Transcript Document

The Prostate Net Prostate Cancer Symposium
Inaugural Meeting
New York City
October 6, 2009
Emerging Treatments on the Horizon
Celestia S. Higano MD, FACP
Professor
Medicine and Urology
University of Washington
Member, Fred Hutchison Cancer Research Center
Many Potential New Therapeutic
Agents on the Horizon
 AR targeted hormonal therapy
–
Abiraterone
– MDV3100
 Immunotherapy
–
Provenge
– Ipilimumab
 Other emerging therapies
Prostate Cancer Clinical Disease States
Clinically
Localized
Disease
Rising
PSA
Clinical
Metastases:
Hormone
sensitive
Rising PSA:
Castration
resistant
Scher H et al. PCWG2. J Clin Oncol. 2008; 26:1148-59.
Clinical
Metastases:
Castration
resistant
Pre-chemo
Clinical
Metastases:
Castration
resistant
1st Line
Docetaxel
Clinical
Metastases:
Castration
resistant
Sipuleucel-T (Provenge®)
Dendritic Cell Vaccine
 Leukapheresis
 Culture
Tumor specific antigen
 Infusion
Dendritic cell
~ 40 hours
Antigen
Loading
Precursor
APC
In vivo
T cell
activation
Dendritic
cell
Antigen
Processing
Antigen-loaded APC
T cells
attack
tumor cells
Phase III IMPACT Trial
P
R
O
G
R
E
S
S
I
O
N
Treated at
Physician
discretion
SipuleucelAsymptomatic
T
or Minimally
Q 2 weeks
Symptomatic
2:1
x3
Metastatic
Treated at
Castrate
Physician
Placebo
discretion
Resistant
and/or Salvage
Q 2 weeks
Prostate
Protocol
3
x
Cancer
(N=512)
PrimaryPreendpoint:
Overall Survival
chemotherapy
Secondary
endpoint:
Time to Objective Disease Progression
S
U
R
V
I
V
A
L
IMPACT Overall Survival
Percent Survival
100
P = 0.032 (Cox model)
HR = 0.775 [95% CI: 0.614, 0.979]
Median Survival Benefit = 4.1 Mos.
75
Sipuleucel-T (n = 341)
Median Survival: 25.8
Mos.
50
25
0
0
Placebo (n = 171)
Median Survival: 21.7 Mos.
6
12 18 24 30 36 42 48 54 60 66
Survival (months)
Schellhammer, Higano, Berger et al, AUA Annual Meeting 2009.
Toxicity
 Chills
 Fever
 Headache
Issue Surrounding Sipuleucel-T
for FDA Review
Pros
Cons
 Overall survival benefit
 No improvement of TTP
 Consistent data
 No pain palliative data
compared across
studies
 Favorable toxicity profile
 Strong demand from
patients
 No effect on PSA
 Administration issues
 Cost
 Other issues
CTLA-4 Blockade Activates Antigen
Specific T-Cell Responses
1. Co-stimulation via CD28
ligation transduces T cell
activating signals
2. CTLA-4 ligation on activated
T cells down-regulates T cell
responses
T cell Activation
T cell
3. Blocking CTLA-4 ligation
enhances T cell responses
T cell Inactivation
T cell Activation
T cell
T cell
CTLA-4
CTLA-4
TCR
MHC
TCR
CD28
B7
MHC
CTLA-4
TCR
MHC
CD28
CD28
B7
Anti-CTLA4
mAb
APC
APC
APC
Ipilimumab (Anti-CTLA 4 antibody)
 Phase II Ipi alone and with single dose
radiation
 Phase III trial
 Ipi and GVAX
Radiation promotes cross-presentation
of tumor associated antigens
Anti-CTLA4
mAb
CTLA4
Anti-CTLA4
mAb
CTLA4
Modified after: Demaria, et al, Int. J. Radiation Oncology Biol. Phys., Vol. 63, No. 3, pp. 655–666, 2005
Ipilimumab Phase II
1st Treatment Cycle
Dosing q 3wk x 4
Screening
Follow Up or Additional
Treatment Cycle(s);
Assessments q 3 mos
XRT
-28
-2
1
IPI
22
IPI
43
IPI
64
IPI
421 (Days)
(14 months)
Or until PD
85
Cohort 1
Mono
Cohort 2
XRT in NoCHEMO
Cohort 3
XRT in CHEMO
10 mg/kg IPI
XRT + 10 mg/kg IPI
Chemo naïve
n = 16
XRT + 10 mg/kg IPI
Chemo experienced
n = 18
n =16
Slovin, Beer, Higano et al GU ASCO 2009
Immune-Related Adverse Events
Mono
N=16
ALL
XRT in NoCHEMO
N=16
≥ G3
Skin
9 (56.3%)
GI
12 (75%)
6 (37.5%)
Liver or
Abnormal LFTs
4 (25.0%)
3 (18.9%)
Endocrine
4 (25.0%)
ALL
XRT in CHEMO
N=18
>= ≥ G3
ALL
≥ G3
2 (12.5%)
4 (22.2%)
3 (16.7%)
3 (16.7%)
2 (11.1%)
4 (25.0%)
4 (25.0%)
2 (12.5%)
* Subjects are only counted once in each AE category.
