ROLE / RESPONSIBILITIES OF THE CLINICAL RESEARCH NURSE PRACTITIONER
CLINICAL TRIAL STATUS
CONCLUSIONS
WHERE DO WE GO FROM HERE?
Future advances for CED in DIPG treatment include:
• Choosing the right agents for infusion
• Developing better agents and treatment regimen
• Improving instruments and technique for easier and accurate surgical targeting
• New catheter designs
• Single catheter infusion system vs multi-catheter infusion system
• Better understanding and control of drug distribution, clearance and time sequence
• Development of computer models/algorithms to predict drug distribution
• Single infusion vs repeat infusions or prolonged infusion of the agent
REFERENCESBidros, D. S., Liu, J. K., & Vogelbaum, M. A. (2010). Future of convection-enhanced delivery in the treatment of brain tumors. Future Oncology, 6(1), 117-125.
Guisado, D. I., Singh, R., Minkowitz, S., Zhou, Z., Haque, S., Peck, K. K., . . . Thakur, S. B. (2016). A Novel Methodology for Applying Multivoxel MR Spectroscopy to Evaluate Convection-Enhanced Drug Delivery in Diffuse Intrinsic Pontine Gliomas. American Journal of Neuroradiology, 37(7), 1367-1373.
Vanan, M. I., & Eisenstat, D. D. (2015). DIPG in Children – What Can We Learn from the Past? Frontiers in Oncology, 5.
Warren K.E. (2012) Diffuse intrinsic pontine glioma: poised for progress. Frontiers in Oncology 2, 2012; 2:205.
Zhou, Z., Luther, N., Ibrahim, G. M., Hawkins, C., Vibhakar, R., Handler, M. H., & Souweidane, M. M. (2012). B7-H3, a potential therapeutic target, is expressed in diffuse intrinsic pontine glioma. Journal of Neuro-Oncology, 111(3), 257-264.
Zhou, Z., Singh, R., & Souweidane, M. (2016). Convection-Enhanced Delivery for Diffuse Intrinsic Pontine Glioma Treatment. Current Neuropharmacology, 15(1), 116-128.
MSK PROTOCOL 11-011
Convection Enhanced Delivery of 124I-8H9 for Diffuse Intrinsic Pontine Glioma: A Novel Surgical Approach Maria Donzelli, MSN, RN, CPNP,* Memorial Sloan Kettering Cancer Center, New York, NY
©2013, MSKCC
POST OPERATIVE CARE
OBSERVATION
• Neuro check hourly during 124I-8H9 infusion
• Daily: Neuro/ Physical Exam
• Monitor for DLTs (dose limiting toxicity)
MEDICATIONS
• Thyroid Meds: SSKI®(Saturated Solution of Potassium Iodide) / Cytomel® (Liothyronine) daily
• Steroids: +/- Dexamethasone
SCANS • MRI Brain SPECT w/w/o
• PET/CT or PET/MRI for dosimetry evaluation
LABS• Research Lab for PK
(pharmacokinetic) studies
• Daily: CBC, CMP, PT/PTT
RADIATION SAFETY • Follow radiation safety precautions
ANTICIPATED TOXICITIES/SIDE EFFECTS
LIKELY POSSIBLE RAREPain, discomfort at the incision site
Headache Double vision Coma
Nausea Wound infection
Weakness in facial muscles
Potentially uncontrollable seizures
Vomiting Seizures Difficulty speaking or swallowing
Death
Fever Myoclonus Weakness in arms or legs
Inaccurate infusion cannula placement
Loss of feeling in face, arms or other parts of the body, or difficulty walking or controlling movement
* There may be other side effects that are not predicted *
FOLLOW UP
MANDATED FOLLOW UPAfter hospital discharge, the patient will be seen weekly for one month (30 days) at MSK.
Week 1 Week 2 Week 3 Week 4Neuro Exam ■ ■ ■ ■Performance Score ■ ■ ■ ■Labs: CBC, CMP, PT/PTT
■ ■
Research Labs (radioactivity or antibody levels)
■ ■
Labs: TSH ■PET/CT or PET/MRI ■MRI Brain ■Suture Removal ■Thyroid Protection Meds
■ ■
RECOMMENDED FOLLOW UP AFTER DAY 30
Monthly visits for physical / neuro exam, performance score for life with the local team
MRIs at the discretion of the primary oncologist; copy of scans and clinical
updates to be sent to MSK
DISCLOSURE Memorial Sloan Kettering has exclusively licensed the 8H9 used in this trial to Y-Mabs Therapeutics, Inc.
