NEUROBLASTOMA OVERVIEW
Neuroblastoma Background
What is Neuroblastoma? Cancer of neural crest cells that give rise to sympathetic neural ganglia and adrenal medulla.1
NEURAL CREST CELLS Endoderm
NEUROBLASTOMA OVERVIEW
Diverse pattern of presentation and prognosis that can range from spontaneous regression to aggressive metastatic tumors.1
Melanoblasts ECTOMESYNCHYMAL CELLS
Osteoblasts
Fibroblasts
Chondroblasts
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REFERENCES
Ectoderm
1| Irwin, M.S., & Park, J.R. (2015). Neuroblastoma: Paradigm for precision medicine. Pediatric Clinics of North America, 62(1), 225-256.
Odontoblasts
Cementoblasts
Schwann Cells
NEUROBLASTS
Sympathetic Neuron Sensory Neuron
Motor Neuron
Please see continued Important Safety Information for Unituxin on slides 4-10.
Neuroblastoma Risk Classification: HISTOPATHOLOGY
NEUROBLASTOMA OVERVIEW
The International Neuroblastoma Pathology Classification (INPC) system used to designate whether the tumor tissue has favorable or unfavorable histologic features.1
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tissue samples
Undifferentiated
Stroma-poor
Unfavorable Histology
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Neuroblastoma
REFERENCES
1| Armideo, et al. J Adv Pract Oncol, 2017;8:44–55, https://doi.org/10.6004/jadpro.2017.8.1.4, 2| Image from Ohio State University, http://www.bmi.osu.edu/cialab/mia_nb.php
Differentiating
Stroma-rich
Favorable Histology
Please see continued Important Safety Information for Unituxin on slides 4-10.
Neuroblastoma Risk Classification: DNA INDEX1
Favorable
X2 NEUROBLASTOMA OVERVIEW
46
HYPERDIPLOID: More than 46 chromosomes DNA index >1
Unfavorable
HYPODIPLOID: Less than 46 chromosomes DNA index <1
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REFERENCES
1| Irwin, M. S., & Park, J. R. (2015). Neuroblastoma: Paradigm for precision medicine. Pediatric Clinics of North America, 62(1), 225-256.
Please see continued Important Safety Information for Unituxin on slides 4-10.
Neuroblastoma Risk Classification: MYCN AMPLIFICATION1
NEUROBLASTOMA OVERVIEW
MYCN: Oncogene on chromosome 2 MYCN amplification is a poor prognostic Indicator
MYCN = v-myc avian myelocytomatosis viral oncogene neuroblastoma-derived homolog.
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Unfavorable
MYCN
Detected by using FISH with MYCN-labeled probe
Considered “amplified” if
10+ copies are identified
FISH = Fluorescence in situ hybridization REFERENCES
1| Irwin, M. S., & Park, J. R. (2015). Neuroblastoma: Paradigm for precision medicine. Pediatric Clinics of North America, 62(1), 225-256.
Please see continued Important Safety Information for Unituxin on slides 4-10.
The Antibody Therapy Team Unituxin® (dinutuximab) Injection
Unituxin is a chimeric anti-GD2 monoclonal antibody consists of “multiple parts” part human, and part mouse
meaning having one clone, man-made
MURINE
Chimeric anti-GD2 monoclonal antibody
NEUROBLASTOMA OVERVIEW
HUMAN MOUSE
100%
CHIMERIC
33%
HUMANIZED
10%
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REFERENCES
1| Yang et al. Drugs Future. 2010;35(8)665. 2| Ward et al. CA Cancer J Clin. 2014;64(2):83-103.3| Cohn et al. J Clin Oncol. 2008;27(2):289-297. 4| American Cancer Society. Survival rates for neuroblastoma based on risk groups. http://www.cancer.org/cancer/neuroblastoma/detailedguide/neuroblastoma-survival-rates. Revised January 22, 2016. Accessed April 13, 2016. 5| Irwin, M. S., & Park, J. R. (2015). Neuroblastoma: Paradigm for precision medicine. Pediatric Clinics of North America, 62(1), 225-256.
