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
•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
3F8
•
8H9- IgG(1) targets B7H3
•
3F8 - IgG(3) which binds to GD2
•
labeled by iodogen, retains
immunoreactivity, 50 mCi 131I/mg
8H9
•
intravenous 3F8: detection and
treatment of neuroblastoma
labeled with I-124 and I-131
8H9+
Neg Control
•
Targeting the sanctuary site with
radioimmunotherapy (RIT)
•Safe
•Outpatient setting
1h
2d
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
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
Pediatric Orphan Diseases Tackled To Date
>560 injections,140 patients
Primary CNS Tumors
Tumors Metastatic to the CNS
•Ependymoma
•Medulloblastoma
•Choroid Plexus Carcinoma
•Chordoma
•Atypical Teratoid
Rhabdoid Tumor
•Embryonal Tumor w/
Rosettes
•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
IMPROVED SURVIVAL CNS NB WITH INCORPORATION OF RIT
GTR
↓
CSI
↓
Temodar/CPT11
↓ +/- PBSCI
With intraOmmaya 131-I-MoAb
as adjuvant ;
J Neurooncol 2010;97(3):409-18.
↓
IT 131I-MoAb*
↓
3F8/GM-CSF
↓
Temodar po
Accutane po
Historical
Months from CNS detection of NB
Patient #1:
Salvage
Regimen
PFS 10 yrs+ since CNS NB
Patient #2:
Salvage
Regimen
PFS 8 yrs since CNS NB
Patient #1:LM MB, PFS at 6 years,
Patient #2: LM tRB. CSF+, PFS at 8 years
Pt #1
Salvage Regimen
Multifocal CNS NB
MRI brain/spine: extensive cerebral, cerebellar, spinal, intraocular lesions
Ophthalmology Exam
Right eye
Left eye
Multifocal CNS NB
JAMA 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 evaluation
risk 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
“Team Science”
124I-8H9
delivered by CED
124I-8H9
binding
to the tumor:
Imaged by PET
scanner
Objectives
PRIMARY
• To determine the maximum tolerated dose of 124I8H9
SECONDARY
• To estimate tissue radiation doses and volumes of
therapeutic distribution
• To assess the toxicity profile
• To assess overall survival
Study Design
•Target accrual: 24 patients
•6 Dose Levels
Dose
Level
mCi/mg 8H9
Infusion
rate
Infusion
Volume
Infusion
time (min)
mCi
N
1
0.25
3-6
1.8-2.2
<10 ml/min
~250 ml
~25 -50
2
0.5
3-6
1.8-2.2
<10 ml/min
~500 ml
~50 – 100
3
0.75
3-6
1.8-2.2
<10 ml/min
~750 ml
~75 – 150
4
2.50
3-6
1.8-2.2
<10 ml/min
~2500 ml
~284 – 523
5
3.25
3-6
1.8-2.2
<10 ml/min
3250 ml
359 – 673
6
4.00
3-6
1.8-2.2
<10 ml/min
4000 ml
434 - 823
Serial PET-CTs, Days 0, 2, 4, 6, 8
Serial PETCTs, Days
0, 2, 4, 6, 8
Results
Lesion, Brain, Red Marrow, and Total-Body Absorbed Doses
Mean Absorbed Dose (rad)
Brain and Head
Patient
Lesion
PeriCerebr
Caudate
Craniu
lesion
al
Eyes
Nucleus
m
Shell*
Cortex
Lent
White Red
Thalami
Nucl
Matter Marrow
Total
Body
0.16
0.19
0.061
Dose Level 1: 250 mCi
Pt 1 CD
Pt 2 JF
Pt 3 BL
98
61
208
38
23
82
0.27
0.24
0.92
0.59
0.53
2.1
0.59
0.53
1.9
0.072
0.065
0.22
0.29
0.26
1.0
0.44
0.39
1.5
0.37
0.34
1.3
0.13
0.14
0.48
Pt 4 RD
438
199
2.7
0.59
0.59
0.73
2.8
4.4
3.7
Pt 5 CW
Pt 6 HU
Pt 7 EW
33
521
267
16
211
122
0.015
3.0
0.34
0.034 0.032 0.0038 0.016
0.66 0.66 0.82
3.2
0.76 0.70 0.082 0.37
0.024
5.0
0.56
0.022
4.2
0.48
0.63
0.44
0.92
0.60
0.66
0.72
699
1,160
328
574
1.28
1.16
1.2
1.10
2.1
1.9
1.8
1.6
0.46
0.30
0.48
0.35
Dose Level 2: 500 mCi
Mean
SD
1.2
1.02
0.34
0.32
1.4
1.2
1.0
* < 5 grams of normal brain
doses: ~100-1,000 rad
 Lesion
 Normal-tissue (including Brain) doses:
~1 rad
<< Threshold for any
acute effect
Kinetics and Dosimetry
Results
Lesion and Normal-Tissue* Absorbed Doses - Dose Level 2
Mean Absorbed Dose (rad)
Lesion
Spinal
Cord
Stomach
Wall
Heart
Wall
Kidneys
Thyroid
Urinary
Bladder
wall
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
Patient
Dose Level 2: 500 mCi
* Identifiable on PET images
doses: ~100-1,000 rad
 Lesion
 Normal-tissue doses: ~1 rad
<< Threshold for any
acute effect
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
hu3F8
FDA Designated
Orphan Drug for
Neuroblastoma
Now in 3 different active
clinical trials at MSKCC
FDA Designated Orphan
Drug for Osteosarcoma
MultiCenter randomized
Expand to other GD2
expressing tumors?
Stem cells in
other malignancies?
CREATING HOPE ACT
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
Any orphan disease: sickle cell anemia,
Bipartisan Effort,
cystic fibrosis, pediatric AIDS,
Tay-Sachs disease, pediatric cancers
Pres Obama, 2011
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
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