UK Prostate Trials for 10th Uro-Onc meeting 2013
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Transcript of UK Prostate Trials for 10th Uro-Onc meeting 2013
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Overview of current prostate
cancer trials
Nicholas James
Professor of Clinical OncologyUniversity of Birmingham
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Introduction
Overview of portfolio
Trends in cancer trials in prostate cancer
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Prostate cancer treatment paradigms
ClinicallyLocalized
Hormone/CastrateRefractory
Local treatmentChemotherapy,
new hormone therapies,
Radium-223, etc
Hormonal
Relapsedand
Newly diagnosed M+
T1/2 T3/4 N+ M+ HRPC
Low risk High risk
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Prostate cancer treatment paradigms
ClinicallyLocalized
Hormone/CastrateRefractory
Local treatmentChemotherapy,
new hormone therapies,
Radium-223, etc
Hormonal
Relapsedand
Newly diagnosed M+
T1/2 T3/4 N+ M+ CRPC
Low risk High risk
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Trials in locally advanced disease
Genetics/
Molecular
mechanism
Surgery
1stline
treatment
Subseque
nt
treatment
QoL/Primary
Care/Data
collection/
Symptom
control
Imaging
Diagnosis
PROSTATE CSG PORTFOLIO MAP C PROSTATE CANCER PURPLE = FUNDED/IN SET-UPYELLOW = OPEN/RECRUITING
Version:August2013
Localised
DevelopedbyNCRICSGs&NCRN
INDEX
Active
surveillance
RADICAL
S
ProSpareII
Locally Advanced
NEPTUNE
S
TAMPEDED
ELINEATE
PACE
STAMPEDE
PATCHP
elvicIMRT*
PROCONv3.0
NCRN2484: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase III Study of ARN 509 in Men with Non-Metastatic (M0) Castration-Resistant Prostate Cancer (SPARTAN)
NCRN2324: Pilot study to evaluate the feasibility to image inflammati on in solid tumours with PBR28 and fluorodeoxyglucose (FDG) positron
emission tomography (PET).
* - Linked to translational study RAPPER
RADICAL
S
ProSpareII
NCRN2483
NCRN2483
NCRN2324
NCRN2324
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9 /9 /1 3 p ub li c. uk cr n. or g. uk /S ea r ch /S tu dy De ta il .a sp x? St ud yI D =1 35 99
public.ukcrn.org.uk/Searc h/StudyDetail.aspx?StudyID=13599 1/2
UK Clinical Research Network : Portfolio Database User Guide
Welcome to the UK Clinical Research Network Study Portfolio
NB: The information displayed below does not replace the protocol. The latest protocol versionshould always be consulted before making clinical decisions.
AdUP: AdNRGM;VDEPT + GMCSF in locallyrecurrent p rostate cancer
AdUP: A Phase I Clinical Trial of a replication defectivetype 5 adenovirus vector expressing nitroreductaseand GMCSF (AdNRGM) given via trans--perineal,template--guided, intra--prostatic injection, followed byintravenous CB1954, in patients with locally relapsedhormone--refractory Prostate Cancer.
Topic
Cancer
Portfolio Eligibility
Automatically eligible
ISRCTN 06254734
EudraCT 2007--700341--13
MREC N 12_SC_0660
UKCRN ID 13599
WHO ID
Research Summary
The main purpose of this trial is to determine safety and tolerability of a gene therapy strategyfor the treatment of locally relpased prostate cancer. The gene therapy is based on theintraprostatic injection of a viral vector (AdNRGM) carrying a gene called GMCSF which is ableto induce a strong immune response against the prostate cancer, and a gene called NTR whichis able to convert an inactive compound called CB1954 (prodrug) to a powerful anti--cancerdrug. To ensure coverage of the whole prostate the vector will be administered by multiplestereotactically--guided intraprostatic injections. 48 hours after the injection of the viral vector,the prodrug CB1954 will be administered intravenously. It is expected that the combination ofthe immune response induced by the GMCSF and the activation of the prodrug C1954 operatedby NTR within the tumour tissue will result in the death of a significant number of prostatecancer cells.
Study Type Interventional
Design Type Treatment
Disease(s) Prostate
Phase I
Current Status Open
Closure Date 1/31/2015
Global Sample Size 15
Geographical Scope Single Centre
Lead Country England
Open to new sites No
Additional Information
If you are a patient or relative this link will take you to a description of the trial in plain Englishon CancerHelp UK.
