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CANM Annual Scientific Meeting 2016 Pamela Zabel, MSc Pharm Assistant Professor No Financial Interest I do not have 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 Topics Ideal Tx RP 131 I sodium iodide 131 I MIBG 90Y Theraspheres 223Ra chloride 89Sr chloride 177Lu DOTATATE (comprehensive Radioisotope Tx Session 6: 1:30-5 pm Saturday) Properties of Ideal Therapeutic Radiopharmaceutical 1. Type of Emission 2. Energy 3. Effective t ½ 4. Target to Non-target ratio 5. Internal Radiation Exposure Patient & External Radiation Exposure Public 6. Expense and Availability 7. Purity, Sterility, Apyrogenicity (hrdays) (internaliz’n auger) $$$ Health Canada Approval Provincial Reimbursement HTA Budget silos Oncology/Imaging Sodium Iodide-131 Production Fission U-235 (byproduct of Mo-99 production nuclear reactors) U-235 (n,f) Te-131 (30 hr) I-131 192 keV beta364 keV gamma (I-127 3-4X concentration) Emissions 89% 81% 90% of radiation dose 10% of radiation dose Half-Life 8.04 days Solution clear, colourless 0.2% thiosulfate (reducing agent, keep Iodide in ionic form) avoid air space and air contact CO2 + H2O H2CO3 acidic pH volatile I2 pH 7.5 - 9.0 (slightly basic) , phosphate buffer, EDTA stabilizer Capsules Hard gelatin capsule with phosphate buffer NOTE: No concerns iodine or sulfur allergies. Iodide mass < iodide in normal salt consumption Thiosulfate natural breakdown product AA (2-17mg urine/24hr) SNM Practice Guidelines http://snmmi.files.cms-plus.com/docs/I-131_V3.0_JNM_pub_version.pdf Sodium Iodide-131 t½ = 11.43 days 95.3% emitted as α particles 3.6% emitted as β particles 1.1% emitted as γ or X-rays Calcium analogue Highly focused irradiation tumour mets Less irradiation of bone marrow than beta Pharmaceuticals Blocking Radioiodine Uptake SNM 2012 guidelines http://snmmi.files.cms-plus.com/docs/I-131_V3.0_JNM_pub_version.pdf Dietary Sources of Significant Amounts of Iodine SNM 2012 guidelines http://snmmi.files.cms-plus.com/docs/I-131_V3.0_JNM_pub_version.pdf 131I MIBG (iobenguane) 131I MIBG (iobenguane) Uptake Mechanism (A) NET1 Norepinephrine transporter Type 1 (Active transport) Localizes • Adrenergic tissues • Catecholeamineproducing tumours & mets • Palliative Therapy • High Risk Neuroblastoma • Pheochromocytoma • Paraganglioma • Expanded Access protocol 131I MIBG (iobenguane) Normal uptake • Liver, spleen, salivary glands, myocardium, adrenal medulla, colon, bladder (thyroid) Excretion • Kidneys, large bowel • 40-55% 24 hr urine • 70-90% 4 days • 5-18 mCi/kg • 90-120 min • If >12 mCi/kg stored stem cells 13 y.o. Female Neuroblastoma • right retroperitoneal recurrence • Multiple bone Kayano K Kinuya S, http://dx.doi.org/10.1155/2015/189135 131I • • • • • • MIBG (iobenguane) Tx Side Effects Nausea and vomiting (24-48 hrs) Hypertension Short-term loss of appetite Jaw pain (parotid gland swelling)and/or dry mouth Discomfort from the urinary Foley catheter Decreased platelets and neutrophils Late effects • Hypothyroidisms 5-20% pts • Secondary malignancies 3-5% pts • Myelodysplastic syndrome • AML MIBG Tx High Dose Neuroblastoma pediatric • Sick Kids Hospital 2014 MIBG suite • St Justine Montreal • London • https://www.sickkids.ca/pdfs/centres/gfcc/60936SickKids%20MIBG%20Parent%20Education%20Guide.pdf EANM drug interactions MIBG See withdrawal time recommendations each drug Eur J Nucl Med 35:1039-1047, 2008 Sympathomimetics Calcium channel blockers Decongestants Antipsychotics Tricyclic antidepressants CNS stimlulants Y-90 Theraspheres BTG UK (manuf Nordion) Y-90 Theraspheres BTG UK (manuf Nordion) Hepatocellular Ca Glass microspheres 20-30 um (i.a. liver) 1.2-8 million /dose over 5 min via hepatic artery Transartertial embolization Tc-99m MAA imaging ensure no shunting->lungs/GIT Interventional radiology BC, Montreal, Edmonton, London Licensed Canada and Europe HCC c/s Portal Vein Thrombosis Liver neoplasia FDA “Humanitarian Device” brachytherapy device Y-90 