This document provides information about clinical trials in cancer conducted by Cancer Research UK Clinical Trials Units (CRCTU). It discusses the history and mission of the Birmingham CRCTU, which was established in 1976. The CRCTU conducts academically-led cancer trials across all ages, treatment modalities, and trial phases. Its portfolio includes trials in cancers such as breast, hematological malignancies, and pediatric cancers. The CRCTU has had clinical impacts in many cancer types and over £33.5 million in funding from 2007-2012. It also discusses strategic initiatives in areas like liver cancer, pediatric oncology, and hematological malignancies trials networks. Examples are provided of trials that have influenced clinical practice or

1. Clinical Trials in Cancer

2. CR-UK CLINICAL TRIALS UNITS
Glasgow
Liverpool
Birmingham
(paediatrics)
Birmingham
London
• ICR
• UCL
Wales
Southampton
2

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
3

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
4

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
5

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
6

7. CANCER TRIALS PORTFOLIO
Renal, 3%
Prostate, 3%
Skin, 4%
Upper GI, 5%
Bladder, 5%
Breast, 11%
Ovarian, 1%
Lung, 2%
Non Specific, 3%
Sarcoma, 2%
Mixed Primary, 4%
Lung, 2%
Paed, 22%
Liver, 4%
Liver-non
cancer, 2%
Haematology
Malignancies, 20%
Head and
Neck, 1%
Brain, 1%
Gynaecology, 1%
7

8. CLINICAL IMPACTS
FROM 2007-2012
clinical
impacts
in wide
range of
cancers
Total Live and Pre-live funding
> £33.5 Million
8

9. Renal, 3%
Prostate, 3%
Skin, 4%
Upper GI, 5%
Bladder, 5%
Breast, 11%
Ovarian, 1%
Lung, 2%
Non Specific, 3%
Sarcoma, 2%
Mixed Primary, 4%
Lung, 2%
Paed, 22%
Liver, 4%
Liver-non
cancer, 2%
Haematology
Malignancies, 20%
Head and
Neck, 1%
Brain, 1%
Gynaecology, 1%
9

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
10

11. CHANGING CLINICAL PRACTICE IN
BREAST CANCER
11

12. 12

13. NEAT TRIAL:
ANTHRACYCLINES
IMPROVE SURVIVAL:
Poole et al NEJM 2006 355
(18) 1851-1862
NEATSCIENCE: BENEFIT IN CEP 17 DUPLICATED
CASES
Bartlett et al Lancet Oncol. 2010 Mar;11(3):266-74.`
13

14. CONFIRMING IN A
META-ANALYSIS
Bartlett et al EJC 2010;8(3):
12)
TESTING THE NEW HYPOTHESIS
APPROVED BY CR UK CTAAC and
PARTNERSHIP FUNDING WITH PHARMA
14

15. DUCTAL CARCINOMA IN SITU (DCIS)
15

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
16

17. MARMOT REPORT

3 unnecessary breast cancer diagnoses/treatments for
one life saved.
17

18. Adele Frances
18

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.
19

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
Pathology Central review confirms low risk criteria
Randomise
Active monitoring
Surgery
20

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
21

22. INTRODUCING NEW TREATMENTS IN
HAEMATOLOGY
22

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
23

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?
AZA/VPA pre-treatment on
MAGE-specific CTL
recognition of a
hematopoietic target
Goodyear et al
Blood 2010
24

25. RIC-AZA PHASE II TRIAL
PROF. CHARLIE CRADDOCK
DLI
administration
…
Day
0
FMC RIC
ALLOGRAFT
Day
30
Day
60
Day
90
Day
120
5-AC
36mg/m2
5days
5-AC
5-AC
5-AC
Day
150
5-AC
(if relapse/mixed
chimerism)
Day
365
5-AC
25

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 posttransplant on Azacitidine on immune parameters posttransplant
26

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
27

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
28

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
29

30. le
yc
C
1
le
yc
le
yc
C
C
le
yc
C
le
yc
9
9
6
6
3
3
)
ZA
(A
ls
)
(C
tr
)
ZA
(A
ls
)
(C
tr
)
ZA
(A
ls
)
(C
tr
en
t
m
ls
)
(C
tr
1.010 9
C
le
yc
1
ea
t
tr
le
yc
C
C
re
le
yc
)p
ZA
(A
C
No. of CD4+CD25+CD127loFoxP3+ cells/L
IMPACT OF AZA ON T REG NUMBERS
2.010 9
1.510 9
p=0.0127
5.010 8
0
Goodyear et al Blood 2011
30

31. OVERALL SURVIVAL ACCORDING TO
TUMOUR SPECIFIC CD8+ T CELL RESPONSE
p= 0.02
31

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 antitumour activity by AZA may prevent disease relapse

The potential for epigenetic manipulation of GVHD and GVL requires
further examination in a randomised trial
32

33. 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
34

35. 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
36

37. NATIONAL CHILDHOOD CANCER AND LEUKAEMIA
TRIALS UNIT
CCTT
37

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)
38

39. NEUROBLASTOMA
2/3 of children with metastatic
neuroblastoma relapse within 2 years
At relapse average survival less than 6
months
39
3
9

40. CURRENT FRONT-LINE CLINICAL TRIAL
40

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…
41

42. CHALLENGES

Small patient numbers

Non-standard salvage therapy regimes

Multiple potential therapeutic targets
42

43. 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
44

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
45

46. DESIGN
Phase II, randomized, open label, 4-arm factorial trial
BEVACIZUMAB
RANDOMISATION
Relapsed/
Refractory
Neuroblastoma
fulfils eligibility
criteria
BACKBONE
RANDOMISATION
Temozolomide
Temozolomide
+ Bevacizumab
Temozolomide
+ Irinotecan
Temozolomide
+ Irinotecan +
Bevacizumab
46