Best PSA Changes: Each Subject
Best PSA Change from Baseline (%)
100.00
50.00
0.00
-50.00
-100.00
Mono
XRT in NoCHEMO
XRT in CHEMO
Summary of Objective Responses
Treatment
Group**
RECIST Response
SD
5
(45.5%)
PR*
1
(9.1%)
CR
1
(9.1%)
XRT in NoCHEMO
N=13
SD
11
(84.6%)
XRT in CHEMO
N=6
SD
3
(50%)
10 mg/kg
monotherapy
N=11
*Not confirmed
** Patients with measurable disease
Phase III Trial of Radiation plus
Placebo or Ipilimumab
 Must have received prior docetaxel
 No more than 2 prior chemotherapy regimens
 At least one bone lesion that has not been
irradiated
 Not eligible
–
Men with auto-immune diseases
– Prior treatment with strontium or samarium
Where is immunotherapy going?
 Provenge likely to be approved
–
Who should get it?
 GVAX is dead for now
–
Survival data for Vital 1 in progress in
Seattle
 Ipililumab just starting phase III
–
Can this type of agent be used in the
community?
– Stand by…
ZD4054: a specific-ETAR antagonist
ET-1
ETAR
ET-1
ETBR
Vasodilatation
Metastasis
Apoptosis
Disease progression
Clearance of ET-1
Angiogenesis
Osteoblast stimulation
ZD4054 specifically
blocks ETAR, with no detectable activity at ETBR
Invasion
Morris CD et al. Br J Cancer 2005;92:2148–2152
Randomized Phase II Trial
Overall Survival
1.0
Proportion of patients alive
0.9
0.8
0.7
0.6
ZD4054 15 mg versus placebo: HR=0.65
80%CI=(0.49, 0.86); P=0.052
0.5
ZD4054 10 mg versus placebo: HR=0.55
80%CI=(0.41, 0.73); P=0.008
0.4
ZD4054
0.3
0.2
0.1
ITT population
15 mg
n=98
10 mg
n=107
Placebo
n=107
Number of deaths, n
Median OS, months
Chemotherapy use*, n (%)
34
23.5
27 (28)
33
24.5
28 (26)
51
17.3
25 (23)
Placebo
ZD4054 15mg
ZD4054 10mg
0.0
0
50 100 150 200 250 300 350 400 450 500 550 600 650
Time to death (days)
*Patients receiving chemotherapy, including docetaxel after trial entry,
700 750 800 850
Enthuse Phase III Trials
 Non-metastatic CRPC
–
531 of 1500
 Asymptomatic metastatic CRPC
–
Fully accrued, n=580
– Results Q2 2010, 2011 ASCO
 Symptomatic metastatic CRPC
–
591 of 1044
Other On-going Phase III Trials in CRPC
 CALGB docetaxel +/- bevacizumab (Avastin®)
–
Results 2010 ASCO
 SWOG docetaxel +/- atrasentan
–
694 of 930 accrued
 Docetaxel +/- VEGF Trap
–
800 of 1200 accrued
 Docetaxel +/- ZD 4054
–
591 of 1044
Take Home Messages
 More active drugs
 Many on-going and planned registration trials
 Lots of potential!
 Need patient participation to make progress!
ARS
Ipilimumab and GVAX
Patient 12 (5 mg/kg)
Baseline
Gerritsen et al ASCO 2006
3 months
Patient 8
Bone Scan Improvement
Patient 8 (3 mg/kg)
Baseline
6 Months
GVAX Cellular Vaccine
LNCaP
PC3
DC
Ward et al. Cancer Immunol Immunother. 2002:51:351.
Antigenloaded DC
GVAX Proposed Mechanism of Action
CD8 T Cell
GM-CSF
LNCaP
/ PC-3
cells
Antigen
Antigen(s)
Lymphatics
Dendritic cell
CD4 T Cell
Lymph Node
Skin
TUMOR
Antibodies
CTLS
B CELLS
IFN
γ
GVAX Immunotherapy
 6 injections each leg or arm
(12 injections each time)
 Treatments every 3 weeks
 Injection site redness and
itching
Data on file, Cell Genesys, Inc.
