Download Sipuleucel-T - Mediterranean School Of Oncology

Mediterranean School of
Oncology, 15 june. Rome
New immunomodulatory therapies
in prostate cancer
G. Di Lorenzo
Oncologia
AOU Federico II
Napoli
1. Growing scientific literature
2. Results (in terms of efficacy)
3. Several ongoing studies
Vaccines: We know
WE DON’T KNOW
1. it works in all patients
1. Sipuleucel and Poxvirus vaccine:
on immune
system
2. action
Correct
end-points
2. Efficacy (in a subset of patients)
3. Markers of responses
3. Safety of SIP. and POX. agents
4. Combinations with other agents
(CT, RT, OT, targeted therapy)
Nat Rev Immmunol 2010 Aug
Advances in basic immunologic
Immunoregulatory pathways
Proapoptotic stimuli (radiation, chemotherapy) trigger apoptosis of tumor cells and phagocytosis by
antigen-presenting dendritic cells (DCs). Tumor-associated antigens (TAA) are processed and presented by
major histocompatibility complex (MHC) class II molecules on the DC surface to naïve CD4helper T cells
(TH0). A subset of peptides is also delivered into the cytoplasm of DCs and “cross-presented” by MHC class
I molecules to CD8T cells. If the DCs are sufficiently activated, they upregulate costimulatory B7
(CD80,CD86) and the CD40 receptor. If a cognate T cell exists, it is activated by the combination of MHCpeptide and costimulation, leading to upregulation of CD40L, which provides a retrograde signal for
optimum activation of DCs. Fully activated or “licensed” DCs make TH1 polarizing cytokines, like
interleukin (IL)-12, which drive differentiation to the TH1 cytokine-producing pathway. Subsequently,
activated DCs can activate TAA-specific CD8T cells, which proliferate and differentiate into cytotoxic T
lymphocytes. Insufficient DC activation can lead to polarization of helper TH2 cells (which favors
Tumor
humoral immunity, ie, B cells) and expansion of inhibitory regulatory Treg cells. IFN, interferon; TGF,
transforming growth factor.
Central role of Dendritic Cells
Apoptosis
IFNg
IFNg
NK
DC
CD40
CD40L
IL-12
B7
CD28
THO
MHC
TAA
IL-6
TGFb1
IL-4,
IL-10
TH1
IL-2
IFNg
Treg
TH2
CD8+
CTL
CD28-B7,
4-1BB-4-1BBL
DC
IL-4
B
Recent Frontline Randomized Trials of Vaccines for CRPC
Institution
(Trial)
Multicenter
(IMPACT or
D9902B)
Multicenter
(VITAL-1)
Population
Standard
Arm
Experimental Arm
Results
Asymptomatic
metastatic
chemonaïve CRPC
Placebo
Sipuleucel-T
Improved overall
survival with
vaccine
Asymptomatic metastatic
chemonaïve CRPC
Docetaxel +
prednisone
GVAX
Closed prior to
completion for
futility
chemonaïve CRPC
prednisone
29 april 2010: FDA approved sipuleucel for
Closed after interim
CRPC asymptomatic
or
minimally symptomatic
Multicenter
Symptomatic metastatic
Docetaxel +
analysis showed
(VITAL-2)
Multicenter
phase II
randomized
trial
Asymptomatic
metastatic
chemonaïve CRPC
Placebo
GVAX + docetaxel
Prostvac +
co-stimulatory
molecules
CRPC, castration-resistant prostate cancer; ECOG, European Cooperative Oncology Group;
GM-CSF, granulocyte-macrophage colony-stimulating factor.
