Clinical trial NCT03566199
Conditions: Diffuse Intrinsic Pontine Glioma
Sponsor: Sabine Mueller, MD, PhD
Start date: 2018-05-22; Completion date: 2021-03-31
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase I/II trial studies the side effects of panobinostat nanoparticle formulation MTX110 (MTX110) in treating participants with newly-diagnosed diffuse intrinsic pontine glioma. Panobinostat nanoparticle formulation MTX110 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of repeated administration of MTX110 co-infused with gadoteridol given by intratumoral convection enhanced delivery in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG).

SECONDARY OBJECTIVES:

I. To determine the clinical efficacy of repeated administration of MTX110 given by intratumoral convection-enhanced delivery (CED) in children with newly diagnosed DIPG in the confines of a phase I and early efficacy study.

OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.

Participants receive panobinostat nanoparticle formulation MTX110 intratumorally (IT) by CED infusion on day 1 or days 1 and 2 as determined by dose level. Courses repeat every 4-8 weeks for up to 24 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment participants are followed up at 30 days and then every 2 months.

Arms: arm 1: Participants receive panobinostat nanoparticle formulation MTX110 IT by CED infusion on day 1 or days 1 and 2 as determined by dose level. Courses repeat every 4-8 weeks for up to 24 months in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Panobinostat Nanoparticle Formulation MTX110 intervention 2: Convection-Enhanced Delivery (CED)
Intervention descriptions: intervention 1: Given IT intervention 2: Undergo CED

Protocol documents:
Prot_SAP_000.pdf: 
TITLE: PNOC015: An Open Label Single Arm Phase I/II study of MTX110 delivered by 
convection-enhanced delivery (CED) in patients with diffuse intrinsic pontine glioma (DIPG) 
previously treated with external beam radiation therapy
PNOC Protocol #: PNOC-015
Version Number: 2.0
Version Date: 6/20/2019
IND 135229
Revision History
Version 1.0
05/02/2017
Version 1.1
08/26/2017
Version 1.2
10/19/2017
Version 1.3
10/24/2017
Version 1.4
10/31/2017
Version 1.5
12/04/2017
Version 1.6
04/04/2018
Version 1.7
06/25/2018
Version 1.8
10/22/2018
Version 1.9
04/08/2019
Version 2.0
06/20/2019
NCT# 03566199


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Study Chair 
Sabine Mueller, MD, PhD, MAS
University of California, San Francisco
 
Email: Sabine.Mueller@ucsf.edu
Co-Study Chair
Cassie Kline, MD, MAS
 
Cassie.Kline@ucsf.edu
Surgical Study Chairs 
Nalin Gupta, MD, PhD
Mark Souweidane, MD
 
PNOC Co-Project Leader
Michael Prados, MD
University of California, San Francisco
Coordinating Center
Pacific Pediatric Neuro-Oncology Consortium
Sandler Neurosciences Building
Statistician
Annette Molinaro, PhD
UCSF Department of Neurosurgery
 
Study Nurses
Shannon Raber, RN, PNP, MS
Carly Hoffman, RN, MS, CPNP-AC, CPON


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Pacific Pediatric Neuro-Oncology Consortium Institutions 
Ann & Robert H. Lurie Children’s Hospital of 
Chicago
PI: Angela Waanders, MD, MPH
Co-PI: Stewart Goldman, MD
 
Children’s Hospital Los Angeles
PI: Ashley Margol, MD
Co-PI: Nathan Robison MD
Children’s National Medical Center
PI: Lindsay Kilburn, MD
Co-PI: Roger Packer, MD
Dana-Farber Cancer Institute 
Harvard University
PI: Susan Chi, MD
Co-PI: Daphne Haas-Kogan, MD
Doernbecher Children’s Hospital 
Oregon Health & Science University
PI: Kellie Nazemi, MD
Co-PI: Rebecca Loret de Mola, DO
Johns Hopkins Hospital
PI: Kenneth Cohen, MD MBA
Co-PI: Eric Raabe, MD 
Nationwide Children’s Hospital
PI: Mohamed AbdelBaki, MD
Co-PI: Jonathan L. Finlay, M.B. Ch.B. F.R.CP.
 
Rady Children’s Hospital
University of California, San Diego 
PI: John Crawford, MD, MS
Co-PI: Jennifer Elster, MD
Seattle Children’s Hospital
University of Washington, Seattle
PI: Sarah Leary, MD
Co-PI: Nicholas Vitanza, MD
St. Jude Children’s Research Hospital
PI: Amar Gajjar, MD
Co-PI: Christopher Tinkle, MD


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St. Louis Children’s Hospital
Washington University in St. Louis
PI: Karen Gauvain, MD, MSPH
Co-PI: Josh Rubin, MD, PhD
 
Texas Children’s Hospital
PI: Patty Baxter, MD
Co-PI: Will Parsons, MD PhD
 
 
The Children’s Hospital of Philadelphia
PI: Jane Minturn, MD PhD
Co-PI: Kristina Cole MD, PhD
 
 
The Hospital for Sick Children
PI: Eric Bouffet, MD
Co-PI: Annie Huang, MD PhD
 
UCSF Benioff Children’s Hospital 
University of California, San Francisco 
PI: Sabine Mueller, MD, PhD, MAS
Co-PI: Cassie Kline, MD, MAS
 
University of Florida
PI: Sri Gururangan, FRCP
Co-PI: Duane Mitchell, MD PhD
 
University of Minnesota and Children’s Hospital 
Minnesota
PI: Chris Moertel, MD
Co-PI: Anne Bendel, MD
University of Utah
PI: Nicholas Whipple, MD, MPH
Co-PI: Carol Bruggers MD
 
Collaborating Sites:
Memorial Sloan Kettering Cancer Center
PI: Mark Souweidane, MD
UCSF Benioff Children’s Hospital Oakland (in connection with UCSF Benioff Children’s 
Hospital San Francisco)
PI: Tabitha Cooney, MD
 
Massachusetts General Hospital (in connection with DFCI)
PI: David Ebb, MD
 


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PROTOCOL SIGNATURE PAGE
Protocol No.: PNOC 015         
Version Date: 06/20/2019
1. I agree to follow this protocol version as approved by the UCSF Protocol Review 
Committee (PRC), Institutional Review Board (IRB), and Data Safety Monitoring 
Committee (DSMC). 
2. I will conduct the study in accordance with applicable IRB requirements, Federal 
regulations, and state and local laws to maintain the protection of the rights and welfare 
of study participants. 
3. I certify that I, and the study staff, have received the requisite training to conduct this 
research protocol. 
4. I have read and understand the information in the Investigators’ Brochure (or 
Manufacturer’s Brochure) regarding the risks and potential benefits. I agree to conduct 
the protocol in accordance with Good Clinical Practices (ICH-GCP), the applicable 
ethical principles, the Statement of Investigator (Form FDA 1572), and with local 
regulatory requirements. In accordance with the FDA Modernization Act, I will ensure 
the registration of the trial on the www.clinicaltrials.gov website. 
5. I agree to maintain adequate and accurate records in accordance with IRB policies, 
Federal, state and local laws and regulations.
Study Chair
Printed Name
Signature
Date
Participating Site(s) Pacific Pediatric Neuro-Oncology Consortium Institutions
Principal Investigator
Printed Name
Institution
Signature
Date


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ABSTRACT
Title
An Open Label Single Arm Phase I/II study of MTX110 delivered by 
convection-enhanced delivery (CED) in patients with diffuse intrinsic 
pontine glioma (DIPG) previously treated with external beam 
radiation therapy
Patient population
Children with newly diagnosed diffuse intrinsic pontine glioma 
(DIPG), previously treated with focal radiotherapy.
Rationale for Study
The overall median survival of children with DIPG is approximately 9 
months, and remains unchanged despite decades of clinical trial 
research. The only standard of care is focal radiotherapy but 
essentially all children die of this disease. New therapeutic strategies 
are urgently needed. One of the potential reasons for failure of 
treatment is the blood-brain and blood-tumor barriers, which exclude 
potentially effective therapeutic agents. Direct delivery by convection-
enhanced techniques can overcome this barrier and ensure adequate 
drug exposure to tumor cells. MTX110 is a soluble from of 
panobinostat. Panobinostat has been shown in pre-clinical models to 
be effective at slowing tumor growth in patient-derived brainstem 
xenografts, and these findings were seen both among carriers of 
histone mutations and wildtype histone models. The hypothesis of this 
study is that repeated direct delivery via convection-enhanced delivery 
(CED) of MTX110 will increase progression-free and overall survival 
in children with newly diagnosed DIPG following standard of care 
radiotherapy. This trial will assess the safety and preliminary efficacy 
of this strategy.
Primary Objective
To determine the safety and tolerability of repeated administration of 
MTX110 co-infused with gadoteridol given by intratumoral CED in 
children with newly diagnosed DIPG. 
Secondary Objective
To determine the clinical efficacy of repeated administration of 
MTX110 given by intratumoral CED in children with newly 
diagnosed DIPG in the confines of a phase I/II study.
Exploratory 
Objectives 

To assess the magnetic resonance image-guided intracranial 
injection procedure in patients with DIPG by correlating the 
observed distribution of gadoteridol to pre-treatment modeling of 
the drug distribution utilizing predictive imaging software.

To assess Quality of Life (QOL) in pediatric patients with newly 
diagnosed DIPG treated with MTX110 co-infused with gadoteridol 
given by intratumoral CED.

To perform central review of imaging to explore MR qualitative 
and quantitative measures as markers of disease response and/or 
progression and treatment effect in comparison to institutional 
evaluation of disease response and/or progression.


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Study Design
This is an open-label, ascending dose, single arm phase I/II study of 
MTX110 delivered by CED in patients with DIPG following standard 
of care focal radiotherapy. We will start with a single dose drug 
concentration of 30 M using a total volume of 3mL and administer 
MTX110 on day 1 only; we will then first dose escalate by the number 
of days MTX110 is given: 30 M concentration, 3 ml total volume, 
administration will occur on day 1 and 2. We then will start to dose 
escalate the total volume that is being administered on days 1 and 2. 
Once the RP2D total volume has been determined, we will then 
escalate the concentration of MTX110 that is being administered on 
days 1 and 2. The accelerated dose escalation design will allow intra-
patient dose escalation. The concentration of gadoteridol (ProHance) 
will be 0.5 mM which is the same concentration that is being used for 
other PNOC studies; both agents will be combined and co-infused via 
the same catheters. A maximum of 2 catheters will be placed. 
Number of patients
The number of subjects enrolled will depend upon the DLTs observed 
and the number of dose levels tested as the study progresses in 
accordance with an accelerated dose escalation design (ATD) 
followed by a 3+3 design. The ATD is expected to enroll 1 to 7 
subjects with a minimum of 5 patients in the 3+3 design. Additional 
subjects might be needed if dose de-escalations need to occur. After 
review of the initial dose levels as well as achieved coverage areas of 
the tumor, the study team will also assess if additional dose levels 
should be tested to achieve adequate tumor coverage. In the pilot 
efficacy study we will enroll a total of 19 evaluable subjects.
Duration of Therapy
Eligible subjects will receive MTX110 after completion of standard 
focal radiotherapy (minimum of 28 days, maximum of 14 weeks from 
radiation therapy). Treatment will occur every 4-8 weeks. Treatment 
will continue for up to 24 months or until tumor progression or 
intolerable toxicity. If subjects continue to derive clinical benefit, 
discussion with investigators and study sponsor will determine 
feasibility and clinical appropriateness to continue therapy beyond 24 
months.
Duration of Follow 
up
All subjects will be followed for safety, time to tumor progression and 
overall survival. 
Duration of study
The study will reach completion approximately 3 years from the time 
the study opens to accrual.
Study Drugs
MTX110 is a water soluble formulation of panobinostat, administered 
via CED; concentration of gadoteridol (ProHance) will be 0.5 mM in 
all dose levels; both agents will be combined and co-infused via the 
same catheters.


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Safety Assessments
We will use CTCAE version 4.0 for adverse event reporting; surgical 
complications will be graded as outlined in the protocol. Subjects will 
undergo clinical evaluation and brain MR imaging prior to any CED 
to assess for related toxicity, as well as tumor status. Toxicity is 
defined per standard pediatric phase I guidelines including 
interruption of planned therapy > 10 weeks to allow for recovery from 
toxicity of prior CED MTX110 injection. 
Efficacy Assessments
We will assess the preliminary efficacy using overall survival at 12 
months (OS12) in 19 evaluable DIPG patients treated within the 
expansion cohort which will include subjects treated as part of the 
dose escalation portion of the trial on the recommended phase 2 dose 
(RP2D). The most recent Children’s Oncology Group study that 
treated children newly diagnosed with DIPG with a combination of 
radiation therapy and temozolomide resulted in an OS12 rate of 40% 
(SD ± 6.5%). A sample size of 19 patients achieves 80% power to 
detect a difference of 30% using a one sided exact binominal test. The 
target significance level is 5% and the actual significance level is 
3.5% with this test. If 12 or more patients are alive at 12 months, the 
null hypothesis that OS12 is 40% will be rejected.
Unique Aspects of 
this Study
This is the first study to evaluate the safety and preliminary efficacy of 
the use of repeated CED of MTX110 with real time gadoteridol 
imaging in children with DIPG.


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EXPERIMENTAL DESIGN SCHEMA
Phase I Study 
Open to patients 2 years to less than or equal to 21 years of age with newly diagnosed DIPG who 
have completed focal radiotherapy (to begin treatment ≥ 28 days to ≤ 14 weeks from completion 
of radiation therapy). Enrollment occurs after completion of radiation therapy.
We will assess an anticipated 7 dose levels using an accelerated, intra-patient dose escalation 
scheme: 

Dose level 1: Single CED of 30 M MTX110 on 1 day (day 1); Total volume 3 mL

Dose level 2: Repeated CED of 30 M MTX110 on 2 consecutive days (days 1, 2); Total volume 6 mL (3 
mL on each day)

Dose level 3: Repeated CED of 30 M MTX110 on 2 consecutive days (days 1, 2); Total volume 8 mL (4 
mL day on each day)

Dose level 4: Repeated CED of 30 M MTX110 on 2 consecutive days (days 1, 2); Total volume 10 mL (5 
mL day on each day)

Dose level 5: Repeated CED of 30 M MTX110 on 2 consecutive days (days 1, 2); Total volume 12 mL (6 
mL day on each day)

Dose level 6: Repeated CED of 60 M MTX110 on 2 consecutive days (days 1, 2); Total volume 12 mL (6 
mL day on each day)

Dose level 7: Repeated CED of 90 M MTX110 on 2 consecutive days (days 1, 2); Total volume 12 mL (6 
mL day on each day)
Once these dose levels have been assessed, a detailed review of the safety and efficacy data will 
be performed and the study team will discuss with the FDA and the DSMC to determine either 
further dose escalation or enrollment into the phase II study.
**Of note, timing of follow-up day 2 infusion will be determined pending patient’s return to pre-infusion 
baseline neurological exam or equal or less than grade 1 toxicities, but will occur no later than 48 hours after 
completion of infusion on day 1; if patient’s neurological exam has not returned to pre-infusion baseline by 48 
hours from completion of day 1 infusion, day 2 CED procedure will be canceled.  
Newly Diagnosed Diffuse 
Intrinsic Pontine Glioma
Phase II Study (Expansion Cohort)
A total of 19 subjects will be enrolled to assess the clinical efficacy of the RP2D within the 
confines of this pilot study. 


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LIST OF ABREVIATIONS
AA
Anaplastic astrocytoma
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
ATD
Accelerated titration design
AUC
area under the curve
BUN
blood urea nitrogen
CBC
complete blood cell (count)
CED
Convection-Enhanced Delivery
CNS
Central Nervous System
CR
complete response
CRC
Clinical Research Coordinator
CRF
case report form
CSF
cerebral spinal fluid
CT
computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
DFS
disease-free survival
DIPG
Diffuse intrinsic pontine glioma
DLT
dose limiting toxicity
DSMC
Data and Safety Monitoring Committee
DSMP
Data and Safety Monitoring Plan
EGFR
Epidermal growth factor receptor
EFS
Event-free survival
EIAED
enzyme-inducing anti-epileptic drug
FDA
Food and Drug Administration
GBM
Glioblastoma multiforme
GCP
Good Clinical Practice
GDL
Gadolinium liposomes
HAT
Histone acetylase
HDAC
Histone deacetylase
HDFCCC
Helen Diller Family Comprehensive Cancer Center


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HGB
Hemoglobin
HGG
High grade glioma
IND
investigational new drug application
IP
investigational product
IRB
Institutional Review Board
IT
intratumoral
IV
intravenous
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI
National Cancer Institute
OR
Operating room
ORR
overall response rate
PD
Progressive disease
PFS
Progression-free survival
PK
Pharmacokinetics
PO
Per os (by mouth, orally)
PR
partial response
PRC
Protocol Review Committee (UCSF)
QoL
Quality of Life
RCD
Real-time convective delivery
RP2D
Recommended phase 2 dose
SD
stable disease
SD
standard deviation
SGPT
serum glutamic pyruvic transaminase
ULN
upper limit of normal
Vd
Volume of distribution


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TABLE OF CONTENTS
ABSTRACT.....................................................................................................................................6
EXPERIMENTAL DESIGN SCHEMA..........................................................................................9
ABSTRACT
6..............................................................................................
1.
OBJECTIVES....................................................................................................................14
1.1
Primary Objective..................................................................................................14
1.2
Secondary Objective..............................................................................................14
1.3
Exploratory Objectives ..........................................................................................14
2.
BACKGROUND ...............................................................................................................14
2.1
Convection Enhanced Delivery .............................................................................14
2.2
Real-time Imaging of Convection Enhanced Delivery (RCD)..............................16
2.3
Diffuse Intrinsic Pontine Glioma (DIPG), CED, MTX110...................................17
2.4
Study Agent ...........................................................................................................32
2.5
Rationale ................................................................................................................34
3.
Study Design......................................................................................................................35
3.1
Characteristics........................................................................................................35
3.2
Number of Subjects................................................................................................35
3.3
Inclusion Criteria ...................................................................................................35
3.4
Exclusion Criteria ..................................................................................................37
4.
REGISTRATION PROCEDURES ...................................................................................38
4.1
General Guidelines.................................................................................................38
4.2
Reservation and Registration Process....................................................................39
5.
Agent Administration.........................................................................................................39
5.1
Regimen Description .............................................................................................39
5.2
Dose Administration..............................................................................................43
5.3
Dose Limiting Toxicity (DLT) ..............................................................................46
5.4
General Concomitant Medication and Supportive Care Guidelines......................46
5.5
Dosing Modifications and Delays..........................................................................48
6.
Treatment plan ...................................................................................................................48
6.1
Study Calendar.......................................................................................................50
6.2
Observations and Procedures.................................................................................51
6.3
Long Term/Survival Follow-up Procedures ..........................................................54
6.4
Off-Treatment Criteria...........................................................................................54
6.5
Off Study Criteria ..................................................................................................54
7.
ADVERSE EVENTS.........................................................................................................55
7.1
Adverse Event Characteristics...............................................................................55
7.2
Adverse Event Monitoring.....................................................................................57
7.3
Adverse Event Reporting.......................................................................................57
7.4
Serious Adverse Events and Expedited Reporting ................................................58


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7.5
Secondary Malignancy...........................................................................................60
8.
PHARMACEUTICAL INFORMATION..........................................................................60
8.1
Study Agent ...........................................................................................................60
9.
EVALUATION CRITERIA..............................................................................................61
9.1
Response Criteria...................................................................................................61
9.2
Imaging Analyses...................................................................................................64
10.
STATISTICAL CONSIDERATIONS...............................................................................64
10.1
Study Design/Endpoints ........................................................................................64
10.2
Dose Escalation......................................................................................................65
10.3
Sample Size and Accrual .......................................................................................67
10.4
Stratification Factors..............................................................................................68
10.5
Analysis of Endpoints............................................................................................68
11.
DATA REPORTING / REGULATORY REQUIREMENTS...........................................68
11.1
Data Reporting.......................................................................................................69
11.2
PNOC Oversight and Monitoring Plan..................................................................69
11.3
Multicenter Communication..................................................................................70
11.4
Record Keeping and Record Retention..................................................................70
11.5
Coordinating Center Documentation of Distribution ............................................70
11.6
Regulatory Documentation....................................................................................71
REFERENCES ..............................................................................................................................72
APPENDIX A Performance Status Criteria ..................................................................................76
APPENDIX B Enzyme Inducing and Recommended Non-Enzyme Inducing Anti-Convulsants; 
Drugs to avoid....................................................................................................................77
APPENDIX C PNOC Institutions Required Regulatory Documents............................................79
APPENDIX D Required Data and Time Table for Submission....................................................80
APPENDIX E PNOC Data and Safety Monitoring.......................................................................81
APPENDIX F Information Sheet on Possible Drug Interactions..................................................84
APPENDIX G Age Appropriate Blood Pressure and Heart Rate Measures .................................86
APPENDIX H Imaging Guidelines for PNOC Studies.................................................................88


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1. OBJECTIVES
1.1
Primary Objective
To determine the safety and tolerability of repeated administration of MTX110 co-infused with 
gadoteridol given by intratumoral convection enhanced delivery in children with newly 
diagnosed DIPG.
1.2
Secondary Objective
To determine the clinical efficacy of repeated administration of MTX110 given by intratumoral 
CED in children with newly diagnosed DIPG in the confines of a phase I and early efficacy 
study.
1.3
Exploratory Objectives 
To assess the magnetic resonance image-guided intracranial injection procedure in patients with 
DIPG by correlating the observed distribution of gadoteridol to pre-treatment modeling of the 
drug distribution utilizing predictive imaging software.
To assess Quality of Life (QOL) in pediatric patients with newly diagnosed DIPG treated with 
MTX110 co-infused with gadoteridol given by intratumoral CED.
To perform central review of imaging to explore MR qualitative and quantitative measures as 
markers of disease response and/or progression and treatment effect in comparison to 
institutional evaluation of disease response and/or progression. 
2. BACKGROUND
2.1
Convection Enhanced Delivery
CED is a delivery modality which utilizes bulk flow, or fluid convection, established as a result 
of a pressure gradient rather than a concentration gradient [1]. Through the maintenance of such 
a pressure gradient from the delivery cannula tip to the surrounding tissues, CED is able to 
distribute small and large molecules to clinically significant target volumes (centimeters rather 
than millimeters) [1, 2]. Small or large particles are easily distributed within the brain via CED 
[3, 4]. The advantages of CED over diffusion based delivery include: (i) an expanded volume of 
distribution (Vd); (ii) a uniform concentration of the infused therapeutic within the target Vd; 
(iii) the delivery of the vast majority of the infused therapeutic within the target volume [2]. 
CED distribution is enhanced by the arterial pulsations within the brain’s perivascular spaces [5]. 
Additionally, an improved understanding of the complexities of the extracellular matrix and its 
effects on convection has led to better distribution [6-8]. For example, technical CED infusion 
parameters, such as cannula size and shape, infusion rate (usually 0.2–5.0 μL/min or 0.012–0.3 
mL/h), infusate concentration, and tissue sealing time, have been defined and refined to improve 
distribution of study agents while limiting potential toxicities and morbidities [9-11]. 