Main Inclusion Criteria
Patients who present with biopsyprovenlocal recurrence of prostate cancerfollowing radical radiotherapy and a risingPSA while on androgen suppression withLHRH agonist therapy or after bilateralorchidectomy. A rising PSA is defined as 3
Main Exclusion Criteria
Patients with a prostate or tumour which isdeemed clinically unsuitable for transperinealtemplateguided injection. Patients who havepreviously been treated with prostatebrachytherapy. Patients who have receivedchemotherapy, radiotherapy or
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Prostate cancer treatment paradigms
ClinicallyLocalized
Hormone/CastrateRefractory
Local treatmentChemotherapy,
new hormone therapies,
Radium-223, etc
Hormonal
Relapsedand
Newly diagnosed M+
T1/2 T3/4 N+ M+ CRPC
Low risk High risk
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Trials in locally advanced disease
Genetics/
Molecular
mechanism
Surgery
1st line
treatment
Subseq
uent
treatm
ent
QoL/Primary
Care/Data
collection/
Symptom
control
Imaging
Diag
nosis
PROSTATE CSG PORTFOLIO MAP C PROSTATE CANCER PURPLE = FUNDED/IN SET-UPYELLOW = OPEN/RECRUITING
Version:August2013
Localised
DevelopedbyNCRICSGs&N
CRN
INDEX
Active
surveillance
RADICALS
ProSpareII
Locally Advanced
NEPTUNE
STAMPEDED
ELINEATE
PACE
STAMPEDE
PATCHP
elvicIMRT*
PROCONv3.0
NCRN2484: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase III Study of ARN 509 in Men with Non-Metastatic (M0) Castration-Resistant Prostate Cancer (SPARTAN)
NCRN2324: Pilot study to evaluate the feasibility to image inflammation in solid tumours with PBR28 and fluorodeoxyglucose (FDG) positron
emission tomography (PET).
* - Linked to translational study RAPPER
RADIC
ALS
ProSpareII
NCRN2483
NCRN2483
NCRN2324
NCRN2324
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Non-interventional trials
Genetics/
Molecular
mechanism
Surgery
1st line
treatment
Subse
quent
treatment
QoL/Primary
Care/Data
collection/
Symptom
control
Imaging
Diagn
osis
PROSTATE CSG PORTFOLIO MAP A PROSTATE CANCER PURPLE = FUNDED/IN SET-UPYELLOW = OPEN/RECRUITING
Version:August2013
Observational/Non-Medical
DevelopedbyNCRICSGs&NCRN
NCRN428: BiopSaveBiopSave: Validation of a novel proteomic blood test for the diagnosis of prostate cancerNCRN426: Safety and immunogenicity of GSK Herpes Zoster vaccine in solid tumoursNCRN452: A Registry of Patients With a Confirmed Diagnosis of Adenocarcinoma of the Prostate Presenting With Metastatic Castrate-Resistant Prostate CancerNCRN518: A performance evaluation study of Urosen's ELISA test in the detection of prostate cancer in patients attending for prostate biopsy on the basis of raised serum PSAand/or abnormal DRENCRN2324: Pilot study to evaluate the feasibility to image inflammation in solid tumours with PBR28 and fluorodeoxyglucose (FDG) positron emission tomography (PET).
FAB-IE
NCRN452
VoxTox
Active
monitoring
systemf
or
prostatecancer
Managing
HotFlushes
&Night
sweats
Physical
Rehabfor
cancer
survivors
IMPACCT
Programme
Grant
ACT
Couple
intervention
forprostate
cancer
Trans-FAST/
CHHIP
CRU
K
Stratified
Medicine
Study
Histoscanning
fordetection,
localisa
tion&
Monitoring
Protein
sCTFT
&BOR
ISas
BM
s
COMP
ARe
NCRN
428
PROMIS
Urinary&
serum
proteom
icsin
prostate
cancer
RAPPER
PROGENE
IMPACT
ProMPT
MolMech
OfAndrogen
Escape
GenCab
UKGPCS
NCRN426
Prostate
Stereotactic
Body
Radiotherapy
Prostate
Mechanical
characteristics
PROMIS
CRUK
Stratified
Medicine
Study
ESCAPE
Survivorship
StratInMale
Uro-Genital
Cancers
NCRN
518
PROGENY
NCRN2324
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Future CRPC treatment
Clinical trial
Observation
2nd-line hormone Rx*
No metastases
Abiraterone
Docetaxel
Symptomatic
Docetaxel
Radium 223
Cabazitaxel
Docetaxel
Abiraterone
Enzalutamide
Metastases
Asymptomatic
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General trends hormone therapy
New agents TAK700, ARN 509, ODM201
Current agents in new settings first line,
neoadjuvant, M0 CRPC
Combination trials with modulators of
refractory behaviour
HSP90 inhibitors
GDC0068, 0980
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Trials of immunotherapies
CV9104
DCVAC
AdUP Prostvac
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Trials of chemotherapy
Cabazitaxel 20mg/m2
Cantata docetaxel vs cabazitaxel in
Stampede docetaxel arm pts relapsing
One trial docetaxel vs docetaxel + X
No new chemotherapy agents in trial in UK
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Trials of novel therapies
Tasquinimod
Cabozantinib
Vemurafenib in BRAF V600 mutants
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General trends - markers
Large number of tissue/blood collection
protocols
Most in data generating phase
Small number in validation phase
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General trends - imaging
PROMIS
assessing multi-parametric MRI indiagnostic pathways
Functional Assessment of Bone Metastases-Integrin Expression (FAB-IE) Imaging av3 integrin expression in skeletal
metastases with 99mTc-maraciclatide Single-PhotonEmission Computed Tomography
NCRN2324: Pilot study to evaluate the feasibility
to image inflammation in solid tumours withPBR28 and fluorodeoxyglucose (FDG) positronemission tomography (PET).
