Download What is translational research?

Translational Research and
Clinical Trials
Barriers in international trials including regulatory problems
Thursday 21st March 2013
Iain McNeish
Professor of Gynae Oncology
Institute of Cancer Sciences
University of Glasgow, UK
Translational Research and
Clinical 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, MAGEA3/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, MK1775, LY222880, BIBF1120, pazopanib, Fragmin, SB-485232,
oregovomab, squalamine lactate, GSK2110183, tasquinimod,
amatuximab, Hu3S193, AMG102, CRLX101, E7389, …….
Translational
research
What
is translational
research?
‘Ask a question in the clinic
and then answer it in the lab’
Emil Freireich
Translational
Alternative research
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…
Kaplan-Meier Estimate of the Time to a Major Cytogenetic Response
O'Brien S et al. N Engl J Med 2003;348:994-1004
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
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
2012 ASCO Annual Meeting. Abstract No:LB5000
J 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
Translational Research and
Clinical 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
Relative survival (%)
Why we need translational research
Vaughan et al Nat Rev Cancer (2011) 11:719
Coleman et al Lancet (2011) 377:127
Conventional chemotherapy….
Median PFS and HR (95% CI)
16.1
16.4
16.4
15.3
15.4
1.000
0.990
0.998
1.094
1.052
(0.838-1.141)
(0.832-1.136)
(0.918-1.244)
(0.888-1.206)
Bookman et al (2009) JCO 27:1419-1425
Ovarian cancer is not one disease
Köbel et al PLoS Med (2008) 5:332
Current view of ovarian cancer biology
KRas
Vaughan et al Nat Rev Cancer (2011) 11:719
PI3K
b-catenin
PTEN
ARID1A
PI3K
IL-6/HIF1a
p53
BRCA1/BRCA2/HRD
Rb
PI3K/Ras
TRAMETINIB in low grade serous
ovarian cancer (LOGS) Study
CI: Charlie Gourley - Edinburgh
LOW GRADE SEROUS OVARIAN CANCER
Well-diff grade I low-grade
• 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 2008
Wong Ket al, AM J Path 2010
Pearce et al, Lancet Oncol 2012
DISTINCT SOMATIC MUTATIONS IN LOWGRADE AND HIGH-GRADE SEROUS
CARCINOMA
KRAS/BRAF/ERBB2 Mutation
%
ERBB2
12 bp ins
%
75
TP53 Mutation
75
50
BRAF
BRAF
50
KRAS
KRAS
?
SBT
LG
HG
25
25
SBT
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.
LG
HG
cadherin
mutations ERRB2
LOW-GRADE SEROUS CA
RTK
b-catenin
mutations
KRAS PI3K
mutations
BRAF
PTEN
AKT
b-catenin
mTOR
MEK
b-catenin
cyclin E
MAPK (ERK)
LEF/TCF
cyclin D1 GLUT1
TP53
progression
survival
proliferation
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)
NICC: Nintedanib in Clear Cell Cancer
CI: Ros Glasspool, Glasgow
International CI: Mansoor Mirza, Copenhagen
SGCTG/NCRI/NSGO
EORTC/GINECO
Histologically Distinct
First described in 1939 as mesonephroma ovarii
Ccells arranged in tubules, nests or cysts,
Clear, glycogen rich cytoplasm.
Immunophenotype: ER and WT1 -ve
High Grade Serous
Clear Cell Carcinoma
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
‘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.’
Rahman et al (2012) Hum Pathol 43:2179
Interleukin-6 and ovarian cancer
Proliferation
Platinum resistance
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
Plasma IL-6 (pg/ml)
CRP as biomarker of IL-6 levels
25
20
15
Spearman r= 0.869
10
5
0
0
20
40
60
80 100 120
CRP
CRP
100
10
LLOQ
1
2
3
4
5
6 6 10 14 18
Time (weeks)
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
Trial Design
Chemotherapy
90 pts with
progressive or
relapsed CCC of
ovary within 6
months of
previous
platinum.
Plus up to 30
women with
endometrial CCC
R
A
N
D
O
M
I
S
E
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 Aims
Investigate:
• 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 Challenges
1. Money
NICCC sample collection alone = £91,000
24 tumour biopsies = £20,000
Courier costs = £47,000
Likely cost of translational research = £1,500,000
Whole genome sequencing = £2000 each
Bioinformatician to analyse = £60,000 p.a.
2. Infrastructure
-80 freezers and centrifuges
3. Quality
Plasma processing across 8 countries…
The Primal Scream moments
1. Unnecessary hurdles
Appallingly slow bureaucracy
2. Human tissue legislation
Frankly Kafka-esque and byzantine
The utterly random – e.g. no sample is allowed to leave Germany
3. Custodianship
Who 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’
‘It’s like wading through treacle’
1. 14th Feb 2011
Investigator requests access to FFPE samples from large trial
2. 6th October 2011
TMG writes to investigator to confirm access permitted
3. 18th April 2012
Researcher receives release agreement contracts from TMG
4. 17th July 2012
Decision made that 3rd party company required to cut samples
5. 29th January 2013
Contracts signed for block cutting
6. March 2013
Investigator still not received any samples.
Translational researcher after meeting with
tech-transfer/regulatory affairs team
Ownership and IP
1.
2.
3.
4.
5.
6.
Company M owns the patent on germline mutation testing.
Clinical trial – funded by Charity C
All patients gave blood for germline DNA analysis
Trial sponsor – NHS
Samples now at University I
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