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A major advance in the safe and potentially efficacious use of CED in neurosurgery has been the 
development of real-time convective delivery (RCD), which utilizes magnetic resonance imaging 
to visualize the CED process with the aid of co-convected contrast agents [11-16]. The use of 
RCD allows physicians to directly monitor the distribution of therapeutics within the brain. Thus, 
reflux along the CED catheter or leakage outside the target area, especially at higher flow rates, 
can be monitored and corrective steps taken, such as retargeting the catheter or altering the rate 
of infusion [17, 18]. RCD techniques will be used in this study –which represents an important 
advancement because several recent clinical trials that utilized CED for the delivery of 
therapeutics to the brain, but which lacked effective imaging monitoring, did not meet clinical 
endpoints, including trials for treatment of neurodegenerative disease, and neoplastic conditions 
[19-24].
These clinical trials have demonstrated the promise of CED as a therapeutic option for patients 
with recurrent high grade gliomas with a relatively low toxicity profile associated with therapy. 
Clinical Neuro-Oncologic Studies 
Although a large number of therapeutic options have been examined for CED, only a few agents 
have been formally studied in clinical trials. Some of the more prominent clinical trials studying 
CED include: TP‐38, cintredekin besudotox, IL‐4 pseudomonas exotoxin, paclitaxel, AP 12009, 
and cotara. 
Sampson et al. used CED infusion of TP‐38 which is a chimeric protein that fuses TGF‐α with a 
genetically modified Pseudomonas exotoxin. Overall survival was 28 weeks with a subset 
survival of 33 weeks in the 20 patients with no residual disease and 20.1 weeks in patients with 
residual disease [25]. There was one patient that at the time of publication had a survival of 260 
weeks. The toxicities with TP‐38 included 5 patients with seizures who had previous seizure 
disorders. Grade 3 or 4 toxicity was seen in 2 patients [26]. 
Cintredekin besudotox was tested in 51 patients over the series of three phase I clinical trials for 
recurrent high grade gliomas. There was an overall survival rate of 45.9 weeks post‐treatment, 
with 9 patients exhibiting progression free survival for 1 year and seven patients with 
progression free survival of 2 years [27]. There were grade 3 or 4 toxicities reported with 
headache, convulsion, and hemiparesis; six patients developed hemiparesis. A phase III trial was 
completed for cintredekin besudotox that was randomized against Gliadel wafers for recurrent 
GBM. The median survival was comparable between CED and Gliadel wafers at 36.4 weeks and 
35.3 weeks respectively. Despite no statistical significance in improved survival for 
CED‐administered therapy, inadequate drug distribution and improper catheter placement might 
explain the results [28].
A recombinant cytotoxin that is a fusion between IL‐4 and Pseudomonas exotoxin was applied 
by CED in a phase I clinical trial for recurrent gliomas [29]. When comparing the recombinant 
cytotoxin to resection alone the overall median survival of recurrent GBM was 5.8 months and 
5.3 months, respectively [25]. There were no noted systemic toxicities, and the most common 
adverse events were cerebral edema, seizures, and headaches.


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For infusion of paclitaxel for recurrent grade III or IV gliomas, Lidar et al. demonstrated an 
overall median survival of 7.5 months. However, there was a significant number of treatment 
related adverse events including transient neurological deterioration from cerebral edema (20%), 
bacterial infections (15%), and chemical meningitis (30%) [30]. 
AP 12009, an antisense oligonucleotide that binds to TGF‐β2 mRNA to inhibit translation, was 
studied in three phase I/II clinical trials for CED that demonstrated a median overall survival of 
44 weeks for glioblastoma multiforme (GBM) and 146.6 weeks for patients with anaplastic 
astrocytoma (AA) [31]. There were 29 treatment‐related toxicities, but these were mostly minor 
and limited to grade 2 and 3 toxicities.
Cotara, an immunotoxin with an antibody specific for histone H1‐DNA complex that was labeled 
with 131I, was studied in 51 patients enrolled in phase I and II studies. This treatment achieved a 
median survival in GBM patients of 37.9 weeks [32]. Eighteen patients had a grade 3 or 4 
neurological toxicity, while four patients had grade 3 systemic toxicities [2].
These clinical trials have demonstrated the promise of CED as a therapeutic option for patients 
with recurrent high grade gliomas with a relatively low toxicity profile associated with therapy. 
2.2
Real-time Imaging of Convection Enhanced Delivery (RCD)
The use of RCD in this trial will allow direct visualization of the study drug and improved 
estimation and standardization of the therapeutic contact time. RCD will be used at the beginning 
of the infusion and then periodically throughout the infusion, depending on the estimated 
infusion time for each individual subject. With advancements in magnetic resonance imaging 
(MRI), the technology now exists to allow for prospective, real-time imaging of the CED 
injection - which has the potential to ensure more accurate and consistent delivery of the full 
dose of drug to the tumor. MRI Interventions and BrainLab have developed FDA-approved, head 
coil, delivery catheters and skull fixation devices that are MRI compatible and allow for real-
time imaging of the CED injection. Dr. Russell Lonser at Ohio State University has used the 
SmartFlow catheter (MRI Interventions) and ClearPoint MRI guided neuronavigation device 
(MRI Interventions) to deliver a biologic therapy into patients with brain stem glioma. Dr. Mark 
Souweidane at Memorial Sloan Kettering is using the flexible BrainLab catheter for CED for 
children with DIPG. The flexible BrainLab catheter allows longer infusion times compared to the 
SmartFlow catheter system. Gadolinium is added to the study drug to allow for RCD. Prior work 
has shown that gadoteridol (ProHance®) is biocompatible with the MTX110 and can be safely 
injected in combination into the tumors of study subjects. Further, Dr. Bankiewicz has shown 
that this approach is safe and feasible in non-human primates when infused to midline structures 
of the brain including the brainstem (unpublished data, please see below for more detail). 
Gadolinium-based contrast agents are not approved for intracerebral administration, although the 
enhancement seen on standard gadolinium-MRI exams is the result of gadolinium leaking from 
tumor vessels into the surrounding cerebral tissues. Nonionic gadolinium-based contrast agents 
have been safely administered intrathecally at 0.5 mL to detect CSF leaks. Gadolinium has also 
been administered intracerebrally to patients in two studies using CED [16]. 


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ProHance® is a nonionic contrast agent manufactured by Bracco Diagnostics that has been used 
clinically for many years. The addition of ProHance® to MTX110 has been successfully tested 
for compatibility. ProHance® contains 279 mg/mL of gadolinium and during a typical 
intravenous administration, a 70 kg man would receive approximately 3,906 mg of gadolinium. 
In this study a maximum of 0.03 mL of ProHance® of a 1:10 dilution will be added to 3.0mL of 
MTX110 yielding <1.0 mg/mL of gadolinium. 
Pre-clinical Neuro-Oncologic Studies 
CED has been used to effectively deliver therapy within the central nervous system (CNS) in 
small animals with or without tumors [4, 33-36], canines with spontaneous brain tumors [37, 38], 
and primates [11, 39]. In canines, similar CED-delivered agents failed to show clinical or 
pathological adverse effects in normal or brain tumor-bearing animals [37, 38], while confirming 
clinical efficacy and highlighting the importance of RCD to maximize tumor coverage and 
minimize inappropriate infusions. Convection of gadolinium liposomes (GDL) in nonhuman 
primate brain has confirmed the lack of toxicity and ability to monitor the infusion process in a 
larger brain using RCD methods similar to those for humans [11, 40]. Recently, in vivo CED of 
magnetic nanospheres conjugated to an antibody that selectively binds to the epidermal growth 
factor receptor (EGFR) mutant (EGFRvIII) found on glioblastoma xenografts, not only allowed 
specific tumor visualization on MRI, but through an apoptotic mechanism, was associated with 
targeted cell death with sparing of normal astrocytes [41] .
These and other preclinical data [42] argue for the importance of a delivery platform [17] that 
utilizes RCD to monitor therapeutic distribution and potential complications associated with 
CED in the brain tumor patient [18]. 
2.3
Diffuse Intrinsic Pontine Glioma (DIPG), CED, MTX110
Gliomas are the most common brain tumor type in children. High-grade gliomas (HGG), 
including anaplastic astrocytomas (AA) and glioblastomas (GBM), are the most aggressive 
gliomas with 5-year survival rates of less than 20% in the pediatric population. If these tumors 
occur within the pons – diffuse intrinsic pontine glioma (DIPG) – the expected outcomes are 
even worse, with a median survival of approximately 9 months. Despite several decades of 
research, outcomes and treatment strategies for these children has not significantly changed and 
essentially all children die from this disease. For children with DIPG no standard treatment has 
been established although most children are treated with focal irradiation. Once DIPG recurs or 
progresses, there are very few treatment options and most children die of their disease within a 
very short timeframe on the order of months. One prior study reported an event-free survival 
(EFS) defined as the time from progression to time of death, clinical deterioration or imaging 
based progression to be 2 months [43]; however published data on progression free survival 
(PFS) or EFS for progressive DIPGs is limited. Clearly new therapies and strategies are needed.
One of the reasons for treatment failure is the presence of an intact blood-brain and blood-tumor 
barrier, with tight packing of cellular structures within the brainstem. These anatomic barriers are 
a significant obstacle to the effective delivery of many small-molecule drugs and most biological 
therapeutics. As mentioned above, CED utilizes a pressure gradient to distribute pharmacologic 
agents by bulk flow of fluid through tissue interstitial spaces. CED markedly improves drug 


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distribution within the brain when compared with non-CED injections or the implant of drug 
eluting polymers, both of which rely on passive diffusion. Additionally, CED results in far 
greater drug concentration while minimizing systemic exposure and toxicity. Here, we propose a 
phase I clinical trial to assess the safety and early efficacy of repeated CED infusion of MTX110 
in children with DIPG. 
Histone modifier mutations drive tumorigenesis
DNA and histones provide the main building blocks for nucleosomes, the structural units of 
chromatin that are important for packaging DNA. Changes in the structural configuration of 
chromatin to a relatively active (open) or inactive (condensed) form alters the accessibility of 
DNA for transcription, ultimately affecting gene expression. One of the major ways that 
transcription factor binding to DNA is regulated is through changes in chromatin conformation, 
which in turn is governed by chemical modifications such as the acetylation and deacetylation of 
lysine residues of core nucleosomal histones. These changes are under the control of opposing 
activities of histone deacetylase (HDAC) and histone acetylase (HAT), and lead to altered gene 
expression, including genes involved in cell cycle regulation, differentiation and apoptosis. 
Acetylation is generally linked to an ‘open’ chromatin state that is ready for transcription or that 
corresponds to actively transcribed genomic regions, whereas deacetylation is associated with a 
closed or inactive state, leading to gene repression. The relative degree of histone acetylation and 
deacetylation therefore controls the level at which a gene is transcribed. HDAC also has crucial 
roles in cell cycle proliferation and apoptosis, including transcription factors such as p53, NF-kB 
and E2F1, which play key roles in tumorigenesis and anti-tumor response, as well as proteins 
that do not directly regulate gene expression but instead regulate DNA repair (Ku70), the cellular 
cytoskeleton (a-tubulin) and protein stabilization (Hsp90). Notably, among non-histone HDAC 
substrates, Hsp90 plays a major role in the proper folding and stability of several major 
oncoproteins. HDAC activity also regulates cell protein turnover via the aggresome pathway, 
which if disrupted, results in the accumulation of polyubiquitinated misfolded protein 
aggregates, leading to cell stress and caspase-dependent apoptosis. These observations have 
extended the mechanism of anti-tumor activity of panobinostat and other HDAC inhibitors to 
include effects on non-histone proteins, implicated in multiple oncogenic pathways, in 
conjunction with epigenetic changes[44].
Targets of MTX110, Histone 3.3 and 3.1 K27M mutations, are expressed in DIPGs
The most prevalent molecular alterations of pediatric HGGs involve recurrent alterations of 
genes regulating epigenetic modifications of the genome[45, 46]. Genome-wide studies have 
identified recurrent hotspot mutations in histone H3, family 3A (H3F3A) and histone cluster 1, 
H3b (HIST1H3B), which encode the histone H3 variants H3.3 and H3.1 respectively. Recent 
genetic studies have revealed that malignant gliomas in children often show recurrent missense 
mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3.[45, 47, 
48] Approximately 70% of DIPG [49] cases harbor a mutation which results in a substitution of 
the amino-acid lysine (K) to methionine (M) at position 27 of H3.3 (K27M mutation, hereafter), 
which is associated with shorter survival in DIPG patients compared with patients with non-
mutated H3.3[49].This was the first example of a human tumor driven by direct mutation of a 
histone gene. Point mutations of H3F3A and HIST1H3B genes occur at hotspots at amino acid 
residue 27 resulting in lysine to methionine (K27M) amino acid change. Mutations lead to 


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marked changes of the epigenome resulting in distinct methylation signatures.[50, 51] Recent 
studies have shown that there also seems to be a difference between the two K27M mutations in 
that children harboring the H3.1K27M mutation have a worse clinical outcome compared to 
children with harboring the H3.3K27M.[49] K27M-mutated tumors are associated with the worst 
survival with a median overall survival of only 12 months. 
In vitro pre-clinical models of MTX110
Using brain tumor samples collected from children in the United States and Europe, Grasso et al 
found that the drug panobinostat and similar gene-regulating drugs may be effective at treating 
DIPG. Using DIPG cell cultures from 16 patients, Grasso et al screened 83 existing and potential 
cancer drugs and found that HDAC inhibitors consistently slowed cancer cell growth in DIPG 
cell lines, and inhibited DIPG growth and extended survival in a DIPG mouse model. 
Approximately 80 percent of DIPG tumors have a specific mutation in a histone gene, H3K27M, 
which blocks the ability of methyltransferase to methylate histones. The panobinostat and similar 
gene-regulating drugs may be effective at treating DIPG. Using DIPG cell cultures from 16 
patients, Grasso et al screened 83 existing and potential cancer drugs and found that HDAC 
inhibitors consistently slowed cancer cell growth in DIPG cell lines, and inhibited DIPG growth 
and extended survival in a DIPG mouse model.[52]
MTX110 was evaluated for HDAC enzyme inhibition and glioma cell cytotoxicity in three 
studies as shown in Table 1. 
Table 1: MTX110 Pharmacology Studies
Midatech 
Study 
Reference
Study Description
Notes and Main Findings
University of 
Bristol Study
Cytotoxicity in DIPG cells
IC50 = 10nM. SF8628 DIPG cells incubated 
with MTX110 for 72 hours.
MTX110- 
V0031T
Cytotoxicity in U87MG 
cells
IC50 = 10nM. U87MG glioblastoma cells 
incubated with MTX110 for 48 or 72 hours.
MTX110- 
V0024P
HDAC enzyme inhibition
HDAC enzyme inhibition, 
cell- based assay
MTX110 and panobinostat DMSO had 
comparable enzyme inhibiting potency across 
HDAC 1-11 enzymes (see Table 3 below)
MXT110 (10.9nM) and panobinostat DMSO 
(2.6nM) had similar IC50 values against HDAC 
Class I/II enzymes.
MTX110 was a highly potent inhibitor of HDAC, with IC50 values for HDAC1-11 enzymes 
comparable to panobinostat DMSO solutions (Tables 1 and 2). Similarly, MTX110 showed 
comparable inhibition of HDAC Class I and II enzymes in cell based assays (Table 1). 


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MTX110 was similarly highly potent as a cytotoxic agent in U87MG glioma and human DIPG 
cell lines, with an IC50 of 10nM (Table 1). This is consistent with a published study which 
demonstrated panobinostat to be an effective cytotoxic agent across 14 different DIPG cell lines, 
with IC50 values in the range 20-2000nM [52]. The same authors demonstrated efficacy of 
panobinostat.
DMSO solutions in a DIPG xenograft mouse model after intraperitoneal administration at doses 
of 10 and 20 mg/kg and after CED administration of 2μM panobinostat DMSO solution 
(4μL/minute) for 12.5 minutes. 
Table 2: HDAC Enzyme Inhibition (Study MTX110-V0024P) 
IC50 for HDAC enzyme inhibition (nM)
HDA
C 1
HDA
C 2
HDA
C 3
HDA
C 4
HDA
C 5
HDA
C 6
HDA
C 7
HDA
C 8
HDA
C 9
HDA
C 10
HDA
C 11
Panobinostat (MTX110)
8.6
16
4.0
567
110
7.5
1820
56
927
20
1380
Panobinostat (DMSO)
1.6
5.0
0.8
1550
166
1.8
3680
52
1040
13
1670
 
Use of HDAC inhibition via panobinostat in oncology and in DIPG
Panobinostat (Farydak™) has been approved as a medicinal product for oral use in the US and 
EU for the treatment of multiple myeloma and has undergone extensive preclinical and clinical 
safety evaluation to support this indication. No panobinostat product suitable for direct brain 
delivery by CED is available. 
MTX110 is a novel, soluble, panobinostat formulation undergoing experimental evaluation for 
administration by CED to treat certain brain tumours. The safety evaluation program for 
MTX110 therefore focused on physicochemical characterisation of the formulation and 
toxicological evaluation of direct delivery of MTX110 into brain parenchyma by CED. 
The studies included: qualification of assays to quantify levels of panobinostat in plasma and 
brain tissue samples; confirmation of pharmacological potency as an inhibitor of HDAC, and as 
a cytotoxic agent in glioblastoma and DIPG cells; plasma and brain distribution, and toxicologic 
evaluation of MTX110 after CED delivery in rats and pigs. 
Panobinostat (Farydak™) is currently being investigated in late phase clinical trials for adults 
with T cell lymphoma and has recently been approved in the US and EU for the use in adults 
with relapsed refectory myeloma. Systemic (oral) administration of panobinostat at effective 
doses in hematological malignancies, however, has been associated with significant toxicity – 
such as thrombocytopenia and cardiac toxicity. There is clinical evidence that panobinostat does 
not cross the blood brain barrier when given systemically at tolerated doses. It has been used to 
reactivate latent HIV in adult patients to facilitate the therapeutic effect of antiretroviral therapy 
to some following oral panobinostat administration. Panobinostat was not detectable in the CSF 
of these patients at any time point [53] . 


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The fact that panobinostat seems to be the most efficacious clinically available drug against 
DIPG cells, that oral dosing is likely to cause unacceptable systemic toxicity and that it does not 
penetrate the CNS makes it of considerable interest as a treatment for DIPG by CED. However, 
its use is limited by poor water solubility. Drugs need to be water soluble at physiological pH to 
be delivered to the brain by CED. Midatech Pharma has recently identified a soluble formulation 
(MTX110) through complexation with hydroxypropyl-β-cyclodextrin that enables CED delivery 
at potentially chemotherapeutic doses. 
Pharmacokinetics of MTX110 delivered via CED in animal models
The nonclinical ADME of panobinostat were established during the development of other 
panobinostat products. The brain distribution of panobinostat after administration of MTX110 by 
CED was evaluated in rats and pigs to support clinical CED delivery, as listed in Table 3. 
Table 3: MTX110 Pharmacokinetic Studies 
Midatech 
Study 
Reference 
Study 
Description 
Dose 
(μM) 
No. 
Animals 
Measurements & Observations 
MTX110- 
R0021K 
Rat CED single 
dose brain 
distribution 
study
3
30
300
14
6
6
Plasma and brain panobinostat 
concentrations were measured 
(n=2/time) at time 0, 0.5, 2, 6, 24, 48 
and 72 hours (3μM) or 0, 2 and 6 hours 
(30 and 300μM) after CED into the 
brainstem (3μM) or striatum (30 and 
300μM). MTX110 was cleared from the 
brain with a t1/2 of approximately 3 
hours.
MTX110- 
S0023T 
Pig CED single 
dose brain 
distribution 
study
30
1 (0d)
One pig was dosed by CED into the 
striatum and thalamus and sacrificed at 
Time 0 for brain panobinostat 
distribution analysis (as part of the 
toxicology study). The distribution of 
MTX110 in brain tissue followed the 
infusion distribution predicted by the 
MRI planning software.
Three groups of male Wistar rats were treated with MTX110 by CED with as shown in Table 4. 


