Translational Research andClinical Trials
Barriers in international trials including regulatory problems
Thursday 21st March 2013
Iain McNeishProfessor of Gynae Oncology
Institute of Cancer SciencesUniversity of Glasgow, UK
Translational Research andClinical Trials
• What the hell is translational research?
• Why translational research matters in Gynae cancer
• Examples of good translational cancer research
• Why we have to work internationally
• Primal scream - regulations
Agents in recruiting trials in ovarian cancer:clinicaltrials.gov 13/3/2013 (abridged)
Imatinib, vorinostat, veliparib, revlimid, lysophosphatidic acid, bendamustine, OVAX, N-acetylcysteine, olaparib, rucaparib, AZD0530, lovastatin, flutamide, MK-4827, Juice-plus, SU5416, decitabine, MAGE-A3/NYESO-specific T cells, CP-4055, MORAb-033, MAGE-A1 vaccine, abogovomab, karenitecin, farletuzumab, sorafenib, panitumumab, trabectidin, KHK2866, fenretinide, AMG386, AGS-8M4, catumaxomab, bevacizumab, celecoxib, DC vaccine, Ad5-delta24-RGD, AVE0005, EGEN-001, temsirolimus, CDX-1307, removab, gefitinib+anastrazole, perifosine, SGI-110, CTA-H19, ispinesib, p53 synthetic long peptide vaccines, HIPEC, IMRT, NGR-hTNF, erlotinib, belotecan, valproate, exemestane, pertuzumab, pegaspargase, EGEN-001, intra-peritoneal aerosol high-pressure chemotherapy, BSI-201, denileukin diftitox, MK-1775, LY222880, BIBF1120, pazopanib, Fragmin, SB-485232, oregovomab, squalamine lactate, GSK2110183, tasquinimod, amatuximab, Hu3S193, AMG102, CRLX101, E7389, …….
Translational research
‘Ask a question in the clinic and then answer it in the lab’
Emil Freireich
What is translational research?
Translational researchAlternative definition?
Translational cancer research must address two questions:
1. Which patients will respond to my new drug?
2. How can I identify those patients with a simple, cheap, reliable test?
‘Ask a question in the clinic, answer it in the lab then go back and prove it in the clinic’
The ideal translational pathway
1. Identify clinically relevant scientific target/pathway/process
2. Grant support - years of scientific endeavour
3. Extensive data from cell lines and patient samples
4. In vivo data - small bald mice ‘cured’ of human cancer
5. Trials grant from NHMRC/Wellcome Trust/Bank manager
6. Phase I trial – drug safe with no side effects
7. Phase II trial - clinical activity in drug-resistant cancer
8. Establish collaboration with Mega-pharm
9. Phase III trial redefines standard of care for your cancer
10. Retire to Bermuda, collecting Nobel Prize en route
Identify your target…
Peter Nowell and David Hungerford
Make your drug…
Phase I…
Druker et al. N Engl J Med 2001;344:1031
Phase III…
O'Brien S et al. N Engl J Med 2003;348:994-1004
Kaplan-Meier Estimate of the Time to a Major Cytogenetic Response
Treat another cancer while you’re at it
Demitri et al. N Engl J Med 2002; 347:472
Dare to dream of your Nobel Prize…?
If only everything was as simple as CML
Gefitinib (Iressa)
EGFR signalling – the basics
http://www.wikipathways.org/index.php/Pathway:WP437
The AstraZeneca ‘oh bloody hell’ moment
Giaccone G et al. JCO 2004;22:777-784
©2004 by American Society of Clinical Oncology
Translational research to the rescue
Lynch et al. N Engl J Med 2004; 350:2129
‘.. then go back and prove it in the clinic’
Maemondo et al. N Engl J Med 2010; 362:2380
EGFR – more object lessons
Karapetis et al. N Engl J Med 2008; 359:1757
Karapetis et al. N Engl J Med 2008; 359:1757
However, cetuximab in NSCLC
EGFR in ovarian cancer
2012 ASCO Annual Meeting. Abstract No:LB5000J Clin Oncol 30: 2012 (suppl; abstr LB5000)
Ignace B. Vergote et al
Conclusions: In the overall study, maintenance erlotinib after first-line treatment in ovarian cancer did not improve progression-free or overall survival
Randomized phase III study of erlotinib vs observation in patients with no evidence of disease progression after first-line platin-based chemotherapy for ovarian carcinoma: A GCIG-EORTC study
Translational Research andClinical Trials
•What the hell is translational research?
