BCCT Showcase - Cancer Research UK Clinical Trials Unit

Clinical Trials in Cancer

2

CR-UK CLINICAL TRIALS UNITS

Glasgow

Liverpool

Birmingham London• ICR• UCL

WalesSouthampton

Birmingham (paediatrics)

3

HISTORY OF THE CRCTU

Trials unit established in 1976 by George Blackledge Within Queen Elizabeth Hospital

In 1983 secured funding from Cancer Research Campaign (now Cancer Research UK) Moved under the auspices of the University of Birmingham

Accredited by: UK Clinical Research Centre UK National Cancer Research Institute Cancer Research-UK as a Key Centre for Early Drug

Development trials

4

MISSION

To translate cutting edge science into improved patient care, both rapidly and safely, through the design and conduct of large multi-centre/international randomised trials as well as smaller more data intensive phase I trials of novel therapies

Making a difference

5

REMIT Academically –led Cancer Trials

Across all age groups All modalities of treatment Phase I-III trials For Local and National Investigators

KEY STRENGTHS Several decades of expertise

Trial design and trial delivery Core funding from Cancer Research UK

Outstanding /Forefront score at 2012 QQR High success rate in funding applications Major strategic initiatives

6

STRATEGIC INITIATIVES Aug 2009: Liver NIHR BRU Early Phase Trials Team

Integrated programme; translational from biology to bedside

High volume of trials

April 2010: Designated National Trials Unit for Children’s Cancer

National and international leadership

Innovative trial designs for rare diseases

Jan 2011: LLR Trials Acceleration Programme

National leadership

National disease /site network

Dec 2012: Birmingham Surgical Trials Consortium

Collaborative project within BCCT

7

Bladder; 5%

Breast; 11%

Lung; 2%

Sarcoma; 2%

Paed; 22%

Brain; 1%

Gynaecology; 1%Haematology Malignancies; 20%

Head and Neck; 1%

Liver; 4%

Liver-non cancer; 2%

Lung; 2%

Mixed Primary; 4%

Non - Specific; 3%

Ovarian; 1%

Prostate; 3%

Renal; 3%

Skin; 4%Upper GI; 5%

CANCER TRIALS PORTFOLIO

8

CLINICAL IMPACTS

FROM 2007-2012clinical

impacts in wide range of cancersTotal Live and Pre-live funding

> £33.5 Million

9

Bladder; 5%

Breast; 11%

Lung; 2%

Sarcoma; 2%

Paed; 22%

Brain; 1%

Gynaecology; 1%Haematology Malignancies; 20%

Head and Neck; 1%

Liver; 4%

Liver-non cancer; 2%

Lung; 2%

Mixed Primary; 4%

Non - Specific; 3%

Ovarian; 1%

Prostate; 3%

Renal; 3%

Skin; 4%Upper GI; 5%

10

VIGNETTES FROM PAST AND FUTURE

Changing clinical practice in Breast Cancer

Introducing new treatments in Haematology

Influencing paediatric oncology treatment internationally

Developing immune-based therapies

Developing personalised medicine

Developing new strategic areas

11

CHANGING CLINICAL PRACTICE IN BREAST CANCER

12

13

NEAT TRIAL: ANTHRACYCLINES IMPROVE SURVIVAL: Poole et al NEJM 2006 355 (18) 1851-1862

NEATSCIENCE: BENEFIT IN CEP 17 DUPLICATED CASESBartlett et al Lancet Oncol. 2010 Mar;11(3):266-74.`

14

CONFIRMING IN A META-ANALYSISBartlett et al EJC 2010;8(3): 12)

TESTING THE NEW HYPOTHESIS

APPROVED BY CR UK CTAAC and PARTNERSHIP FUNDING WITH PHARMA

15

DUCTAL CARCINOMA IN SITU (DCIS)

16

OVER DIAGNOSIS OF EARLY BREAST CANCER

Over diagnosis is diagnosing healthy women with ‘breast cancer’ who would never otherwise have acquired a breast cancer diagnosis in their lifetime

2000 women screened 3 yearly over 20 years 17.6- 11.4 lives saved 8.6 - 2.3 over diagnosed Duffy J Med Screen 2010

21,683 women diagnosed with breast cancer in 2006 equivalent to 7000 unnecessary breast cancer diagnoses per year in UK Jorgensen JRSM 2010

17

MARMOT REPORT

3 unnecessary breast cancer diagnoses/treatments for one life saved.