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Table 4: Rat CED Pharmacokinetic Study Design 
Group 
No. 
Group Name 
Dose concentration (μM 
panobinostat) 
Sampling time points (2 rats/time 
point) 
1 
MTX110-low 
3
0, 0.5, 2, 6, 24, 48, 72 hours after 
infusion 
2 
MTX110-inter 
30 
0, 2, 6 hours after infusion 
3 
MTX110-high 
300
0, 2, 6 hours after infusion 
For Group 1 rats (3 μM), the catheter tip was placed stereotactically into the brain stem. The 
solution was administered at a CED infusion rate of 1 μL/minute for 5 minutes (5 μL volume of 
infusion). For Group 2 rats (30 μM), and Group 3 rats (300 μM) the catheter tip was placed into 
the left striatum. Solutions were administered at a CED infusion rate of 2.5 μL/minute for 4 
minutes (10μL volume of infusion). 
Brain panobinostat concentrations are shown in Table 5. Concentrations were dose-related but 
increased sub-proportionally with increasing dose. Peak brain concentrations in the infused 
hemispheres of 1.9, 3.4 and 36.6 ng/g were measured for the 3, 30 and 300 μM solutions, 
respectively. If it is assumed that all drug is located within the convected tissue (assumed to be 
3x the infusion volume), the peak concentrations equate to concentrations in the convected tissue 
of 253, 227 and 2,440 ng/g, equating to approximately 0.7, 0.7 and 7 μM. At the 300 μM dose, 
brain concentration declined with time after convection with a tentative half-life of 2 to 3 hours. 
Table 5. Brain panobinostat concentrations after CED administration of MTX110 in rats 
Brain concentration (ng/g)
Dose 3μM
Dose 30μM
Dose 300μM
Time (h) 
Brain Stem
Brain
Right Brain
Left Brain
Right Brain
Left Brain
0 hours 
BLQ
1.58
BLQ
BLQ
36.6
BLQ
0 hours 
1.07
1.97
BLQ
BLQ
20.9
BLQ
2 hours 
0.76
1.81
3.41
BLQ
15.0
BLQ
2 hours 
BLQ
0.87
2.67
BLQ
19.8
BLQ
6 hours 
BLQ
0.86
BLQ
BLQ
6.53
BLQ
6 hours 
BLQ
BLQ
BLQ
BLQ
8.70
BLQ
LOQ = 0.75ng/g 
In plasma, very low concentrations of panobinostat were measured in occasional samples (Table 


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6). 
Table 6. Plasma panobinostat concentrations after CED administration of MTX110 in rats
Plasma concentration (ng/mL)
Time
Dose 3μM
Dose 30μM
Dose 300μM
0 hours
0.59
BLQ
BLQ
0 hours
BLQ
BLQ
BLQ
2 hours
0.28
BLQ
BLQ
2 hours
BLQ
0.66
BLQ
6 hours
BLQ
1.06
BLQ
6 hours
BLQ
0.88
0.643
LOQ = 0.25 ng/mL (3μM dose); 0.5ng/mL (30 and 300μM doses) 
A single Large White (Landrace) pig was treated with MTX110 by CED as shown in Table 7. 
Two catheters were implanted, one into white matter (striatum, left hemisphere) and one into 
grey matter (thalamus, right hemisphere) using stereo-guidance. A recessed-step catheter design 
attached to subcutaneous ports was used for this study [54](supplied by Renishaw). The accuracy 
of catheter targeting was verified by post-operative MRI. 
Infusion of MTX110 30μM (10.47 μg panobinostat/mL) was performed by gradually ramping up 
the infusion rate, monitoring in real-time with MRI. Serial T2/FLAIR imaging was performed 
during infusions to allow monitoring of infusate distribution. Immediately on completion of CED 
infusion, the pig was euthanized for drug distribution analysis. A map showing the areas sampled 
is shown in Figure 1 below for one of 6 brain slices of 1cm thickness (as shown in the inset 
diagram). The sampling pattern was replicated for each of the 6 slices. Sample numbers 1-3 form 
an inner-perimeter around the catheter tip, and sample numbers 4-6 form an outer perimeter. 
Table 7. Pig CED Pharmacokinetic Study Design 
Animal 
Number 
Brain Region 
Convected 
Day of 
termination
Infusion Volume 
(μL) 
Panobinostat 
Dose (μM)
MTX110 (Pig 
No. 4) 
White matter (left)
Grey matter (right) 
Day 0
1500μL
750μL
30μM
30μM


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Figure 1. Punch biopsy sampling sites in Pig 4 
Brain panobinostat concentration data are shown in Table 8 for each of the sample numbers and 
slice letter codes shown in Figure 1. Drug was measurable in several regions away from the 
catheter location indicating successful convection of the dose. The average peak concentration 
was 1,042 ng/g, which is equivalent to approximately 3 μM. 


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Table 8. Brain panobinostat concentrations for punch biopsy samples in Pig 4 (see Figure 1 for 
sample map) 
Left Brain Slice Letter Code (ng 
panobinostat/g)
Right Brain Slice Letter Code (ng 
panobinostat/g)
A
B
C
D
E
F
A
B
C
D
E
F
1
BLQ
BLQ
49.8
35.9
BLQ
BLQ
BLQ
BLQ
BLQ
BLQ
67.3
BLQ
2
7.79
BLQ
19.2
BLQ
BLQ
BLQ
BLQ
BLQ
BLQ
5.98
52.0
BLQ
3
BLQ
BLQ
6.70
9.63
BLQ
BLQ
BLQ
BLQ
BLQ
433
BLQ
BLQ
4
BLQ
5.40
1650
71.5
BLQ
BLQ
BLQ
BLQ
BLQ
19.4
BLQ
BLQ
5
BLQ
BLQ
BLQ
6.60
BLQ
BLQ
BLQ
BLQ
BLQ
BLQ
11.1
BLQ
6
BLQ
BLQ
197
1.42
BLQ
BLQ
BLQ
BLQ
BLQ
BLQ
BLQ
BLQ
Safety of MTX110 given via CED in animal models
The brain toxicity of MTX110 was evaluated in rats and pigs treated using CED in two studies, 
as listed in Table 9. 
Table 9: MTX110 Pharmacokinetic and Toxicity Studies 
No. Animals
Midatech 
Study 
Reference
Study 
Description
Dose (μM)
72h
14d
Measurements & 
Observations
0 (aCSF)
3
3
0 (HPBCD)
3
3
0.3
3
3
1
3
3
3
3
3
10
3
3
MTX110- 
R0022T 
Rat CED 
Single Dose 
CNS 
Toxicity 
Study 
30
3
3
Rats were dosed by 
CED into the brainstem 
and sacrificed 72 hours 
or 14 days after dosing. 
Brains were examined 
in detail for 
histopathological 
changes and no drug-
related histophatologic 
changes were seen.
MTX110- 
Rat CED 
7d
14d
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R0226T
Single Dose 
CNS 
Toxicity 
Study
0 (Saline)
30
100
300
4
4
4
4
-
-
-
-
CED into the brainstem 
and sacrificed 7 days 
after dosing. Brains 
were examined in 
detail for 
histopathological 
changes. The 
maximum non-
neurotoxic 
concentration of 
MTX110 was 
determined to be > 300 
μM. 
7d
14d
MTX110- 
R0227T; 
MTX110-
R0197T
Rat CED 
Single Dose 
CNS 
Toxicity 
Study
0 (Saline)
1000
3000
4
4
4
-
-
-
Rats were dosed by 
CED into the striatum 
and sacrificed 7 days 
after dosing. Brains 
were examined in 
detail for 
histopathological 
changes. The 
maximum non-
neurotoxic 
concentration of 
MTX110 was 
determined to be about 
1000 μM.
7d
14d
MTX110- 
S0023T 
Pig CED 
Single Dose 
CNS 
Distribution 
and 
Toxicity 
Study 
0 
30
30
-
1
-
1
-
1
Pigs were dosed by 
CED into the brainstem 
and sacrificed 7 days or 
14 days after dosing. 
Brains were examined 
in detail for 
histopathological 
changes and no drug-
related histophatologic 
changes were seen.
aCSF – artificial cerebrospinal fluid; HPBCD – hydroxypropyl-β-cyclodextrinRat Studies
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Table 10. Rat CED Toxicity Study Design 
Group 
No.
Group Name
Dose (μM 
Panobinostat)
No. Rats (72 
hours)
No. Rats (14 
Days)
1
aCSF Control
0
3
3
2
HPβCD Control
0
3
3
3
MTX110 - HIGH-2
30
3
3
4
MTX110 - INTER-1
1
3
3
5
MTX110 - INTER-2
3
3
3
6
MTX110 - HIGH
10
3
3
Test and control solutions were administered to the rats by CED. A catheter tip was placed 
stereotactically into the brain. Solutions were administered at an infusion rate of 1 μL/minute for 
5 minutes (5 μL volume of infusion). Target accuracy was confirmed with infusion of dye into 
the brain stem of one additional animal using the same infusion parameters, and visualized at 0 
hours post infusion. Either 72 hours or 14 days after dosing, the animals were killed for 
histopathological examination of the brain. 
The rats tolerated CED treatment well, and there were no adverse in-life observations. One rat 
treated at 30μM was found dead the morning after dosing with no cause of death established. In 
other rats, intraventricular administration of MTX110 was well tolerated. Histopathological 
examination revealed no toxicity and the catheter damage associated with the route of 
administration was limited and repaired readily. At 72 hours, the initial points of catheter entry 
were visible in the majority of animals. Lesions at the point of entry were in the visual cortex in 
the region of the pineal gland, and comprised focal necrosis with astrocytosis, macrophage 
infiltrates and haemorrhage. The largest lesion was in an a CSF control, and extended to the 
superior colliculus; there was also a linear lesion in neuropil near the aqueduct. Similar linear 
lesions in the neuropil close to the aqueduct were seen in several animals. Similarly, there were 
linear lesions comprising focal vacuolation and astrocytosis with a macrophage infiltrate in the 
region of the cerebellar carbuncle and extending down towards the pontine nuclei. This area is 
very close to the 4th ventricle, an area that would have the potential to be a region where a 
relatively high concentration of the test item could be expected, but given the lack of a dosage 
relationship (the lesion was most pronounced in the animals given 1.0 μM MTX110), it was 
likely that this lesion was also procedural in nature. 
One rat in each of the 1 and 3 μM groups had small focal lesions of linear nature in the cerebellar 
lobules. These were similar in appearance with a localized loss of neurons, a macrophage 
infiltrate and a minimal astrocytosis and were consistent with localized trauma from the 
procedure; they were also considered to represent localized damage in the region of the needle 
path. Immunohistochemical (IHC) stains clarified the nature of the lesions in the visual cortex 
and the other areas that were considered to be traumatic. The appearance was one of a focal loss 
of neurons, with the area having been populated by macrophages and a reactive astrocytosis. The 
IHC stains indicated the lesions were a little more extensive than first appeared on the H and E 
sections. The appearance strongly suggested the lesions were related to the procedure following a 
well-recognised pattern for traumatic lesions in the CNS. 
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revealed the occasional necrotic neuron in some animals. These were seen within the boundaries 
of the lesions that resulted from the trauma associated with the route of administration, and when 
present only occurred at an incidence of one or two per field. There was no evidence of any 
neuronal damage resulting from the presence of Panobinostat. There were no changes seen at the 
highest dose that were not present in the other dose groups. As such it was considered that at 72 
hours there were no toxic changes associated with the administration of MTX110. After 14 days, 
the initial points of entry were still visible in the majority of the animals. The lesions had a 
similar appearance but showed signs of resolution. No new lesions had developed in the period 
between the sacrifices, and the lesions that were associated with the route of administration were 
generally smaller and clearly resolving. 
Pig Studies
Three Large White (Landrace) pigs were treated with MTX110 by CED or left untreated as 
shown in Table 11. The catheter type and placement mimicked those to be used in the proposed 
protocol. 
Table 11. Pig CED Toxicity Study Design 
Animal 
Number
Brain Region 
Convected
Day of 
termination
Infusion 
Volume (μL)
Panobinostat Dose 
(μM)
Toxicology: 
MTX110 
(Pig 1)
PONS
Day 7
100μL
30μM
MTX110 
(Pig 2)
PONS
Day 14
100μL
30μM
Control 
(Pig 3)
Untreated Control
Day 14
N/A
N/A
A single catheter (Renishaw) was implanted into the target area (pons brain stem). The accuracy 
of catheter targeting was verified by post-operative MRI. Infusion of MTX110 30μM (10.47 μg 
panobinostat/mL) was performed by gradually ramping up the infusion rate, monitoring in real-
time with MRI. Serial T2/FLAIR imaging was performed during infusions to allow monitoring 
of infusate distribution. The total time of infusion was 47 minutes. If appropriate, the animals 
were allowed to recover from anaesthesia. The pigs were euthanized by terminal anesthesia and 
the brain was explanted. The brain was orientated optimally for sectioning along the CED 
catheter tracks, embedded in paraffin wax, and sectioned to generate 9 sections of brain (12 
samples) for each pig. Sections were stained with haematoxylin and eosin for histopathologic 
examination, and special stains were used to assess damage to specific cell types as follows: 
NeuN (neuronal cell specific marker), GFAP (glial fibrillary acidic protein, a glial cell specific 
marker), Fluorojade (neuronal degeneration stain) and IBA-1 (a microglia marker). 
Both MTX110-treated toxicology pigs had some hind leg weakness following recovery from 
surgery. Pig 2 recovered quickly over 24 hours, whereas Pig 1 had weakness in the right leg for 2 
days and in the left leg for 5 days after treatment. Hind edema was also noted in Pig 1, which 
partially responded to administration of non-steroidal analgesia. After detailed consultation with 
a veterinarian, the weakness was attributed to surgical positioning and prolonged anaesthesia 


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(approximately 6 hours) in this pig and not to MTX110, as such effects have been observed 
previously in animals undergoing extended anaesthesia. Eating and drinking in both animals was 
normal. There were no physiological signs of brain stem dysfunction in either pig. 
Histopathological examination of the pig killed after 7 days clearly showed the needle track in 
the sections, which included the thalamus and the pons. At this time-point there was 
haemorrhage and a cellular response that was GFAP negative and IBA-1 positive, indicating a 
macrophage/microglial response with no apparent astrocytosis (Figure 2). A little perivascular 
cuffing was seen in the region of the needle track in the sections of the pons. The amount of 
haemorrhage appeared to be more than was seen in the rodent study (MTX110-R0022T). 
There were occasional vacuoles containing myelin bodies adjacent to the areas of the needle 
track, a finding indicative of some previous neuronal loss. This was particularly evident in the 
section from the distal pons where there was a focal lesion but no clear needle track, probably an 
indication that this was the site of delivery of the test item. However, the changes were not 
markedly worse than in the other areas of the needle track, and are consistent with the pathology 
expected from the procedure. 
In the animal euthanized after 14 days, the needle track was still clearly visible in the sections 
that included the thalamus and the pons. At this time-point the haemorrhage had largely resolved, 
and the cellular response remained GFAP negative and IBA-1 positive. Many 
macrophages/microglia could be seen to be containing pigment, presumed to be hemosiderin. 
No new lesions developed in the period between the sacrifices, and the lesions that were 
associated with the route of administration were generally smaller and clearly resolving. 
Examination of the sections stained with Fluorojade indicated that there was no active necrosis 
or apoptosis in either of the treated animals. There were no microscopic findings recorded in the 
control animal. 
The route of administration therefore appeared to be well-tolerated, and the lesions caused by the 
procedure appeared to be resolving readily over the period of the study. The damage that was 
seen to have occurred was limited to the needle track and the area immediately adjacent to it. The 
NeuN staining indicated that the path of the needle was in the main passing through areas of low 
neuronal density, and as such the neuronal loss seen in the area of the track probably represents a 
very small loss of neurons in numerical terms, and an insignificant loss in biological terms. 
In conclusion, the intracranial administration of MTX110 was well-tolerated. There was no 
toxicity associated with the administration of the test item and the damage associated with the 
route of administration was limited and showed signs of repair in the time course evaluated. 
Safety of MTX110 formulation
All excipients used in the formulation of MTX110 are widely used pharmaceutical ingredients 
that have established safety profiles in the concentrations used. Hydroxypropyl-β-cyclodextrin 
(HPBCD) is commonly used to improve the solubility of drugs for intravenous use, but has not 
previously been delivered directly to the brain by CED. However, HPBCD is administered at 
very high intravenous doses as a component of some marketed drug products, and compassionate 
use in children with Niemann Pick Type C has involved intrathecal delivery of high doses 


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(200mg) to the brain that appear to be well tolerated. Matsuo et al (2014) delivered doses up to 
200mg (10mg/kg) or 300mg (15mg/kg) to a single patient (20kg child weight assumed) twice 
weekly for 23 months[55]. This was reported to be well tolerated although the 300mg dose was 
stopped when an elevated CSF tau level was detected. Maarup et al (2015) delivered 200mg 
HPBCD intrathecally to a 12-year old child with NPC, with only subclinical hearing loss at high 
frequency noted.[56] In an on-going NIH clinical trial, doses of 50 to 400mg HPBCD have been 
administered to 12 NPC patients intrathecally and are also reported to be well tolerated, except 
that Grade 1 ototoxicity has been observed in 2 patients. 
A dose of 200mg is more than 160 times higher than the dose of HPBCD that would be delivered 
in MTX110 panobinostat solution for infusion by CED, assuming a convection volume of 12mL 
of 10μM panobinostat in 100μg HPBCD/mL solution. 
Flow rate assessment of CED in non-human primates
Two non-human primates (NHP) were treated with CED of gadolinium (Dr. K Bankiewicz, 
personal communication). Once the target was selected, infusion of 2mM MR-visible tracer 
(ProHance, Bracco) was performed by CED by means of small (16G) on the left and large (14G) 
cannula on the right side of the brain. After visualization of gadolinium infusion at the cannula 
tip, the infusion rate was ramped up from an initial 1 (16G cannula) or 4 μL/min (14G cannula) 
to a maximum of 33 μL/min. NHP1 received an infusion on the left thalamus with the 16G 
cannula and on the right thalamus and brainstem with the 14G cannula. NHP2 was infused 
bilaterally in the thalamus with the 14G cannula. The total infusion volume per hemisphere was 
245 and 1090 μL on left or right side respectively for one animal (NHP1, left thalamus: 246 μL; 
right thalamus: 438 μL; right brainstem: 655 μL) and 340 μL for the other (NHP2) in each 
thalamus. There was no observed toxicity that was related to the infusion with the respective 
volumes and infusion rates. 
CED experience in children with DIPG
There are several studies that support the feasibility of placing catheters safely into the brainstem 
and obtaining adequate coverage of a therapeutic agent using CED in humans. A feasibility study 
using co-infused imaging tracers with interleukin-13-Pseudomonas exotoxin in children with 
DIPG has shown that clinically relevant distributions of agents can be achieved in humans 
through the use of CED [57]. In a recent report of 2 children with DIPG and one patient with 
Parkinson’s disease, Chittiboina et al. showed that cannulas for CED can be accurately placed 
under direct MRI guidance using a similar navigation system proposed for this study [58]. The 
same group had previously shown that real-time image guided CED of therapeutic agents is 
feasible in children with brainstem lesions [16]. A case report by Saito et al. demonstrates a 
clinical response to a brainstem located high grade glioma to CED of nimustine hydrochloride 
[59]. Another case report demonstrated safe and effective delivery of carboplatin using CED in a 
5 year old with DIPG [60]. The technical feasibility of CED in the brainstem is also supported by 
a report from Anderson et al. that used CED of topotecan for the treatment of 2 children with 
DIPG [61]. The first patient underwent CED 210 days after initial diagnosis and completion of 
radiation therapy at time of tumor progression. A total dose of 0.403 mg topotecan in 6.04 ml 
over 100 hours was administered. The second patient was treated 24 days after the initial 
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With respect to volume of distribution, other groups have shown that coverage of the total tumor 
volume appears to be safe in children with DIPGs. At the recent meeting of the International 
Society Pediatric Neuro-Oncology (ISPNO, 2016 Liverpool), Dr. Steven Gill (Bristol University, 
UK) presented results following CED with carboplatin in children with DIPG. The range of 
infusion volumes and infusion rates (using four catheters) was 2.76 to 11.22 ml and 9-20 µl/min, 
respectively. Some subjects developed transient neurological symptoms such as weakness, ataxia 
and dysarthria, but overall, the treatment was well tolerated.
Dr. Mark Souweidane (Memorial Sloan Kettering Hospital, New York City; Surgical co-study 
chair on this proposal) is currently conducting a clinical trial using CED with a radiolabeled 
antibody for children with DIPG (NCT 01502917). The majority of the tumor volume can be 
covered with infusion volumes of 4000 L without significant adverse effects In this study, 
repeated CED was an option if the patient was without clinical or radiographic evidence of 
disease progression. There were no serious adverse events definitively related to surgery in 
children undergoing retreatment. The lower age limit is 2 years for this trial further supporting 
this age cut off in the current protocol. Dr. Souweidane is also utilizing repeated CED every 4 
weeks after the initial infusion with no safety concerns reported to date62.
Human experience of CED of MTX 110
The preclinical safety of MTX110 Panobinostat Solution for Infusion has been evaluated by 
Midatech in collaboration with Bristol University to support experimental use by CED 
administration on a compassionate named patient supply basis. Patient treatments involved CED 
administration of MTX110 on one or two consecutive days at doses between 10 and 30 μM 
panobinostat; all patients treated to date are listed in the table below (Table 12). Further, UCSF 
conducted a single patient IND trial using MTX110 in a child with progressive DIPG. The CED 
procedure completed in the compassionate use protocol uses the same BrainLab navigation and 
catheter system and similar intra-operative MRI monitoring proposed in the current protocol. 
The patient underwent 2 cycles of CED treatment with MTX110. Both cycles included 
placement a single catheter and were deemed tolerable. In the first cycle, the patient received a 
total of 1.5mL of drug infusion and experienced transient grade 1 sinus tachycardia and 
hypertension in the post-operative period. The patient went on to experience grade 1 dysphagia, 
grade 2 gait disturbance, and grade 1 abducens and oculomotor nerve disorder a few weeks after 
hospital discharge. Imaging done at time of new symptoms was concerning for tumor 
progression; however, contribution of local inflammation from CED therapy could not be ruled 
out and patient was started on increased dexamethasone for symptom management. In the second 
cycle, the patient received a total of 4.2mL of drug infusion. After this cycle, the patient 
experienced grade 2 respiratory disorder due to lung atelectasis in the post-operative disorder, 
worsening left-side weakness, and grade 3 dysphagia. All symptoms were improving at time of 
hospital discharge on post-operative day 8. During both CED cycles, the patient received 
prophylactic dexamethasone to decrease local edema. Dexamethasone was tapered appropriately 
over hospital course with each cycle. During cycle 2, the patient also received a 24-hour course 
of mannitol in effort to decrease any component of edema that was contributing to increased 
dysphagia and weakness. The patient remains alive at the time of this protocol. Overall, these 
experiences provide supporting evidence of safety and starting dose for the current trial.


