A Randomized Phase II Study of OGX-427 (Apatorsen) Plus
Docetaxel Versus Docetaxel Alone in Relapsed/Refractory Metastatic Urothelial Cancer:
Hoosier Cancer Research Network GU12-160 (TPS 4577)
T. Choueiri1, N. Hahn2, A. Alva3 , R. Lauer4, R. Dreicer5, J. Picus6, R. Pili7, A. Balar8, G. Sonpavde9,
J. Hoffman-Censits10, E. Guancial11, R. Alter12, M. Regan1, C. Jacobs13, P. Stewart13, S. Pal14, J. Rosenberg15
1Dana-Farber
Cancer Institute, Boston MA, 2Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore MD, 3University of Michigan
Comprehensive Cancer Center, Ann Arbor MI, 4University of New Mexico Cancer Center, Albuquerque NM, 5Cleveland Clinic, Cleveland OH, 6Siteman Cancer Center,
Washington University, St Louis, MO, 7Indiana University Melvin and Bren Simon Cancer Center, Indianapolis IN, 8New York University Cancer Institute, New York NY,
9University of Alabama Comprehensive Cancer Center, Birmingham AL, 10Kimmel Cancer Center, Thomas Jefferson University, Philadelphia PA, 11 Wilmot Cancer
Center, University of Rochester, Rochester NY, 12John Theurer Cancer Center, Hackensack University Medical Center, Hackensack NJ, 13OncoGenex Pharmaceuticals,
Inc., Bothell WA, 14City of Hope Comprehensive Cancer Center, Duarte CA, 15Memorial Sloan-Kettering Cancer Center, New York NY
ABSTRACT
Background: Heat shock protein 27 (Hsp27) is overexpressed in many cancers including bladder, lung,
prostate, and breast. Increased Hsp27 has been
associated with inhibition of chemotherapy-induced
apoptosis, increased tumor cytoprotection, and
development of treatment resistance. OGX-427
(apatorsen) is an antisense oligonucleotide designed to
bind Hsp27 mRNA, inhibiting production of the Hsp27
protein. Inhibition of Hsp27 has been shown to increase
apoptosis, inhibit tumor growth, and sensitize tumor
cells to chemotherapy in a variety of malignancies,
including urothelial cancer. Results of preclinical and
phase 1 studies suggest that addition of apatorsen to
chemotherapy is well tolerated and may improve
treatment efficacy. Borealis-2 is a randomized,
multicenter, phase 2 study of apatorsen in combination
with docetaxel (DOC) vs. DOC alone in locally
advanced/metastatic bladder cancer patients who
received at least one line of prior platinum-based
therapy. The primary objective is to evaluate overall
survival. Secondary objectives include comparisons of
safety and tolerability, disease response, serum levels
of Hsp27 and other pathway-related proteins.
Associations between clinical outcomes, levels of Hsp27
and other proteins, and circulating tumor cells will be
evaluated. Methods: Patients (N=200) are randomized
in a 1:1 ratio following stratification (time from prior
systemic chemotherapy; Bellmunt criteria). Up to 2
prior systemic therapies are allowed. Treatment-arm
patients receive three loading doses of apatorsen (600
mg) followed by up to ten 21-day treatment cycles
(apatorsen on Days 1, 8, and 15 and DOC 75 mg/m2 IV
on Day 1). Control-arm patients receive DOC 75 mg/m2
IV on Day 1 of each cycle. Treatment may continue until
disease progression, unacceptable toxicity, completion
of ten cycles, or patient withdrawal. Patients who
discontinue DOC due to toxicity after ≥2 cycles and do
not have disease progression may receive maintenance
therapy with apatorsen. One interim futility analysis will
be performed. The trial will not be stopped early based
on efficacy.
INTRODUCTION
 Current treatments for urothelial carcinoma
have limited success in preventing tumor
recurrence and/or progression, and overall
mortality rates have remained fairly constant.
 Apatorsen, a second generation antisense
oligonucleotide (ASO) that inhibits expression of
Hsp27, which has been shown to increase
apoptosis, inhibit tumor growth, and sensitize
tumor cells to chemotherapy in a variety of
malignancies, including urothelial cancer.
 This open label, randomized phase 2 study will
evaluate whether suppression of Hsp27
production when with apatorsen in combination
with docetaxel can prolong survival time
compared to docetaxel alone in this patient
population.