64.1 hr t ½ Beta- avg 0.937 Mev Y-90 glass microspheres comparison to human hair Patient Flow Y-90 Theraspheres Y-90 Theraspheres Patient Selection Non-infiltrative tumour type <70% bulk disease or tumour nodules “countable” AST/ALT < 5X ULN Tumour volume <50% and albumin >3 g/dL Bilirubin < 2 mg/dL HCC: <50% tumour burden, no ascites, N bilirubin, albumin > 3 g/dL Liver mets pt: ECOG 1-2, Karnofsky > 60%, liver only/dominant, completed chemo Y-90 glass microspheres comparison to human hair Tumour Vascularity Pretreatment angiogram demonstrating hepatic vein (hyperdynamic) flow Atassi et al. Radiographics 2008;28 (1): 81-99 45 day post-treatment angiogram demonstrating elimination of tumor vascularity while preserving normal parenchymal flow slide from Theasphere EU slidedeck Lung Shunt Fraction 150 MBq Tc-99m MAA injected microcatheter hepatic artery after coil embolization of all visiible non-hepatic arterial blood flow Ant and posterior ROI Lung and liver to determine geometric mean LSF = lungs/(liver+lungs) *100% Dose Calculation Y-90 Theraspheres Amount of radioactivity required to deliver the dose to the liver target is calculated using the following formula: Activity Required = (GBq) [Desired Dose (Gy)] [Liver Mass* (kg)] 50 This excludes the lung fraction (F) as measured by Tc-99m MAA. Equation Corrected for F: Activity Required = (GBq) [Desired Dose (Gy)] [Liver Mass* (kg) ] 50 [1-F] Examples 120 Gy dose, Liver Mass of 1301 ml (CT) x 1.03 G/ml = 1.34 kg 10% lung shunt F=0.1 Calculated Activity with 1% residual waste Possible Treatment Window and Dose Vial Y-90 Theraspheres Y-90 Theraspheres 5 High Risk Factors pre-Tx A retrospective study (121 patients from 5 clinical trials) Risk factors associated 48% serious ADR & 11/12 deaths infiltrative tumor type “Bulk disease” (tumor volume > 70% liver volume, or tumor nodules too numerous to count) AST or ALT > 5 times ULN bilirubin > 2 mg/dL tumor volume > 50% combined with albumin < 3 g/dL 89Sr chloride Metastron (GE Amersham) Bone pain palliation skeletal mets 89Sr chloride, reactor produced, room temp storage, t ½ 50.6 days, beta emax 1.43 MeV Bone Pain palliation skeletal metastases SrCl2 148 MBq dose injected iv 1-2 min Hydration 500 ml + (oral) Hematology; pts predose platelet >60,000 and leukocyte > 2400 t ½ biological of 4-5 days (80% renal, 20% fecal) 30-35% bone 10-14 days (long retention osteoblastic regions) 89Sr chloride Metastron (GE Amersham) Combination tx low dose cisplatin/carboplatin improves pain palliation (91% response for pain palliation) Pts best if Karnofsky performance score (KPS) >60 significant pain relief similar to external beam radiotherapy, possibly more thrombocytopenia (Sr-89 and Sm-153 EDTMP covered CCO) initial pain relief ~ 3 days ( 25 days) 80% pts some relief (35% Osterhof 2003) 5-20% complete remission of pain 10% patients ↑ pain 3 d-7 3-6 month duration palliation 20-30% ↓drop platelets (nadir 5-6 wk, recovery 12 wk) Radium-223 chloride t½ = 11.43 days 95.3% emitted as α particles 3.6% emitted as β particles 1.1% emitted as γ or X-rays 223Ra 11.43 d α 5.78 MeV 219Rn 3.96 s α 6.88 MeV 215Po 1.78 ms Calcium analogue Highly focused irradiation tumour mets Less irradiation of bone marrow than beta α 7.53 MeV 211Pb 36.1 m 211Bi 2.17 m β− 1.37 MeV α β− (0.27%) 584keV 211Po 516 ms α 6.68 MeV (99.73%) 6.68 MeV 207Tl 4.77 m β− 1.42 keV 207Pb stable 223Radium-223 Xofigo® Bayer 6 mL in vial ( often 2 per pt LHSC..1-3) 6.6 MBq of 1100 kBq/ml (at reference date) (April 18, 2016 new NIST 10% Castration Resistent Prostate Cancer CRPC With symptomatic bone mets No known visceral metastatic disease 6 doses, once every 4 weeks Order deadline Tuesday 5pm for Wed-Friday the next week injection Blood results need to be checked by Oncology before order placed. Shelf-life: 28 days (typically 2 weeks after reference date) minor long lived radionuclide impurities *Actinium-227 (22 year t ½) Thorium-227 (18.7 day t ½) Health Canada approval: Dec 2013 