ABSTRACTDiffuse Intrinsic Pontine Glioma (DIPG) is a rare, inoperable, and universally fatal childhood cancer affecting the brainstem. Approximately 250 – 300 children are diagnosed with DIPG each year with a median survival of 9 months. There is currently no cure or highly effective treatment. Standard treatment is radiation therapy which shrinks the tumor but only has a temporary effect. Chemotherapy has proven to be largely ineffective due to inability to bypass the blood brain barrier which remains largely intact. A phase 1 clinical trial at Memorial Sloan Kettering Cancer Center (MSK) utilizes a novel surgical technique, convection enhanced delivery (CED) to bypass the blood brain barrier and deliver a targeted therapeutic agent called 124I-8H9. An infusion cannula is placed directly to the site of the brainstem tumor and 124I-8H9, a monoclonal antibody that provides targeted radiolabeled immunotherapy is then infused. This clinical trial is the first time CED has been used to administer 124I-8H9 to a human brain. This clinical trial is ongoing. Care of children enrolled on this clinical trial requires complex coordination between neurosurgery, nuclear medicine, radiopharmacy, radiation safety, and radiology; nurse practitioners and nurses play a vital role in the successful monitoring and coordination of care for such patient.
OBJECTIVES
DIPG (DIFFUSE INTRINSIC PONTINE GLIOMA)
DIPG (Diffuse Intrinsic Pontine Glioma) is an aggressive and lethal type of childhood brain cancer that is inoperable.Pathology • High grade malignant solid infiltrative tumor
derived from glial (connective/supporting) cells of the brain
• B7H3 tumor antigen is expressed
Location • Lower brainstem (pons) which controls vital functions (heart rate, breathing, blood pressure)
Prognosis • Universally fatal with average survival of 9 months
Incidence • 250 US cases/year
Median Age • 5 – 9 years at diagnosis
Diagnosis • “Typical” Radiographic and Clinical Presentation
• No biopsy is needed
Clinical Presentation
• Rapid onset of symptoms that worsen quickly
• Short duration of symptoms, most less then 4 weeks
“Classic Triad”
• Cranial Nerve Dysfunction: facial palsy, esotropia
• Long Tract Signs: hyperreflexia, +Babinski, hemiparesis
• Cerebellar Signs: dysmetria, ataxia, dysarthria
Treatment • No cure or highly effective treatment
• Blood Brain Barrier blocks chemotherapy, remains largely intact
Palliative Radiation Therapy (54 – 60 Gy) is standard of care
• Majority respond (75 - 85%), but only temporary
• Tumor progression within 3 – 8 months
Describe the potential benefits of CED of 124I-8H9 as a treatment for DIPG
Describe the ongoing development of CED to allow a more effective therapeutic
delivery technique for DIPG
Discuss the role of the clinical research nurse practitioner /coordinator for
a neurosurgical clinical trial
TYPICAL MRI APPEARANCE OF DIPG
• Tumor margins are not well defined
• Enlarged pons
• No contrast enhancement
• Engulfed basilar artery
CED (CONVECTION ENHANCED DELIVERY)
124I-8H9
124I-8H9 is a radioactive iodine labeled monoclonal antibody that provides targeted brain tumor therapy. It attaches to the B7H3 tumor antigen that is expressed by the DIPG tumor cells.
124I (Iodine 124) 8H9Proton rich isotope that emits radiation to kill the cancer cells with minimal scatter and damage to the normal tissue
Monoclonal antibody that attaches to the B7H3 tumor antigen and binds to the Iodine 124
Half life is 4.18 days Immunotherapy; Enables the body’s immune system to detect and destroy cancer cells
MSK has >12 years experience administering intraventricular 124I-8H9 to treat other similar high grade CNS tumors
124I + 8H9 = Targeted Radioimmunotherapy (RIT)
Surgical approach to deliver therapeutic agents directly into the tumor bed and
bypass the blood brain barrier
A small-gauge infusion catheter is placed in the tumor under MRI guidance (intra-
operative MRI suite) under general anesthesia
Micro infusion pump is used to deliver the therapeutic agent at a slow constant
rate to provide positive pressure and maintain convective flow.
