117 Lu-DOTATATE & 68 Ga-DOTATATE A Prospective Single-Arm, Multi-Centre, Study of the Efficacy and Safety of 177 Lu- DOTATATE Treatment, with individualized dosimetry, in Patients with 68 Ga-DOTATATE PET identified Somatostatin Receptor Positive Neuroendocrine Tumours Cancer Care Ontario NET consortium & UHN experience CANM ACMN Annual Meeting April 20-23 2017 Rebecca Wong
CANM ANNUAL SCIENTIFIC MEETING APRIL 20-23, 2017 TORONTO, ONTARIO I have / had a financial interest, arrangement or affiliation including receipt of honoraria or expenses with a commercial organization that may have a direct interest in the subject matter of my presentation. University Health Network: Employer (Radiation Oncolosgist), PRRT Trial Sponsor Cancer Care Ontario : Trial Funder Centre for Probe Development & Commercialization (CPDC) CanProbe : manufacturer of Lu, Ga-dotatate
Objectives Gain insight into the design features of the CCO Lu177 Dotatate clinical trial Gain insight into the lessons learned through the first 6 months of trial operation Future directions of PRRT in Ontario
PRRT for Ontario Expert panel recommendations (2011) o Single arm trial o RN specific pt support o Tumor board o Centers of expertise/radiation safety o Radiopharmaceutical partner for sustainability Create a durable solution to PRRT access through a HC approvded clinical trial https://www.cancercare.on.ca/cms/one.aspx?portalid=1377&pageid=86867
Lessons learned Pulling the pieces together Individualized dosimetry Clinical implementation across the consortium Early Experience
Supply DOTATATE Lu-177 Gallium Generators Supplier Australia Europe Europe Gallium generator Located at PET facility 10m life span Ga68 t1/2 68mins
Sourcing the amino acids No commercially available Arginine/lysine products Constitution at sites? Constitution at central pharmacy (not a long term solution yet) Who, Where, How, Quality, Safety
Individualized dosimetry pt flow Lu 30m NM (Hr 4) NM (hr 24) NM Hr 72) Time range: 4+4h 24±6h 72±6h Amino acids (1 litre, 4hr) Inpt/outpt Rm Home Cycle 1 Cycle 2 D1 D2 D3 D4 Renal tolerance 23Gy cumulative Max 150% per dose standard max 800mCi ID max: 1100mCi Ljungberg et al Hybride Imaging for patient specific Dosimetyr in radionuclide therapy Diagnostics 5,296-317, 2015 Region of interest
Setting up individualized dosimetry Camera specific sensitivity factor Converting counts (from images) to dose Physics, math, computer programing, image repository, and radiation segmentation Verification for clinical use
Key dates Oct 19 2010 Ontario neuroendocrine expert panel first convened May 2012 Consortium approved Dec 2014 Funding approval April 7 2015 Pre Health Canada meeting Mar 31 2016 Lu 177 and Ga 68 DMF, protocol CTA to Health Canada May 13 2016 NOL received May 19 2016 OCREB provincial approval Jul 7 2016 PMH local activation Jul 15 2016 1 st patient registration Jul 20 2016 1 st Ga68 Aug 30 2016 1 st Lu177DOTATATE/AA produced and administered (PMH) Mar 21 2017 2 nd Site opened (London) April 2017 3 rd and 4 th Site had study start up meeting (Odette, Juravinski) 12
Early results (april 14 2017) 16 patients enrolled (1 London) 34 cycles delivered 27 gallium scans delivered o 15 1 st gallium and 12 2 nd Gallium 3 pt completed all 4 cycles Outcomes All patients tolerated treatment well 3 had Gd 3 toxicity (1 constipation, 1 dizziness) None attributable to treatment 1 pt died from progressive disease after cycle 1 was delivered 13
Patient impact of individualized dosimetry 1 2 3 4 200 300 300 300 200 256 200 146 200 300 300 300 140 130 60 200 129 55 200 300 300 200 300 200 200 300 200 300 200 132 200 200 200 200 200 Of 34 doses delivered, 21 are for repeat cycles 12/21 (57%) pts had dose escalation 6/21 (28%) pts had dose reduction 3/21 (14%) standard dose of 200mCi Permit isotoxic dose delivery Does this translate into improved response /reduced toxicity?
Renal dose delivery at treatment completion Total renal dose delivered within 10% of renal tolerance (23Gy) Support clinical integrity of individualized dosimetry
Dose to tumor Dose to selected tumors: median 16 (range 1-37) Gy Where data is available SD across cycles median 2.9 (ranged from 0.6-13)Gy suggesting dose to tumor reasonably consistent across cycles Does dose correlate with SUV uptake, somatostatin receptor density? Dose response effect? Retreatment risks? Combination with systemic therapy? Combination with external beam?
External Beam RT Dose (tumor, normal tissues) Accuracy Spatial relationship Dose response Quality of RT correlated with effectiveness Does it apply to PRRT? Ahmed et al radiosensitivity differences between liver metastases based on primary histology suggest implications for clinical outcomes after Stereotactic body radiation therapy IJROPB 95, 5, 1399-1404, 2016
Future Trial will complete accrual in 4 years (2021), primary outcome 2022. NDS (new drug submission to HC) if appropriate Other clinical indications for Lu177 dotatate (adjuvant, early metastatic, neoadjuvant, combined therapy?) Ontario set up for investigation and delivery of PRRT for other diseases? Collaborations
Take Home Message Ontario trial is not just a trial created the infrastructure/clinical expertise for radionuclide therapy in Ontario Early results suggest favorable toxicity profile Clinical impact from individualized dosimetry Set the stage for Ontario to make meaningful contribution and collaboration to defining role of PRRT for NET and other cancers
Acknowledgements CCO & staff, NET executive, Provincial NET chair PMHF CPDC/Canprobe/ Apolab/QIPCM/Ozmosis OTN Clinical & research depts radiation, medical, surgical, imaging, endocrine, pathology, contracts, clinical research Research (clinical) coordinators Patients CNET Dr. Jean- Mathieu Beauregard Site PIs Dr. David Laidley Dr. Sten Myrehaug Dr. Rosalyn Jeurgens