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

…