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Table 12. Pediatric patients treated with MTX110 via CED through compassionate use.
Patient Number
Treating Centre
Number of MTX 110 Doses Received to 
Date
  
10
3
 1
1
 1
1
 
2
1 from October 2016
Summary of adverse events with cut off date Oct 31, 2018 of the current study. 
To date, we have enrolled subjects and completed monitoring and DSMC approval of the first 
4 dose levels as per the ATD. There were no DLTs at any dose level. Table 13 details related 
adverse events reported to date.
Table 13. Adverse events probably, possibly or definitely related to protocol therapy:
Maximum grade across all cycles
Grade 1
Grade 2
Grade 3
Grade 4
Toxicity
Dose level
# Evaluable Patients
Fatigue
4
1
1
-
-
-
Summary of preclinical and clinical data
In summary, the relevant preclinical and clinical studies support the exploration of CED of 
MTX110 in children with DIPG: 
(1) The target of MTX110 is highly expressed in human DIPGs
(2) Human derived DIPG cell lines are sensitive to MTX110 
(3) CED leads to effective distribution within the brainstem
(4) CED of MTX110 under real time imaging is feasible 
(5) Published evidence supports the feasibility of CED in children with DIPG
(6) Five total pediatric patients with DIPG receiving MTX110 via CED support safety of 
delivery of MTX110 via the proposed CED protocol.
2.4
Study Agent
Agent: MTX110 a water soluble formulation of panobinostat for administration via Convection 
Enhanced Delivery. MTX110 is a lyophilized powder produced under aseptic conditions. The 
product in reconstituted using normal saline. The appearance of the final solution is a clear 


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colorless solution.
The composition of each vial of MTX110 is provided below. 
Active Ingredient
Function
Amount per 10ml vial
Panobinostat free base
Active
0.14mg
Excipients
Hydroxypropyl-β-cyclodextrin
Improve solubility
4.00mg
Sodium hydroxide
pH adjustment
0.39mg
Sodium citrate dihydrate
Improve solubility
0.21mg
Citric acid
Improve solubility
0.64mg
Mechanism of Action
MTX110 is a pan-HDAC inhibitory, which promotes activity of methyltransferase to methylate 
histones, leading to chromatin remodeling and increased cell cycle regulation, cellular 
differentiation and controlled apoptosis.
How the drug is supplied 
 
MTX110 is supplied as a white to off-white lyophilized powder in 10mL sealed amber-glass 
vials which, on reconstitution, provides a clear colorless solution. Each vial contains 14mg 
panobinostat base.
Storage and handling
MTX110 should be stored refrigerated (2-8°C). Refer to ‘Instructions for Use’ for reconstitution 
and dilution.
Side Effects
Human Toxicity: As outlined above, 7 human subjects with DIPG have received repeated doses 
of MTX110 via CED which was tolerated well. 
As per Table 13, to date, the only adverse event that was considered related to MTX110 was 
fatigue, at grade 1.
Important Treatment Considerations with MTX110
The CED direct delivery method proposed herein will in theory minimize these side effects 
significantly given the limited systemic exposure. This is supported by an ongoing GBM study 
that shows limited systemic toxicity with CED-directed brain tumor treatment (Dr. Butowski, 
UCSF; NCT02022644; personal communication). 
Neutropenia
Neutropenic complications should be managed promptly with antibiotic support. G-CSF may be 
used to manage neutropenia at the investigator’s discretion. 
Thrombocytopenia
Thrombocytopenia complications should be managed promptly with platelet transfusions as 


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clinically indicated and at the investigator’s discretion.
Pregnancy
The pregnancy category of MTX110 is D. Women of childbearing potential should be advised to 
avoid becoming pregnant while receiving treatment with MTX110. If a pregnancy is reported, 
the pregnancy should be followed until the outcome becomes known.
2.5
Rationale
Based upon the background information concerning intra-tumoral delivery by CED and pre-
clinical and clinical studies using MTX110 in animal models, we propose a Phase 1 and 
early efficacy trial of CED of MTX110 in children with DIPG. There is an unmet need for 
effective therapy for this disease, which has no standard of care treatment other than 
radiotherapy. All children die from disease progression, with a median survival time of 9 
months. This trial will utilize repeated intratumoral CED of MTX110 in children with 
newly diagnosed DIPG, following initial treatment with radiotherapy. We will assess the 
safety of MTX110 (up to 12 mL total volume and up to 90 M concentration) delivered by 
CED. We will utilize an accelerated titration design (ATD) scheme. 
2.5.1
Dose Escalation Rationale
The dose escalation design in this study begins with escalation of dose 
administration on consecutive days followed by total volume escalation and lastly 
followed by dose concentration escalation. The proposed dose volume escalation 
offers a larger volume of MTX110 to be delivered with each subsequent dose level 
of MTX110, up to 6 mL per treatment for 2 consecutive days of treatment per cycle 
(total volume 12 mL). This volume escalation provides for a larger volume of the 
tumor to be treated each time and ideally reaches the greatest treatment coverage of 
tumor. 
Once the RP2D volume is reached, the concentration of MTX110 will then be 
escalated. The starting concentration of MTX110 in this study is 30 M. This dose 
has been previously used in the compassionate use protocols outlined in Section 2.3 
and appears to be tolerable in human subjects. Based on the volume of distribution 
to volume of infusion (Vd:Vi) ratio (Study MTX110-S0023T), a drug concentration 
of 30 M is anticipated to result in a tissue drug concentration of 10 M throughout 
the treatment volume. This concentration is higher than the in vitro IC50 of < 
100nM, shown to have cytotoxic effects in patient-derived DIPG cell lines and also 
exceeds the dose of 2 µM, shown to be effective in in vivo studies of CED with 
MTX110 in murine models of DIPG and glioblastoma. However, additional pre-
clinical evidence in murine models treated with CED has demonstrated that much 
larger concentrations of MTX110 should be tolerable and higher concentrations may 
offer greater therapeutic benefit. To date, MTX110 doses up to 300 µM have been 
delivered via CED in rodent models and no animal has demonstrated excess 
toxicity, including no clinically relevant central nervous toxicity and no toxicity on 
histopathology tissue review (Study MTX110-R0021T; Study MTX110-R0226T). 
In higher concentrations up to 1000 µM of MTX110 delivered the brain, post-
treatment tissue demonstrated mild gliosis on histopathology (Study MTX110-


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R0227T; Study MTX110-R01197T). Given the tolerability of such high 
concentrations in murine models up to 300 µM, we propose to dose escalate to a 
maximum of concentration of 90 µM in the current study, with the goal to ensure 
therapeutic levels of MTX110 are reached throughout the CED treatment volume. 
3. STUDY DESIGN
3.1
Characteristics
This is an open-label, PNOC multi institution, Phase I/II study of MTX110 delivered by CED in 
patients with DIPG previously treated with external beam radiation therapy.
3.2
Number of Subjects
The number of subjects enrolled will depend upon the DLTs observed and the number of dose 
levels tested as the study progresses in accordance with an ATD. 
Once each dose level has been assessed, a detailed review of the safety and efficacy data will be 
performed and discussed with the FDA and the DSMC to discuss either further dose escalation or 
enrollment into the phase II portion of the study. Additional subjects might be needed if dose de-
escalations need to occur. At least 26 subjects will be enrolled.
Dose Administration
Initially, an accelerated titration design (ATD) will be employed. This design has the advantage of 
potentially reducing the number of subjects treated at sub-efficacious doses, and decreasing the 
accrual time for the trial. Each cohort will consist of one subject. The first subject will be started 
at dose level 1. A 14-day window of evaluation for toxicities is required for at least one subject at 
each dose level before determining the dose for the next cohort. 
3.3
Inclusion Criteria 
Patients must have eligibility evaluations performed within 14 days prior to registration (unless 
otherwise stated) and must meet all inclusion and none of the exclusion criteria. In addition, the 
patient must be thoroughly informed about all aspects of the study, including the study visit 
schedule, required evaluations and all regulatory requirements. The written informed consent must 
be obtained from the patient or their legal guardian prior to enrollment. The following criteria 
apply to all patients enrolled onto the study unless otherwise specified. Tumor biopsy is not 
required prior to enrollment on study, unless imaging characteristics are not consistent with DIPG 
diagnosis and as detailed in 3.2.1. The Inclusion Criteria will be applied after patients have 
completed radiotherapy and within the given time frame per observation as listed below. 
Enrollment into the trial occurs after completion of radiation therapy and if all eligibility criteria 
are met. 


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3.3.1 Patients with newly diagnosed DIPG by MRI; defined as patients with a pontine 
location and diffuse involvement of at least 2/3 of the pons are eligible without 
histologic diagnosis. For lesions with typical imaging features, biopsy is neither 
encouraged nor required for eligibility. Tumors that are biopsied will be eligible if 
proven to be supportive of the diagnosis of a DIPG. Consensus of diagnosis by the 
study team must be met. 
3.3.2 Patients who have completed focal radiotherapy within 14 weeks from time of 
enrollment are eligible.
3.3.3 Treatment must begin at a minimum of 4 weeks after, but no later than 14 weeks 
after, the date of completion of focal radiotherapy. 
3.3.4 Prior Chemotherapy: Patients should be at least 30 days from last chemotherapy dose 
prior to start of CED infusion, with exception of antibody half-lives. For antibody 
therapies, at least 3 half-lives of the antibody after last dose of monoclonal antibody 
should have passed prior to CED infusion. Patients less than 30 days from last 
chemotherapy dose should be discussed with the study chair(s).
3.3.5 Prior Radiation: Patients must have received prior treatment with standard focal 
radiotherapy as part of initial treatment for DIPG and had their last dose at least 4 
weeks prior to and no later than 14 weeks from the first CED treatment. Patients 
beyond 14 weeks from radiation therapy but with stable disease should be discussed 
with the study chair.
3.3.6 Age ≥ 2 years of age to  21 years. Patients younger than 3 years of age may be 
enrolled on study at the discretion of the Study Chair(s) if supporting evidence that 
brainstem lesion represents a brainstem glioma.
3.3.7 Karnofsky 50 for patients >16 years of age and Lansky 50 for patients  16 years 
of age (see Appendix A). Patients who are unable to walk because of paralysis, but 
who are able to moblize using a wheelchair, will be considered ambulatory for the 
purpose of assessing the performance score.
3.3.8 Life expectancy of greater than 12 weeks measured from the date of completion of 
radiotherapy.
3.3.9 Corticosteroids: Patients who are receiving dexamethasone must be on a stable or 
decreasing dose for at least 1 week prior to registration.
3.3.10 Organ Function Requirements 
3.3.10.1
Adequate Bone Marrow Function defined as:

Peripheral absolute neutrophil count (ANC) 1000/mm3 and

Hemoglobin 8g/dl and

Platelet count 100,000/mm3 (transfusion independent, defined as not 
receiving platelet transfusions for at least 7 days prior to enrollment) and


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
Normal coagulation defined as normal INR or per institutional guidelines.
3.3.10.2
Adequate Renal Function defined as:

Creatinine clearance or radioisotope GFR  70mL/min/1.73 m2 or

A serum creatinine based on age/gender as follows:
Age
Maximum Serum
Creatinine (mg/dL)
Male
Female
2 to < 6 years
0.8
0.8
6 to < 10 years
1
1
10 to < 13 years
1.2
1.2
13 to < 16 years
1.5
1.4
≥ 16 years
1.7
1.4
The threshold creatinine values in this table were derived from the Schwartz formula 
for estimating GFR utilizing child length and stature data published by the CDC.
3.3.10.3
Adequate Liver Function defined as:

Bilirubin (sum of conjugated + unconjugated) 1.5 x upper limit of normal 
(ULN) for age and

SGPT (ALT) 110 U/L and

Serum albumin 2 g/dL.
3.3.11Adequate Neurologic Function defined as:

Patients with seizure disorder may be enrolled if on non-enzyme inducing 
anticonvulsants and well controlled.
3.3.12The effects of MTX110 on the developing human fetus are unknown. For this reason 
women of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry, for the 
duration of study participation and 4 months after completion of MTX110 injection 
administration. Should a woman become pregnant or suspect she is pregnant while 
she or her partner is participating in this study, she should inform her treating 
physician immediately. 
3.3.13A legal parent/guardian or patient must be able to understand, and willing to sign, a 
written informed consent and assent document, as appropriate.
3.4
Exclusion Criteria
3.4.1 Patients who had clinical and/or radiographic (MRI) progression of tumor following 
external beam radiation therapy.


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3.4.2 Patients with metastatic disease, including leptomeningeal or subarachnoid 
disseminated disease.
3.4.3
Patients with tumor morphology or other imaging findings that predict poor 
coverage of the majority of the tumor including significant tumor volume outside the 
pons or presence of large cysts within the tumor that would prevent adequate tumor 
coverage by CED. Patients with concern for adequate tumor coverage based on 
tumor morphology should be discussed with the study chairs. 
3.4.4 Patients who are receiving any other tumor-directed therapy.
3.4.5 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to MTX110 or gadolinium.
3.4.6 Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements.
3.4.7 Female patients of childbearing potential must not be pregnant or breast-feeding. 
Female patients of childbearing potential must have a negative serum or urine 
pregnancy test within 14 days of registration. 
3.4.8 Patients who are unable to return for follow-up visits or obtain follow-up studies 
required to assess toxicity to therapy. Telemedicine visits are acceptable. 
3.4.9 Patients with MRI or clinical evidence of uncontrolled tumor mass effect are 
excluded; the assessment of mass effect should be made by the study chairs and study 
neurosurgeons prior to any planned CED treatment. 
3.4.10Untreated symptomatic hydrocephalus determined by treating physician.
3.4.11Subjects with prolonged QTc (> 450 msec) will be excluded from the study. 
Important note: The eligibility criteria listed above are interpreted literally and cannot be 
waived.
4. REGISTRATION PROCEDURES
4.1
General Guidelines
Patients must meet all inclusion criteria and no exclusion criteria should apply. The subject or 
their legal parent/guardian must have signed and dated an approved, current version of all 
applicable consent and/or assent forms. To allow non-English speaking patients to participate in 
this study, bilingual health services will be provided in the appropriate language when feasible.
Registration materials will be submitted to the PNOC Operations Office as described below. 


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The PNOC Operations Office will forward eligibility checklist including source documentation 
to the Study Chair or Co-Chair as well as the Project Leader or Co-Project Leader of PNOC for 
review of eligibility and sign off. 
Eligible patients will be registered using the UCSF OnCore® database that is used for all PNOC 
trials. Treatment on protocol therapy cannot be initiated prior to receiving the registration 
confirmation email from the PNOC Operations Office.
4.2
Reservation and Registration Process
The wait-list for study slots will be maintained by the PNOC Operations Office. Investigators 
can view updated information about slot availability and registration process updates on the 
PNOC Member’s SharePoint website using their secure login and password, or by emailing a 
request 
. 
To place a subject on the waitlist, investigators are to send an email  
 with the following information: Study number, Subject age, 
Consent signed date (or estimate), and Expected start date (if found eligible).
To register a subject for the study, the subject demographics (gender, ethnicity, race, month & 
year of birth, country code, disease site, histology, diagnosis date, name of treating physician and 
study specific information) along with a signed consent form and HIPAA authorization (if 
applicable to your institutions regulatory guidelines) will be emailed to the PNOC Operations 
Office 
. The subject will be given the status of consented in 
OnCore®.
When the eligibility checklist has been completed the member institution PI and/or Coordinator 
will upload the completed eligibility checklist along with copies of any supporting documents 
into the subject’s OnCore® record.
Once the necessary documents have been received and the subject eligibility has been confirmed, 
the PNOC Operations Office will send a confirmation e-mail to the institutional PI(s) and 
Research Coordinator(s) with the subject’s study ID and dose information. 
Detailed subject screening and registration instructions can also be found on the PNOC 
Member’s SharePoint Wiki.
5. AGENT ADMINISTRATION
5.1
Regimen Description
Treatment will be administered to subjects after admission to an inpatient facility. Appropriate 
dose modifications are described in Section 5.5. No investigational or commercial agents or 
therapies, other than those described below, may be administered with the intent to treat the 
subject's malignancy. 


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Recommended synopsis of sequence of study events (site-specific set-up may vary with the 
approval of study chairs):
The procedure will take place in an operating room (OR) associated with an intraoperative MRI 
(iMRI) scanner, in order to facilitate confirmation of catheter placement and monitoring of 
infusate distribution. The configuration of the transfer system, and MR gantry allows rapid 
movement of an anesthetized and immobilized patient from the operating room to the MR bore, 
which is only separated by a door from each other. Specific surgical procedures can also be 
performed under sterile conditions within the actual MR room using MR-compatible equipment. 
The tumor target and trajectory will be selected and planned using the BrainLab navigation 
system based upon an imaging study obtained prior to the date of the procedure. The 
experimental agent will be delivered using the BrainLab Flexible Catheter system. This system is 
currently being used for CED in children with DIPG at Memorial Sloan Kettering Hospital (PI: 
Mark Souweidane), and for a single patient CED treatment with MTX110 performed at UCSF 
(PI: Sabine Mueller). 
1. A pre-surgical MRI (with DTI sequences) will be used in conjunction with the 
BrainLab iPlan software package for planning catheter placement, with a maximum of 2 
catheters placed into the tumor. With each treatment, a new planning MRI will be 
obtained and the trajectory and location of the catheter(s) optimized. The planning MRI 
will be obtained within 14 days prior to the scheduled procedure. 
2. Following induction of general anesthesia, and immobilization of the subject’s head, 
a maximum of 2 catheter(s) will be placed with the assistance of MRI-guided 
neuronavigation using standard neurosurgical techniques. Catheter position will be 
confirmed by an MRI study prior to initiation of drug infusion. If the subject received a 
prior CED of MTX110, a new catheter location will be selected to avoid overlap of the 
infusate. Repeated T1-weighted sequences will be collected in real-time during the 
infusion to monitor infusate distribution. The maximum volume will be based on the 
subject’s dose level. 
3. We will monitor the initial infusate distribution with real-time MR imaging 
(approximately every 15 minutes with a duration for each sequence of about 5-8 
minutes), with the final component of the highest infusion volumes being done with the 
patient awake so that clinical assessments can be performed, as feasible. Each patient will 
be monitored with repeated imaging under general anesthesia until 1.2 to 1.6 cc are 
infused (equals to approximately 2 to 2.5 hours assuming an average infusion rate of 10 
microliters/minute). The patient will then be woken up from general anesthesia. The 
reminder of the volume (depending on the dose level) will be infused while the patient is 
awake. If needed, sedating medications will be used to avoid agitation. At the end of the 
infusion, the patient will be brought back to the MRI scanner for a final series of images. 
If there are any concerns in regards to clinical signs or vital signs, imaging might be 
obtained at anytime during the infusion if clinically indicated. The table below describes 
the approximate infusion times for each dose level assuming a maximum infusion rate of 
10 microliters per minute. The estimated total anesthesia time including catheter 
placement and initial infusion time of 2-2.5 hours is estimated to be 5.5 hours. 


