First-Line Randomized Phase 2 Study of
Gemcitabine/Cisplatin plus Apatorsen or Placebo in
Patients with Advanced Bladder Cancer:
The International Borealis-1 Trial
Joaquim Bellmunt, Bernhard Eigl, Elżbieta Senkus, Yohann Loriot,
Przemyslaw Twardowski, Daniel Castellano, Normand Blais, Srikala
S. Sridhar, Cora N. Sternberg, Margitta Retz, Brent Blumenstein,
Cindy Jacobs, Patricia S. Stewart, Daniel Petrylak
Disclosures
Research Support/P.I.
Sanofi –Aventis, Millenium/Takeda, Novartis
Consultant
OncoGenex, Sanofi‐Aventis, Janssen, Dendreon, ImClone, Astellas, Millenium/Takeda, Celgene
Honoraria
Sanofi‐Aventis, Janssen, Dendreon, ImClone
Scientific Advisory Board
OncoGenex, Sanofi‐Aventis, Janssen, Dendreon, ImClone, Astellas, Pfizer, Novartis, Pierre Fabre, Merck, Genentech
Hsp27 (cell survival chaperone protein) Inhibits Apoptosis via Cell
Death and Proteotoxic Stress Pathways Enhancing Pro-survival Pathway
Promotes aggressive tumors and treatment resistance
Extensive preclinical proof of principle studies in GU and
other tumor models
Rocchi P et al. Cancer Res. 2005;65(23):11083-11093;
So A et al. Curr Genomics. 2007;8(4):252-261;
Zoubeidi A et al. Cancer Res. 2010;70(6):2307-2317;
Shiota M et al. Cancer Res. 2013;73(10):3109-3119;
Cornford PA et al. Cancer Res. 2000;60(24):7099-7105.
Background
•
Hsp27: cell survival chaperone protein
– Expression correlates with cancer stage and
grade
– Associated with poor survival prognosis in
numerous cancers
•
Apatorsen (OGX-427): 2nd generation
antisense oligonucleotide (ASO) designed to
inhibit heat shock protein 27 (Hsp27)
•
Inhibition of Hsp27:
– Enhances apoptosis,
– Inhibits EMT and metastasis,
– and sensitizes cancer cells to therapy, including
hormone and chemotherapy
Transcription
Translation
Study Design
Randomized, first-line, placebo-controlled, multinational phase 2 study in
urothelial cancer conducted in 50 centers in 7 countries
Advanced bladder cancer • Chemo‐naive
• Stratified ‐ PS
‐ visceral disease
R
A
N
D
O
M
I
Z
E
D
N = 179
1:1:1
Control (n=61)
• Gemcitabine/cisplatin
• Placebo
Apatorsen 600 mg (n=58)
• Gemcitabine/cisplatin
• Apatorsen 600 mg IV x 3 loading 
600 mg q1w
Apatorsen 1000 mg (n=60)
• Gemcitabine/cisplatin
• Apatorsen 600 mg IV x 3 loading 1000 mg q1w
Endpoints
Primary
• Overall survival*
Secondary
• Safety
• Optimal dose for Phase 3
• Overall response rate
• Disease control rate
• Duration of response, PFS
• Biomarker effects
*Patients were to continue to receive weekly Study Drug maintenance until disease progression or the patient fulfills one of the other reasons for withdrawal (tox, others) Statistical Methods
• Primary endpoint: Overall survival
• A vs B(600mg) or A vs C(1000) (60 vs 60), A vs (B+C) (60 vs 120)
 Specifications applicable to all scenarios:
 Assuming exponential survival distribution, Arm A MST estimated = 14 mo
 Hypothesized hazard ratio = 0.5 (0.65 – 0.71)
 # pts per arm = 60
 One-sided significance criterion for each comparison = 0.05
(overall one-sided alpha = 0.15)
 Target power for each comparison = 90%
 Comparison A vs (B+C) assumes that both comparisons had the same
hazard ratio
Demographics
Gem/Cis + Placebo
n=61
Gem/Cis + Apatorsen 600 mg
n=58
Gem/Cis + Apatorsen 1000 mg
n=60
Median age (yrs) (range)
64
(37‐77)
66
(52‐78)
64
(37‐84)
Age ≥75
6 (10%)
2 (3%)
6 (10%)
Male (%)
52 (85%)