Ontario Funding NDFP : March 9, 2015 BC and Quebec also have controlled reimbursement NIST primary standard adjustment (10% ↑ dose April 2016) Page 27 • Radium-223 Dichloride - Site Training V2.1 • Covance ↑) ALSYMPCA Phase III trial (approvals FDA/HC) Parker C et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369:213-223. Control pts tx : SOC radiation, glucocorticoid, antiandrogens ketoconazole, estrogens. Median time to first skeletal event 9.8 15.6 months Median OS 11.314.9 mo Median time to Opiod use 6.9 …longer Mean hospitalization days 14.6 8.1 Pharmacokinetics Ra-223 Blood time 15 4 72 min hr hr %ID 20 4 0.4 + 8% + 1% + 0.2% range 9-33% 2-6% 0.2-0.7% Pharmacokinetics Ra-223 Gastrointestinal Tract: Intestinal activity evident by 10 minutes Secreted from blood small intestine wall No Hepatic or hepatobiliary excretion Variable bowel transit times, 76% bowel elimination at 7 days 49% GIT at 4 hrs (19-69%) with 40% small intestine 59% GIT at 24 hrs (22-93%) with 45% ULI 52% GIT at 48 hrs (8-79%) with 17% LLI 33% GIT at 72 hrs (3-70%) Urinary Excretion 2% at 24, 48 hrs Bone Uptake 61% at 4 hr (44-77%) Only trace amounts in sweat, saliva (not like I-131) NO DOSAGE ADJUSTMENT • Renal Disease • Liver Disease • Hepatobiliary disease • ?bowel obstruction concerns Absorbed Dose Target organ mGy/3.65 MBq dose 73kg patient Whole body Osteogenic cells Red Marrow Stomach 84 4205 506 1 Small Intestine 27 ULI 118 LLI 170 Kidney 12 Bladder 15 http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Public_assessment_report/human/002653/WC500156174.pdf Clinical Trial ADR http://omr.bayer.ca/omr/online/xofigo-pm-en.pdf Required Haematology before product ordered! Patient Selection b/f 1st tx Neutrophils (ANC) Platelets Hbg > 1.5 X 10 9/l >100 x 109/l >10 g/dl Before subsequent tx Neutrophils (ANC) Platelets > 1.0 X 10 9/l >50 x 109/l If not recovered within 6 weeksreassess benefit/risk NM needs to know blood counts have been ok’d medical oncology prior to ordering doses. Patient instructions Radium-223 No restrictions related to external radiation and for contact with other people Follow good hygeine/handwashing Constantly 7 days after each dose Use condoms for sex Partner avoid pregnancy 6 months hydrate Flush toilet X 2 after use Wear gloves and then wash hands if anyone cleans up bodily fluids (fecal, vomit, urine) Seal Disposables in plastic for garbage Soiled underwear /clothing ->wash promptly & separately Sensitive Border Detectors 35 Lu-177 DOTATATE Continue saline and AA infusion Blanchet EM et al Pheochromocytoma and paraganglioma: Current Functional And future molecular imaging. http://journal.frontiersin.org/Journal/10.3389/fonc.2011.00058/full Renal and hematological toxicity? PRRT 177Lu-DOTA-Octreotate Peptide Radionuclidic Radiation Therapy 177Lu-DOTA-Octreotate (=DOTATATE) Luthera (AAA Advanced Accelerator Applications) Phase III trials progressive midgut carcinoid Orphan Drug Status Europe/USA (+Ga68 DOTATATE) LHSC 1999-2011 PRRT In-111 octreotide Tx + chemo SAP treatments 177Lu DOTATATE Nov 2011 Jun/Nov2013 Investigator CTA Safety Registry TrialsLuDOTATATE Approved Edmonton Mar 2013, London March 2014 London included Amino Acid solution as Investigational Drug 200 patients (50 done to date) 177Lu-DOTATATE LHSC Production/QC Cof A specification acceptance & release 2-3 hour Radiopharmacy Aseptic production/QC Sterile addition DOTATATE solution to isotope vial Heating 80 deg x 30 min 7 QC tests Sterile filtration final vial Assays, labelling, Patient doses Release for Patient use 2-3 patient doses assayed 2014 Radiation Safety In-patient Special therapy rooms lead lined C7 Males sit Flush 2X Hand sink wash Signage Room prep tech 30min Renal Protective Amino Acids Minimize Renal retention potential kidney radiotoxicity Basic AA 2.5% Lysine /2.5% Arginine saline Rotterdam study EJNM 30:9-15, 2003 Globally used 1 hr b/f LuDOTATATE & 1000 ml/5 hrs 177LuDOTATATE Infusion 30 min infusion Patient void after infusion