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Dose Level (#) and 
associated infusion 
volume
# catheters
Approximate Infusion 
Time with 1 Catheter
(using maximum 
infusion rate of 10 
microliter/min; adding 
30 min to achieve 
maximum infusion rate)
Approximate Infusion 
Time with 2 Catheters
(using maximum infusion 
rate of 10 microliter/min; 
adding 30 min to achieve 
maximum infusion rate)
#1: 3 ml
1
5.5 hours
2.25 hours
#2: 3 ml day 1 & 2
1
5.5 hours
2.25 hours
1
7 hours
n/a
#3: 4 ml day 1 & 2
2
n/a
3.5 hours
1
9 hours
n/a
#4: 5 ml day 1 & 2
2
n/a
4.5 hours
1
12.5 hours
n/a
#5*: 6 ml day 1 & 2
2
n/a
6.5 hours
*Dose levels 6 and 7 would also take approximately the same time as Dose level 5 as the volume 
is the same amount
4. We anticipate that changes to the infusion parameters and catheter placement may be 
required based on observations from the real-time MR images. We describe two possible 
scenarios below, but it is also possible that unforeseen distribution variations may occur:
a.
If there is evidence of backflow of the infusate along the catheter, the infusion 
rate may be slowed. If backflow continues to be present on repeated imaging, the 
catheter(s) position will be adjusted. In general, this will involve advancement of 
the catheter 2-5 mm within the intra-operative MR scanner using sterile 
techniques. If after the adjustment there is evidence of ongoing backflow, this 
catheter will not be used for the infusion.
b. If distribution from a specific catheter placement is observed outside of the target 
volume (based on T2-weighted images) the catheter may be advanced or 
withdrawn along the same trajectory (same as in (a)); or the infusion stopped and 
the catheter repositioned along a different trajectory. If the catheter has to be 
repositioned along a different trajectory, the subject will be transferred to the OR. 
The catheter will be removed; a new trajectory will be selected by the study team 
and a new catheter will be placed. In this event, we anticipate that the same entry 
point and burr hole can be used, but it is also possible that a new entry point may 
be necessary (e.g. to avoid a vascular structure). Once the new catheter is inserted, 
placement will be confirmed with an MR scan. Once the position is confirmed, 
the infusion will be re-started. 
5. As described above, once a stable infusion rate is achieved, we will monitor under real 
time imaging for approximately 2-2.5 hours under general anesthesia for each subject in 
the iMRI scanner. Imaging will be performed at least every 15 minutes. This timing of 


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imaging will allow us to observe an infusion volume of a minimum of 1.2 – 1.6 mls with 
an expected distribution volume of approximately 2.4-3.5 mls using an average infusion 
rate of 10 microliters/min. This should be sufficient to assess adequate distribution and 
assess backflow. 
a.
Once adequate distribution is confirmed and as clinically feasible, the subject will 
be transferred to the adjacent OR, removed from pin fixation, awakened, and 
extubated. The subject will then be monitored in an area close to the MR scanner, 
either in the adjacent OR or post-anesthesia care unit (PACU), or transferred to 
ICU for completion of infusion. Once the subject is awake enough to follow 
commands, we will perform neurologic assessments every hour appropriate to the 
patient’s level of consciousness and age, and continuous vital sign monitoring 
with blood pressure checked at least every 15 minutes. During this time, subjects 
may receive sedative and analgesic medications as needed. At the end of the 
infusion, we will obtain additional MR images to assess the final volume of 
distribution using the intra-operative MR scanner. 
b. If subjects are assigned to a dose level that will repeat CED of MTX110 on day 2, 
the subject will be transferred to the intensive care unit after completion of the 
day 1 CED and carefully monitored overnight. The catheters will remain in place. 
Only subjects who recover to baseline or ≤ grade 1 toxicities will be considered 
for day 2 infusion (not applicable to dose level 1). If they meet criteria to start the 
2nd day of CED of MTX110, the subject will be transferred back to the intra-
operative MR scanner. The position of the catheter(s) will be confirmed and we 
will monitor under real time imaging for approximately 2-2.5 hours (same as for 
the Day 1 CED). Children who can tolerate imaging without anesthesia will not 
be sedated. Children who will not tolerate imaging without anesthesia, will be 
anesthetized. We will then follow the same sequence of events as outlined for 
Day1. 
6. Once the final CED is completed, catheters will be removed following the completion of 
the infusion; this will either occur in the OR or in the monitoring unit close to the OR. 
7. Continue to repeat cycles every 4-8 weeks, until tumor progression or the development of 
adverse events.
8. For each subject, each catheter infusion will be initiated at a rate of 1 microliter/min and 
increased by a maximum of 5 microliters/min every 15 minutes under real-time imaging. 
The infusion rate increase will be performed sequentially for each catheter. If there are 
any concerns regarding the infusate distribution, the infusion rate will be reduced. The 
infusion rate will increase to a maximum of 10 microliters/min for the initial CED 
procedure for each subject. If this infusion rate is tolerated (following the same criteria as 
for dose escalation in 10.2, if toxicity is thought to be related to rate of infusion), the 
maximum rate will increase to 15 microliters/min for the next CED procedure and only as 
clinically indicated. The subject’s vital signs will be continuously monitored during the 
infusion. The rate of the infusion will be under the discretion of the study team but will 
never exceed the maximum allowed rate. 
 
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each CED. 
5.2
Dose Administration
Table 5.2.1. Dose levels.
Dose level
Concentration MTX110
Total Volume (ml)
Day of therapy
1
30 M 
3
Day 1
2
30 M 
6 (3mL each day)
Day 1, 2
3
30M 
8 (4mL each day)
Day 1, 2
4
30 M 
10 (5mL each day)
Day 1, 2
5
30 M 
12 (6mL each day)
Day 1, 2
6
60 M
12 (6mL each day)
Day 1, 2
7
90 M
12 (6mL each day)
Day 1, 2
If dose levels 6 or 7 are not tolerated, dose de-escalation levels will be implemented as per Table 
5.2.2. For example, if dose level 6 is not tolerated, dose level 5a will be tested and if dose level 7 
is not tolerated, dose level 6a will be tested.
Table 5.2.2. Optional dose de-escalations pending toxicity. 
Dose level
Concentration MTX110
Total Volume (ml)
Day of therapy
5a
45 M
12 (6mL each day)
Day 1, 2
6a
75 M
12 (6mL each day)
Day 1, 2

MTX110 will be delivered by 1 or 2 catheters surgically placed in an intratumoral (IT) 
location.

The concentration of gadoteridol (ProHance®) will be 0.5 mM for both dose levels; both 
agents will be combined and co-infused using the same catheters.

Maximum infusion rate will be increased as stated above in 5.1, utilizing the same criteria 
for escalation as will be used for overall dose level escalation (section 10.2). 

Timing of 2nd infusion (applicable to dose level 2 and higher) will be determined pending 
subject’s return to pre-infusion baseline neurological exam or ≤ grade 1 toxicities (with 
exception of toxicities anticipated to be within normal limits of post-operative recovery-
listed below), but will occur no later than 48 hours after completion of infusion on day 1, 
i.e. if subject’s neurological exam has not returned to pre-infusion baseline or has 
evidence of toxicities > grade 1 by 48 hours from completion of day 1 infusion, the 2nd 
CED procedure will be canceled.

The following toxicities are anticipated to be within normal limits of post-operative 
recovery and will not preclude initiation of the 2nd (day 2) infusion:


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o
Grade 2 headache
o
Grade 2 pain
o
Grade 2 nausea

If vomiting occurs during post-operative recovery, initiation of the 2nd (day 2) infusion 
may proceed only if vomiting is improving and the participant has 4-6 hours without 
emesis prior to dose administration.
5.2.1
Preparation of MTX110
 
Preparation of MTX110
Refer to ‘MTX110 Instructions for Use’ in SharePoint for more information. The product should 
be reconstituted by adding the specified amount of normal saline (see table below) via a sterile 
needle into the vial. The vial should be gently swirled to ensure complete reconstitution. 
Table 5.2.3 Saline volumes required for reconstitution
Required dose
Volume of normal saline
30μM (10.49μg/mL)
See note below
40 μM (13.98 μg/ml)
10ml
60 μM (20.97 μg/ml)
6.7ml
90 μM (31.46 μg/ml)
4.5ml
To achieve 30 micromolar concentration, mix 7.5 ml of the 40 micromolar panobinostat with 2.5 
ml sterile saline for injection in an empty sterile vial. 
5.2.2
Addition of ProHance® to MTX110 injection 
The research pharmacist will combine MTX110 solution to an empty glass vial for mixing with 
ProHance®. The final concentration of Prohance should be 0.5 mM. The pharmacist will 
confirm that this is the concentration in the final mixture.
List of Materials
1. Appropriate number of vials containing MTX110 injection
2. One vial ProHance® 
3. Two 3 mL syringes with 3/4” 22 gauge needle
4. One 10 mL with 1” 20 gauge needle
5. Two 20 ml syringes with 1” 20 gauge needle
6. 2 sterile 15 or 30 mL vials
7. One 1 mL syringe with needle
8. Sterile saline for injection
9. Alcohol swabs
Preparation of ProHance® Working Solution
1.       Use 3 mL syringe to draw up 1 mL of Prohance (0.5 mmol)
2.       Inject 1 mL ProHance into empty 15 or 30 mL sterile multiuse vial
3.       Use 20 mL syringe and draw up 9 mL sterile saline for injection
4.       Inject saline into vial with ProHance


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5.       Swirl to mix
6.       Label vial as ProHance working Solution 1:10 Dilution (50 mM)
During reconstitution, dilution, and filling, exposure to air should be minimized. Inspect for 
visual particles and filter if necessary. For Convection Enhanced Delivery, the product should be 
filled into the syringes within 24 hours of use. The combined solution will then be drawn up into 
a Medfusion 3500 or 4000 compatible 10 mL Luer-lock syringe and delivered to the OR. 
5.2.3
Instruction for drug administration with real-time imaging 
List of Required Materials
1. MTX110 injection with gadoteridol added
2. BrainLab catheter
3. Neuronavigation hardware and software
4. Medfusion 3500/4000 MRI-compatible pump 
5. Medfusion 3500/4000 compatible up to 10-20 mL Luer-lock syringe
6. Biohazard/sharps container for disposal of vector
Procedure
Note: site-specific procedures that differ from the procedures below must be 
submitted to the study chairs for review and approval. 
1) Surgical planning allowing up to 2 catheters into the tumor will be performed on a MRI 
scan acquired up to14 days prior to surgery. 
2) The iMRI suite consists of a neurosurgical operating room separated by shielded doors 
from a 3T GE large bore MRI scanner (model 750W). On the day of surgery the subject 
will be transported to the OR and placed under general anesthesia. 
a.
All members of the team who are present in the MRI suite must have documented 
MRI safety training. Existing standard procedures for MR safety in the iMRI suite 
will be followed.
b. A member of the anesthesiology department must remain present for the entire 
procedure.
3) Using the pre-operative planning MR scan, and the BrainLab navigation system, 
BrainLab flexible catheter(s) will be inserted through burr hole(s) following pre-
determined trajectories and depths, and secured to the calvarium using supplied guide 
ports. Prior to insertion, the catheter will be primed with MTX110/gadoteridol mixture.
4) After catheter insertion, the patient will be transported to the iMRI scanner and an MRI 
scan will be obtained to confirm catheter position. 
5) Imaging will be performed intermittently during the initial infusion to monitor the 
distribution of the agents and for adjustments of catheter placement and infusion rate. The 
infusion volume for each catheter will be based on MR images of gadoteridol distribution 
acquired during the infusion procedure. 
6) Once a stable infusion rate has been established for both catheters, the remaining duration 
of infusion has been estimated, and as clinically feasible, the subject may be transferred 
to the PACU or ICU to complete the infusion. Repeat MR imaging will occur at 
completion of the CED infusion. Subjects that cannot tolerate MRI without 
sedation/anesthesia will need to be sedated or undergo repeat anesthesia for the end of 


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infusion scan.
7) After completion of infusion at each dose level, the catheter(s) will be removed 
depending on the dose level. For example, the catheter will removed on day 1 at dose 
level 1, day 2 at dose level 2, etc. 
8) It is recognized that experience is likely to result in minor refinements of this procedure. 
Such refinements will not require amendment of the protocol as long as they do not 
increase the risk for the subject.
9) Timing of follow-up infusions on day 2 will be determined pending subject’s return to 
pre-infusion baseline neurological exam or ≤ grade 1 toxicities, but will occur no later 
than 48 hours after completion of infusion on day 1, i.e. if subject’s neurological exam 
has not returned to pre-infusion baseline by 48 hours from completion of day 1 infusion, 
the CED procedure on day 2 will be canceled and catheters removed. 
5.3
Dose Limiting Toxicity (DLT) 
Toxicity will be assessed according to the NCI Common Terminology Criteria for Adverse 
Events Version 4.0 (CTCAE v4.0).
The Dose Limiting Toxicity Period will be the first 14 days from the start of the CED procedure. 
Dose limiting toxicity (DLT) will be defined as:

Any intolerable (as deemed by the patient or investigator) grade 2 or any grade 3 or 
higher neurological toxicity felt to be attributable to the CED infusion procedure or to the 
MTX110 injection with gadoteridol within a period of 14 days after the infusion.

Any systemic treatment related grade 3 or higher hematologic or non-hematologic 
toxicity (after maximal medical management of nausea/vomiting/diarrhea) within a 
period of 14 days after the infusion.
If multiple toxicities are seen, the presence of a dose limiting toxicity should be based on the 
most severe toxicity experienced. 
Dose modifications are described in Section 5.5. 
5.4
General Concomitant Medication and Supportive Care Guidelines
All concurrent medical conditions and complications of the underlying malignancy will be 
treated at the discretion of the treating physician according to acceptable local standards of 
medical care. Subjects should receive analgesics, anti-emetics, antibiotics, anti-pyretics, and 
blood products as necessary. Although warfarin-type anticoagulant therapies are permitted, 
careful monitoring of coagulation parameters is imperative, in order to avoid complications of 
any possible drug interactions. All concomitant medications, including transfusions of blood 
products, will be recorded on the appropriate case report form. 
Guidelines for treating certain medical conditions are discussed below; however, institutional 


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guidelines for the treatment of these conditions may also be used. The concomitant therapies that 
warrant special attention are discussed below.
Edema after CED
Standard post-operative edema immediately after CED treatment should be managed as per 
institutional guidelines, with anticipation that patient be tapered off dexamethasone as soon as 
clinically tolerated. 
If edema is suspected due to worsening neurological symptoms or signs, the subject should 
undergo MR imaging to assess for possible edema or hemorrhage. The subject may be placed on 
dexamethasone, and/or the dose increased up to 0.3 mg/kg/day with a maximum of 16 mg/day or 
per institutional standard. Length of therapy will depend on clinical symptoms. 
Antiemetic Medications
Dexamethasone and a 5-HT3 blocker (e.g., ondansetron or granisetron) may be administered to 
all subjects as premedications unless contraindicated for the individual subject. Anti-emetics will 
also be prescribed as clinically indicated during the study period.
Colony Stimulating Factors
Though unlikely to be needed, the use of granulocyte colony-stimulating factor (G-CSF) is 
permitted to treat subjects with neutropenia or neutropenic fever but not to allow for eligibility.
 
Dietary Restrictions
None.
Prohibited Medications
No drug interaction studies have been conducted specifically with MTX110. The drugs shown 
below are noted in the Prescribing Information for other panobinostat marketed products as 
interacting with panobinostat when administered orally. The relevance of these interactions to 
MTX110 delivered by CED is considered to be low in view of its very localized infusion directly 
into tumour tissue. 
Because there is a potential for interaction of MTX110 injection with other concomitantly 
administered drugs through the cytochrome P450 system, strong inhibitors and inducers of 
CYP3A, CYP2D6 as well as anti-arrhythmic medicines (including amiodarone, disopyramide, 
procainamide, quinidine and sotalol) and drugs that are known to prolong the QT interval 
(including chloroquine, halofantrine, clarithromycin, methadone, moxifloxacin, bepridil and 
pimozide) are to be avoided the week prior to and the week following every CED infusion.The 
case report form must capture the concurrent use of all other drugs, over-the-counter 
medications, or alternative therapies. Appendix B presents guidelines for identifying 
medications/substances that could potentially interact with the study agent. Treatment with 
these agents and any other that interact with MTX110, should be avoided whenever possible 
and must be avoided the week prior to and following every CED infusion.
Additionally, the following therapies are not permitted during the trial:

Other anti-neoplastic therapy, including cytotoxics, targeted agents, endocrine therapy or 


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other antibodies. 

Radiotherapy other than what was used as part of primary treatment.

Any prior or concurrent investigational therapy is not permitted.
5.5
Dosing Modifications and Delays
The PNOC Study Chair or Co-Chair must be notified of any dosage modifications prior to 
the implementation of the dose modification. Any delays in starting the next CED 
treatment beyond 10 weeks must be discussed with the study chairs.
Each subject will be treated with CED of MTX110 based upon their dose level assignment. The 
intent is to treat every 4-8 weeks, as long as there is no evidence of tumor progression within the 
treated area, or intolerable toxicity. 
Intra-subject modification will be allowed where: dose escalation (following dose levels in table 
5.2.1) is permitted if a subject experiences a toxicity of grade 0 or 1; dose de-escalation will be 
followed if the toxicity is dose limiting toxicity (DLT) or worse (i.e., an intolerable grade 2 or 
grade 3 and above, as defined in Section 5.3); while the dose will remain unchanged if a subject 
experiences a moderate toxicity (i.e., moderate grade 2). At the second occurrence of any grade 2 
toxicity during the first treatment cycle, or the first DLT occurrence during the first treatment 
cycle, the ATD will be transitioned to a standard 3+3 dose escalation design. That is, two 
additional subjects will be accrued at the dose level that triggered the transition. As in a standard 
3+3 dose escalation design, there are three possible scenarios for this cohort of 3 subjects, if 
there are (is):

two or three DLTs, the RP2D will be defined as the next lower dose level;

zero DLTs (i.e., the transition from the ATD to the 3+3 design was triggered by the 
second occurrence of a grade 2 toxicity as opposed to a DLT and no DLTs were observed 
in the additional 2 subjects), then dose escalation will occur based on Table 5.2.1; 

one DLT, an additional 3 subjects will be entered at the same dose level. 
In the last scenario with six subjects at the current dose there are two subsequent scenarios: 

only one DLT and then dose escalation can occur based on Table 5.2.1. 

more than one DLT and then the next lower dose level is the RP2D. 
6. TREATMENT PLAN
Subjects with a radiographic diagnosis of DIPG are potentially eligible for this protocol. 
Eligibility requirements and treatment begin after the completion of standard of care 
radiotherapy. Each subject will sign a consent form and complete eligibility procedures prior to 
enrollment, and baseline procedures prior to any study procedure. Treatment consists of 
intratumoral treatment of MTX110 by CED. The intent is to treat every 4-8 weeks with CED 
infusions for up to 24 months or until tumor progression or intolerable toxicity. If subjects 
continue to derive clinical benefit, discussion with investigators and study sponsor will 
determine feasibility and clinical appropriateness to continue therapy. Treatment consists of 
placement of up to 2 CED catheters into the tumor. The placement of catheters at the time of 
surgery is planned based on an MRI obtained prior to the procedure, using a predictive 


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placement algorithm. The infusions are done under direct MR guidance, using co-infused 
gadoteridol, to assess leakage and tumor volume coverage. Toxicity is assessed during and after 
each CED infusion, with the protocol defined dose limiting toxicity period being 14 days after 
each CED procedure. Subjects may be treated at the time of progression after discussion with the 
Study Chair(s) and Neurosurgical Chair(s), if the progression occurs outside of the previously 
treated area, and if the treating physician feels the subject is experiencing clinical benefit. 
Baseline and on-study laboratory studies, and every 4-8 week MRIs are done to assess toxicity 
and tumor status, as described in the study calendar, for up to 24 months or until progression or 
intolerable toxicity. After completing all study treatment, final assessments will be performed, 
including a 30-day toxicity check. All subjects are followed for toxicity, progression-free 
survival and overall survival. 


