1. Tackling Orphan Diseases in Pediatrics Kim Kramer, MD Associate Member Departments of Pediatrics Memorial Sloan-Kettering Cancer Center New York Sophie Davis School of Biomedical Education Research Conference November 12, 2013

2. Orphan Diseases A disease for which no drug therapy has been developed because the small market would make the research and the drug unprofitable May be a rare disease (prevalence< 200,000 people) May be common disease that has been ignored (TB, cholera, typhoid, malaria) : far more prevalent in developing countries than in the developed world.

4. Barrier to Cure: Increasing Incidence of CNS Metastases from Solid Tumors, 10-20% overall

5. Radioimmunotherapy for Pediatric Cancers

6. A Bold Question Can we cure an incurable cancer in the brain?

7. 8H9 8H9- IgG(1) targets B7H3 labeled by iodogen, retains immunoreactivity, 50 mCi 131 I/mg 8H9 3F8 3F8 - IgG(3) which binds to GD2 intravenous 3F8: detection and treatment of neuroblastoma labeled with I-124 and I-131 8H9+ Neg Control

8. 1h2d Targeting the sanctuary site with radioimmunotherapy (RIT) Safe Outpatient setting

9. Objectives Primary: to determine the response rate and overall survival of pts with high risk CNS tumors treated with RIT Secondary to assess toxicities of serial injections of RIT

10. Eligibility –recurrent CNS or LM Malignancy or high risk LM tumor at Dx –3F8 or 8H9 +reactive tumors tested on frozen tumor tissue by IHC CNS RIT

11. Pediatric Orphan Diseases Tackled To Date >560 injections,140 patients Primary CNS Tumors Ependymoma Medulloblastoma Choroid Plexus Carcinoma Chordoma Atypical Teratoid Rhabdoid Tumor Embryonal Tumor w/ Rosettes Tumors Metastatic to the CNS Melanoma Rhabdomyosarcoma Retinoblastoma Neuroblastoma

12. Toxicity Profile Transient headache, fever, vomiting common within 24 hrs of injection (self-limited, manageable with acetaminophen, anti-emetics) High mean CSF: blood ratio achieved – 131 I-3F8 62.5 cGy/mCi: 1.5 – 131 I-8H9: 49.7 cGy/mCi: 2.7

13. With intraOmmaya 131-I-MoAb as adjuvant ; J Neurooncol 2010;97(3):409-18. Historical Months from CNS detection of NB IMPROVED SURVIVAL CNS NB WITH INCORPORATION OF RIT GTR ↓ CSI ↓ Temodar/CPT11 ↓ +/- PBSCI ↓ IT 131 I-MoAb * ↓ 3F8/GM-CSF ↓ Temodar po Accutane po

14. PFS 10 yrs+ since CNS NB PFS 8 yrs since CNS NB Patient #1:Patient #2: Salvage Regimen

15. Patient #1:LM MB, PFS at 6 years, Salvage Regimen Patient #2: LM tRB. CSF+, PFS at 8 years Pt #1

16. Multifocal CNS NB MRI brain/spine: extensive cerebral, cerebellar, spinal, intraocular lesions

17. Ophthalmology Exam Left eye Right eye

18. Multifocal CNS NB JAMA Opthal 2013

20. Conclusions injections manageable in outpatient setting acute side effects self-limited favorable CSF:blood ratio survival improvement as consolidation long term side effects in survivors need to be monitored:  neurocognitive evaluation  risk of secondary malignancies (t-AML, secondary CNS)  short stature

21. DIPG Approximately 200 children per year/US,between 5-9 years of age 10-15% of all childhood CNS tumors Presentation rapid onset cranial nerve palsies and ataxia Inoperable; RT standard of care but palliative Uniformly poor prognosis, fatal; 90% children die within 12-18 months No advances in over 40 years

22. 124 I-8H9 delivered by CED “Team Science” 124 I-8H9 binding to the tumor: Imaged by PET scanner

23. Objectives PRIMARY To determine the maximum tolerated dose of 124 I- 8H9 SECONDARY To estimate tissue radiation doses and volumes of therapeutic distribution To assess the toxicity profile To assess overall survival

24. Dose Level mCi N mCi/mg 8H9 Infusion rate Infusion Volume Infusion time (min) 10.253-61.8-2.2 <10  l/min~250  l ~25 -50 20.53 - 61.8-2.2 <10  l/min~500  l ~50 – 100 30.753 - 61.8-2.2 <10  l/min~750  l ~75 – 150 42.503 - 61.8-2.2 <10  l/min~2500  l ~284 – 523 53.253-61.8-2.2 <10  l/min3250  l 359 – 673 64.003-61.8-2.2<10  l/min4000  l434 - 823 Target accrual: 24 patients 6 Dose Levels Study Design