• Why translational research matters in Gynae cancer
•Examples of good translational cancer research
• Why we have to work internationally
• Primal scream - regulations
Vaughan et al Nat Rev Cancer (2011) 11:719
Rela
tive
surv
ival
(%)
Coleman et al Lancet (2011) 377:127
Why we need translational research
Bookman et al (2009) JCO 27:1419-1425
Median PFS and HR (95% CI)
16.1 1.00016.4 0.990 (0.838-1.141)16.4 0.998 (0.832-1.136)15.3 1.094 (0.918-1.244)15.4 1.052 (0.888-1.206)
Conventional chemotherapy….
Ovarian cancer is not one disease
Köbel et al PLoS Med (2008) 5:332
Current view of ovarian cancer biology
Vaughan et al Nat Rev Cancer (2011) 11:719
p53BRCA1/BRCA2/HRDRbPI3K/Ras
ARID1API3KIL-6/HIF1a
PI3Kb-cateninPTEN
KRas
TRAMETINIB in low grade serous ovarian cancer (LOGS) Study
CI: Charlie Gourley - Edinburgh
LOW GRADE SEROUS OVARIAN CANCER
• Often presents early in association with serous borderline tumour
• Increased risk in patients with a history of endometriosis (HR 2.11, 1.39-3.20, p<0.0001)
• Median/mean age: 43/45 years• Comprises 10-15% of serous carcinoma• Resistant to conventional chemotherapy• For stage II-IV disease: median PFS 19 m;
median OS 81 m
Gershensen D et al, Gynec Oncol 2008Wong Ket al, AM J Path 2010
Pearce et al, Lancet Oncol 2012
Well-diff grade I low-grade
KRAS/BRAF/ERBB2 Mutation
Singer G, et al. J Natl Cancer Inst. 2003;95(6):484-486.Singer G, et al. Am J Pathol. 2002;160(4):1223-1228.Nakayama K, et al. Cancer Biol Ther. 2006;5(7):779-785.
BRAF
KRAS
75
50
25
BRAF
KRAS
SBT LG HG
?
BRAF
KRAS
75
50
25
BRAF
KRAS
BRAF
KRAS
75
50
25
75
50
25
BRAF
KRAS
SBT LG HG
?
TP53 Mutation
%
75
50
25
%
75
50
25
%
75
50
25
75
50
25
%
SBT LG HG
ERBB212 bp ins
DISTINCT SOMATIC MUTATIONS IN LOW-GRADE AND HIGH-GRADE SEROUS
CARCINOMA
KRAS
BRAF
MEK
MAPK (ERK)
cyclin D1 GLUT1
progression survival proliferation
LOW-GRADE SEROUS CA
RTK
cadherin
b-catenin
b-catenin
b-catenin
LEF/TCF
PI3K
AKT
mTOR
PTEN
TP53
cyclin E
mutations
mutations
mutations
ERRB2
TREATMENT OF LOW-GRADE SEROUS OVARIAN CANCER: RETROSPECTIVE DATA
• Response to platinum-based chemo: <5%• First line: 4% response, 88% disease stabilisation
(Schmeler et al, Gynecol Oncol, 2008)• Second line: 3.7% response, 60% disease stabilisation
(Gershenson et al, Gynecol Oncol, 2009)
• Response to hormonal therapy: around 10%• Response to endocrine therapy 9% in retrospective
analysis (Gershenson et al, Gynecol Onc, 2012)• ER+/PR+ had longer TTP than ER+/PR- (p=0.053, 64
patients)
GOG 239 study
• Phase II study of MEK inhibitor AZD 6244 100 mg b.d • 52 pts • Primary endpoint: response rate• Heavily pretreated (58% at least 3 prior treatment
regimens)• 15% response rate, 65% stable disease• Median PFS 11 months• 6% BRAF, 41% KRAS, 15% NRAS• No correlation between mutation status and response
LOGS study
• Randomised 2-arm Phase II/III study of MEK trametinib vs control in relapsed low grade serous ovarian cancer
• Control arm nominated prior to randomisation• Weekly paclitaxel• Weekly topotecan • Pegylated liposomal doxorubicin• Letrozole• Tamoxifen
• 80 centres across USA and UK• 2 (very similar) protocols with data combined into one