OBJECTIVES
DESIGN
Study Opened April 2013
175 of 200 Patients Enrolled
PRIMARY:
 Ascertain whether docetaxel administered in
combination with apatorsen improves survival
compared to docetaxel alone
SECONDARY:
 Compare the safety and tolerability of
apatorsen in combination with docetaxel to
that of docetaxel alone
 Compare overall response rate (ORR) and
progression-free survival (PFS) rates between
the arms
SCREEN & STRATIFY ELIGIBLE PATIENTS:
 Time from prior systemic chemotherapy
 Bellmunt criteria1
RANDOMIZATION
N=200
Experimental Arm
(Arm A):
 Evaluate the effect of therapy on peripheral
blood circulating tumor cells (CTC)
Apatorsen: Starting within
5 days of randomization, 3
loading doses at 600 mg IV
days -9 to -1,
followed by weekly doses
 Age > 18 years

ECOG Performance Status 0 or 1

Histologically documented metastatic or
inoperable, locally-advanced urothelial
carcinoma
 Measurable disease with lesion(s) that can be
accurately measured in at least one
dimension by RECIST v1.1 criteria
 Must have received prior systemic platinumbased chemotherapy for urothelial carcinoma
Docetaxel: 75 mg/m2 IV
every 21 days
Control Arm (Arm B):
Docetaxel: Starting within
5 days of randomization,
75 mg/m2 IV
every 21 days
Maximum of 10 docetaxel
cycles
ALABAMA
University of Alabama Comprehensive Cancer Center, Birmingham
INDIANA
Indiana University Melvin and Bren Simon Cancer Center, Indianapolis
IU Health Ball Memorial Hospital, Muncie
IU Health Central Indiana Cancer Centers, Indianapolis
IU Health Goshen Hospital, Goshen
MASSACHUSETTS
Dana-Farber Cancer Institute, Boston
MICHIGAN
University of Michigan Comprehensive Cancer Center, Ann Arbor
MISSOURI
Washington University, Siteman Cancer Center, St. Louis
NEBRASKA
Nebraska Cancer Specialists, Omaha
NEW HAMPSHIRE
Dartmouth-Hitchcock Medical Center, Lebanon
NEW JERSEY
John Theurer Cancer Center, Hackensack University, Hackensack
Rutgers Cancer Institute of New Jersey, New Brunswick
NEW MEXICO
Memorial Medical Center, Las Cruces
University of New Mexico Cancer Center, Albuquerque
Maximum of 10 docetaxel
cycles
NEW YORK
Memorial Sloan-Kettering Cancer Center, New York
New York University Cancer Institute, New York
Roswell Park Cancer Institute, Buffalo
Wilmot Cancer Center, University of Rochester, Rochester
OHIO
Cleveland Clinic, Cleveland
Seidman Cancer Center, University Hospitals, Cleveland
Apatorsen Maintenance:
weekly doses
until disease progression
PENNSYLVANIA
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia
SOUTH CAROLINA
Hollings Cancer Center, Medical University of South Carolina,
Charleston
WISCONSIN
Froedtert & The Medical College of Wisconsin, Milwaukee
FOLLOW FOR SURVIVAL
METHODS
Patients will be randomized with equal
probability to one of two arms, designated
as the Experimental Arm (A) and the
Control Arm (B).
AVAILABLE SITES
MARYLAND
Sidney Kimmel Comprehensive Cancer Center at
Johns Hopkins University, Baltimore
University of Maryland Greenebaum Cancer Center, Baltimore
 Evaluate the association of urothelial
carcinoma expression of Hsp27 measured by
IHC in archival tissue
ELIGIBILITY CRITERIA
As of May 21, 2015
CALIFORNIA
City of Hope Comprehensive Cancer Center, Duarte
UCLA Jonsson Comprehensive Cancer Center, Los Angeles
USC Norris Comprehensive Cancer Center, Los Angeles
 Evaluate the effect of therapy with docetaxel
and apatorsen on serum Hsp27 levels and
other serum proteins
 Isolate tumor and germ-line DNA to allow
future investigations to determine if somatic
mutations are associated with treatment
outcome
ACCRUAL STATUS
1. Bellmunt et al. J Clin Oncol. 2010 Apr 10;28(11):1850-5.
CONTACT INFORMATION
Hoosier Cancer Research Network
500 N. Meridian Street, Suite 100
Indianapolis, IN 46204
317.921.2050
www.hoosiercancer.org
OncoGenex Pharmaceuticals, Inc.
19820 North Creek Parkway, Suite 201
Bothell, WA 98011
425.686.1500
www.oncogenex.com
First Author:
Toni Choueiri, MD: [email protected]
CLINICALTRIALS.GOV
IDENTIFIER
NCT01780545
This research is supported by OncoGenex
Technologies Inc. The Borealis-2TM trial is part
of OncoGenex’s ORCA (Ongoing studies
evaluating treatment Resistance in CAncer)
program encompassing clinical trials of
apatorsen. For more information, please visit
www.orcatrials.com
ASCO JUNE 2015