25. Serial PET-CTs, Days 0, 2, 4, 6, 8

27. Results Lesion, Brain, Red Marrow, and Total-Body Absorbed Doses Mean Absorbed Dose (rad) Brain and Head PatientLesion Peri- lesion Shell* Caudate Nucleus Cerebr al Cortex Craniu m Eyes Lent Nucl Thalami White Matter Red Marrow Total Body Dose Level 1: 250  Ci Pt 1 CD98380.270.59 0.0720.290.440.370.130.16 Pt 2 JF61230.240.53 0.0650.260.390.340.140.19 Pt 3 BL208820.922.11.90.221.01.51.30.480.061 Dose Level 2: 500  Ci Pt 4 RD4381992.70.59 0.732.84.43.7 1.0 Pt 5 CW33160.0150.0340.0320.00380.0160.0240.0220.630.60 Pt 6 HU5212113.00.66 0.823.25.04.20.440.66 Pt 7 EW2671220.340.760.700.0820.370.560.480.920.72 Mean6993281.281.2 0.341.42.11.80.460.48 SD1,1605741.161.101.020.321.21.91.60.300.35 * < 5 grams of normal brain  Lesion doses: ~100-1,000 rad  Normal-tissue (including Brain) doses: ~1 rad << Threshold for any acute effect

28. Mean Absorbed Dose (rad) Patient Lesion Spinal Cord Stomach Wall Heart Wall KidneysThyroid Urinary Bladder wall Dose Level 2: 500  Ci Pt 4 RD4380.0582.01.10.561.40.99 Pt 6 HU5210.120.140.220.0351.20.033 Pt 7 EW2670.310.690.680.430.530.64 Mean4090.160.940.670.341.00.55 SD1300.130.960.440.270.460.48 Kinetics and Dosimetry Results Lesion and Normal-Tissue* Absorbed Doses - Dose Level 2  Lesion doses: ~100-1,000 rad  Normal-tissue doses: ~1 rad << Threshold for any acute effect * Identifiable on PET images

29. Preliminary Conclusions CED with 124 I-8H9 for pts with non –progressive DIPG appears safe (doses 0.25-0.75 mCi) No DLTs High tumor:non tumor ratio achieved Overall survival analysis ongoing ?what dose should be considered for phase II consideration Can enough RT via CED 124 I-8H9 be safely delivered to improve survival for pts with DIPG?

30. Reaching Children Worldwide

31. Where to go from here? Limitations of the Past Drug availability- never studied on multicenter/consortium trials IND regulatory restrictions- -cost of producing clinical grade drug -cost of Data Monitoring/Safety on consortium trials

32. Overcoming Barriers hu3F8 FDA Designated Orphan Drug for Neuroblastoma Now in 3 different active clinical trials at MSKCC FDA Designated Orphan Drug for Neuroblastoma Now in 3 different active clinical trials at MSKCC FDA Designated Orphan Drug for Osteosarcoma MultiCenter randomized FDA Designated Orphan Drug for Osteosarcoma MultiCenter randomized Expand to other GD2 expressing tumors? Stem cells in other malignancies? Expand to other GD2 expressing tumors? Stem cells in other malignancies? CREATING HOPE ACT

33. Priority Voucher Program Tropical Diseases Pres Bush, 2007 Priority Voucher Program Tropical Diseases Pres Bush, 2007 Pharm develops drug Tropical Diseases (malaria, TB, leishmaniasis) Pharm develops drug Tropical Diseases (malaria, TB, leishmaniasis) Priority Voucher from FDA for any unrelated drug or may sell voucher Voucher value: up to $500 million Priority Voucher from FDA for any unrelated drug or may sell voucher Voucher value: up to $500 million Creating Hope Act Bipartisan Effort, Pres Obama, 2011 Creating Hope Act Bipartisan Effort, Pres Obama, 2011 Any orphan disease: sickle cell anemia, cystic fibrosis, pediatric AIDS, Tay-Sachs disease, pediatric cancers 30 million US patients Any orphan disease: sickle cell anemia, cystic fibrosis, pediatric AIDS, Tay-Sachs disease, pediatric cancers 30 million US patients Offers the best chance of encouraging pharm to develop treatments for children 1) no cost to taxpayers 2) profitable for pharm

34. Commitment At MSKCC –Pediatrics: Drs Nai-Kong Cheung, Brian Kushner, Shakeel Modak, Ira Dunkel, Steven Gilheeney, Yasmin Khakoo, Kevin De Braganca; PNPs: Ester Dantis, Ursula Tomlinson, Cheryl Fischer, Mary Petriccione, Maria Donzelli, –Research Nurses and Data Managers: Lea Gregorio, Elizabeth Chamberlain, Samantha Leyco, Joseph Olechnowicz –Neurosurgery: Drs Mark Souweidane and Jeffrey Greenfield –Nuclear Medicine : Drs Steven Larson, Neeta Pandit-Taskar, Jorge Carrasquillo, Samuel Yeh –Medical Physics: Drs. Jason Lewis, Pat Zanzonico, John Humm –Radiation Safety: Christopher Horan –Radiation Oncology: Dr. Suzanne Wolden

35. Commitment At the National Level: Children’s Oncology Group Pediatric Brain Tumor Consortium (PBTC) New Approaches to Neuroblastoma Therapy (NANT) Other Major Pediatric Cancer Hospitals

36. Commitment At the Federal Level: FDA-Orphan Drug Program National Institutes of Health Congressman Michael McCaul Congressman Chris Van Hollen Childhood Cancer Caucus

37. New York : Challenges and Miracles NEW YORK: CHALLENGES AND MIRACLES

38. Field of Dreams Team Gathering

46. *The Historically Underserved …