GVAX is manufactured by BioSante Pharmaceuticals, Lincolnshire, IL.
higher death rate in
combin. arm
Improved
survival with
vaccine
NEW TARGETS IN CRPC CRPC
Sipuleucel-T (Provenge)
sipuleucel-T is an autologous active
cellular immunotherapy that activates the
immune system against prostate cancer
Sipuleucel-T: Patient-Specific Therapy
Day 1
Leukapheresis
Day 2-3
sipuleucel-T is
manufactured
Day 3-4
Patient infused
Apheresis Center
Dendreon
Doctor’s Office
COMPLETE COURSE OF THERAPY:
Weeks 0, 2, 4
SIPULEUCEL
Eravamo nel 2006 !!!
IMPACT STUDY
Randomized Phase 3 IMPACT Trial
(Immunotherapy Prostate AdenoCarcinoma Treatment)
Asymptomatic or
Minimally
Symptomatic
Metastatic
Castrate
Resistant
Prostate Cancer
(N=512)
Primary endpoint:
Secondary endpoint:
Sipuleucel-T
Q 2 weeks x 3
2:1
Placebo
Q 2 weeks x 3
P
R
O
G
R
E
S
S
I
O
N
Treated at
Physician
discretion
Treated at
Physician
discreation
and/or Salvage
Protocol
Overall Survival
Time to objective Disease Progression
S
U
R
V
I
V
A
L
Eligibility Criteria
● Metastatic androgen independent prostate cancer
● Life expectancy of at least 6 months
● Serum PSA  5.0 ng/mL
● Castate level of testosterone (<50 ng/dL) achieved
via medical or surgical castration
● Adequate hematologic, renal, and liver function
● Negative serology for HIV 1 & 2, HTLV-1, and
Hepatitis B & C
Statistical Analysis Plan
● Stratification Factors
 Bisphosphonate use
 Primary Gleason Score
 Number of bone metastases
● Analyses
 Interim: one
 Final: p<0.043 required for statistical significance
Patient Demographics and Baseline
Characteristics
Sipuleucel-T
(N = 341)
Placebo
(N = 171)
72 (49-91)
70 (40-89)
Race, white (%)
89.4
91.2
ECOG status, 0 (%)
82.1
81.3
Gleason Score ≤ 7 (%)
75.4
75.4
Bone only (%)
50.7
43.3
Soft tissue only (%)
7.0
8.2
Bone & soft tissue (%)
41.9
48.5
> 10 bone mets (%)
42.8
42.7
Bisphosphonate use
48.1
48.0
Prior docetaxel (%)
15.5
12.3
Age, median yrs (range)
Disease localization
Baseline Median Laboratory Values
Sipuleucel-T
(N = 341)
Placebo
(N = 171)
Serum PSA, ng/mL
51.7
47.2
Serum PAP, U/L
2.7
3.2
Alk, Phosphatase, U/L
99.0
109.0
Hemoglobin, g/dL
12.9
12.7
LDH, U/L
194.0
193.0
6.2
6.0
WBC, 103/mL
IMPACT Overall Survival: Primary Endpoint Intentto-Treat Population
100
P = 0.02 (Cox model)
HR = 0.78 [95% Cl: 0.61-0.98)
Median Survival Benefit = 4.1 Mos.
Percent Survival
75
Sipuleucel-T (n= 341)
Median Survival: 25.8
50
Mos.
25
Placebo (n= 171)
Median Survival: 21.7 Mos.
0
0
6
12
18
24
30
36
42
Survival (Months)
48
54
60
66
Overall Survival Summary
% Survival (K-M estimates)
