QA & imaging biomarkers within the framework of clinical trials

L Fournier, Y Liu, N de Souza, P Bourguet For the Imaging Group - EORTC Imaging biomarkers in clinical trials: role

Clinical trial = validation of the imaging Imaging biomarker Imaging biomarker = endpoint of

2 Imaging biomarkers in clinical trials: role

Clinical trial = validation of the imaging biomarker Imaging biomarker Imaging biomarker = endpoint of clinical trial

3 Imaging biomarkers in clinical trials

• In oncology clinical trials: imaging is almost always present • “Endpoints for FDA approval in oncology drugs” Johnson, JCO 2003;21:1404-1411 • 1990-2002: 57 molecules approved • 18 (32%) on OS • 29 (51%) on response criteria or PFS  MEASURED ON IMAGING

4 Imaging biomarkers: interrogating biology

Diffusion MRI PET- FDG  Cellularity  Cell metabolism

MRSpectroscopy  Molecular composition

Perfusion imaging  Angiogenesis

BOLD MRI  Hypoxia O O2 2 O2

Hanahan & Weinberg, Cell 2011 Innovative imaging biomarkers: hurdles

• Upstream • Technical validation  understand the conditions for reliable quantification • Clinical trial • Complexity of imaging technologies • Safety issues related to new imaging contrast agents • Standardisation of image acquisition across multivendor platforms • Variable post-processing options Centers selected for their clinical not their imaging expertise

6 Upstream: technical validation

• Pre-clinical and clinical phase • Phantom studies • Repeatability (test-retest) • • Variability between machines • Variability between image processing techniques

Upstream: technical validation

ADC: apparent diffusion coefficient Repeatability studies 15-20% CV

Variability of ADC in abdomen Donati, Radiology 2009 Kim, Radiology 2010

Upstream: technical validation

QuIC-ConCePT (Quantitative Imaging in Cancer: Connecting Cellular Processes with Therapy) : an IMI funded project

• 18FLT-PET and ADC (1.5T and 3T) • Technical (and biological) validation • N De Souza, Institute of Cancer Research and Royal Marsden Hospital • Y Liu, EORTC

Upstream: technical validation Phantom studies

BW= 1776 Hz/px Courtesy of N De Souza

BW=2442 Hz/px

ADC profile

Fat suppression Ghosting Uniformity Upstream: technical validation

Test-retest & repeatability studies: after standardisation/optimisation

Courtesy of N De Souza

Variability of ADC in ovarian cancer <5%

Variability of ADC in lung (1.5T) <10% Routine biomarkers: size Thiam, Fournier ECR 2010 Reproducibility study: RECIST size criteria

RECIST 1.0 RECIST 1.1 Kappa Intra Inter Intra Inter Target 0.82 0.90 0.82 0.78 lesions

Non target 0.90 0.95 0.90 0.95 lesions

New 0.58 0.64 0.58 0.64 lesions Total 10-15 % Overall 0.73 0.76 0.80 0.73 response disagreement rate Routine biomarkers: renal function

Prigent Semin Nucl Med 2008

Clinical decisions What of Imaging QA

Routine imaging biomarkers Current QA Only relevant information

15 Current QA Not relevant with current scanners and reading stations

16 Current QA

17 What of Imaging QA

Advanced imaging biomarkers EORTC 62072/VEG110727 phase III clinical trial soft tissue sarcoma What must be avoided pazopanib vs placebo Hypothesis: patients with FDG-PET response (ΔSUVmax ≥ 25%), the PFS is 12 weeks longer than in patients without PET response Day -14 to -1 TKI Courtesy of Y Liu

• 44 patients enrolled • 36 BL/33FU PET with good visual quality • Low compliance to the imaging guidelines

required %compliance Actual Uptake Time BL 60 ±5 min 39% (15/35) 56-64 min

FU 60 ±5 min 51% (18/35) 56-64 min

BL+FU 60 ±5 min 31% (11/35) 56-64 min

<1/2 patients could be used for FU±5 min from 37% (13/35) 56-89 min quantitative assessment actual BL  No conclusion could be drawn due to FU±10 min from 60% (21/35) 56-89 min actual BL inadequate sample size. 19 EORTC infrastructure

Courtesy of Y Liu

Quality management system • ISO 9001:2000 (AFAQ) • ISO 13485:2003 (GMED) • Annex II section 3 directive 93/42/EEC (Europe) • CMDCAS SQ (Canada) • 510 (k) and the 21 CFR part 11 (US) 20 Easy image EORTC infrastructure uploading

direct information export from DICOM header Courtesy of Y Liu Local site from

Online quality control

Easy to measure

central review form

Automatic email contact to the sites and the manager team

21 Risk management for imaging biomarker-driven studies Trial related documents CLINICAL CENTERS P A Imaging agent production T Scan calibration I 2b. Obtain the accreditations before site activation 3. Enrollment E N INVESTIGOR Recruit and treat patients T 2a. Obtain the approvals of regulatory bodies

Quality Assurance & Quality Control CLINICAL

DATA 1. Trial development

IMAGING PLATFORM Liu et al, Lancet Oncol 2015

Central review 6. Imaging Imaging 6. analysis

Reader 1 Reader 2 Adjudicator Trial monitoring and management • Early engagement with experts • Preliminary data design • Understanding of biological mechanism • Selection of appropriate criteria • Early definition of statistical consideration Courtesy of Y Liu • Involving patient advocacy • Site selection Before site • Evidence of scanner calibration activation • Elaboration of standard operating procedures • Organization of imaging central review • Evidence of proper site training

• Data protection • Compliance electronic processes During accrual • Perform quality assurance and quality control • Data management and tracking • Documentation

At the end of • Closure of database the trial • Statistical analysis and report Conclusion

• We should be able to do better than size! • Metabolic imaging, Diffusion-weighted MRI • Involve imaging specialists when designing the trial • Choose the right technique, criteria & know its limits • Reasonable & manageable protocols (taking into account different levels of expertise) • Allocate resources ($$ and personnel) • Even advanced imaging is cheaper than most targeted therapies

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