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6.1
Study Calendar
For additional details refer to the Observations and Procedures (6.2) and Long Term Follow-up 
(6.3) sections.
1Depending on dose level, a second day of study treatment, with vital signs and toxicity assessment, will be performed.
2 Hourly assessment of neurologic function, and continuous vital sign monitoring with blood pressure checked at least every 15 
minutes. 
3For females of childbearing age
4QoL assessments will take place at the following time points – baseline prior to initial surgery, every 3 months throughout 
Study Day/Visit
Eligibility 
(-14 days)
Baseline 
prior to 
each CED 
infusion 
(-7 days)
Day of 
surgery 
for each 
CED 
infusion1
Day after 
surgery 
for each 
CED 
infusion 
(+1 day)
Day 4 after 
surgery for 
each CED 
infusion 
(+/- 1 day)
Weeks 1 
& 2 after 
each CED 
infusion
End of 
Treatment 
Visit 
(EOT)
30 Day 
Toxicity
Follow
-Up
Clinical procedures
Consent Form
X
Study Treatment 
X
Physical + Neuro 
Exam
X
X
X
X
X
Vital Signs
X
X2
X
X
Medical History
X
Toxicity 
assessment
X
X
X
X
X
X
X
Disease Status
X
Performance 
Status
X
X
X
X
X
Concomitant 
Medications
X
X
X
X
X
X
Survival 
X
ECG
X
X
X5
X5
X
Laboratory procedures
CBC w/ Diff 
X
X
X
X
Serum Chemistry
X
X
X
X
Serum or urine 
pregnancy test3 
X
X
Imaging procedures
Brain MRI/Spine 
MRI6
X
X7
X
Research Studies 
Collection of 
circulating tumor 
DNA
X
X
Quality of Life Assessments
QoL 
assessment4
X
X4
X4


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therapy, and EOT visit.The Pediatric Quality of Life (PedsQL) questionnaire will be used for participants 5-17 years old and the 
Functional Assessment of Cancer Therapy-Brain (FACT-Br) will be used for participants 18-21 years old.
5 ECG is required at the end of each day of CED infusion – not required separately on Day After Surgery if recorded after Day 2 
CED has completed.
6Spinal MRI only required at eligibility; as clinically indicated at other time points to coincide with Brain MRI. 
7MRI prior to CED to be within 14 days of CED procedure
6.2
Observations and Procedures
The first CED infusion may take place no sooner than 28 days and no later than 14 weeks from 
the last day of radiotherapy (unless previously approved by the study chairs). Telemedicine visits 
are acceptable.
Eligibility (within 14 days of registration) See Section 3.3 for Inclusion/Exclusion Criteria

Signed consent form

Physical and neurological examination

Brain and Spine MRI (to assess disease status and to rule out mass effect) 

Complete medical history including initial and/or other pre-radiotherapy imaging (MRIs), 
baseline symptoms, history of prior treatments and any residual toxicity relating to prior 
treatment 

Karnofsky for subjects > 16 years of age and Lansky for subjects  16 years of age (See 
Appendix A)

Concomitant medication assessment

Complete blood count (CBC) with differential and platelet count

Blood chemistry assessment, including: Alkaline phosphatase, aspartate 
aminotransferase/alanine aminotransferase (ALT/AST), total bilirubin, calcium, 
phosphorus, blood urea nitrogen (BUN), creatinine, total protein, albumin, glucose, 
potassium, sodium, chloride, bicarbonate

Serum or urine pregnancy test (for females of childbearing age) 

ECG
Baseline visit prior to first CED infusion (-7 days except for MRI and QOL). Eligibility tests 
done within 7 days prior may be used for Baseline Visit and do not have to be repeated.

Physical and neurological examination

Vital signs 

Karnofsky or Lansky Performance Status

Disease status assessment

Concomitant medication assessment

Laboratory Procedures:
o
CBC with differential and platelet count
o
Blood Chemistry including: Alkaline phosphatase, aspartate 
aminotransferase/alanine aminotransferase (ALT/AST), total bilirubin, calcium, 
phosphorus, blood urea nitrogen (BUN), creatinine, total protein, albumin, 
glucose, potassium, sodium, chloride, bicarbonate, INR (INR as per institutional 
guidelines prior to surgical procedure)
o
Serum or urine pregnancy test for females of childbearing age

ECG

Brain MRI acquired within 14 days of surgery to be used for catheter placement planning 


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by iPlan® Flow with the intent to place up to 2 catheters into the tumor. MR sequences 
include standard T1- and T2-weighted sequences, iron-sensitive sequences, as well as 
DTI sequences. Spinal MRI as clinically indicated.

Blood draw for circulating tumor DNA collection to be scheduled with standard of care 
laboratory evaluations.

Quality of life assessments (-3 weeks)
 
Day of surgery for each CED infusion (Note, the subject will likely be admitted to hospital for 2-
5 nights depending on the dose level. Prior similar studies demonstrate that most subjects can be 
discharged within this time frame barring unforeseen complications)

Catheter(s) placed under general anesthesia by surgical image-guided neuronavigation, and 
position confirmed by MR imaging. 
o
Correct catheter placement is defined as within the tumor.

Continuous vital sign assessment and every 1 hour neuro check assessment when awake 
until completion of the procedure*

Study treatment*

Toxicity assessment*

ECG*
*Based on dose level, if a second day of CED infusion is conducted, these 
assessments will be required following that infusion
Day after each day of CED infusion 

Physical and neurological examination

Vital signs 

Karnofsky or Lansky Performance status

Toxicity assessment

Concomitant medications assessment
Day of discharge - Patient should meet the following criteria for day of discharge

No further CED infusions required for that treatment cycle

Return of toxicities to baseline or ≤ grade 2, with the exception of adverse events thought 
to be irreversible or with potential for slow recovery, as long as patient is deemed safe for 
discharge by primary team. 
Day 4 after surgery after each CED infusion

Toxicity assessment via phone or clinic visit
Weeks 1 and 2 after every CED infusion (+/- 3 days) 

Physical and neurological examination

Vital signs 

Complete blood count (CBC) with differential and platelet count

Serum chemistry, including: Alkaline phosphatase, aspartate aminotransferase/alanine 
aminotransferase (ALT/AST), total bilirubin, blood urea nitrogen (BUN), creatinine, total 
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
Karnofsky or Lansky Performance status

Toxicity assessment

Concomitant medications assessment
 
Prior to each CED infusion (2nd infusion and every infusion thereafter) 

MRI of brain, and spine if indicated, for disease assessment within 14 days prior to the 
next CED infusion

Blood draw for circulating tumor DNA collection to be scheduled with standard of care 
laboratory evaluations

If stable or responsive disease, then follow “Pre-treatment visit” procedures and then 
procedures as above.
Subjects will receive CED infusions every 4-8 weeks until disease progression or intolerable 
toxicity. Treatment will continue for up to 24 months or until tumor progression or 
intolerable toxicity. If subjects continue to derive clinical benefit, discussion with 
investigators and study sponsor will determine feasibility and clinical appropriateness to 
continue therapy.
Pre-treatment visit prior to the 2nd CED infusion and every infusion thereafter (-7 days)

Physical and neurological examination

Vital signs 

Karnofsky or Lansky Performance Status

Toxicity Assessment

Disease status assessment

Concomitant medication assessment

Laboratory Procedures:
o
CBC with differential and platelet count
o
Blood Chemistry including: Alkaline phosphatase, aspartate 
aminotransferase/alanine aminotransferase (ALT/AST), total bilirubin, calcium, 
phosphorus, blood urea nitrogen (BUN), creatinine, total protein, albumin, 
glucose, potassium, sodium, chloride, bicarbonate, INR (per standard of care) 
o
Serum or urine pregnancy test for females of childbearing age

ECG
Quality of life assessments will occur every 3 months (+/- 3 weeks) while subjects receive 
protocol therapy. 
*Once all CED infusions are completed, and no further CED infusions are planned:
End of Treatment Visit (+/-14 days except Quality of Life assessments which can be +/- 21 days)

MRI of brain, and spine if indicated, (does not have to be repeated if done within 30 days 
of end of treatment)

Physical and neurological examination

Karnofsky or Lansky Performance Status

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
Concomitant medications assessment

Blood draw for circulating tumor DNA collection to be scheduled with standard of care 
laboratory evaluations

ECG

Quality of life assessments (unless performed within the 2 months prior)
30 Day Toxicity Check (+7 days)
These assessments may be done via phone 30 days after the last day of treatment.

Toxicity assessment - related AEs must continue to be followed until resolution or return 
to baseline.

Concomitant medication assessment
6.3
Long Term/Survival Follow-up Procedures
Subjects who are off-treatment will be followed by chart review and/or telephone contact every 
two months or until an off-study criterion is met, to collect disease and survival status 
information. This information will be recorded in the OnCore® eCRFs due at Follow-up. 

Subjects who are off-treatment will be followed until death. Subjects who expire without 
confirmation of disease status will be considered to have progressive disease at the time 
of death.

Subjects will be followed to collect any adverse events that are possibly, probably or 
definitely related to the study drug, until resolution of those events. 
6.4
Off-Treatment Criteria
Treatment may continue until one of the following criteria applies:

Disease progression

General or specific changes in the subject's condition render the subject unacceptable 
for further treatment in the judgment of the investigator

Unacceptable adverse events

The subject, parent or legal guardian refuses further treatment on this protocol,

Pregnancy
The “Off Treatment Date” and reason for discontinuation must be documented by the attending 
investigator in the medical record and recorded in two places within OnCore®, in the ‘Follow-
Up’ section of OnCore® as well as in the ‘PNOC End of Treatment eCRF.’
The “Off Arm Date” must be documented in the ‘Treatment’ section of OnCore®. The ‘Off Arm 
Date” should correspond with the “Off Treatment Date” and is the date the subject was 
discontinued from protocol treatment. 
The “Last Treatment Date” is recorded in two places within OnCore®, in the ‘Follow-Up section 
of OnCore®’ as well as in the ‘PNOC End of Treatment eCRF’. “Last Treatment Date” is 
defined as the last date that the subject received protocol based therapy. 
6.5
Off Study Criteria
Subjects will be considered Off Study for the following reasons:

Subject determined to be ineligible.


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
Parent, subject, or guardian withdraws consent for continued participation and all 
follow-up activities.

Subject death while on study. 

Completion of protocol specific follow up period. 
The date and reason for the subject coming off study must be documented in the ‘Follow-Up’ 
section of OnCore® as well as the ‘PNOC End of Treatment eCRF’. No data will be collected 
after the “off study” date.
7. ADVERSE EVENTS
An adverse event (also known as an adverse experience) within this protocol is defined as any 
untoward medical occurrence associated with the study procedure (placement of catheters) or use of 
the drug, whether or not considered to be procedure or drug related. (Please follow directions for 
routine reporting provided in the Data Reporting section). Additionally, all serious adverse 
events must be reported in an expedited manner to allow for optimal monitoring of subject safety 
and care. The Expedited Reporting sections in this protocol provide guidelines for expedited 
reporting.
7.1
Adverse Event Characteristics 

CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
Surgical adverse events that cannot be graded by CTCAE terminology (e.g., prolonged 
intubation) will be reviewed on a weekly basis by the Investigator and by the Data and 
Safety Monitoring Committee (DSMC) per their established reviewing schedule. Please 
see Appendix E PNOC Data Safety and Monitoring Plan for more information. All other 
events that can be graded by CTCAE terminology will use the CTCAE grading. This 
includes wound infections, hemorrhage, cerebral spinal fluid (CSF) leak, and respiratory 
and neurologic adverse events.

Attribution of the AE:
-
Definite – The AE is clearly related to the study treatment including surgical 
procedure.
-
Probable – The AE is likely related to the study treatment including surgical 
procedure.
-
Possible – The AE may be related to the study treatment including surgical 
procedure.
-
Unlikely – The AE is doubtfully related to the study treatment including surgical 
procedure.
-
Unrelated – The AE is clearly NOT related to the study treatment including surgical 
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7.1.1
Suspected 
A suspected adverse reaction is defined as any adverse event for which there is a reasonable 
possibility that the drug or study procedure caused the adverse event. For the purposes of IND 
safety reporting, “reasonable possibility” indicates that there is evidence to suggest a causal 
relationship between the drug/study procedure and the adverse event. A suspected adverse 
reaction implies a lesser degree of certainty about causality than an adverse reaction.
7.1.2
Unexpected 
An adverse event or suspected adverse reaction is considered unexpected if it is not listed in the 
investigator brochure or package insert(s), or is not listed at the specificity or severity that has 
been observed, or, if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan or elsewhere in the current 
application. 
“Unexpected,” as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically mentioned 
as occurring with the particular drug under investigation.
Adverse events that would be anticipated to occur as part of the disease process are considered 
unexpected for the purposes of reporting because they would not be listed in the investigator 
brochure. For example, a certain number of non-acute deaths in a cancer trial would be 
anticipated as an outcome of the underlying disease, but such deaths would generally not be 
listed as a suspected adverse reaction in the investigator brochure.
Some adverse events are listed in the Investigator Brochure as occurring with the same class of 
drugs, or as anticipated from the pharmacological properties of the drug, even though they have 
not been observed with the drug under investigation. Such events would be considered 
unexpected until they have been observed with the drug under investigation. For example, 
although angioedema is anticipated to occur in some subjects exposed to drugs in the ACE 
inhibitor class and angioedema would be described in the investigator brochure as a class effect, 
the first case of angioedema observed with the drug under investigation should be considered 
unexpected for reporting purposes.
7.1.3
Serious
An adverse event or suspected adverse reaction is considered serious if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: 

Death

Life-threatening adverse event

Inpatient hospitalization ≥ 24 hours or prolongation of existing hospitalization 
by ≥ 24 hours

A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life function

Congenital anomaly/birth defect, or cancer

Event that changes the risk/benefit ratio of the study
Important medical events that may not result in death, are life threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include allergic 
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or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.
7.1.4
Life-threatening
An adverse event or suspected adverse reaction is considered life threatening if, in the view of 
either the investigator or sponsor, its occurrence places the subject or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. 
7.2
Adverse Event Monitoring
PNOC uses the web-based OnCore® Clinical Trials Management System for monitoring and 
recording of Adverse Events (AEs) including all adverse reactions considered “serious” (also 
called Serious Adverse Events, or SAEs).
All Adverse Events entered into OnCore® will be reviewed on a weekly basis by the PNOC 
Operations Office. The PNOC Operations Office will discuss the toxicity, grade, and relationship 
to study intervention for all AEs in question.
In addition, all Serious Adverse Events (SAEs) will be reviewed and monitored by the UCSF 
DSMC on an ongoing basis, and will be discussed at the UCSF DSMC meeting, which take 
place every six (6) weeks. Please see Appendix E PNOC Data Safety and Monitoring Plan for 
more information. 
7.2.1 Surgical Adverse Event Grading
Anticipated Adverse Effects
Complications related to the surgical procedure will be documented. ‘Minor’ are those defined as 
leading to little or no effect on function, and not resulting in a significant increase in hospital 
stay. ‘Major’ complications are those resulting in permanent sequelae with functional limitations, 
or those leading to a significant increase in hospital stay. Surgical adverse events that cannot be 
graded by CTCAE terminology (e.g., prolonged intubation) will be reviewed on a weekly basis 
by the Investigator and by the Data and Safety Monitoring Committee (DSMC) per their 
established reviewing schedule. All other events that can be graded by CTCAE terminology will 
use the CTCAE grading. This includes wound infections, hemorrhage, cerebral spinal fluid 
(CSF) leak, and respiratory and neurologic adverse events.
7.3
Adverse Event Reporting
All Adverse Events (AEs) will be entered into OnCore®. Appendix D includes detailed 
information about PNOC reporting timelines.
The study period during which AEs and SAEs must be reported begins after informed consent is 
obtained and ends 30 days following the last administration of study treatment. After this period, 
only SAEs that are attributable to study treatment should be reported. Subjects removed from 
therapy for unacceptable adverse event(s) will be followed until adverse event(s) resolves or 
returns to baseline status.
The PNOC Investigator will assign attribution of the possible association of the event with use of 
the study therapy, and this information will be entered into OnCore®. The Investigator must also 
comply with all reporting requirements to their institutional Data and Safety Monitoring 
Committee (DSMC) and Institutional Review Board (IRB). 


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7.4
Serious Adverse Events and Expedited Reporting 
All Adverse Events which meet the definition of ‘Serious’ as well as other medically significant 
events described below require expedited reporting to PNOC. Below are instructions for 
recording and reporting of these events. Please contact the PNOC Operations Office  
with any questions regarding expedited reporting requirements for 
this study. See 7.1.3 for the definition of an SAE.
All SAEs (see above definition) on any PNOC trial, regardless of relationship, must be 
reported to PNOC via OnCore and Email within one business day of first PI awareness, even 
if the SAE is ongoing. The SAE must be followed until resolution:

OnCore: All SAEs must be entered into the Subject Console in OnCore 
(https://oncore.ucsf.edu/ > Subject Console > SAE Tab on left). The OnCore SAE 
record should be updated immediately as new information becomes available until the 
SAE is resolved. (Toxicity segment MUST be completed. Don’t forget to click “Add” 
button.) Please refer to the “PNOC OnCore SAE Entry Guide: Field by Field” for more 
information.

Email: Please also email 
with, at minimum, the following 
information: 
In the subject line: “SAE: Subject PNOC ID” (e.g. “SAE: PNOCxxx-1”)
In the body of the email: Subject PNOC ID and the OnCore assigned SAE number

Site IRB: Each PNOC site is also responsible for following their own IRB guidelines 
for reporting SAEs.
SAE Data Entry in AE CRF:
All SAEs must also be entered into the AE CRF for that Cycle (Subject Console > Forms by 
Status/Forms by Visit). This entry must take place within 10 days of the last day of the Cycle in 
which the SAE occurred, or as soon as possible in the case of an SAE that was discovered late. 
Please reference the “PNOC OnCore SAE Reporting and Entry” in SharePoint for more 
information. 
SAE Deviations:
If the protocol procedures around SAEs are not followed (e.g. reporting timelines or dose 
modifications), a Deviation may also need to be entered in OnCore (Subject Console > Deviation 
Tab on left). Please reference the “PNOC Deviation Reporting Guidelines” in SharePoint for more 
information. 
7.4.1
Medically Significant Events
Email notification to PNOC Operations Office 
 within one 
business day of first PI awareness:

Reports of pregnancy exposure (pregnancy encompasses the entire cycle of 
pregnancy and delivery, perinatal and neonatal outcomes, even if there were no 
abnormal findings; both maternal and paternal exposure is collected)

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
Overdose (with or without an SAE)

Abuse (use for non-clinical reasons with or without an SAE)

Inadvertent or accidental exposure
7.4.2
PNOC Reporting to the UCSF Data and Safety Monitoring Committee
If a death occurs during the treatment phase of the study, or within 30 days after the last 
administration of the study drug(s), and is determined to be related either to the 
investigational drug or to any research related procedure, the Study Chair and the PNOC 
Operations Office must be notified by the member institution within 1 business day. The 
Study Chair or the PNOC Operations Office must then notify the UCSF DSMC Chair, or 
qualified alternate, within 1 business day of this notification. The contact may be by 
phone or e-mail. Each participating site will follow their institutional reporting guidelines 
to institutional DSMC. 
7.4.3
PNOC Reporting to UCSF Institutional Review Board (IRB)
The PNOC Operations Office must report events meeting the UCSF IRB definition of 
“Unanticipated Problem” (UP) within 10 business days of awareness of the event. 
Each participating site will follow their institutional reporting guidelines to the IRB.
7.4.4
 PNOC Reporting to the Food and Drug Administration (FDA) 
If the study is being conducted under an IND, the PNOC Operations Office is responsible 
for determining whether or not the suspected adverse reaction meets the criteria for 
expedited reporting in accordance with Federal Regulations (21 CFR §312.32). 
The PNOC Operations Office must report in an IND safety report any suspected adverse 
reaction that is both serious and unexpected. The Sponsor-Investigator (PNOC) needs to 
ensure that the event meets all three definitions: 

Suspected adverse reaction 

Unexpected

Serious 
If the adverse event does not meet all three of the definitions, it should not be submitted 
as an expedited IND safety report.
The timeline for submitting an IND safety report to FDA is no later than 15 calendar 
days after the PNOC Operations Office determines that the suspected adverse reaction 
qualifies for reporting (21 CFR 312.32(c)(1)). 
Any unexpected fatal or life-threatening suspected adverse reaction will be reported to 
FDA no later than 7 calendar days after PNOC initial receipt of the information (21 CFR 
312.32(c)(2)). 
Any relevant additional information that pertains to a previously submitted IND safety 
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soon as the information is available (21 CFR 312.32(d)(2)). 
7.4.5
 PNOC Reporting to Midatech Pharma (supplier of MTX110 injection)
The Sponsor-Investigator (PNOC) is responsible for reporting of serious adverse events 
to Midatech Pharma. SAEs should be reported to the Chief Medical Officer at Midatech 
Pharma 
 within one business day 
using the same criteria described in Section 7.4.3 PNOC Reporting to the UCSF Data and 
Safety Monitoring Committee. Additionally, copies of all PNOC safety reports to the 
FDA and any related correspondence should be simultaneously copied to Midatech. 
Periodic safety reports with tabulation of all AEs and SAEs should be provided to 
Midatech every 3 months during the study. 
7.5
Secondary Malignancy
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 

Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML]) 

Myelodysplastic syndrome (MDS) 

Treatment-related secondary malignancy 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol. 
8. PHARMACEUTICAL INFORMATION
8.1
Study Agent
8.1.1
MTX110 injection
Product description: MTX110 is the study agent supplied by Midatech Pharma. The 
drug is a formulation of liquid panobinostat. This agent is not FDA approved for the 
treatment of primary CNS brain tumors or brainstem glioma (DIPG). 
How the drug is supplied: The product is presented 10 ml amber glass vials at a 
concentration of 40μM (13.98μg/ml).
Storage and handling: The product is shipped under refrigerated conditions (2°C to 
8°C). On receipt at the pharmacy, the product should be removed for the shipping 
package and stored at refrigerated conditions (2°C to 8°C) prior to reconstitution for use. 
Ordering: Pharmacy will order directly from Midatech Pharma.