Pretreatment and Guidelines for Pain Management1 TIMELINE
Sodium Chloride Injection, USP (0.9%; 10 mL/kg IV infusion)
1hr
before
before
10-20hrs
2hrs
Unituxin treatment
After
These guidelines are based on protocol from the COG-ANBL0032 study
For 1hr
Antihistamine 0.5-1.0 mg/kg diphenhydramine (50mg maximum) IV infusion
Acetaminophen* NEUROBLASTOMA OVERVIEW
20min
(10-15 mg/kg; maximum dose 650 mg)
Morphine sulfate†‡ (50 μg/kg IV infusion; then 20-50 μg/kg/h continuous IV infusion)
IV=intravenous; USP=US Pharmacopeia. * Administer ibuprofen (5-10 mg/kg) q6h as needed for control of persistent fever or pain. † Consider using fentanyl or hydromorphone if morphine sulfate is not tolerated. ‡ If pain is inadequately managed with opioids, consider use of gabapentin or lidocaine in conjunction with IV morphine. § Up to once every 2 hours followed by an increase in the morphine sulfate infusion rate in clinically stable patients.
q4-6hrs as tolerated
q4-6hrs as needed for fever or pain
IMMEDIATELY PRIOR
Administer additional doses (25-50 μg/kg) as needed§
17.5 mg/m2/d IV infusion
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REFERENCES
1| Unituxin [package insert]. Research Triangle Park, NC: United Therapeutics Corporation; 2015.
Please see continued Important Safety Information for Unituxin on slides 4-10.
Antibody Therapy Treatment Overview:1,2 The Unituxin antibody therapy regimen is
6
cycles in length
Cycles 1
2
3
4
5
Unituxin
Unituxin
Unituxin
Unituxin
Unituxin
GM-CSF
IL-2
GM-CSF
IL-2
GM-CSF
RA
RA
RA
RA
RA
~1
month
NEUROBLASTOMA OVERVIEW
GM-CSF = granulocyte-macrophage colony-stimulating factor; IL-2 = interleukin 2; RA = 13-cis-retinoic acid. Adapted from Yu et al.1
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REFERENCES
1| Unituxin [package insert]. Research Triangle Park, NC: United Therapeutics Corporation; 2015. 2| Yu et al. N Engl J Med. 2010;363(14):1324-1334.
6 RA
CLINICAL TRIALS DATA
Side Effects Reported from ANBL0032 Please see continued Important Safety Information for Unituxin on slides 4-10.
Study Design1,2
Randomization ITT 1:1
Overview:
CLINICAL TRIALS DATA
Randomized, openlabel, multicenter trial to determine whether adding dinutuximab, GM-CSF, and IL-2 to standard isotretinoin therapy after intensive multimodal therapy improves outcomes in patients with high-risk neuroblastoma Efficacy End Points:
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Primary, event-free survival; Secondary, overall survival REFERENCES
n=226
RA
Unituxin/RA
X5 Ch14.18 GM-CSF
X6 RA only
or IL-2 RA
X1 RA only n=113
1| Yu et al. N Engl J Med. 2010;363(14):1324-1334. 2| Data on file. United Therapeutics Corporation. Research Triangle Park, NC 27709. March 2014.
GM-CSF = granulocytemacrophage colonystimulating factor; IL-2 = interleukin 2; RA = 13-cis-retinoic acid.
n=113
Please see continued Important Safety Information for Unituxin on slides 4-10.
WIP
Selected Adverse Events by Treatment Cycle in Patients Receiving Unituxin® (dinutuximab) Injection1* Key
Side Effect
All Grades
Pain-related AEs†
Grades 3-4
* Adverse events (all grades) occurring in ≥5% of patients
CLINICAL TRIALS DATA
Capillary leak syndrome‡ ‡ Grade 5 adverse reactions occurred in 1 patient only with IL-2.
Injection
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REFERENCES
need data
Cycles 1
2
3
4
5
6
49% 28%
† Grade 3 pain refers to pain or severe pain or use of analgesics severely interfering with activities of daily living; Grade 4 pain refers to disabling pain.
Hypersensitivity reaction
FPO
6%
25%
15% <5%
7%
10%
Unituxin GM-CSF RA
Unituxin IL-2 RA
1| Data on file. United Therapeutics Corporation. Research Triangle Park, NC 27709. March 2014.
GM-CSF=granulocyte-macrophage colony-stimulating factor; IL-2=interleukin 2; RA=13-cis-retinoic acid.
7% Unituxin GM-CSF RA
35% 17%
13%
13% Unituxin IL-2 RA
5%
5%
<5%
<5%
<5%
Unituxin GM-CSF RA
RA
Please see continued Important Safety Information for Unituxin on slides 4-10.