Continue saline and AA infusion Radiation Level 1 m Radiation Reading 30 minutes after infusion,(+ void) 24 hours after imaging before discharge ~30 4-7 uSv/hr (7.4 GBq LuDotatate) Future AAA publication NETTER-1 trial PhaseIII trial, randomized preliminary results significant improvement PFS and survival FDA submissions Orphan Drug Canada timing? Collaborations? Provincial reimbursement IPSEN SSRT antagonist development CCO provincial trial partially funded Ontario Labour intensive, funding for Ga 68 generators Health Technology Assessments Is Globally impacting Reimbursement Norway • • • • • Clinical trials need to be designed with Control comparator arm New study Ra-223+abiraterone+pred in asymptomatic/mild mCRPC Standardized QOL, pain measurement, Patient reported outcomes needed Total costing evaluations need to be collected prospectively Health Technology Assessments need this info to authorize funding Britain NHS Fall 2015 decided to discontinue funding ($7500/tx monthx6) (+15 other drugs removed including Lu177 DOTATATE Conclusions therapeutic radiopharmaceuticals available to target cancer NB! Inclusion & exclusion criteria Multidisciplinary collabor’n medical oncologists Post therapy follow up for patients and ultimate outcomes are necessary Controlled studies needed for funding AUC Evidence Based Appropriate Use Criteria US Protecting Access to Medicare Act 2014 SNMMI Newsline Nov 2015:President Hossein Jadvar Jan 2017 : Reimbursement for Advanced Imaging Jan 2017 only if approved Appropriate Use Criteria (AUC) Evidence based evaluations of decision pathways Many NM studies lack evidence based AUC vs alternatives Urgent need NM AUC research (others ranking NM low) Bone scans malignant disease V/P embolism FDG Pet restaging Malignancy Hepatobiliary for abdominal pain SNMMI (EANM, CANM) need to focus on development evidence based NM AUC with literature review, randomized studies, impact on patient management, cost effectiveness Important NM research focus needed maintain NM clinical HTA used Ontario for FDG reimbursement new norm Need more Controlled Pt outcome studies (with/without NM) Questions? Experiences at other sites using Radium? (Bayer, Lise and Grace) Interactions with patients Med Oncologist/NM physician/NM Technologists Other questions? Ra-223 Contamination concern if internalized Gamma emission allows for contamination monitoring by standard gamma detector probes No alpha-radiation specific equipment needed to monitor for radium-223 Wipe tests Counter efficiency can be determined using authentic radium-223 dichloride sample* Contamination clean-up Decontomination solution with EDTA solution (eg RadiacWash) *Technical samples are provided on particular demand only Page 53 • Radium-223 Dichloride - Site Training V2.1 • Covance Thyrogen (recombinant TSH) Thyroid Remnant Ablation (JNM 47:648 2006) rhTSH Thyroid hormone withdrawal Stat.sig? T ½ eff thyroid remnant Blood radiation dose 3.7GBq 68 + 49 hr 48 + 53 hr yes 40 + 10 mGy 62 + 23 mGy yes Thyroid effective t ½ ↑ (longer retention) Blood clearance faster (lower) Better Target/Background Lower effective radiation dose Faster renal excretion (faster discharge hospital) (see JNM 49:1445,2008 and JNM 47:648,2006) Production Process: NORWAY 227Ac Actinium 227 generator • → 227Th → 223Ra 227Ac- generator t ½ 21.8 years Decay Thorium-227 • retained on generator with Ac-227 • t ½ 18.7 days Ra-223 • Equilibrium (~11 days ingrowth) • Ra-223 milked from generator • Purified, sterilization, QC, release • Ship globally Separate Radium-223 from Actinium-227 and Thorium227 Further purify Radium-223 Drug substance solution Formulate and autoclave: Drug Product Page 55 • Radium-223 Dichloride - Site Training V2.1 • Covance Manufacturer (IFE) Storage Facility Regional Hub Nuclear Medicine Frankfurt Airport Hospitals BOE Multiple Canadian Airports Shelf Life Day 0 Day 10 Order deadline Tuesday eve (cancel by Wed 430 pm) Day 15-25 Inject Wed-Fri Press release March 