47. INTERNATIONAL COLLABORATION
International Sponsor
University of Birmingham CRCTU
CI Andy Pearson
8 National Coordinating Centres
National coordinating investigator
identified in each country
20-26 Sites
Principal investigator in each site
• Regulatory submissions
• Initiation of sites
• Monitoring
• Funding
Ruth Ladenstein - Austria
Hervé Rubie – France
Aurora Castellano – Italy
Victoria Castel - Spain
Jochen Rößler - Germany
Huib Caron – Netherlands
Karsten Nysom - Denmark
47

48. BEACON COLLABORATING PARTNERS


CRCTU-BEACON team
o Elena Brogden
o Dee Wherton
o Keith Wheatley
o Veronica Moroz
o Pam Kearns
The Institute of Cancer Research – The
Royal Marsden Hospital
o Chris Jones
o David Collins
o Martin Leach
o Mu Koh
o Keiko Miyazaki
o Regan Barfoot
• Functional Imaging
o Andrew Peet
o CRUK FI Programme
• Leeds Institute of Molecular Medicine
o Sue Burchill
• SIOPEN
o Peppy Brock
o Executive Board
• ITCC
o Birgit Geoerger
o Clinical Trials Committee
• Funders
o Cancer Research UK
o Imagine for Margo
o Roche – Genentech
o Raphael Rousseau
o Celine Pallaud
• Patients and families
48

49. PAEDIATRIC TRIAL PORTFOLIO
TRIALS OPEN BY END OF 2013
Hodgkin
lymphoma
b-NHL
Hepatoblastoma
no CCTT trial
medullo/PNET
LGG
ALL
HR
Neuroblastoma
Ewings
RMS
CNS GCT
Proportion of patients at first diagnosis eligible for a trial 2012/13
~67%
49

50. DEVELOPING IMMUNE-BASED
THERAPIES
50

51. USING DENDRITIC CELLS TO STIMULATE IMMUNE
RESPONSES
Dan Palmer, Syed Hussain, Neil Steven, Simon Olliff, Stuart Curbishley, Dave
Adams

52. STIMULATING IMMUNE RESPONSES
TO TREAT HEPATOCELLULAR CARCINOMA
Hepatocellular carcinoma




5th commonest cause of cancer death
Promoted by defective immune responses
Poor prognosis and few effective treatments
Evidence of activity of immunotherapy
Response to cytokine therapy & adoptive immunotherapy
Takayama 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
52

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
DCV
Patients
with HCC
Low dose
cyclophosphamide
TACE
20% absolute
improvement
in 1-year PFS
No DCV rates
53

54. 2008 CLINICAL RESPONSE AND FALL IN AFP AFTER DC
VACCINATION WITH AUTOLOGOUS DCS PULSED WITH HEPG2
LYSATES
Caudate
lobe
lesion
Pre-treatment
8 x 3cm
3 cycles
3 x 2cm
5 cycles
3 x 2cm
Palmer et al Hepatology 2009
54

55. PHASE II STUDY OF ADOPTIVE IMMUNOTHERAPY USING
DENDRITIC CELLS PULSED WITH TUMOUR LYSATE IN PATIENTS
WITH HEPATOCELLULAR CARCINOMA
SAFE
•134 infusions in 34 patients
•no serious toxicity
EVIDENCE OF EFFICACY
•25 patients received >3 vaccine infusions
•disease control rate 28%
Palmer et al Hepatology 2009
55

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
56

57. 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
58

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
59

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
60

61. NATIONAL MATRIX STUDY
Series of single arm phase II trials within a single protocol
Drug 1
Biomarker 1
Drug 4
etc

Biomarker 3
Drug 3

Biomarker 2
Drug 2

Biomarker 4

Biomarker 5

Biomarker 6

Biomarker 7

Biomarker 8

etc
61

62. FULL DETAILS STILL UNDER-WRAPS
WE CAN REVEAL MORE NEXT YEAR
62

63. DEVELOPING NEW STRATEGIC AREAS
63

64. PHASE III RANDOMISED CONTROLLED TRIAL
COMPARING ALTERNATIVE REGIMENS FOR ESCALATING
TREATMENT OF INTERMEDIATE AND HIGH-RISK
OROPHARYNGEAL CANCER
COMPARE
CI: PROF HISHAM MEHANNA
INSTITUTE OF HEAD AND NECK STUDIES AND EDUCATION,
SCHOOL OF CANCER SCIENCES, UNIVERSITY OF BIRMINGHAM
64

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
65

66. CompARE
Population
Intermediate or high risk OPC, 16-70yrs, ECOG PS 0-1, Fit for surgery and chemotherapy.
RANDOMISE 630 patients
Stratify 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)
Arm 1 (Control)
Concomitant
Cisplatin + RT
Arm 2:
Surgery+Arm1
Arm 3:
Induction TPF +
Arm 1
Arm 4: Cisplatin +
Dose-escalated RT
Interim
stages
(1yr DFS)
Efficacy
stage
Primary Outcome
Overall survival
Secondary Outcomes
Disease 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
66

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
67

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
68

69. ACKNOWLEDGMENTS

CRCTU Directors






Keith Wheatley
Cindy Billingham
Dan Rea
Neil Steven
Charlie Craddock
Sarah Bowden
THE CRCTU TEAM

All CRCTU investigators incl;
 Hisham Mehanna
 Gary Middleton
 Adele Francis

Funders
 CRUK
 LLR
 EU FP7
 NIHR
 Imagine for Margot
 Brain Tumour Trust
 Industrial Partners