translational research and clinical trials barriers in international trials including regulatory...

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