09, 2015 Bayer introduces Xofigo, a novel treatment for prostate cancer, now publicly funded for patients in Ontario Innovation creates a unique new option for patients with bone metastases as a result of metastatic castration resistant prostate cancer Bayer Inc. announces today the availability of Xofigo (radium Ra 223 dichloride) in Ontario, for the treatment of patients with castration-resistant prostate cancer (CRPC) with symptomatic bone metastases and no known visceral metastatic disease.i Sunnybrook Health Sciences, which was a lead Canadian clinical trial site, saw the first commercial patient in Ontario and will be one of several institutions to continue to make Xofigo available to patients. Public funding for Xofigo in Ontario will be administered through Cancer Care Ontario’s New Drug Funding Program, an important step for providing Ontario patients access to this new treatment. New Drug Funding Program Drug list & Eligibility Criteria https://www.cancercare.on.ca/common/pages/UserFile.aspx?fileId=343400 New Drug funding program (NFDP) created 1995 from Ontario Public Drug Programs Reimbursement drug costs to cancer centres, newer expensive IV cancer drugs for OHIP patients Drug cost only administered in hospitals (not clinics) outpatient (not in-patients) Health Canada approved indications only Evaluation by Ontario Drug Quality and Therapeutics Committee Rigorous Evidence based evaluation of efficacy, cost effectiveness compared to alternatives Supporting guidelines required 38 drugs, with restricted clinical criteria (includes Sr-89) CCO Eligibility Form https://www.cancercare.on.ca/common/pages/UserFile.aspx?fileId=327389 Approved drug list New Drug Funding Program & Eligibility Criteria https://www.cancercare.on.ca/common/pages/UserFile.aspx?fileId=343400 • • • CRPC with symptomatic bone mets/no visceral mets Eligibility forms submit CCO before tx start Medical/radiation oncologist consult req’d • • No combo cabazitaxel, enzalutamide or abriaterone Can combine with other therapies • If use Ra223 pre-Docetaxel no subsequent funding for post-Docetaxal tx. • Cancer centres Submit CCO eClaims monthly with supporting documents 59 Pharmacokinetics Ra-223 Blood clearance rate? Bone uptake rate? Major route of excretion? Timeline of excretion? Excretion through sweat? Contact concerns? Side effects? Side effect incidence? Radium-223 Waste Disposal After administration, the materials used in connection with the preparation and administration are to be treated as radioactive waste, stored in secure areas Radium-223 has a physical half-life of 11.4 days Final decay product is non-radioactive Pb-207 After 10 half-lifes, the activity has decayed to < 0.1 % of starting activity CNSC limits for Actinium-227 RN impurity Page 61 • Radium-223 Dichloride - Site Training V2.1 • Covance Decay Correction (Supplied to User) Time-zone-specific decay (DK) correction tables are provided to determine the administration volume on the day of administration Example for Europe (12 noon CET) Day from reference date -14 -13 -12 -11 -10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Physical decay factor 2.34 2.20 2.07 1.95 1.83 1.73 1.62 1.53 1.44 1.35 1.27 1.20 1.13 1.06 1.00 0.94 0.89 0.83 0.78 0.74 0.69 0.65 0.62 0.58 0.55 0.51 0.48 0.45 0.43 Page 62 • Radium-223 Dichloride - Site Training V2.1 • Covance Before the reference date, the activity is higher than certified activity Reference date: 6000 kBq radium-223 per vial After the reference date, the activity is lower than certified activity 177Lu-DOTATATE LHSC logistics LHSC Logistics CCO Interim Eligibility Form 1st dose Order 177Lu-chloride from IDB 2-3 weeks prior Isotope Production in Nuclear Reactor GMP production IDB Holland isotope precursor QC CofA GMP (2400 -3800 euros for 1-3 patients) Shipment FrankfurtTorontoLondon (1000 euros) GMP sterile precursor DOTATATE kit ApoteekA15 frozen GMP CofA Amino Acid Lysine/Arginine infusions (150 euros) Pharmacy( English labels)
