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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. - PowerPoint PPT Presentation
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Tackling Orphan Diseases in Pediatrics
Kim Kramer, MDAssociate Member
Departments of PediatricsMemorial Sloan-Kettering Cancer Center
New York
Sophie Davis School of Biomedical Education Research Conference
November 12, 2013
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.
Barrier to Cure: Increasing Incidence of CNS Metastases from Solid Tumors, 10-20% overall
Radioimmunotherapy for Pediatric
Cancers
A Bold Question
Can we cure an incurable cancer in the brain?
8H9
• 8H9- IgG(1) targets B7H3
• labeled by iodogen, retains immunoreactivity, 50 mCi 131I/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
1h 2d
Targeting the sanctuary site with radioimmunotherapy (RIT)
•Safe
•Outpatient setting
ObjectivesPrimary:• 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
• 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
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
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-3F8 62.5 cGy/mCi: 1.5– 131I-8H9: 49.7 cGy/mCi: 2.7
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 131I-MoAb*
↓
3F8/GM-CSF
↓
Temodar po
Accutane po
PFS 10 yrs+ since CNS NBPFS 8 yrs since CNS NB
Patient #1: Patient #2:
Salvage Regimen Salvage Regimen
Patient #1:LM MB, PFS at 6 years,
Salvage Regimen
Patient #2: LM tRB. CSF+, PFS at 8 years
Pt #1
Multifocal CNS NB
MRI brain/spine: extensive cerebral, cerebellar, spinal, intraocular lesions
Ophthalmology Exam Left eyeRight eye
Multifocal CNS NBJAMA Opthal 2013
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 evaluationrisk of secondary malignancies (t-AML, secondary CNS)short stature
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
124I-8H9 delivered by CED
“Team Science”
124I-8H9 binding to the tumor: Imaged by PET scanner
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
Dose Level
mCi
NmCi/mg 8H9
Infusion rate
Infusion Volume
Infusion time (min)
1 0.25 3-6 1.8-2.2 <10 l/min ~250 l ~25 -50
2 0.5 3 - 6 1.8-2.2 <10 l/min ~500 l ~50 – 100
3 0.75 3 - 6 1.8-2.2 <10 l/min ~750 l ~75 – 150
4 2.50 3 - 6 1.8-2.2 <10 l/min ~2500 l ~284 – 523
5 3.25 3-6 1.8-2.2 <10 l/min 3250 l 359 – 673
6 4.00 3-6 1.8-2.2 <10 l/min 4000 l 434 - 823
•Target accrual: 24 patients•6 Dose Levels
Study
Design
Serial PET-CTs, Days 0, 2, 4, 6, 8
Serial PET-CTs, Days 0, 2, 4, 6, 8
Results
Lesion, Brain, Red Marrow, and Total-Body Absorbed Doses
Mean Absorbed Dose (rad)
Brain and Head
Patient LesionPeri-
lesion Shell*
Caudate Nucleus
Cerebral
Cortex
Cranium Eyes Lent
Nucl Thalami White Matter
Red Marrow
Total Body
Dose Level 1: 250 Ci
Pt 1 CD 98 38 0.27 0.59 0.59 0.072 0.29 0.44 0.37 0.13 0.16Pt 2 JF 61 23 0.24 0.53 0.53 0.065 0.26 0.39 0.34 0.14 0.19Pt 3 BL 208 82 0.92 2.1 1.9 0.22 1.0 1.5 1.3 0.48 0.061
Dose Level 2: 500 Ci
Pt 4 RD 438 199 2.7 0.59 0.59 0.73 2.8 4.4 3.7 1.0
Pt 5 CW 33 16 0.015 0.034 0.032 0.0038 0.016 0.024 0.022 0.63 0.60Pt 6 HU 521 211 3.0 0.66 0.66 0.82 3.2 5.0 4.2 0.44 0.66Pt 7 EW 267 122 0.34 0.76 0.70 0.082 0.37 0.56 0.48 0.92 0.72
Mean 699 328 1.28 1.2 1.2 0.34 1.4 2.1 1.8 0.46 0.48SD 1,160 574 1.16 1.10 1.02 0.32 1.2 1.9 1.6 0.30 0.35
* < 5 grams of normal brain
Lesion doses: ~100-1,000 rad
Normal-tissue (including Brain) doses: ~1 rad
<< Threshold for any
acute effect
Mean Absorbed Dose (rad)
Patient Lesion Spinal Cord
Stomach Wall
Heart Wall Kidneys Thyroid
Urinary Bladder
wall
Dose Level 2: 500 Ci
Pt 4 RD 438 0.058 2.0 1.1 0.56 1.4 0.99
Pt 6 HU 521 0.12 0.14 0.22 0.035 1.2 0.033
Pt 7 EW 267 0.31 0.69 0.68 0.43 0.53 0.64
Mean 409 0.16 0.94 0.67 0.34 1.0 0.55
SD 130 0.13 0.96 0.44 0.27 0.46 0.48
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
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?
Reaching Children Worldwide
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
Overcoming Barriers
hu3F8hu3F8
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 ACTCREATING HOPE ACT
Priority Voucher ProgramTropical
DiseasesPres Bush, 2007
Priority Voucher ProgramTropical
DiseasesPres 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
voucherVoucher value: up to
$500 million
Priority Voucher from FDA
for any unrelated drug or may sell
voucherVoucher 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 pharmOffers the best chance of encouraging pharm to develop treatments for children 1) no cost to taxpayers 2) profitable for pharm
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
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
Commitment
At the Federal Level:
FDA-Orphan Drug Program
National Institutes of Health
Congressman Michael McCaul
Congressman Chris Van Hollen
Childhood Cancer Caucus
New York : Challenges and Miracles
NEW YORK: CHALLENGES AND MIRACLES
Field of Dreams
Team
Gat
herin
g
*The H
istoric
ally
U
nderserve
d
…