24 Mos.
36 Mos.
48 Mos.
Sipuleucel-T
52.1
31.7
20.5
Placebo
41.2
23.0
16.0
Survival Consistency Between Population Subsets
Favors sipuleucel-T
Bisphosphonate Use: Yes
No
Primary Gleason Grade:  4
≤3
No. Bone Metastases: > 10
≤ 10
Disease Localization: Single
Bone + Soft Tissue
ECOG Performance Status: 1
0
Age: Above Median
Below Median
PSA: Above Median
Below Median
LDH: Above Median
Below Median
Alkaline Phos: Above Median
Below Median
Hemoglobin: Above Median
Below Median
0.0
0.5
1.0
1.5
Hazard Ratio (95% Confidence Interval)
Survival Results Confirmed by Multiple Sensitivity
Analyses
Favors sipuleucel-T
Primary Model (Adj. for PSA, LDH)
Unadjuste/Log Rank
Adjusted for Docetaxel Use and Timing
PCa-Specific Survival
0.0
0.78
P = 0.032
0.77
P = 0.023
0.78
P = 0.036
0.77
P = 0.036
0.5
1.0
Hazard Ratio (95% Confidence Interval)
1.5
Following Therapy after study treatment
Effect after
docetaxel
censoring
Time to Objective Disease Progression
● Secondary endpoint
● Results
 Independent radiologic review
 HR = 0.951 (95% CI: 0.77, 1.17); P = 0.628
(log rank)
● Consistent with other trials in advanced prostate
cancer
Most Common Adverse Events ( 5%) Higher Rate in
Sipuleucel-T (≤ 0.05)
Sipuleucel-T
(N = 338)
Placebo
(N = 168)
%
%
Chills
54.1
12.5
Pyrexia
29.3
13.7
Headache
16.0
4.8
Influenza-like illness
9.8
3.6
Hypertension
7.4
3.0
Hyperhidrosis
5.3
0.6
Prefered Term
Serious Adverse Events*
Safety Population
SAE Prefered Term
Prefered Term
Any SAE
Pyrexia
Cerebrovascular accident
Pulmonary embolism
Spinal cord compression
Nausea
Atrial fibrillation
Dehydration
Cardiac failure congestive
Pneumonia
Hematuria
Deep vein thrombosis
Renal failure acute
* Occurring in  4 patients.
Sipuleucel-T
(N = 338)
Placebo
(N = 168)
%
24.0
1.8
1.8
1.2
1.2
0.9
0.9
0.9
0.6
0.6
0.6
0.3
0.3
%
23.8
0.6
1.8
0.0
1.2
0.6
0.6
0.6
1.2
1.2
1.2
1.8
2.4
Consistency Across Phase 3 Studies
D9901*
(N = 127)
D9902A*
(N = 98)
IMPACT**
(N = 512)
Integrated**
(N = 737)
0.586
0.786
0.775
0.735
p = 0.010
p = 0.331
p = 0.032
p < 0.001
4.5
3.3
4.1
3.9
sipuleucel-T
34%
32%
32%
33%
placebo
11%
21%
23%
20%
Hazard Ratio
p-value
Median Survival Benefit
(months)
36-Month suvival (%)
* Unadjusted Cox model & log rank
** Cox model adjusted for PSA and LDH
Summary
● First active immunotherapy to demonstrate
improvement in overall survival for advanced
prostate cancer
● Highly favorable benefit to risk profile
● Short duration on therapy
● Potential to create new treatment paradigm in
oncology
Major concerns on sipuleucel
• Little RR or PSA decline (3%)
(how it correlates with OS?)
•Price
( 93000 dollars for 3 administrations)
•Efficacy in subset of patients
•(active in all patients?)
•Adjuvant and neoadjuvant setting?
Good news for US patients !!!