18

Adele Frances

19

OBJECTIVES

To evaluate the effectiveness, cost effectiveness and acceptability of no surgical intervention in patients with newly diagnosed, mammogram detected asymptomatic, low risk DCIS.

To define the natural history of low risk DCIS and to predict those patients who require surgery because their DCIS is at risk of progression to invasive disease.

20

LORIS: A multicentre, prospective, Phase III, randomised controlled trial, incorporating an internal feasibility study with stratified 1:1 randomisation

Low or Intermediate Grade DCIS on Vacuum Biopsy

Active monitoring Surgery

Pathology Central review confirms low risk criteria

Randomise

21

OUTCOME MEASURES

Primary outcome measure Ipsilateral invasive breast cancer free survival rate Secondary outcome measures • Overall survival • Mastectomy rate • Time to mastectomy • Time to surgery • Patient reported outcomes (PRO) • Health resource utilisation • Assessment of predictive biomarkers

Potential for major practice

changing outcome

22

INTRODUCING NEW TREATMENTS IN HAEMATOLOGY

23

RELAPSE IS THE MAJOR CAUSE OF TREATMENT FAILURE IN PATIENTS ALLOGRAFTED FOR AML

35-80% allografted for AML relapse: according to disease biology and remission status at time of transplant

Disease relapse occurs early >80% in first year post-transplant

Outcome in patients who relapse after a Reduced intensity conditioning (RIC) allograft for MDS/AML is poor

24

NOVEL STRATEGY TO REDUCE THE RISK OF RELAPSE AFTER ALLOGENEIC STEM CELL TRANSPLANT IN MDS/AML

Epigenetically manipulate the allo-reactive response post transplant?

Goodyear et al Blood 2010

AZA/VPA pre-treatment on MAGE-specific CTL recognition of a hematopoietic target

25

RIC-AZA PHASE II TRIAL

PROF. CHARLIE CRADDOCK

Day 0

FMC RIC

ALLOGRAFT

Day 30

5-AC36mg/m2 5days

Day 60

Day 120

Day 90

Day 150

Day 365

5-AC 5-AC 5-AC 5-AC5-AC

DLI administration

(if relapse/mixed chimerism)…

26

OBJECTIVES

Primary To assess the tolerability of post-transplant Azacitidine

in patients with AML using a RIC regimen

Secondary To document the impact of post-transplant Azacitidine

on the kinetics of disease relapse

Adjunctive biological studies to study the effect of post-transplant on Azacitidine on immune parameters post-transplant

27

PATIENT COHORT

• 51 patients registered (22 registered pre-transplant, 29 registered post-transplant)

• 37 patients commenced Aza at a median of 55 days post Tx

• 14 patients withdrawn because of:

- post-transplant complications (n=8)

- withdrawal of consent (n=3)

- ineligibility/screening failure (n=3)

• Minimum follow up 12 months

28

CLINICAL RESULTS

• 32 patients completed at least 3 cycles of AZA and 16 patients completed 10

• Of patients who commenced AZA only 4 experienced treatment delay because of hematological toxicity

• 4 patients developed chronic limited GVHD but none chronic extensive GVHD

• 16 of 37 patients relapsed at a median of 8 months• 13 of 33 patients transplanted in remission relapsed

29

AZA INDUCES A TUMOUR SPECIFIC CD8+ T CELL RESPONSE

• 16/28 patients demonstrated CD8+ T cell responses to tumour specific peptides

• Induction of CD*+ T cell response to tumour specific peptides not noted in control population

30

IMPACT OF AZA ON T REG NUMBERSN

o. o

f C

D4

+C

D2

5+

CD

12

7lo

Fo

xP

3+

ce

lls

/L

0

5.0108

1.0109

1.5109

2.0109

p=0.0127

Goodyear et al Blood 2011

31

OVERALL SURVIVAL ACCORDING TO TUMOUR SPECIFIC CD8+ T CELL RESPONSE

p= 0.02

32

CONCLUSIONS

Azacitidine is well tolerated post allograft and is associated with a notably low incidence of chronic GVHD