51 (88%)
45 (75%)
Karnofsky ≤80%
23 (38%)
19 (33%)
16 (27%)
Visceral Disease
43 (70%)
33 (57%)
42 (70%)
Liver
23 (38%)
14 (24%)
15 (25%)
Lung
19 (31%)
11 (19%)
14 (23%)
Bone
0 (0%)
1 (2%)
4 (7%) 17 (28%)
20 (34%)
15 (25%)
LN only
Reasons for Discontinuing Study
Therapy
Reason
Gem/Cis
+ Placebo n=61
Gem/Cis + Apatorsen 600 mg
n=58
Gem/Cis + Apatorsen 1000 mg
n=60
Disease progression
43 (70%)
27 (47%)
23 (38%)
Adverse event
2 (3%)
13 (22%)
23 (38%)
Withdrawal
7 (11%)
5 (9%)
6 (10%)
Symptomatic deterioration
1 (2%)
2 (3%)
2 (3%)
Delay > 4 weeks
0 (0%)
0 ()%)
2 (3%)
Death
0 (0%)
1 (2%)
1 (2%) Safety Results:
≥ Grade 3 Nonlaboratory AEs
MedDRA Preferred Term
Any
Hypertension
Pulmonary embolism
Urinary tract infection
Back pain
Sepsis/Urosepsis
Abdominal pain
Decreased appetite
Fatigue
Asthenia
Bone pain
Hematuria
Nausea
Deep vein thrombosis
Diarrhea
Pneumonia
Vomiting
Gem/Cis + Gem/Cis + Gem/Cis + Placebo
Apatorsen 600 mg Apatorsen 1000 mg
n=61 (%)
n=58 (%)
n=60 (%)
54 (89)
7 (11)
8 (13)
2 (3)
2 (3)
2 (3)
1 (2)
1 (2)
4 (7)
2 (3)
1 (2)
0 (0)
1 (2)
0 (0)
3 (5)
3 (5)
2 (3)
54 (93)
12 (21)
7 (12)
2 (3)
3 (5)
5 (9)
4 (7)
3 (5)
1 (2)
3 (5)
2 (3)
1 (2)
1 (2)
3 (5)
2 (3)
3 (5)
2 (3)
58 (95)
10 (17)
4 (7)
9 (15)
7 (12)
2 (3)
2 (3)
3 (5)
4 (7)
1 (2)
2 (3)
3 (5)
3 (5)
0 (0)
1 (2)
0 (0)
1 (2)
Safety Results:
≥ Grade 3
Laboratory
Toxicity
MedDRA Preferred Term
Gem/Cis + Apatorsen 600mg
n=58 (%)
Gem/Cis + Apatorsen
1000 mg
n=60 (%)
Any
Any
47 (77)
50 (86)
53 (88)
Hematology
Any
39 (64)
45 (78)
51 (85)
Neutropenia
Anemia
Thrombocytopenia
Lymphopenia
26 (43)
23 (38)
13 (21)
16 (26)
28 (48)
24 (41)
17 (29)
15 (26)
34 (57)
28 (47)
22 (37)
19 (32)
Any
36 (59)
35 (60)
30 (50)
Hyperuricemia
Hypokalemia
Elevated creatinine
Hypoalbuminemia
Elevated AST or ALT
Hyperbilirubinemia
Hyperkalemia
Hypocalcemia
27 (44)
5 (8)
2 (3)
1 (2)
2 (3)
0 (0)
4 (7)
3 (5)
18 (31)
6 (10)
3 (5)
3 (5)
2 (3)
3 (5)
1 (2)
1 (2)
20 (33)
3 (5)
2 (3)
1 (2)
1 (2)
0 (0)
2 (3)
0 (0)
Serum Chemistry
1000 mg dose:
Early study treatment
discontinuation in 38% of
patients; infusion
reactions in 30% despite
steroid prophylaxis
Gem/Cis + Placebo
n=61 (%)
Overall Efficacy Results
n=61
Gem/Cis +
600 mg Apatorsen
n=58
Gem/Cis + 1000 mg Apatorsen
n=60
Gem/Cis +
600 or 1000 mg Apatorsen
N=118
15.0 mo
15.3 mo
15.6 mo
15.6 mo
Survival HR
0.856 0.898
0.867
Log‐rank p value 0.25
0.32
0.23
7.5 mo
7.5 mo
7.5 mo
PFS HR
0.830
0.927
0.867
Log‐rank p value
0.20
0.37
0.22
57%
50%
53%
Parameter
Median survival Median PFS Response (CR+PR)
Gem/Cis + Placebo
6.2 mo
61%
Survival and PFS by Study Arm
Survival
PFS
Control (n=61)
600 mg (n=58)
1000 mg (n=60)
Control (n=61)
600 mg (n=58)
1000 mg (n=60)
Prognostic Factors in First Line
Multivariate analyses of prognostic factors1 and confirmation using
bootstrap sampling (N=199) showed 9 variables with most
prognostic significance (in order of significance)
Externally confirmed in other series2:
•
•
KPS (≥80% vs <80%) Note: median 80%; range 30-100%
Visceral metastasis (bone, lung, liver)
•
•
•
•
•
•
•
Hemoglobin
Liver metastasis
LDH
Alkaline phosphatase
Lung metastasis
Albumin
Bone metastasis
Prognostic
factors/ OS
Bajorin D1
MVAC
Bellmunt J2
Pac/Cis/Gem
0
33 mo
32.8 mo
1
13.4 mo
17 mo
2
9.3 mo
9.6 mo
Risk factors: KS<80, visceral mets
1Bajorin
D et al. J Clin Oncol. 1999;17:3173-81.
J et al. Cancer. 2003;95:751-7.