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Stability: When stored in vials at 5°C the product remains stable for at least 42 days. 
Once reconstituted the product should be used within 24 hours.
Route of administration: Intratumoral infusion via convection enhanced delivery 
(CED). See Section 5.0 for specific details.
Accountability: The investigator, or a responsible party designated by the investigator, 
will be responsible for drug accountability and this will be managed per each PNOC 
institution guidelines. 
9. EVALUATION CRITERIA
Although response is not the primary endpoint of this trial, subjects with measurable disease will 
be assessed by standard imaging criteria. 
9.1
Response Criteria 
9.1.1
Definitions
Evaluable for toxicity. All subjects will be evaluable for toxicity from the time of their 
first treatment with MTX110 injection.
Evaluable for objective response. Only those subjects who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for response. These subjects will have their 
response classified according to the definitions stated below. (Note: Subjects who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered 
evaluable.)
Evaluable Non-Target Disease Response. Subjects who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease. The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions. 
9.1.2
Disease Parameters
Measurable disease 
Measurable disease is defined as lesions that can be accurately measured in two 
dimensions (longest diameter to be recorded) with a minimum size of no less than double 
the slice thickness.
All tumor measurements will be recorded in millimeters or decimal fractions of 
centimeters. Previously irradiated lesions are considered non-measurable except in cases 
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All measurements will be taken using a ruler or calipers. All baseline evaluations will be 
performed as closely as possible to the beginning of treatment and never more than 30 
days before the beginning of the treatment.
The same method of assessment and the same technique will be used to characterize each 
identified and reported lesion at baseline and during follow-up. 
Non-measurable disease
Non-measurable disease is all other lesions (or sites of disease), including small lesions 
(< double the slice thickness). 
Target and Non-target lesion
Tumor dimensions are determined by measurement of the longest tumor dimension and 
its perpendicular for each target lesion. For most CNS tumors, only one lesion/mass is 
present and therefore is considered a “target” for measurement/follow up to assess for 
tumor progression/response. If multiple measurable lesions are present, up to 3 can be 
selected as “target” lesions. Target lesions should be selected on the basis of size and 
suitability for accurate repeated measurements. All other lesions will be followed as non-
target lesions (including CSF positive for tumor cells). The lower size limit of the target 
lesion(s) should be at least twice the thickness of the slices showing the tumor to decrease 
the partial volume effect.
Tumor Measurements
Regarding MRI imaging, the sequence that best highlights the tumor (T1 enhanced or T2 
weighted or FLAIR images) will be chosen to determine response criteria. The same 
sequence should be used for serial measurements. Response determination will be based 
on a comparison of an area [W (longest diameter of the target lesion) x T (transverse 
measurement, perpendicular to W)] between the baseline assessment and the study date 
designated in the follow-up Report Form. Reports for the follow-up exams should 
reiterate the measurements obtained at baseline for each target lesion. Nontarget lesions 
or newly occurring lesions should also be enumerated in these reports, and changes in 
non-target lesions should be described.
1. For MRI imaging, the longest diameter can be measured from the axial plane or the 
plane in which the tumor is best seen or measured. The longest measurement of the tumor 
is referred to as the width (W). 
2. The perpendicular measurements should be determined - transverse (T) measurement, 
perpendicular to the width in the selected plane.
3. The cystic or necrotic components of a tumor are not considered in tumor 
measurements. Therefore only the solid component of cystic/necrotic tumors should be 
measured. If cysts/necrosis composes the majority of the lesion, the lesion may not be 
“measurable”.
Options:


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
If the cyst/necrosis is eccentric, the W and T of the solid portion should be measured, 
the cyst/necrosis will be excluded from measurement

If the cyst/necrosis is central but represents a small portion of the tumor (< 25%), 
disregard and measure the whole lesion

If the cyst/necrosis is central but represents a large portion of the tumor, identify a 
solid aspect of the mass that can be reproducibly measured

Leptomeningeal tumor spread is usually not a target lesion, and usually cannot be 
measured accurately. Presence and location of leptomeningeal tumor spread should 
be noted and change in extent/thickness assessed on follow up studies.
Overall Response Assessment:
The overall response assessment takes into account response in both the target and non-
target lesion, and the appearance of new lesions, where applicable, according to the 
criteria described in the table below. The best overall response is the best response 
recorded from the start of the treatment until disease progression/recurrence (taking as 
reference for progressive disease the smallest measurements recorded since the treatment 
started). The subject's best response assignment will depend on the achievement of both 
measurement and confirmation criteria.
Target 
Lesion(s)
Non 
Target 
Lesion (s)
New 
Lesions
Overall 
Response
Best Response for this 
Category Also Requires
CR
CR
No
CR
> 8 weeks confirmation
CR
IR/SD
No
PR
PR
CR/IR/SD
No
PR
> 8 weeks confirmation
SD
CR/IR/SD
No
SD
documented at least > 4 weeks 
from baseline
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR – Complete Response; PR – Partial Response; SD – Stable Disease; PD – 
Progressive Disease; IR – Incomplete Response
Response Criteria for Target/Non-Target Lesions:
Response criteria are assessed in 2 dimensions – the product of W x T.
To assess response/progression, the ratio is calculated: W x T (current scan) divided by 
W x T (reference scan). Development of new disease or progression in any established 
lesions is considered progressive disease, regardless of response in other lesions – e.g. 
when multiple lesions show opposite responses, the progressive disease takes precedence.
For purposes of this study, response criteria for target lesions are:
Complete Response (CR): Complete disappearance of all known disease for at least 8 
weeks. Complete response is dated from the time all lesions have disappeared on a stable 
or decreasing dose of corticosteroids.
Partial response (PR): A reduction of at least 50% in the size of all measurable tumors 


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as quantitated by the sum of the products of the largest diameters of measurable lesions 
and maintained for at least 8 weeks on a stable or decreasing dose of corticosteroids. 
Partial response is dated from the time of first observation. In addition, there can be no 
appearance of new lesions or progression of any lesion.
Stable Disease (SD): A decrease of <50% or an increase of <25% in the sum of the 
products of the largest diameters of measurable lesions and no evidence of new lesions 
for at least 4 weeks on a stable or decreasing dose of corticosteroids.
Progressive Disease (PD): ≥ 25% increase in the sum of the products of the largest 
diameters of the measurable lesions or the appearance of one or more new lesions. 
9.1.3
Duration of Response
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started).
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented.
Duration of stable disease: Stable disease is measured from the start of the CED infusion 
treatment until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started, including the baseline measurements. 
9.1.4
Progression-Free Survival
PFS is defined as the duration of time from diagnosis to time of progression or death, 
whichever occurs first.
9.1.5
Overall survival
OS is defined as the duration of time from diagnosis to time of death. 
9.2
Imaging Analyses
At the end of the study, all images will be evaluated by central review. Please see Appendix H 
for details. All imaging from initial diagnosis and/or prior to radiotherapy, as well as available 
imaging collected on study and/or in follow up must be submitted for central review and study 
analyses. Examples of imaging analyses may include, but are not limited to, descriptive 
correlation of imaging characteristics and clinical outcomes, and imaging correlates with 
treatment response or resistance.
10. STATISTICAL CONSIDERATIONS


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10.1
Study Design/Endpoints
This is an open-label, prospective, multi institutional safety and early efficacy protocol. All 
subjects will be treated at a PNOC Institution or participating institution for this study. The 
primary endpoint is safety; the secondary endpoint is a preliminary estimate of efficacy.
Primary Endpoint:

Safety and toxicity measurements of repeated CED administration of MTX110 following 
standard of care focal radiotherapy using CTCAE version 4.0 in newly diagnosed 
subjects with DIPG.
Secondary Endpoint:

OS at 12 months (OS12) in newly diagnosed subjects with DIPG.
Exploratory Endpoints:

Assessment of observed distribution of gadoteridol compared to pre-treatment modeling 
of the drug distribution utilizing predictive imaging software.

The Quality of Life exploratory endpoint associated with this study will be descriptive 
and will be limited to frequency tables and summary statistics.

To perform central review of imaging to explore MR qualitative and quantitative 
measures as markers of disease response and/or progression and treatment effect in 
comparison to institutional evaluation of disease response and/or progression.
10.2
Dose Escalation
Initially an accelerated titration design (ATD; diagram 1) will be employed. This design has the 
advantage of potentially reducing the number of subjects treated at sub-efficacious doses, and 
decreasing the accrual time for the trial. Each cohort will consist of one subject. The first subject 
will be started at dose level 1. A 14-day window of evaluation for toxicities is required for at 
least one subject at each dose level before determining the dose for the next cohort. 


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Diagram 1. Accelerated trial design.
Intra-patient dose modification (Diagram 2) will be allowed as follows: dose escalation 
(following the dose levels in Table 5.2.1) is permitted if a subject experiences a toxicity of grade 
0 or 1; dose de-escalation will be followed if the toxicity is dose limiting toxicity (DLT) or worse 
(i.e., an intolerable grade 2 or grade 3 and above, as defined in Section 5.3); while the dose will 
remain unchanged if a subject experiences a moderate toxicity (i.e., moderate grade 2). At the 
second occurrence of any grade 2 toxicity during the first treatment cycle, or the first DLT 
occurrence during the first treatment cycle, the ATD will be transitioned to a standard 3+3 dose 
escalation design. That is, two additional subjects will be accrued at the dose level that triggered 
the transition. As in a standard 3+3 dose escalation design, there are three possible scenarios for 
this cohort of 3 subjects, if there are (is):

two or three DLTs, the RP2D will be defined as the next lower dose level;

zero DLTs (i.e., the transition from the ATD to the 3+3 design was triggered by the 
second occurrence of a grade 2 toxicity as opposed to a DLT and no DLTs were observed 
in the additional 2 subjects), the dose escalation will occur based on Table 5.2.1; 

one DLT, an additional 3 subjects will be entered at the same dose level. 


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In the last scenario with six subjects at the current dose there are two subsequent scenarios: 

only one DLT and then dose escalation can occur based on Table 5.2.1. 

more than one DLT and then the next lower dose level is the RP2D. 
Diagram 2. Intra-patient dose escalation.
10.3
Sample Size and Accrual
The number of subjects enrolled in the safety study will depend upon the DLTs observed and the 
number of dose levels tested as the study progresses in accordance with an ATD followed by a 
3+3 design. The ATD is expected to enroll 1 to 7 subjects with a minimum of 5 subjects in the 
3+3 design. Additional subjects may be enrolled depending on the dose de-escalations, 
expansion of dose exploration, or exploration of intermediate doses that occur. Once these dose 
levels have been assessed, a detailed review of the safety and efficacy data will be performed and 
discussed with the FDA and the DSMC to discuss either further dose escalation or enrollment 
into the efficacy study. 
Secondary Objective: The most recent Children’s Oncology Group study that treated children 
newly diagnosed with DIPG with a combination of radiation therapy and temozolomide resulted 
in an OS12 rate of 40% (SD ± 6.5%). A sample size of 19 patients achieves 80% power to detect 
a difference of 30% using a one sided exact binominal test. The target significance level is 5% 
and the actual significance level is 3.5% with this test. If 12 or more patients are alive at 12 
months, the null hypothesis that OS12 is 40% will be rejected.
Stopping Rules:
Both the ATD and 3+3 have inherent stopping rules; however, it should be noted that this study 
will be stopped for further review by the DSMC and study team as well as FDA by:

The occurrence of 1 or more irreversible neurological deficits that are grade 3 or 
higher and definitely related to the procedure based on evidence on MRI such as 
intraparenchymal hemorrhage, worsening edema or necrosis. 


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
If more than 20% of subjects develop significant, irreversible deterioration during the 
infusion.

If more than 20% of subjects do not get study drug infused due to surgical 
complications during the catheter placement. 
10.4
Stratification Factors
There are no stratification factors.
10.5
Analysis of Endpoints
Intent-to-Treat Population (ITT): The ITT population will include all subjects who are 
enrolled in the study. The ITT population will be the primary population for evaluating efficacy 
and subject characteristics.
As-Treated Population (AT): The AT population will include all subjects who receive at least 1 
dose of study drug. The AT population will be the primary population for evaluating safety.
Analysis of Primary Endpoint

Safety of repeated CED of MTX110 following standard of care focal radiotherapy will be 
assessed by monitoring for adverse events, scheduled laboratory assessments, vital sign 
measurements, and physical examinations for subjects who receive the drug. The severity 
of toxicities will be graded according to the NCI CTCAE v4.0. Adverse events and 
clinically significant laboratory abnormalities (meeting Grade 3, 4, or 5 criteria according 
to CTCAE) will be summarized by maximum intensity and relationship to study drug(s). 
Grade 1 and 2 adverse events will be summarized if related to study therapy. Descriptive 
statistics will be utilized to display the data on toxicity.
Analysis of Secondary Endpoint

We will assess the preliminary efficacy using overall survival at 12 months (OS12) in 19 
evaluable DIPG patients treated within the expansion cohort which will include subjects 
treated as part of the dose escalation portion of the trial on the recommended phase 2 
dose (RP2D). Analyses will be performed after all enrolled subjects have completed 12 
months, or whenever the status of all subjects has been established, whichever comes 
first. The primary analysis will be based on the Kaplan-Meier method. Kaplan-Meier 
estimates and the associated 95% CIs will be calculated for OS12. As described above, if 
12 or more of the 19 patients are alive at 12 months, the null hypothesis that OS12 is 40% 
will be rejected.
Analysis of Exploratory endpoint
The exploratory aims associated with this study will be descriptive and will be limited to 
frequency tables and summary statistics. 
11. DATA REPORTING / REGULATORY REQUIREMENTS


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11.1
Data Reporting
11.1.1
Method
The Principal Investigator and/or his/her designee will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study. Study 
specific Case Report Forms (CRFs) will document safety and treatment outcomes for 
safety monitoring and data analysis. All study data will be entered into OnCore® via 
standardized CRFs in accordance with the CTMS study calendar, using single data entry 
with a secure access account. The Clinical Research Coordinator (CRC) will complete 
the CRFs as soon as possible upon completion of the study visit; the Investigator will 
review and approve the completed CRFs. 
The information collected on CRFs shall be identical to that appearing in original source 
documents. Source documents will be found in the subject’s medical records maintained 
at each PNOC site. For participating sites, source documents will be maintained per 
institutional guidelines. All source documentation should be kept in separate research 
folders for each subject.
In accordance with federal regulations, the Investigator is responsible for the accuracy 
and authenticity of all clinical and laboratory data entered onto CRFs. The PI will 
approve all completed CRFs to attest that the information contained on the CRFs is true 
and accurate. 
All source documentation and CTMS data will be available for review/monitoring by the 
UCSF DSMC and regulatory agencies.
The Principal Investigator will be responsible for ensuring the accurate capture of study 
data. At study completion, when the CRFs have been declared to be complete and 
accurate, the database will be locked. Any changes to the data entered into the CRFs after 
that time can only be made by joint written agreement among the Study Chair, the Trial 
Statistician, and the PNOC Project Leader.
11.1.2
Responsibility for Data Submission
Please refer to Appendix C for data submission timelines.
11.2 PNOC Oversight and Monitoring Plan
Given the complexity and technical requirements of this study, PNOC has determined that this 
should initially be a limited institutional trial (n=2). All subjects will be treated at the University 
of California San Francisco (UCSF) or the Memorial Sloan Kettering Cancer Center, where 
study Surgical Chair Dr. Mark Souweidane has experience in CED technique. Additional PNOC 
institutions will be allowed to open the study if the surgical PI from that site is able to observe in 
person a CED procedure at either UCSF or Memorial Sloan Kettering to learn the particularities 
of the study. The UCSF Helen Diller Family Comprehensive Cancer Center Data Safety 
Monitoring Committee (DSMC) will be the main monitoring entity for this study. The UCSF 
DSMC will work together with UCSF to monitor the study in accordance with the UCSF NCI 
approved Data Safety and Monitoring Plan (DSMP). The DSMC will routinely review all 
adverse events and suspected adverse reactions considered “serious.” The UCSF DSMC will 
audit study-related activities to ensure that the study is conducted in accordance with the 


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protocol, local UCSF standard operating procedures, FDA regulations, and Good Clinical 
Practice (GCP). Significant results of the DSMC audit will be communicated to the IRB and the 
appropriate regulatory authorities at the time of continuing review, or in an expedited fashion, as 
applicable. Please see Appendix E PNOC Data Safety and Monitoring Plan for more 
information.
11.3 Multicenter Communication 
The PNOC Operations Office provides administration, data management, and organizational 
support for the participating sites in the conduct of the clinical trial. The PNOC Operations 
Office will coordinate, at minimum, quarterly conference calls with the PNOC member 
institutions to discuss risk assessment. The following items will be discussed, as appropriate:

Enrollment information 

Cohort updates (i.e. DLTs)

Adverse events (i.e. new adverse events and updates on unresolved adverse events 
and new safety information)

Protocol violations

Other issues affecting the conduct of the study
11.4 Record Keeping and Record Retention
The Principal Investigator for each PNOC institution is required to maintain adequate records of 
the disposition of the drug, including dates, quantity, and use by subjects, as well as written 
records of the disposition of the drug when the study ends per institutional guidelines. 
The site Principal Investigator is required to prepare and maintain adequate and accurate case 
histories that record all observations and other data pertinent to the investigation on each 
individual administered the investigational drug or employed as a control in the investigation. 
Case histories include the case report forms and supporting data including, for example, signed 
and dated consent forms and medical records including, for example, progress notes of the 
physician, the individual's hospital chart(s), and the nurses' notes. The case history for each 
individual shall document that informed consent was obtained prior to participation in the study.
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed subject consent forms).
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study.
In accordance with FDA regulations, the investigator shall retain records for a period of 2 years 
following the date a marketing application is approved for the drug for the indication for which it 
is being investigated; or, if no application is to be filed or if the application is not approved for 
such indication, until 2 years after the investigation is discontinued.
11.5 Coordinating Center Documentation of Distribution 
It is the responsibility of the PNOC Operations Office to maintain adequate files documenting 
the distribution of study documents as well as their receipt (when possible). The HDFCCC 


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recommends that the PNOC Operations Office maintain a correspondence file and log for each 
segment of distribution (e.g., FDA, drug manufacturer, participating sites, etc.).
Correspondence file: should contain copies (paper or electronic) of all protocol versions, cover 
letters, amendment outlines (summary of changes), etc., along with distribution documentation 
and (when available) documentation of receipt.
Correspondence log: should be a brief list of all documents distributed including the date sent, 
recipient(s), and (if available) a tracking number and date received.
At a minimum, the PNOC Operations Office must keep documentation of when and to whom the 
protocol, its updates and safety information are distributed.
11.6 Regulatory Documentation 
Prior to implementing the protocol at each PNOC institution, the protocol, informed consent 
form, HIPAA authorization and any other information pertaining to participants must be first 
approved by the UCSF Institutional Review Board (IRB) and by the PNOC Operations Office. 
Prior to implementing this protocol at the participating sites, approval for the UCSF IRB 
approved protocol must be obtained from the participating site’s IRB. 
Appendix C lists the documents which must be provided to PNOC Operations Office before the 
participating site can be initiated and begin enrolling participants.
Upon receipt of the required documents, PNOC Operations Office will formally contact the site 
and grant permission to proceed with enrollment.


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58.
Chittiboina, P., J.D. Heiss, and R.R. Lonser, Accuracy of direct magnetic resonance 
imaging-guided placement of drug infusion cannulae. J Neurosurg, 2015. 122(5): p. 
1173-9.
59.
Saito, R., et al., Regression of recurrent glioblastoma infiltrating the brainstem after 
convection-enhanced delivery of nimustine hydrochloride. J Neurosurg Pediatr, 2011. 
7(5): p. 522-6.
60.
Barua, N.U., et al., Robot-guided convection-enhanced delivery of carboplatin for 
advanced brainstem glioma. Acta Neurochir (Wien), 2013. 155(8): p. 1459-65.
61.
Anderson, R.C., et al., Convection-enhanced delivery of topotecan into diffuse intrinsic 
brainstem tumors in children. J Neurosurg Pediatr, 2013. 11(3): p. 289-95.
62.
Souweidane MM, Kramer K, Pandit-Taskar N, Zhou Z, Hague S, Zanzonico P, et al. 
Convection-enhanced delivery for diffuse intrinsic pontine glioma: a single-centre, dose-
escalation, phase 1 trial. Lancet Oncol. 2018;19: 1040-50.


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APPENDIX A Performance Status Criteria
Karnofsky
Lansky
Score
Description
Score
Description
100
Normal, no complaints, no evidence 
of disease
100
Fully active, normal.
90
Able to carry on normal activity, 
minor signs or symptoms of disease.
90
Minor restrictions in physically strenuous 
activity.
80
Normal activity with effort; some 
signs or symptoms of disease.
80
Active, but tires more quickly
70
Cares for self, unable to carry on 
normal activity or do active work.
70
Both greater restriction of and less time 
spent in play activity.
60
Required occasional assistance, but is 
able to care for most of his/her needs.
60
Up and around, but minimal active play; 
keeps busy with quieter activities.
50
Requires considerable assistance and 
frequent medical care.
50
Gets dressed, but lies around much of the 
day; no active play, able to participate in 
all quiet play and activities.
40
Disabled, requires special care and 
assistance.
40
Mostly in bed; participates in quiet 
activities.
30
Severely disabled, hospitalization 
indicated. Death not imminent.
30
In bed; needs assistance even for quiet 
play.
20
Very sick, hospitalization indicated. 
Death not imminent.
20
Often sleeping; play entirely limited to 
very passive activities.
10
Moribund, fatal processes 
progressing rapidly.
10
No play; does not get out of bed.


