DWI Case Study - QIBA PDF- MRI Technical Committee. What is IMI?

Transcription

1 DWI Case Study - QIBA PDF- MRI Technical Committee QIBA Annual Meeting May 21, 2014 What is IMI? The Innovative Medicines Initiative (IMI) is the world s largest biomedical /healthcare public-private initiative It is a joint undertaking (JU) between the European Union and the pharmaceutical industry association EFPIA IMI supports precompetitive collaborative research projects whose results will accelerate the development of better and safer medicines for patients, and boost pharmaceutical innovation in Europe Each IMI project is resourced through a cash contribution to Eligible Entities 1 and a matching in-kind contribution from the efforts of staff in EFPIA members own laboratories The total budget for IMI is 2bn ( 1bn cash from the European Commission and 1bn in-kind from EFPIA Participants) IMI is an experiment! Can we transcend legal and cultural barriers so the public-private partnership delivers research that is innovative, internationally leading, and demonstrably improves drug development? 1 Eligible entities: Academia; Small-Medium Enterprises (SMEs) (EU definition); Patient organisations; Non-profit research organisations; Intergovernmental organisations 1

2 What is QuIC-ConCePT? QuIC-ConCePT (Quantitative Imaging in Cancer Connecting Cellular Processes to Therapy) is a precompetitive collaborative research project It is funded through the IMI process with a budget of 16m* Its Participants comprise 8 EFPIA members, 1 SME, and 14 academic /non-profit organisations (including EORTC and several major European Cancer Centres) It also includes collaborations with other companies with imaging device / tracer businesses The consortium was assembled 2010; agreements signed 2011 The project is live from to It will deliver fit-for-purpose qualified imaging biomarkers via a portfolio of innovative work including clinical and preclinical trials, advanced image analysis, tracer development and regulatory documentation *EFPIA in-kind 6.8m; non-efpia 9.2m (of which IMI cash = 7m) What is the unmet need for IBs in oncology? Good IBs not yet available for all the Hallmarks of Cancer 1 Some good IBs exist with good-to-excellent technical validation / qualification these are, therefore, low-medium priority for further investment Morphologic biomarkers, e.g., RECIST, TNM, PFS FDG-PET (Warburg effect) DCE-MRI / DCE-CT (tumour perfusion / permeability) High unmet need for well-qualified IBs to assess interventions that promote tumour cell death / apoptosis or prevent tumour cell proliferation IBs need to be technically validated for international multicentre trials in cancer centres suitable for typical Phase 1 oncology trials interpretable (especially no change in biomarker = ineffective drug ) 1 Hanahan & Weinberg, Cell 144 (2011) 646 2

3 What is the vision for QuIC-ConCePT? Aim is to qualify IBs of tumour cell proliferation, apoptosis, and necrosis that will allow drug developers to reliably demonstrate the modulation of these pathologic processes in tumours in patients in cancer clinical trials. By 2016, drug developers will be able to incorporate these IBs in Phase I trials of investigational therapies confident that the IBs are technically valid, measured change in the IBs faithfully reflects the desired change in the underlying tumour pathology (and no change in IB means no change in tumour pathology) can be deployed in multiple cancer centres in a robust, consistent, ethical, and cost-effective way acceptable to patients What IBs will QuIC-ConCePT qualify? IBs of tumour cell proliferation using 3 -deoxy-3 -[18F] fluorothymidine (FLT) PET IBs of tumour cell death using MRI apparent self-diffusion coefficient (ADC) of water protons IBs of tumour cell apoptosis using caspase PET tracer [ 18 F]ICMT-11 Exploratory objective to devise, evaluate, and introduce IBs of invasion and metastasis FLT a, ADC b already widely used; but mainly single-centre sometimes difficult in important anatomic sites (lung, liver) clinical study design and interpretation difficult particularly when IB is negative (which timepoint, which analysis?) a 42 oncology trials enrolling 1922 patients using FLT as a biomarker in clinicaltrials.gov (33/42 non-neuro) b 75 oncology trials enrolling 6071 patients using ADC as a biomarker in clinicaltrials.gov (53/75 non-neuro) 3