There is preliminary evidence that the induction of CD8+ specific anti-tumour activity by AZA may prevent disease relapse

The potential for epigenetic manipulation of GVHD and GVL requires further examination in a randomised trial

STRATEGIC REQUIREMENT FOR EFFECTIVE EARLY PHASE CLINICAL TRIAL PROGRAMME

FOR HAEMATOLOGICAL MALIGNACIES

• Large catchment area

• Clinical centres of excellence

• Appropriate trial management infrastructure

• Strong basic science

34

NETWORK - SELECTED CENTRES

TREATMENT ACCELERATION PROGRAMME - OBJECTIVES

• To open 4/5 new trials each year • Open within 6 months

• Recruit in timely fashion

• To complete, analyse and publish results two years after recruitment of first patient

• To strengthen translational studies

36

INFLUENCING PAEDIATRIC ONCOLOGY TREATMENT INTERNATIONALLY

37

NATIONAL CHILDHOOD CANCER AND LEUKAEMIA TRIALS UNIT

CCTT

38

FRAMEWORK TO DELIVER INTERNATIONAL CANCER TRIALS

EU-FP7 funded Network of Excellence for children and adolcescents with cancer (total network funding £12M across 32 partners)

39

39

2/3 of children with metastatic neuroblastoma relapse within 2 yearsAt relapse average survival less than 6

months

NEUROBLASTOMA

40

CURRENT FRONT-LINE CLINICAL TRIAL

41

INTRODUCING NEW THERAPEUTIC APPROACHES

Need to define backbone with relatively low toxicity to add new potential molecularly targeted therapies

Need to test targeted therapies Anti-angiogenics, PI3K/mTOR inhibitors, Aurora

Kinase, IGF-1R, ALK inhibitors…

42

CHALLENGES

Small patient numbers

Non-standard salvage therapy regimes

Multiple potential therapeutic targets

BEACON-Neuroblastoma

ITCC 032

A randomized phase IIb trial of Bevacizumab added to Temozolomide ± Irinotecan for children

with refractory/relapsed neuroblastoma

Andy Pearson, Lucas Moreno, Giuseppe Barone, Keith Wheatley, Veronica Moroz, Elena Brogden, Dee Wherton, Nicola Graham, Sue Burchill, Andrew Peet, Pam Kearns

44

BEACON-NEUROBLASTOMA

Hypotheses

New Agent - The addition of bevacizumab to a backbone chemotherapy regimen (temozolomide or irinotecan-temozolomide) demonstrates activity in children with relapsed or refractory neuroblastoma

Backbone - The addition of irinotecan to temozolomide increases the activity of chemotherapy in children with relapsed or refractory neuroblastoma

45

STATISTICAL CONSIDERATIONS

Factorial design Primary Endpoint: ORR after two courses Randomisation stratified

relapsed / refractory disease measurable / evaluable disease early / late relapse (18 months)

BEV randomisation (15% better ORR), (2 stage Minimax Jung)

IRN randomisation: Bayesian methodology

46

DESIGN

Phase II, randomized, open label, 4-arm factorial trial

Relapsed/ Refractory

Neuroblastoma fulfils eligibility

criteria

BACKBONE RANDOMISATION

Temozolomide

Temozolomide + Bevacizumab

Temozolomide + Irinotecan

Temozolomide + Irinotecan + Bevacizumab

BEVACIZUMAB RANDOMISATION

47

INTERNATIONAL COLLABORATION

International Sponsor University of Birmingham CRCTU

CI Andy Pearson

8 National Coordinating CentresNational coordinating investigator

identified in each country

• Regulatory submissions• Initiation of sites• Monitoring• Funding

20-26 SitesPrincipal investigator in each site

Ruth Ladenstein - AustriaHervé Rubie – FranceAurora Castellano – ItalyVictoria Castel - SpainJochen Rößler - GermanyHuib Caron – NetherlandsKarsten Nysom - Denmark