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Endpoints
PSA not a reliable marker
Overall survival is reliable but where to positiontherapies
Too early and salvage may swamp effect Too late and may not be time to see benefit in heavily
pre-treated patients
Failure free survival how to define?
Markers other than PSA
Circulating tumour cells
Cell free DNA
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KaplanMeier Estimates of Radiographic Progression-free Survival, Overall Survival, and Subgroup Analyses at
the Second Interim Analysis.
Ryan CJ et al. N Engl J Med 2013;368:138-148.
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TAK700
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There are issues with our endpoints
SPARC
Satraplatin
SPARC-
prior docetaxelTROPIC-
Cabazitaxel
CALGB 90401
BevacizumabTAX327
DocetaxelIMPACT-
Provenge
.5
.6
.7
.8
.9
1
OverallSurvivalHR
.5 .6 .7 .8 .9 1PFS HR
* Studies that reported both OS and PFS (using a variety ofPFS definitions
Abiraterone--301
Line of
equivale
nce
Prostvac
Trapeze Sr89
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PALLIATIVE ENDPOINTS
BONE EVENTS
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Bone metastases
Orthopaedic
SurgeryRadiation
to BonePathologic
FractureSpinal Cord
compression
SREs are clinically important endpoints
The burden of bone metastases
Pain
Disability
Hospitalizations Cost
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Denosumab Versus Zoledronic Acid in
CRPC Time to First On-Study SRE
Zoledronic Acid 951 733 544 407 299 207 140 93 64 47
Denosumab 950 758 582 472 361 259 168 115 70 39
Subjects at risk:
0
1.00
ProportionofSubjectsWithoutSRE
0 3 6 9 12 15 18 21 24 27
0.25
0.50
0.75
KM Estimate ofMedian Months
Denosumab
Zoledronic acid
20.7
17.1
HR 0.82 (95% CI: 0.71, 0.95)P= 0.0002 (Non-inferiority)
P= 0.008 (Superiority)
Study Month
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PercentofSubjectsWith
FirstSRE
Radiation
to BoneFracture
Surgery
to Bone
Spinal Cord
Compression
20.0
14.7
3.3
0.3
All subjects
0
5
10
15
20
25
30
Denosumab versus zoledronic acid
in CRPC type of SREs
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Alsympca trial
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Change in ALP and PSA
Nilson et al Lancet Oncology 2007. 8 587-94
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Alsympca trial SRE outcomes
Parker et al ESMO 2011.
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SRE frequency in trial of Ra223
vs placebo
28Radium-223 chloride (Alpharadin) impact on overall survival and skeletal-related events in patients with castration-resistant prostate
cancer with bone metastases: A phase III randomized trial (ALSYMPCA). Sartor et al AUA 2012
0
5
10
15
20
25
30
Pathologic Bone Fracture Spinal Cord Compression External beam RT Surgical intervention
Ra-223
Placebo
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Conclusions
Many trials of new hormone therapies
A few trials of non-hormone, non-
chemotherapy drugs
A number of trials of immunotherapy
No new chemotherapy drugs being trialled
Many studies of biomarkers A few studies of imaging
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Crystal ball gazing
New generation hormone therapies will move
into earlier settings
One or more immunotherapy study will
provide positive results
Biomarker studies will struggle to show
benefit
MP-MRI will change diagnostic pathways