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