UK Prostate Trials for 10th Uro-Onc meeting 2013

7/29/2019 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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ClinicallyLocalized




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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ClinicallyLocalized




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

Documents

UK Prostate Trials for 10th Uro-Onc meeting 2013