BCCT Showcase - Cancer Research UK Clinical Trials Unit

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  • Impact in a wide range of clinical arenas Breast, Bladder, Lekaemia, lung
  • cyclophosphamide, methotrexate, and fluorouracil 1941 tumours from 2391 women recruited to NEAT/BR9601 were analysed on tissue microarrays for HER2 and TOP2A amplification and deletion, HER1-3 and Ki67 expression, and duplication of chromosome 17 centromere enumeration probe (Ch17CEP)Chromosome 17 centromere (CEP17) duplication
  • 16 controls and 21 RICAZA patients were analysed at matched time-points post transplant and the frequency was calculated as the number of CD4+CD25+CD127loFoxP3+ cells/ml.Note there was no enrichment of Tregs in BM
  • 2p=0.05, 80% power: n=1502p=0.3, 70% power: n=50
  • Stratified medicine initiative
  • BCCT Showcase - Cancer Research UK Clinical Trials Unit

    1. 1. Clinical Trials in Cancer
    2. 2. CR-UK CLINICAL TRIALS UNITS Glasgow Liverpool Birmingham (paediatrics) Birmingham London • ICR • UCL Wales Southampton 2
    3. 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. 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. 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. 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. 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. 8. CLINICAL IMPACTS FROM 2007-2012 clinical impacts in wide range of cancers Total Live and Pre-live funding > £33.5 Million 8
    9. 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. 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. 11. CHANGING CLINICAL PRACTICE IN BREAST CANCER 11
    12. 12. 12
    13. 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. 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. 15. DUCTAL CARCINOMA IN SITU (DCIS) 15
    16. 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. 17. MARMOT REPORT  3 unnecessary breast cancer diagnoses/treatments for one life saved. 17
    18. 18. Adele Frances 18
    19. 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. 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. 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. 22. INTRODUCING NEW TREATMENTS IN HAEMATOLOGY 22
    23. 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. 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. 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. 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. 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. 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. 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. 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. 31. OVERALL SURVIVAL ACCORDING TO TUMOUR SPECIFIC CD8+ T CELL RESPONSE p= 0.02 31
    32. 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. 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. 34. NETWORK - SELECTED CENTRES 34
    35. 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. 36. INFLUENCING PAEDIATRIC ONCOLOGY TREATMENT INTERNATIONALLY 36
    37. 37. NATIONAL CHILDHOOD CANCER AND LEUKAEMIA TRIALS UNIT CCTT 37
    38. 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. 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. 40. CURRENT FRONT-LINE CLINICAL TRIAL 40
    41. 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. 42. CHALLENGES  Small patient numbers  Non-standard salvage therapy regimes  Multiple potential therapeutic targets 42
    43. 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. 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. 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. 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. 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. 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. 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. 50. DEVELOPING IMMUNE-BASED THERAPIES 50
    51. 51. USING DENDRITIC CELLS TO STIMULATE IMMUNE RESPONSES Dan Palmer, Syed Hussain, Neil Steven, Simon Olliff, Stuart Curbishley, Dave Adams
    52. 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. 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. 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. 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. 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. 57. DEVELOPING PERSONALISED MEDICINE
    58. 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. 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. 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. 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. 62. FULL DETAILS STILL UNDER-WRAPS WE CAN REVEAL MORE NEXT YEAR 62
    63. 63. DEVELOPING NEW STRATEGIC AREAS 63
    64. 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. 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. 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. 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. 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. 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

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