4 Link to QIBA PDF MR Technical Committee is working on a profile for DWI-MR Technical validation deals with same questions QIBA profile focus covers all body parts relevant for diffusion imaging European contributions, including oncology clinical research organization (EORTC) for multi-centre clinical trials Align activities internationally Benefit from potential clinical testing QuIC-ConCePT plans biological validation Activities Collaboration started December 2012 Ambition level 1 Ambition level 2 Ambition level 3 QuIC-ConCePTand QIBA exchange information and plans. Mutual advice. Duplication avoided. QuIC-ConCePTtrials either (a) use QIBA protocols or (b) document deviations with reasons As ambition level 1 but add: QuIC-ConCePTdata contribute to QIBA FDA submission. QIBA data support QuIC-ConCePTengagement with EMA As ambition level 2 but add: Joint funding (e.g. industry, US; EU, or 3 rd -country) secured for additional projects Joint activities on QIBA ADC phantom starting February aiming at a publication end of 2013 (submission), further use of phantom in future EORTC trials Invitation to QuIC-ConCePT specialists to contribute to profile writing on lung and liver and to share imaging protocols as validated in a clinical trial (EORTC) 4

5 Results eposter ISMRM CoV (A, 1.5 T) CoV (B, 3 T) CoV (C, 1.5T) PVP % b b b b b b A spherical phantom shell was 3D-printed with an outer diameter of 194 mm in order to fit into a wide range of MRI coils. Aqueous solutions of polyvinylpyrrolidone(pvp) were mixed in concentrations varying from 0 to 50% by mass PVP to vary the ADC of water protons (1), which exhibited monoexponentialdecay over a wide range of b-values. These solutions were poured into 20 ml polypropylene vials and arranged into a holding plate at the center of the phantom (Fig. 1a). To control temperature, the phantom was filled with ice water (2) and allowed to equilibrate overnight in a refrigerator. The following morning, prior to imaging, more ice was added to maintain the PVP solutions at 0 C, verified by a thermocouple with an accuracy of ±0.3 C. The phantom was imaged at three sites, as a collaboration between RSNA supported QIBA and IMI supported QuIC-ConCePT projects using 1.5 (A, C) and 3 T (B) scanners. A diffusion-weighted SS-EPI sequence with b-values of 0, 500, and 900 s/mm 2 was investigated. Scans were performed multiple times at each site during a single session in order to assess repeatability. Regions-of-interest (ROIs) were selected in the center of each vial and utilized to calculate ADC from b 0 -b 500 and b 0 -b 900 image sets. PVP is able to cover a wide range of physiologically-relevant ADC values. ADC results were consistent between inner-and outer-ring vials, indicating little spatial dependence (over approximately 35 mm). There was significant variation in the measured ADC of the 50% vials: this could be caused by low SNR due to shorter T2s, as well as to insufficient b-values to properly assess this most viscous solution. Susceptibility artifacts due to shell design were observed, but did not appear to adversely affect ADC measurements. Finally, results at 1.5 and 3 T were in agreement with one another, as were results calculated using the b 500 and b 900. Lessons learned Strong interest in collaboration by majority of subject matter experts Industry and EORTC desire truly international standardization Academic collaborators are mainly publication driven Project alignments should be planned ahead of project start or important milestones 5

6 Lessons learned Contributions to QIBA profile writing by QuIC- ConCePT specialists on selected paragraphs can be organized Testing of ADC phantom by QuIC-ConCePT group (external specialists) was easily doable based on clear instructions (imaging manual) Strategic decisions to be made by QIBA regarding: Collaboration with Clinical organizations like EORTC, ACRIN Collaboration with international peers, e.g., ESR Collaboration with public-private partnership organizations like IMI 6