statistical analysis• Accepted by CTEP and CTAAC
LOGS study
• 250 patients over 46 months• Primary endpoint
– PFS (80% power to detect 50% increase from 8-12 months)• Secondary endpoints
– OS– ORR– QoL– Biomarkers of efficacy (K-RAS, B-RAF and others)
• Crossover is allowed at progression
Key patient selection criteria
• Low grade serous ovarian or primary peritoneal cancer (central pathology review)
• Relapse or progression following platinum-based chemo
• Disease assessable by RECIST criteria (version 1.1)
• ECOG performance status 0 or 1• Satisfactory pre-study ophthalmic assessment• Agree to fresh tumour biopsy (mandatory)
Translational considerations
• Tissue collections– Mandatory fresh tissue biopsy – Archival paraffin blocks– Blood for genomic DNA– Circulating tumour DNA at multiple time points – Optional tumour biopsy on progression
Translational aims• Define the molecular biology of the disease
– K-RAS,N-RAS and B-RAF sequencing; HER2 sequencing and amplification status– NGS in patients without the above mutations– Activation of the MAPK/akt/other pathways (phosphoprotein)– Expression microarray analysis
• Identify markers of both MEKi and endocrine sensitivity
– All of the above investigations (comparing to response)– Investigations specifically investigating endocrine sensitivity (TMA)– Comparison of findings from new fresh tumour biopsy with findings from ctDNA at
diagnosis and archival FFPE
• Investigation of mechanisms of resistance– biopsies/ctDNA taken at relapse (exomic sequencing)
CI: Ros Glasspool, GlasgowInternational CI: Mansoor Mirza, Copenhagen
SGCTG/NCRI/NSGO
EORTC/GINECO
NICC: Nintedanib in Clear Cell Cancer
Histologically Distinct
High Grade Serous Clear Cell Carcinoma
First described in 1939 as mesonephroma ovariiCcells arranged in tubules, nests or cysts, Clear, glycogen rich cytoplasm.Immunophenotype: ER and WT1 -ve
Different Clinical Behaviour
• Younger (median 55 v 64 yrs)• Endometrioisis• Venous thromboembolic complications• Hypercalcaemia• More likely to present at an early stage
– (Stage 1: 50% v <20% in HGS)– EORTC-ACTION: 5Y DFS 71% in CCC v 61% in serous cancer
• Advanced stage has a poor prognosis– GCIG meta-analysis of stage III/IV: OS 21.3 v 40.8m and PFS 9.6 v 16.1m for CCC and HGS
respectively– RR to first line chemotherapy 22-56%
• Resistant to chemotherapy at relapse– Response in recurrent disease: <10%*– RR not related to PFI*.
*Takano M et al 2008
Different Biology• TP53 wild type and BRCA mutations rare
• Low levels of chromosomal instability
• ARID1A (46%) PIK3CA (33%) mutations
• Recurrent amplifications with potential targets (PPM1D, Her2)
• Gene expression: striking similarities between ovarian, endometrial and renal cell carcinomas
• Activation pathways involved in hypoxic cell growth, angiogenesis and glucose metabolism
• IL-6 pathway: The IL6-STAT3-HIF signalling pathway,
SWI/SNF complex
Wilson and Roberts (2011) Nat Rev Cancer 11:481
PIK3CA mutations in CCC
Rahman et al (2012) Hum Pathol 43:2179
‘Although PIK3CA mutations were associated with a more favorable prognosis,they did not predict the sensitivity of ovarian clear cell carcinoma cells to PI3K/AKT/mTOR inhibitors.’