2Bellmunt
Statistical Model for Evaluating
Prognostic Risk Factors
•
Prognostic statistical modeling for Survival based on Control Arm only data
– Multiple baseline covariates using proportional hazards regression
– Continuous variables dichotomized at the median
•
Statistical model selected the following baseline covariates:
–
–
–
–
Karnofsky Performance Status (KPS)
Liver involvement
Low hemoglobin
High alkaline phosphatase
•
Coefficients with these 4 prognostic factors used to compute an overall
“statistical model score” (Sms) for each patient
•
Sms evaluated dichotomizing at the overall median for each arm. Patients
classified as “poor” versus “good” prognosis
Good vs Poor Prognosis Using Statistical
Model Score* in Control Arm
Good risk (n=23)
Median 21.9 mo
HR 3.46
Logrank P = 0.0005
Poor risk (n=32)
Median 9.0 mo
*Score based on:
• KPS
• Liver involvement
• Low hemoglobin
• High alkaline phosphatase
n=55 patients with complete baseline data
Additional Analysis in Patients with Poor
Prognosis Disease
• Statistical model score used to explore hypothesis
that Hsp27 inhibition might be relevant to OS in
poor prognosis disease
• Although Control Arm had trend for more poor
prognostic pts (n=32) at baseline, similarly selected
pts in the 600 mg Apatorsen Arm (n=22) showed a
survival benefit (HR = 0.72)
Survival in 600 mg Apatorsen vs Control
Arms by Risk
Good risk
600 mg (n = 31)
Median 22.5 mo
Placebo (n = 23)
Median 21.9 mo
Poor Risk
600 mg (n = 22)
Median 11.9 mo
Placebo (n = 32)
Median 9.0 mo
Good risk: HR = 1.44
Poor risk: HR = 0.72
Survival in 600 mg Apatorsen vs Control
Arms By Most Significant Risk Factor (KPS)
KPS ≥ 90%
600 mg (n = 39)
Median 23.0 mo
Placebo (n = 38)
Median 21.8 mo
KPS ≤ 80%
600 mg (n = 19)
Median 11.9 mo
Placebo (n = 23)
Median 7.8 mo
Karnofsky ≥ 90%: HR = 1.18
Karnofsky ≤ 80%: HR = 0.50
Efficacy Results:
Poor Prognostic Patients*
Parameter
Median survival
Gem/Cis +
Placebo
(n=32)
Gem/Cis +
600 mg Apatorsen
(n=22)
Gem/Cis +
1000 mg Apatorsen
(n=26)
9.0 mo
11.9 mo
10.7 mo
0.770
1.138
21%
36%
12%
4.6 mo
5.6 mo
3.6 mo
0.776
1.098
50%
35%
Survival HR
2 year survival rate
Median PFS
PFS HR
Response (CR+PR)
* Definition of poor risk based on trial
47%
Summary
•
The 600 mg apatorsen dose was more effective than the 1000 mg dose
– 600 mg dose was well tolerated, with similar doses of Gem/Cis compared to placebo
– PFS and survival advantage (HR=0.83 and HR=0.86, respectively)
•
Pts who benefited most with 600 mg apatorsen were pts with poor
prognostic features (lower KPS, liver involvement, high alk phos, lower
hemoglobin), with PFS HR = 0.78 and survival HR = 0.77
– The single most important poor prognostic feature was lower KPS
– Patients with lower KPS in the 600 mg apatorsen arm showed the most survival
benefit, with HR=0.50
•
Biomarker analysis is ongoing ( Hsp27s levels, CLUs and CTCs )
Conclusions
• In this exploratory phase II randomized trial, a trend for OS
and PFS benefit (NS) was seen in patients with poor
prognosis disease treated with first-line Gem/Cis +
apatorsen 600 mg
• Apatorsen may impact the intrinsic biology of patients with
poor risk factors
• Gem/Cis + apatorsen 600 mg merits further evaluation in
patients with urothelial tumors and poor prognostic features
Acknowledgements
•
•
Our patients
Site investigators and their staff
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•
Canada: Normand Blais, Srikala Sridhar, Scott North, Bernhard Eigl, Som Mukherjee, Daniel
Heng , Pawel Zalewski
France: Yohann Loriot, Jean-Christophe Eymard, Frédéric Rolland, Gwenaelle Gravis, Jean-Marc
Ferrero, Bérengère Narciso Raharimanana
Germany: Margitta Retz, Marc-Oliver Grimm, Boris Hadaschik, Martin Schostak, Manfred Wirth,
Christian Thomas, Axel Merseburger, Carsten Ohlman
Italy: Cora Sternberg, Camillo Porta, Fausto Barbieri
Poland: Elzbieta Senkus, Anna Kolodziej, Bogdan Zurawski, Andrzej Wronski, Pawel Wiechno,
Wojciech Rogowski
Spain: Daniel Castellano, Jose Pablo Maroto, Rafael Morales Barrera, Joaquim Bellmunt, Begoña
Mellado, Jose Angel Arranz Arija, Miguel Climent, Xavier Garcia del Muro
United States: Przemyslaw Twardowski, Alexandra Drakaki, Thomas Bradley, Ulka Vaishampayan,
Luke Nordquist, Bruce Roth, Evan Yu, David Quinn, Thomas Hutson, Daniel Petrylak ,Edwin
Posadas
Sponsorship by OncoGenex Pharmaceuticals