GVAX Phase III Trials
 Vital 1
 Vital 2
Phase III Vital 2 Trial
•
•
•


R
Symptomatic
A
GVAX prostate* q21d +
metastatic
N
docetaxel 75 mg/m2 q21d
HRPC
D
1 prior
N=600 O
chemotherapy
M
permitted
Docetaxel 75 mg/m2 q21d +
I
No prior
prednisone 10 mg/d
Z
taxanes
E
Primary end point: Overall survival
Secondary end points: Time to radiologic progression,
time to progression of pain
Closed Aug 2008 by DSMB for excessive deaths
in experimental arm, 67 vs 47
Phase III Vital 1 Trial
R
A
GVAX prostate q14d*
• Asymptomati
N
c metastatic
D
N=60
Trial enrolled 627 patients
HRPC
O
0
• No prior
M
chemotherapy
I Docetaxel 75 mg/m2 q21d +
Z
prednisone 10 mg/d
E
 Primary end point: Overall survival
 Secondary end points: Bone related events,
progression of bone metastases, time to onset of
Terminated
in October 2008 based on futility analysis showing
bone pain
that the trial had less than a 30 percent chance of meeting its
Vital 1 Kaplan-Meier Estimates of Survival
Analysis Stratified by Randomization Factors (ECOG, Gleason Score, and Alkaline Phos.)
Intent-to-Treat Population
(n=621)
1.0-
Arm D+P
Arm G
0.9-
p=0.9422 (log-rank test)
HR=1.01 [95% CI: 0.82, 1.24]
0.8-
Probability of Survival
censored
censored
0.70.60.50.40.391 weeks
0.20.10.0-
Weeks
0
22
44
66
88
No. of Pts
D+P
310
G
311
288
287
258
240
188
176
112
109
Higano et al GU ASCO 2009
110 132
53
64
28
36
154
16
16
176 198
8
10
1
0
220
0
0
Vital 1 Kaplan-Meier Estimates of Survival
Analysis Stratified by Randomization Factors (ECOG, Gleason Score, and Alkaline Phos.)
Patients with a Halabi Predicted Survival Time of ≥18 months
(n=264)
1.0Arm D+P
Arm G
0.9-
Probability of Survival
0.8-
censored
censored
HR= 0.90 [95% CI: 0.61,1.33]
0.70.60.50.4-
0.3-
92 weeks
0.20.10.0ɩ
0
Higano et al GU ASCO 2009
ɩ
22
ɩ
44
ɩ
66
ɩ
ɩ
ɩ
ɩ
ɩ
ɩ
ɩ
88 110 132 154 176 198 220
Vital 1 Kaplan-Meier Estimates of Survival
Analysis Stratified by Randomization Factors (ECOG, Gleason Score, and Alkaline Phos.)
Patients with a Halabi Predicted Survival Time of <18 months
(n=357)
1.0-
Arm D+P
Arm G
0.9Probability of Survival
0.8-
censored
censored
HR= 1.15 [95% CI: 0.88,1.51]
0.70.60.50.40.30.20.1-
97 weeks
0.0ɩ
0
Higano et al GU ASCO 2009
ɩ
22
ɩ
44
ɩ
66
ɩ
ɩ
ɩ
ɩ
ɩ
ɩ
ɩ
88 110 132 154 176 198 220
The Prostate Net Prostate Cancer Symposium
Inaugural Meeting
New York City
October 6, 2009
Emerging Treatments on the Horizon
Celestia S. Higano MD, FACP
Professor
Medicine and Urology
University of Washington
Member, Fred Hutchison Cancer Research Center
Emerging Treatment Protocols
Eric Klein, MD
Phase III Chemoprevention Trials
RRR = 22.5%
PCPT
RRR = 23.5%
REDUCE
Prevention: What I Tell Patients
• Low calorie diet
• Exercise
• Vitamin E and Selenium don’t work
• Data on other dietary changes and supplements not proven
• 5-alpha reductase inhibitors are safe and effective, and
the only intervention supported by results of Phase III
controlled trials
5ARIs for Biochemical Recurrence
Andriole et al, Urology 45:491, 1995
ARTS Study Design
Multicenter, randomized, double-blind,
placebo-controlled trial (n=276)
Screening
Randomization
-3
0
weeks
Baseline
Negative bone scan
PSA
nadir
End of
treatment
Treatment period 2 years
Follow-up
Placebo
Avodart (dutasteride) 0.5mg/day
3
6
9
12
15
Months
18
21
24 +4
months
ARTS Endpoints
• Time to PSA doubling (primary)
• Time to disease progression and percentage of patients with disease progression
• Percentage of patients with treatment response (any PSA decrease or an increase 15%)
• Changes in PSA including:
– Time to PSA rise and percentage of patients with a PSA rise
– Time to PSA progression and percentage of patients with PSA progression
– Absolute and percentage PSA change from baseline and nadir PSA
• Changes in PSA doubling time during treatment
• Disease-related patient anxiety (MAX-PC)
• Safety outcomes