CANM ACMN Annual Meeting April

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1 117 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 Rebecca Wong

2 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

3 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

4 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

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6 Lessons learned Pulling the pieces together Individualized dosimetry Clinical implementation across the consortium Early Experience

7 Supply DOTATATE Lu-177 Gallium Generators Supplier Australia Europe Europe Gallium generator Located at PET facility 10m life span Ga68 t1/2 68mins

8 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

9 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, , 2015 Region of interest

10 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

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12 Key dates Oct Ontario neuroendocrine expert panel first convened May 2012 Consortium approved Dec 2014 Funding approval April Pre Health Canada meeting Mar Lu 177 and Ga 68 DMF, protocol CTA to Health Canada May NOL received May OCREB provincial approval Jul PMH local activation Jul st patient registration Jul st Ga68 Aug st Lu177DOTATATE/AA produced and administered (PMH) Mar nd Site opened (London) April rd and 4 th Site had study start up meeting (Odette, Juravinski) 12

13 Early results (april ) 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

14 Patient impact of individualized dosimetry 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?

15 Renal dose delivery at treatment completion Total renal dose delivered within 10% of renal tolerance (23Gy) Support clinical integrity of individualized dosimetry

16 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 )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?

17 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, , 2016

18 Future Trial will complete accrual in 4 years (2021), primary outcome 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

19 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

20 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