124I-8H9 antibody is infused directly into the tumor by CED to provide targeted radioimmunotherapy
DIPG
CED PROTOCOL DEVELOPMENT2011: MSK IRB Protocol #11-011 opened
A Phase I Study of Convection-Enhanced Delivery of 124I-8H9 for Patients with Non-Progressive Diffuse Pontine Gliomas Previously Treated with External Beam Radiation Therapy
Study PI: Dr. Mark Souweidane
Clinical Trials.gov Identifier: NCT01502917
BRIEF OVERVIEW
TREATMENT PLAN: DOSE LEVELS 1 – 11
Dose Level
mCi 8H9
n mCi/mg 8H9
Infusion Rate (μl/min)
Infusion Vol. (μl)
Infusion Time (min)
1 0.25 3- 6 1.8 – 2.2 ≤10 ~250 25 –50
2 0.5 3- 6 1.8 – 2.2 ≤10 ~500 50 – 100
3 0.75 3- 6 1.8 – 2.2 ≤10 ~750 75 – 150
4 1 3- 6 1.8 – 2.2 ≤10 ~1000 100 – 200
5 2.5 3- 6 1.8 – 2.2 ≤10 ~2500 284 – 523
6 3.25 3- 6 1.8 – 2.2 ≤10 ~3250 Within 24hrs
7 4 3- 6 1.8 – 2.2 ≤10 ~4000 Within 24hrs
7.1 4 3- 6 1.8 – 2.2 7.5 ~4000 Within 24hrs
7.2 4 3- 6 1.8 – 2.2 10 ~4000 Within 24hrs
8 6 3- 6 1.8 – 2.2 10 max ~6000 Within 24hrs
9 8 3- 6 1.8 – 2.2 10 max ~8000 Within 24hrs
10 10 3- 6 1.8 – 2.2 10 max ~10,000 Within 24hrs
11 12 3- 6 1.8 – 2.2 10 max ~12,000 Within 24hrs
Hypothesis: 8H9 may serve as an excellent glioma-targeting agent, and will be most
effectively administered via CED.
Phase I, dose-escalation study of 124I-8H9 in pediatric patients with non-progressive DIPG
who have been previously treated with external beam radiation therapy. Single infusion.
Study design to determine the safety and biologic activity of a range of 124I-8H9
doses and to evaluate the radioactivity of 124I-8H9 in this patient population.
MSK only study
This is the first time 124I-8H9 is being given using CED in the brain stem
ELIGIBILITY
TECHNIQUE
Diagnosis confirmed by a multidisciplinary pediatric neuro-oncology team based on MRI
and clinical evidence. Tissue diagnosis is NOT required.
s/p External beam radiation therapy 54-60 Gy to the brain stem
Minimum of 4 weeks but no more than 14 weeks from the completion of radiation therapy
Non-progressive DIPG. No radiographic or clinical progression post radiation therapy
Lansky or Karnofsky Performance Score ≥50
Prior chemotherapy requires a washout period
Age: ≥ 2 and ≤ 21 years
Minimum Weight: 8kg
The MSK CED trial with 124I-8H9 for patients with non–progressive DIPG is currently accruing
patients to fully assess safety of the therapy. DIRECT CAREGIVER
PATIENT EDUCATOR
COORDINATOR OF CARE
RESEARCHER
Open to accrual
Estimated Enrollment = 64
Ongoing data analysis and assessments
Physical/neuro exam Monitor toxicities/
assess clinical responses
Provide education for patients considering
enrollment
Write and update patient handouts
Coordinate all visits, labs, scans, medications, long
term data collection
Act as a liaison to the community, social
care services
Screen patients for eligibility
Participate in the institutional review process,
writing/reviewing of protocols and consent forms
CED-based therapies for DIPG will continue to evolve with new understanding
of the technique and the disease.
8H9 Monoclonal Antibody
Antigens on cancer cell
Radioactive iodine 124I
124I-8H9 Monoclonal Antibody locked onto B7H3 antigen
GOLD & GRAY FOR CHILDHOOD BRAIN CANCER AWARENESS