30 march 2011:
MEDICARE DECIDE TO PAY FOR PROVENGE
GVAX immunotherapy
GVAX trials
Agent
Description of trial
Prostate
GVAX
Dose escalation of
prostate GVAX in men
with CRPC
Prostate
GVAX
VITAL-1
Open-label,
randomized trial
comparing prostate
GVAX with docetaxel
chemotherapy in men
with asymptomatic
metastatic CRPC
Prostate
GVAX
VITAL-2
Open-label randomized
trial comparing
GVAX+docetaxel vs
Docetaxel in men with
symptomatic
metastatic CRPC
Number of
subjects
80
Phase II
621
Phase III
114 (600
planned)
Status
Clinical results
Completed
Increased
antibody response
to vaccine cell
lines;
well tolerated;
defined dose or
schedule for
Phase III
Closed
Closed after
interim analysis
that showed
inferiority of
experimental arm
Halted
Imbalance of
deaths in
combined
treatment group
(67 vs 47)
Poxvirus immunotherapy
Overall Survival Analysis of a Phase II Randomized
Controlled Trial of a Poxviral-Based PSA-Targeted
Immunotherapy in Metastatic Castration-Resistant
Prostate Cancer
Philip W. Kantoff, Thomas J. Schuetz, Brent A. Blumenstein,
L. Michael Glode, David L. Bilhartz, Michael Wyand, Kelledy Manson,
Dennis L. Panicali, Reiner Laus, Jeffrey Schlom, William L. Dahut,
Philip M. Arlen, James L. Gulley, and Wayne R. Godfrey
Progression-Free Survival (%)
Primary endpoint is progression-free survival
100
Hazard Ratio = 0.88 (95% CI, 0.57 to 1.38)
80
60
40
N
20
Control
PROSTVAC
40
82
Events Median
30
58
3.7
3.8
0
0
1
2
3
4
Survival (Months)
5
6
Overall Survival
overall Survival (%)
100
Hazard Ratio = 0.56 (95% CI, 0.37 to 0.85)
N
80
Control
PROSTVAC
40
82
Deaths Median
37
65
16.6
25.1
60
40
20
0
0
12
24
36
Time (Months)
48
60
Common Adverse Events
PROSTVAC-VF
(n=82)
Adverse Event
Injection site reactions
Erythema
Pain
Swelling
Pruritus
Induration
General disorders
Fatigue
Pyrexia
Peripheral edema
Chills
GI disorders
Constipation
Diarrhea
Nausea
Muscoloskeletal and
connective tissue disorders
Arthralgia
Nervous system disorders
Dizziness
Placebo
(n=40)
No. of
Patients
%
No. of
Patients
%
48
29
23
17
10
58.5
35.4
28.0
20.7
12.2
22
14
5
4
6
55.0
35.0
12.5
10.0
15.0
35
15
11
12
42.7
18.3
13.4
14.6
8
6
4
1
20.0
15.0
10.0
2.5
9
7
17
11.0
8.5
20.7
6
6
2
15.0
15.0
5.0
10
12.2
10
25.0
10
12.2
3
7.5
NOTE. At each level of patient summarization, a patient is counted only once if the patient reported one or more events. Adverse
events are coded according to the Medical Dictionary for Regulatory Activities Version 6.0.
Abbreviation: PROSTVAC-VF, a vaccine containing two recombinant viral vectors (vaccinia and fowlpox) and three immune
costimulatory molecules (B7.1, ICAM-1, and LFA3).
Open questions and considerations on vaccinetherapy
• Prostate cancer is not one disease (hormone sensitive and
castration-resistant)
• PSA kinetics and the apparent disconnect between response
proportion or TTP and survival
• Measurement of immune response with vaccines
Open questions and considerations
• End-points and patients selection
• Combination therapies
Open questions and considerations
•
Prostate cancer is not one disease:
1. The present studies define the target
population (no visceral metastases, no severe
pain, Gleason less of 7, ECOG 0-1) but limited
the ability to generalize these results
Open questions and considerations
•
PSA kinetics and the apparent disconnect between
response proportion or TTP and survival:
1. No PSA response (early increase of PSA)
2. No TTP as correct end-point (in several cases failed)
3. The disconnect between TTP and OS may be a result of
the fact that immunotherapy takes time to have a