48

BEACON COLLABORATING PARTNERS

CRCTU-BEACON teamo Elena Brogdeno Dee Whertono Keith Wheatleyo Veronica Morozo Pam Kearns

The Institute of Cancer Research – The Royal Marsden Hospitalo Chris Joneso David Collinso Martin Leacho Mu Koho Keiko Miyazakio Regan Barfoot

• Functional Imagingo Andrew Peeto CRUK FI Programme

• Leeds Institute of Molecular Medicineo Sue Burchill

• SIOPENo Peppy Brocko Executive Board

• ITCCo Birgit Geoergero Clinical Trials Committee

• Funderso Cancer Research UKo Imagine for Margoo Roche – Genentech

o Raphael Rousseauo Celine Pallaud

• Patients and families

49

PAEDIATRIC TRIAL PORTFOLIO

no CCTT trial

ALL

Hodgkin lymphoma

b-NHL

Hepato-blastoma

medullo/PNET

LGG

HR Neurob-lastoma

Ewings

RMS

CNS GCTProportion of patients at first diagnosis eligible for a trial 2012/13 ~67%

TRIALS OPEN BY END OF 2013

50

DEVELOPING IMMUNE-BASED THERAPIES

Dan Palmer, Syed Hussain, Neil Steven, Simon Olliff, Stuart Curbishley, Dave Adams

USING DENDRITIC CELLS TO STIMULATE IMMUNE RESPONSES

52

Hepatocellular carcinoma 5th commonest cause of cancer death Promoted by defective immune responses Poor prognosis and few effective treatments Evidence of activity of immunotherapy

STIMULATING IMMUNE RESPONSES TO TREAT HEPATOCELLULAR CARCINOMA

Response to cytokine therapy & adoptive immunotherapyTakayama T et al Lancet 2000

HCC is infiltrated by T cells which after in vitro expansion kill autologous tumour Yoong et al J Immunol 1998; Hepatology 1999; Br J Cancer 1999

53

DEVELOPING A CELLULAR CANCER VACCINE

2008 Palmer: Hepatology – single arm trial of immature lysate loaded DC

2011 Steele: Gene Therapy – single arm trial of cytokine-matured antigen transfected DC

2010 - phase 0 study tracking matured DC in vivo 2014 – ImmunoTACE trial matured lysate DCV

Patients with HCC TACE

Low dose cyclophos-phamide

DCV

No DCV

20% absolute improvement in 1-year PFS rates

54

Pre-treatment 3 cycles 5 cycles8 x 3cm 3 x 2cm 3 x 2cm

Palmer et al Hepatology 2009

2008 CLINICAL RESPONSE AND FALL IN AFP AFTER DC VACCINATION WITH AUTOLOGOUS DCS PULSED WITH HEPG2

LYSATES

Caudate lobe lesion

55

PHASE II STUDY OF ADOPTIVE IMMUNOTHERAPY USING DENDRITIC CELLS PULSED WITH TUMOUR LYSATE IN PATIENTS WITH HEPATOCELLULAR CARCINOMA

Palmer et al Hepatology 2009

SAFE

• 134 infusions in 34 patients

• no serious toxicity

EVIDENCE OF EFFICACY

• 25 patients received >3 vaccine infusions

• disease control rate 28%

56

IMMUNOTACE CI DAVE ADAMS

PHASE II STUDY OF DC THERAPY IN HCC PLUS ABLATIVE THERAPY WITH TACE

• Low-dose cyclophosphamide to deplete Regulatory T cells

• TACE..transcatheter-arterial embolisation

• Tumour-pulsed DC injected into tumour site

• Monthly iv DC injections

• Outcomes

• Immune monitoring

• Clinical and radiological response

• Delivery monitored by imaging

DEVELOPING PERSONALISED MEDICINE

58

CANCER RESEARCH UK STRATIFIED MEDICINE PROGRAMME (SMP): PHASE 2

“NATIONAL SCREENING TO NATIONAL TRIALS”