Interleukin-6 and ovarian cancer
Platinum resistance
Proliferation
Migration and invasion
Th17 cell differentiation
MΦ differentiation
Jim Coward
IL-6 in clear cell ovarian cancer
Anglesio et al (2011) Clin Cancer Res 17:2538
Interleukin-6
Spearman r= 0.869
CRP as biomarker of IL-6 levels
Coward et al (2011) Clin Cancer Res 17:6083
Other pathways
Stany et al (2011) PLoS One 6:e21121
Potential Targets
• ARID1A/Baf250a – but how to target?
• PI3K-AKT-mTOR pathway - HELP
• IL-6 pathway – JnJ not interested
• Angiogenesis
• ARID1A/Baf250a – but how to target?
• PI3K-AKT-mTOR pathway -
• IL-6 pathway – JnJ not interested
• Angiogenesis
Trial Design
90 pts with progressive or relapsed CCC of ovary within 6 months of previous platinum.
Plus up to 30 women with endometrial CCC
RANDOMISE
Chemotherapy
Ovary:• PLDH (40mg/m2 d1 q28)• Weekly Paclitaxel (80mg/m2 d1, 8, 15 q28)• Weekly Topotecan iv (4mg/m2 d1, 8, 15 q28)
Endometrium: • Carboplatin (AUC 5) /Paclitaxel 175 mg/m2 q21 • Doxorubicin 60mg/m2 q21
Nintedanib 200mg bd until progression
Primary Endpoint: PFS
Secondary Endpoints: OS, Toxicity, RR, QoL, Q-Twist
Translational Sample Collection
4 co-operative groups, 8 countries, more sites than patients.
Funding obtained from CRUK for sample collection (15/3/2013….)
• FFPE tissue from diagnosis
• Study entry, day 1 of each cycle/ follow up and at progression
o Plasma samples for cytokine analyses
o Samples for circulating tumour DNA
o CRP as a surrogate marker of IL-6 activation
• Biopsy at study entry (and at progression) for UK patients
Translational AimsInvestigate:• ARID1A and PIK3CA in archival FFPE samples
– association with outcome.– changes between archival and fresh biopy.
• Whole genome sequencing (WGS) of archival FFPE looking for targetable mutations. • WGS in relapsed samples – new mutations? different mutation spectrum?• Markers of angiogenesis in plasma• Plasma IL-6 and serum CRP: correlation with PFS and OS and response
The Surmountable Challenges1. Money
NICCC sample collection alone = £91,00024 tumour biopsies = £20,000Courier costs = £47,000
Likely cost of translational research = £1,500,000Whole genome sequencing = £2000 eachBioinformatician to analyse = £60,000 p.a.
2. Infrastructure-80 freezers and centrifuges
3. QualityPlasma processing across 8 countries…
The Primal Scream moments1. Unnecessary hurdles
Appallingly slow bureaucracy
2. Human tissue legislationFrankly Kafka-esque and byzantineThe utterly random – e.g. no sample is allowed to leave
Germany
3. CustodianshipWho owns the samples after trial complete?Who owns the clinical/translational data?IP issues – potential minefield
4. Access after the trial and publication rights‘I contributed a sample, therefore I’m allowed total access’
4.
‘It’s like wading through treacle’1. 14th Feb 2011
Investigator requests access to FFPE samples from large trial2. 6th October 2011
TMG writes to investigator to confirm access permitted3. 18th April 2012
Researcher receives release agreement contracts from TMG
4. 17th July 2012Decision made that 3rd party company required to cut samples
5. 29th January 2013Contracts signed for block cutting
6. March 2013Investigator still not received any samples.
Translational researcher after meeting with tech-transfer/regulatory affairs team
Ownership and IP1. Company M owns the patent on germline mutation testing.2. Clinical trial – funded by Charity C3. All patients gave blood for germline DNA analysis4. Trial sponsor – NHS 5. Samples now at University I6. Company M willing to link germline mutations with response to
platinum chemotherapy
Q: Who owns the data and the information? A: Three sets of lawyers and 15 months later, No Answer
Ownership and IP• ‘Tech-transfer guys don’t really seem to understand the bigger
picture’
• ‘I’ve lost count of the number of times and different people I’ve had to explain the sample acquisition process’
Conclusions• Translational research ever-more important
• Incorporate at trial design stage
• Small phase II easier than large phase III
• Repeat biopsies very important
• Must improve contracts/approvals/tech-transfer processes
• Practice-changing