biologic effect
 Immune response might manifest itself as early dimensional
tumoral increase, due to lymphocyte infiltration and inflammation
and tumor might progress before immunotherapy
does have time to take effect (Hales et al Ann Oncol 2010)
, Nat Rev Clin Oncol 2011)
Gulley et al, Cancer
Imunol Immunother 2010)
γ
Clin Oncol 28:15s, 2010)
Correlation with baseline PSA level
and OS (ASCO 2012)
Baseline PSA (ng/mL)
≤22.1
n
128
>22.1–50.1 >50.1–134.1 >134.1
128
Median OS, m 41.3
27.1
Control
20.1
Difference
28.3
13.0
7.1
128
20.4
15.0
128
18.4
15.6
5.4
HR (95% CI) 0.51 (0.31, 0.85) 0.74 (0.47, 1.17) 0.81 (0.52, 1.24) 0.84 (0.55, 1.29)
2.8
Ongoing PROSTVAC® Studies – NCI Supported
Stage
Study design
Target
Endpoint
Ph2
n=144
Comparison of docetaxel (chemotherapy)
with/without PROSTVAC®
Metastatic prostate cancer
mCRPC
Survival
Ph2
n=65
Comparison of flutamide (antihormone
therapy) with/without PROSTVAC®
Non-metastatic prostate
cancer
Time to progression
(TTP)
Ph2
n=68
Comparison of samarium (radioactive
drug) with/without PROSTVAC®
Metastatic prostate cancer
4 month progression
free survival
Ph2
n=50
Investigate PROSTVAC® in men with PSA
progress
After local therapy (surgery
and/or radiation)
PSA progression at 6
months
Ph1
n=30
Dose-escalation, combination study with
PROSTVAC® and MDX-010 (CTL4antibody)
Metastatic prostate cancer
Safety, PSA response
CT response
Ph1
n=21
Investigate PROSTVAC® by intraprostatic
injection
Progressive or locally
recurrent prostate cancer
Safety, PSA response
Immune response
Ongoing PROSTVAC® Studies in Earlier Stage
Disease Suggest Slower Disease Progression
Non-metastatic disease
Phase 2 study of PROSTVAC® in patients with PSA progression after local therapy
n=29
Median PSA Doubling Time
Pre-treatment
4.4 months
Post-treatment
7.7 months
Source: DiPaola, Gulley, Schlom et al., 2009 Genitourinary Cancers Symposium
Phase 2 study, comparing flutamide (antihormone therapy) with/without PROSTVAC®
Preliminary results, n=26 (will enrol 65 patients)
Time To Progression (TTP)
Without PROSTVAC® (n=13)
85 days
With PROSTVAC® (n=13)
223 days
Source: Gulley, Schlom et al. 2011 Genitourinary Cancers Symposium
Phase 2: Samarium +/- PROSTVAC
2nd Line Treatment of Metastatic PC
Patient Population: CRPC Metastatic to bone
R
A
N
D
O
M
I
Z
E
Arm A: PROSTVAC +
Arm B:
153Sm
153Sm
(n=34)
(n=34)
Vaccine:
rV-PSA/TRICOM s.c. d 1
rF-PSA/TRICOM s.c. d 15, 29, q 4 wks
153Sm:
1 mCi/kg d 8, may be repeated
q 12 wks upon hematologic recovery.
Source: PI Gulley NCI# 7678 in collaboration with Nuc Med
47
QUADRAMET
is a radioactive samarium (153Sm)-chelate that is FDA approved for
palliation of bone metastasis
ECOG 1809 PROSTVAC-Taxotere Sequential
(Opened 2011)
Patient Population: Good Prognosis
Metastatic CRPC (Halabi Predicted
Survival ≥18 months)
R
A
N
D
O
M
I
Z
E
Phase 2 (n=135)
Primary endpoint: OS
Arm A: PROSTVAC  Docetaxel
(n=90)
Arm B: Docetaxel
(n=45)
(No GM-CSF)
Protocol Chair: Doug McNeel; Co-Chair: James Gulley
48
Link: NCT01145508
Percent Overall Survival
Comparing OS of Prostvac alone to Prostvac + Ipilimumab
Prostvac +
Ipilimumab (n=30)
Prostvac
alone (n=32)
Months from On-Study
This compares two studies done at the NCI with Prostvac in metastatic CRPC (Updated 9/21/2010)
D OS
Median Overall Survival
Halabi Predicted Survival
Prostvac alone
26.3 months
17.2 months
9.1 months
Prostvac
and Ipilimumab
34.4 months
18.5 months
15.9 months
Source: Courtesy of Dr Gulley et al, NCI (April 27, 2011)
49
Alive at 24 mos
53%
73.3%
Randomized Phase 3 Trial PROSTVAC
(ASCO 2012) NCT00450463.