SMP Phase 1 (July 2011 - July 2013) Pilot study of national routine molecular screening of patients

with cancer demonstrating feasibility

3 Technology Hubs (Birmingham, Cardiff, Royal Marsden) and 25 hospitals

9000 patients and 40,000 molecular tests

59

CANCER RESEARCH UK STRATIFIED MEDICINE PROGRAMME (SMP): PHASE 2

“NATIONAL SCREENING TO NATIONAL TRIALS”

Focus on lung cancer, primarily late-stage metastatic disease: 2,000 patients per year

Large volume national molecular pre-screening Biopsy and cytology samples rather than resection Multiplexed technology solution

‘National Matrix Study’: national trial testing multiple experimental drugs with treatment allocation according to molecular phenotype

60

NATIONAL MATRIX TRIAL

Competitive bid for Chief Investigator, Statistician, Trials Unit – October 2013

• Chief Investigator: Professor Gary Middleton

• Trial Statistician: Professor Lucinda Billingham

• CRCTU: Steven (PI), Kearns, Middleton, Billingham, Morton, Griffiths, Taniere

61

NATIONAL MATRIX STUDY

Drug 1 Drug 2 Drug 3 Drug 4 etc

Biomarker 1

Biomarker 2

Biomarker 3

Biomarker 4

Biomarker 5

Biomarker 6

Biomarker 7

Biomarker 8

etc

Series of single arm phase II trials within a single protocol

62

FULL DETAILS STILL UNDER-WRAPS

WE CAN REVEAL MORE NEXT YEAR

63

DEVELOPING NEW STRATEGIC AREAS

64

PHASE III RANDOMISED CONTROLLED TRIAL COMPARING ALTERNATIVE REGIMENS FOR ESCALATING TREATMENT OF INTERMEDIATE AND HIGH-RISK OROPHARYNGEAL CANCER

COMPARE

CI: PROF HISHAM MEHANNAINSTITUTE OF HEAD AND NECK STUDIES AND EDUCATION,

SCHOOL OF CANCER SCIENCES, UNIVERSITY OF BIRMINGHAM

65

COMPARE DESIGN

Multi-arm, multi-modal (MAMS) design

Efficient design, allows earlier assessment and substitution of arms

Several arms: assess at successive stages Discard arms that show no promise

66

Arm 1 (Control)Concomitant

Cisplatin + RT

Arm 3:Induction TPF +

Arm 1

Arm 4: Cisplatin + Dose-escalated

RT

Arm 2:Surgery+Arm1

Interim stages

(1yr DFS)

Efficacy stage

Primary OutcomeOverall survival

Secondary OutcomesDisease free survival, Acute and late severe toxicity using CTCAE, QoL using EORTC QLQ-C30 & HN35, EQ-5D &

MDADI (for Swallowing), Cost-effectiveness, Surgical complications Others: Molecular markers

PopulationIntermediate or high risk OPC, 16-70yrs, ECOG PS 0-1, Fit for surgery and chemotherapy.

RANDOMISE 630 patientsStratify Intermediate vs High risk & Centre.

Adjust for Site (Tonsil vs Base of Tongue) and size (T1-3 vs T4) of tumour and nodes (N0-2A vs N2B-3)

CompARE

67

CHANGING CLINICAL PRACTICE WITH CRCTU

CTUs are resource-rich research groups

Systematic reviews, meta-analyses

Clinical trials methodology

Support translation of pre-clinical data Drug development trials Integration of biomarkers into trial design Development of novel end-points for targeted

therapies

Tissue with clinical data sets

68

SUMMARY OF CRCTU’S STRATEGIC AIMS FOR 2012-2017

Develop the strengths in our portfolio including:

Translational opportunities in late phase trials

Integration of Stratified Medicine Programme

Early drug development trials: Haematology and Cell therapy/immunotherapy

Innovative and International trials for rare tumours

ACKNOWLEDGMENTS

CRCTU Directors Keith Wheatley Cindy Billingham Dan Rea Neil Steven Charlie Craddock Sarah Bowden

All CRCTU investigators incl; Hisham Mehanna Gary Middleton Adele Francis

Funders CRUK LLR EU FP7 NIHR Imagine for Margot Brain Tumour Trust Industrial Partners

THE CRCTU TEAM