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Tackling Orphan Diseases in Pediatrics

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. Orphan Diseases.

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Tackling Orphan Diseases in Pediatrics

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  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.

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

  4. Radioimmunotherapy for Pediatric Cancers

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

  6. 8H9 3F8 3F8 - IgG(3) which binds to GD2 intravenous 3F8: detection and treatment of neuroblastoma labeled with I-124 and I-131 • 8H9- IgG(1) targets B7H3 • labeled by iodogen, retains immunoreactivity, 50 mCi 131I/mg 8H9 8H9+ Neg Control

  7. 1h 2d Targeting the sanctuary site with radioimmunotherapy (RIT) • Safe • Outpatient setting

  8. 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

  9. CNS RIT • 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

  10. 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

  11. 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 • 131I-3F862.5 cGy/mCi: 1.5 • 131I-8H9: 49.7 cGy/mCi: 2.7

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

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

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

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

  16. Ophthalmology Exam Left eye Right eye

  17. Multifocal CNS NBJAMA Opthal 2013

  18. 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

  19. 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

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

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

  22. Study Design • Target accrual: 24 patients • 6 Dose Levels

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

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

  25. ResultsLesion, Brain, Red Marrow, and Total-Body Absorbed Doses • Lesion doses: ~100-1,000 rad • Normal-tissue (including Brain) doses: ~1 rad << Threshold for any acute effect

  26. Kinetics and Dosimetry ResultsLesion and Normal-Tissue* Absorbed Doses - Dose Level 2 * Identifiable on PET images • Lesion doses: ~100-1,000 rad • Normal-tissue doses: ~1 rad << Threshold for any acute effect

  27. Preliminary Conclusions • CED with 124I-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 124I-8H9 be safely delivered to improve survival for pts with DIPG?

  28. Reaching Children Worldwide

  29. 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

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

  31. Priority Voucher Program Tropical Diseases Pres Bush, 2007 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 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 Offers the best chance of encouraging pharm to develop treatments for children 1) no cost to taxpayers 2) profitable for pharm

  32. 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

  33. 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

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

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

  36. Team Gathering Field of Dreams

  37. *The Historically Underserved …

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