PROSTVAC
Metastatic
Castrate
Resistant
Prostate Cancer
Minim. symp
(N=1200)
PROSTVAC +
GMCSF
PLACEBO
6 months of treatment
[l1]This
is discussed in the additional remarks provided
P
R
O
G
R
E
S
S
I
O
N
Treated at
Physician
discretion
Treated at
Physician
discreation
and/or Salvage
Protocol
S
U
R
V
I
V
A
L
DC-VAC (Sotio)
• DCVAC/PCa is an active autologous cellular immunotherapy
consisting of dendritic cells (DCs) produced ex-vivo from a
patient’s monocytes which are pulsed with tumor cells killed by
high hydrostatic pressure (HHP) and subsequently activated by a
maturation agent. When the activated autologous DCs are
infused back into the patient with CRPC an immune response is
set up against the cancer which may inhibit progression and
improve overall survival (OS).
• DCVAC/PCa is an autologous cellular suspension, 1×107 pulsed
mature DCs per dose,doses obtained from an autologous sample
• Treatment Period – From 10 to 15 subcutaneous doses of
DCVAC/PCa are administered every month.
Randomized Phase 3 Trial DCVAC/Pca
Plus Chemotherapy versus chemotherapy
Metastatic
Castrate
Resistant
Prostate Cancer
(N=1170)
DCVAC + docetaxel
Q 3 weeks x 10-15
2:1
docetaxel
Q 3 weeks x 3
P
R
O
G
R
E
S
S
I
O
N
Treated at
Physician
discretion
Treated at
Physician
discreation
and/or Salvage
Protocol
S
U
R
V
I
V
A
L
The stratification factors are based on the randomization factors (i.e., Gleason score (<7 or >=7),
number of bone metastasis (<5 or >=5), or bisphosphonate/denosumab use (yes or no). [l1]
[l1]This
is discussed in the additional remarks provided
Take home messages
 An emerging theme in randomized phase II-III studies of
vaccines (eg, sipuleucel-T and Prostvac) in advanced PCa is
one of prolonged survival, without a demonstrable signal of
tumor shrinkage or delay in short-term disease progression.
 The development of vaccine approaches, either alone or in
combination with other modalities, that may lead to objective
measurable disewould be a significant advance in the field ase
responses or delay in short-term disease progression and may
lead to a more rapid and feasible pathway for their clinical
development.
Take home messages
 Optimal patient selection is critical for trials
evaluating vaccines and other immunotherapeutic
agents for Pca
 New end-points, response criteria and markers of
activity are needed
Therapies Shown to Improve OS in mCRPC
Phase 3 data
Number
patients
Stop TX 2°
AE
PSA↓
≥ 50%
Improvement
in Median OS
Hazard
Ratio
P value
Approved
Sipuleucel-T
512
1.5%
2.6%
4.1
(21.7-25.8)
0.78
0.03
2010
Docetaxel
1006
11%
45%
2.9 (16.3-19.2)
0.76
0.004
2004
2.4 (12.7-15.1)
0.70
<0.0001
2010
3.9 (10.9-14.8)
0.65
<0.001
2011
2.8 (11.2-14.0)
0.70
0.0022
4.8 months
0.63
0..0001
39%
Cabazitaxel
755
18%
Abiraterone
1195
19%
Alpha-Radin
900
Enzalutamide
1199
-
29%
54%
2012-13
Thank you...