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APPENDIX B Enzyme Inducing and Recommended Non-Enzyme Inducing Anti-
Convulsants; Drugs to avoid
Recommended Non-enzyme inducing 
anticonvulsants
Generic Name
Trade Name
Gabapentin
Neurontin
Lamotrigine
Lamictal
Levetiracetam 
Keppra
Tigabine
Gabitril
Topiramate
Topamax
Valproic Acid
Depakote, Depakene
Zonisamide
Zonegran
Enzyme inducing anticonvulsants
Generic Name
Trade Name
Carbamazepine
Tegretol
Felbamate
Felbatol
Phenobarbital
Phenobarbital
Phenytoin
Dilantin
Primidone
Mysoline
Oxcarbazepine
Trileptal


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Drugs to avoid
CYP3A Inhibitors 
and inducers
Sensitive substrates 
for CYP2D6
Anti-arrhythmic 
medicines, including:
Drugs that are known 
to prolong the QT 
interval, including:
Ketoconazole
Itraconazole
Fluconazole
Cimetidine
Clarithromycin
Erythromycin
Troleandomycin
Grapefruit juice
Carbamazepine
Rifampin
Rifabutin
Ritonavir
St. John’s wort
Atomoxetine
Desipramine
Dextromethorphan
Eliglustat(e)
Nebivolol
Nortriptyline
Perphenazine
Tolterodine
Venlafaxine
Amiodarone
Disopyramide
Procainamide
Quinidine
Sotalol
Chloroquine
Halofantrine
Clarithromycin
Methadone
Moxifloxacin
Bepridil
Pimozide


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APPENDIX C PNOC Institutions Required Regulatory Documents
Prior to opening a study at any member institution, the following regulatory 
documents must be submitted to the PNOC Operations Office: 

Participating Site IRB approval(s) for the protocol, appendices, informed consent form 
and HIPAA authorization 

Participating Site IRB approved consent form 

Participating Site IRB membership list 

Participating Site IRB’s Federal Wide Assurance number and OHRP Registration 
number 

Curriculum vitae and medical license for each investigator and consenting professional 

Documentation of Human Subject Research Certification training for investigators and 
key staff members at the Participating Site 

Participating site laboratory certifications and normals 

Signed copy of the completed delegation of authority log (found in PNOC Documents > 
Forms)

Signed copy of the protocol signature page

Signed copy of the final contract
Upon receipt of the required documents, the PNOC Operations Office will formally contact the 
site and grant permission to proceed with enrollment. All documents can uploaded directly to 
SharePoint by navigating to your site's page and clicking "Add Documents"
Each PNOC site is responsible for ensuring all regulatory documents in SharePoint are up to 
date. Sites will upload new or revised documents as applicable to reflect any changes, including 
changes in staff and approved/expired documents.


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APPENDIX D Required Data and Time Table for Submission
Form
Submission Timeline
Eligibility Checklist
Complete prior to registration
On Study Forms
Within 14 days of registration
Baseline Assessment Forms
Within 14 days of registration
Treatment Forms
Within 10 days of the last day of the cycle
Adverse Event Report Forms
All AEs are due within 10 business days of the date of 
assessment.
Serious Adverse Event Reporting
Within 1 business day of first PI awareness 
Response Assessment Forms
Within 10 days of the completion of the cycle required for 
response evaluation
Off Treatment/Off Study Forms
Within 14 days of completing treatment or being taken off 
study for any reason
Follow up/Survival Forms
Within 14 days of the protocol defined follow up visit date


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APPENDIX E PNOC Data and Safety Monitoring 
PNOC Data Safety and Monitoring Plan for a Phase 1 Study
It is the responsibility of each PNOC member institution to follow the National Cancer Institute 
(NCI) approved Data Safety and Monitoring Plan (DSMP) for their site, and to be internally 
monitored by a Data Safety Monitoring Committee/Board (DSMC/DSMB) or equivalent as 
approved by the UCSF DSMC. In addition to the guidelines laid out in this document, each 
PNOC member institution must comply with the policies and standards put forward by their own 
institutional DSMC/DSMB. For member institutions that do not follow an NCI-approved DSMP, 
the UCSF DSMC will be considered the “institutional DSMC” mentioned in this document. Such 
institutions will be electronically monitored.  
The institutional DSMC/DSMB activities for this study will include: 

Review of subject data

Review of suspected adverse reactions considered “serious” (SAEs) 

Monitoring every month/ (depending on patient accrual)

Minimum of a yearly regulatory audit
Monitoring and reporting guidelines
All institutional Phase 0 or Phase 1 therapeutic studies are designated with a high risk 
assessment. The data is monitored monthly by the institutional DSMC/DSMB as subjects are 
enrolled and includes all visits monitored up through the Dose Limiting Toxicity (DLT) period. 
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) DSMC is responsible 
for monitoring data quality and patient safety for all HDFCCC institutional clinical studies. In the 
case of all PNOC protocols, the UCSF DSMC will work together with non-UCSF PNOC member 
institution DSMC/DSMBs in order to ensure DSMP compliance. Each non-UCSF DSMC/DSMB 
will be responsible for providing regular monitoring reports to PNOC and the UCSF DSMC. 
These reports will be used by the UCSF DSMC to assess data quality, patient safety, and 
protocol compliance as well as to make decisions about dose escalations, where applicable. 
PNOC and the UCSF DSMC reserve the right to conduct on-site monitoring at any non-UCSF 
member institution if DSMP requirements are not being met. If the need to perform a monitoring 
visit at a non-UCSF member institution arises, source documents will be provided by the 
member institution prior to the visit in order for the UCSF DSMC to monitor protocol compliance, 
patient safety, and to verify data entry. 
The PNOC Operations Office provides administration, data management, and organizational 
support for the PNOC member institutions in the conduct of any PNOC clinical trial. The PNOC 
Operations Office will summarize and communicate adverse events, safety data, and other 
study matters to the PNOC member institutions on a quarterly basis.
The Study Chair is responsible for the overall conduct of any PNOC trial and for monitoring its 
safety and progress at all participating sites (as outlined in the PNOC Study Chair and Co-Chair 
Responsibilities SOP). The Study Chair will conduct continuous review of data and subject 
safety and discuss each subject’s treatment with the PNOC Operations Office. The discussions 
are documented in the PNOC Operations Office meeting minutes.
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The PNOC Operations Office will coordinate, at minimum, quarterly conference calls with the 
PNOC member institutions to discuss risk assessment. The following items will be discussed, as 
appropriate:

Enrollment information

Cohort updates (e.g. DLTs and dose escalations)

Adverse Events (e.g. new AEs, unresolved AEs, and new safety information)

Protocol violations

Other study conduct issues
Dose level considerations
Dose level assignments for any subject scheduled to begin treatment must be confirmed by 
the PNOC Operations Office via e-mail.
If an unexpected Dose Limiting Toxicity (DLT) occurs in a subject treated at any participating 
PNOC member institution, all member institutions must be notified of the DLT by the PNOC 
Operations Office within 1 business day. Member institutions will otherwise be provided with 
final DLT reports as they become available.
Adverse event review and monitoring
PNOC uses the web-based OnCore® Clinical Trials Management System for all patient 
registrations and data entry. The OnCore® System will also track patient level protocol 
compliance and safety information. 
All Adverse Events (AEs) will be entered into OnCore®. 
All Adverse Events entered into OnCore® will be reviewed on a weekly basis by the PNOC 
Operations Office. The PNOC Operations Office will discuss the toxicity, grade, and relationship 
to study intervention for all AEs in question. 
All Adverse Events must be entered into OnCore® within 10 business days of becoming aware 
of the event. Member institutions will submit this information to PNOC via the Adverse Event 
Form within OnCore®. 
In addition, all adverse reactions considered “serious” (also called Serious Adverse Events, or 
SAEs), regardless of relationship, must be entered in OnCore® and reported to the PNOC 
Operations Office within 1 business day. SAEs will be reviewed and monitored by the UCSF 
DSMC on an ongoing basis, and will be discussed at the UCSF DSMC meeting, which take 
place every six (6) weeks. 
If a death occurs during the treatment phase of the study, or within 30 days after the last 
administration of the study drug(s), and is determined to be related either to the investigational 
drug or to any research related procedure, the Study Chair and the PNOC Operations Office 
must be notified by the member institution within 1 business day. The Study Chair or the 
PNOC Operations Office must then notify the UCSF DSMC Chair, or qualified alternate, within 1 
business day of this notification. The contact may be by phone or e-mail.
Increase in adverse event rates
If an increase in the frequency of Grade 3, 4, or 5 Adverse Events (above the rate reported in 
the Investigator Brochure or package insert), the Study Chair or the PNOC Operations Office is 
responsible for notifying the UCSF DSMC at the time the increased rate is identified. 


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If at any time the Study Chair or the PNOC Operations Office halts enrollment or ends the study 
due to safety issues, the UCSF DSMC Chair and Manager must be notified within 1 business 
day via e-mail. The UCSF DSMC must receive a formal letter within 10 business days, and the 
UCSF IRB must be notified.
UCSF data and safety monitoring committee contacts:
UCSF DSMC Chair
UCSF-Box #1705
San Francisco, CA 94115
UCSF DSMC Manager
UCSF-Box #0128
San Francisco, CA 94143
UCSF DSMC Monitors
UCSF-Box #0128
San Francisco, CA 94143


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APPENDIX F Information Sheet on Possible Drug Interactions
Information on Possible Interactions with Other Agents for Patients and Their Caregivers 
and Non-Study Healthcare Team
The patient ____________________________ is enrolled on a clinical trial using the 
experimental agent [agent name]. This clinical trial is sponsored by the Pacific Pediatric Neuro-
Oncology Consortium and [Sponsor-Pharmaceutical Company]. This form is addressed to the 
patient, but includes important information for others who care for this patient. 
[Agent name] interacts with many drugs that are processed by your liver. Because of this, it is 
very important to tell your study doctors about all of your medicine before you start this study. It 
is also very important to tell them if you stop taking any regular medicine, or if you start taking a 
new medicine while you take part in this study. When you talk about your medicine with your 
study doctor, include medicine you buy without a prescription at the drug store (over-the-counter 
remedy), or herbal supplements such as St. John’s wort. 
Many health care prescribers can write prescriptions. You must also tell your other prescribers 
(doctors, physicians’ assistants or nurse practitioners) that you are taking part in a clinical trial. 
Bring this paper with you and keep the attached information card in your wallet. These 
are the things that you and they need to know: 
[Use or delete sections below as appropriate.]
[Agent name] interacts with (a) certain specific enzyme(s) in your liver. 
The enzyme(s) in question is/are [name(s) of CYP isoenzyme(s)], and [insert brief, easy 
explanation of the nature of the interaction, i.e., for inducers: “[agent name] is broken 
down by this enzyme in order to be cleared from your system.”] 
[Agent name] must be used very carefully with other medicines that need these liver 
enzymes to be effective or to be cleared from your system. 
Other medicines may also affect the activity of the enzyme. 
o
[The following text is for agents that are metabolized/cleared by the enzyme.] 
Substances that increase the enzyme’s activity (“inducers”) could reduce the 
effectiveness of the drug, while substances that decrease the enzyme’s activity 
(“inhibitors”) could result in high levels of the active drug, increasing the chance 
of harmful side effects.
o
[The following text is for when the agent requires the enzyme in order to be 
converted from prodrug to active drug.] Substances that increase the enzyme’s 
activity (“inducers”) could result in high levels of the active drug, increasing the 
chance of harmful side effects, while substances that decrease the enzyme’s 
activity (“inhibitors”) could reduce the effectiveness of the drug.
o
[The following text is for when the study agent modulates the enzyme activity.] 
[Agent name] is considered a(n) “[inducer/inhibitor]”of the enzyme, meaning that 
it can affect the levels of other drugs that are processed by that enzyme. This 
can lead to harmful side effects and/or reduce the effectiveness of those 
medications. 
You and healthcare providers who prescribe drugs for you must be careful about adding or 
removing any drug in this category. 


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Before you start the study, your study doctor will work with your regular prescriber to 
switch any medicines that are considered “strong inducers/inhibitors or substrates of 
[name(s) of CYP isoenzyme(s)].”
Your prescribers should look at this web site 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx or consult a medical reference to see 
if any medicine they want to prescribe is on a list of drugs to avoid. 
Please be very careful! Over-the-counter drugs have a brand name on the label—it’s 
usually big and catches your eye. They also have a generic name—it’s usually small and 
located above or below the brand name, and printed in the ingredient list. Find the 
generic name and determine, with the pharmacist’s help, whether there could be an 
adverse interaction. 
[The following are examples of text for common over-the-counter medications or 
supplements that may interact with the study agent.] Be careful: 
o
If you take acetaminophen regularly: You should not take more than 4 grams a 
day if you are an adult or 2.4 grams a day if you are older than 65 years of age. 
Read labels carefully! Acetaminophen is an ingredient in many medicines for 
pain, flu, and cold.
o
If you drink grapefruit juice or eat grapefruit: Avoid these until the study is over. 
o
If you take herbal medicine regularly: You should not take St. John’s wort while 
you are taking [agent name].
o
[Add other specific medications here, if necessary.]
Other medicines can be a problem with your study drugs. 

You should check with your doctor or pharmacist whenever you need to 
use an over-the-counter medicine or herbal supplement. 

Your regular prescriber should check a medical reference or call your 
study doctor before prescribing any new medicine for you. Your study 
doctor’s name is _____________________________________ and he or 
she can be contacted at 
INFORMATION ON POSSIBLE DRUG INTERACTIONS 
You are enrolled on a clinical trial using the experimental agent 
__________________.  This clinical trial is sponsored by the NCI.  
__________________ interacts with drugs that are processed by your 
liver.  Because of this, it is very important to:
Tell your doctors if you stop taking regular medicine or if you start 
taking a new medicine.
Tell all of your prescribers (doctor, physicians’ assistant, nurse 
practitioner, pharmacist) that you are taking part in a clinical trial.
Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement.
__________________ interacts with a specific liver enzyme called 
CYP______, and must be used very carefully with other medicines 
that interact with this enzyme. 
Before you start the study, your study doctor will work with your 
regular prescriber to switch any medicines that are considered 
“strong inducers/inhibitors or substrates of CYP______.”
Before prescribing new medicines, your regular prescribers should 
go to http://medicine.iupui.edu/clinpharm/ddis/table.aspx for a 
list of drugs to avoid, or contact your study doctor.  
Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________. 


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APPENDIX G Age Appropriate Blood Pressure and Heart Rate Measures
Blood Pressure for Children by Age and Height
Blood Pressure Levels for Boys
5th
10th
25th
50th
75th
90th
95th
5th
10th
25th
50th
75th
90th
95th
1
95th
98
99
101
103
104
106
106
54
54
55
56
57
58
58
2
95th
101
102
104
106
108
109
110
59
59
60
61
62
63
63
3
95th
104
105
107
109
110
112
113
63
63
64
65
66
67
67
4
95th
106
107
109
111
112
114
115
66
67
68
69
70
71
71
5
95th
108
109
110
112
114
115
116
69
70
71
72
73
74
74
6
95th
109
110
112
114
115
117
117
72
72
73
74
75
76
76
7
95th
110
111
113
115
117
118
119
74
74
75
76
77
78
78
8
95th
111
112
114
116
118
119
120
75
76
77
78
79
79
80
9
95th
113
114
116
118
119
121
121
76
77
78
79
80
81
81
10
95th
115
116
117
119
121
122
123
77
78
79
80
81
81
82
11
95th
117
118
119
121
123
124
125
78
78
79
80
81
82
82
12
95th
119
120
122
123
125
127
127
78
79
80
81
82
82
83
13
95th
121
122
124
126
128
129
130
79
79
80
81
82
83
83
14
95th
124
125
127
128
130
132
132
80
80
81
82
83
84
84
15
95th
126
127
129
131
133
134
135
81
81
82
83
84
85
85
16
95th
129
130
132
134
135
137
137
82
83
83
84
85
86
87
17
95th
131
132
134
136
138
139
140
84
85
86
87
87
88
89
Age, 
y
BP 
Percentile
SBP, mm Hg
Percentile of Height
DBP, mm Hg
Percentile of Height
Blood Pressure Levels for Girls
5th
10th
25th
50th
75th
90th
95th
5th
10th
25th
50th
75th
90th
95th
1
95th
100
101
102
104
105
106
107
56
57
57
58
59
59
60
2
95th
102
103
104
105
107
108
109
61
62
62
63
64
65
65
3
95th
104
104
105
107
108
109
110
65
66
66
67
68
68
69
4
95th
105
106
107
108
110
111
112
68
68
69
70
71
71
72
5
95th
107
107
108
110
111
112
113
70
71
71
72
73
73
74
6
95th
108
109
110
111
113
114
115
72
72
73
74
74
75
76
7
95th
110
111
112
113
115
116
116
73
74
74
75
76
76
77
8
95th
112
112
114
115
116
118
118
75
75
75
76
77
78
78
9
95th
114
114
115
117
118
119
120
76
76
76
77
78
79
79
10
95th
116
116
117
119
120
121
122
77
77
77
78
79
80
80
11
95th
118
118
119
121
122
123
124
78
78
78
79
80
81
81
12
95th
119
120
121
123
124
125
126
79
79
79
80
81
82
82
13
95th
121
122
123
124
126
127
128
80
80
80
81
82
83
83
14
95th
123
123
125
126
127
129
129
81
81
81
82
83
84
84
15
95th
124
125
126
127
129
130
131
82
82
82
83
84
85
85
16
95th
125
126
127
128
130
131
132
82
82
83
84
85
85
86
17
95th
125
126
127
129
130
131
132
82
83
83
84
85
85
86
Age, 
y
BP 
Percentile
SBP, mm Hg
DBP, mm Hg
Percentile of Height
Percentile of Height
Instructions for using this BP Chart:
1. Measure the patient’s blood pressure using an appropriate size cuff.
2. Select appropriate chart for a female or male patient.
3. Using the “age” row and “height” column to determine if the BP is within the ULN.
These tables were taken from “The Fourth Report on the Diagnosis, Evaluation, and Treatment of High 
Blood Pressure in Children and Adolescents” PEDIATRICS Vol. 114 No. 2 August 2004, pp. 555-576.
Heart Rate Normal Range 


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Age
Heart Rate (bpm)
0–7 days
95–160 (125)
1–3 wk
105–180 (145)
1–6 mo
110–180 (145)
6–12 mo
110–170 (135)
1–3 yr
90–150 (120)
4–5 yr
65–135 (110)
6–8 yr
60–130 (100)
9–11 yr
60–110 (85)
12–16 yr
60–110 (85)
>16 yr
60–100 (80)


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APPENDIX H Imaging Guidelines for PNOC Studies
Pre-Study Imaging Qualification 
The most critical aspect of the advanced imaging being performed in this study is to match 
quantitative exam protocols prior to the initial treatment and at follow-up studies, so that direct 
comparisons of intra-patient parameters can be made. Each PNOC site must be satisfied that 
the anatomic imaging sequences being used at these times satisfy clinical criteria for evaluating 
their patients. Hence, while there should be an attempt to make the protocols as similar as 
possible between institutions, it may not be feasible for them to be identical, and so any 
comparisons that are being made will focus on changes within the patient rather than 
differences among individuals. Please note that the radiologist at each PNOC site should 
interpret the anatomic images for clinical purposes and then send them to UCSF for quantitative 
analysis.
All images generated for each patient should be anonymized and sent to UCSF, either 
electronically or by CD so that they can be evaluated and confirmed that the protocol satisfies 
the requirements of the study. Sites should batch ship all images pertaining to each patient at 
the time the patient comes off treatment. 
Guidelines for Imaging Protocols
Serial exams should be performed on the same 3T MR system using the commercial 8-channel 
or other multi-channel head coil. The sequences may either be performed in a pure axial 
orientation or aligned with the AC-PC line, as is the default at many institutions. Our guidelines 
follow the Consensus recommendations for a standardized Brain Tumor Imaging Protocol in 
clinical trials (Ellingson BM. Neuro-Oncology. 2015).
Recommended outline of MR imaging protocol:
1.
3-plane localizer
2.
T1-weighted pre-gadolinium volumetic images: this high-resolution (3-dimensional 1 mm 
isotropic) acquisition is used as a reference for comparing with the post-gadolinium 
images and to identify signs of hemorrhage. We recommend 3-dimensional isotropic T1-
weighted images using a gradient-recalled echo (GRE) acquisition with inversion 
preparation (IR)
3.
T2-weighted images: used in conjunction with the T2-weighted fluid-attenuated inversion 
recovery (FLAIR) images to define the spatial extent of the T2 lesion. 
4.
FLAIR images: required for defining treatment response using the RANO criteria or 
iRANO criteria as indicated per each study protocol.
5.
Diffusion weighted images: the entire brain should be covered with at least 6 different 
gradient directions at b=1000 and with one acquisition having b=0. The slice thickness 
and spatial resolution should be chosen to allow calculation of maps of apparent 
diffusion coefficient and fractional anisotropy. 
6.
Echo planar gradient echo dynamic susceptibility contrast (DSC) images: A series of 
images should be acquired during the injection of a bolus of 0.1mmol/kg of gadolinium 
contrast agent that is delivered at a rate of 3-5m/s using a power injector and with a 15-
20ml flush of normal saline delivered at the same rate. The dose and timing of 
gadolinium should be kept consistent to facilitate clinical interpretation. Slice thickness 
(3-5mm) and location should be chosen to cover as much of the T2 lesion as possible. 


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The injector delay should be set at 15-30s to allow a good definition of baseline 
intensities from the pre-bolus images. Additionally, the dose and agent should be 
explicitly documented on the MR system during acquisition or labeled in the DICOM 
header.
7.
Post-gadolinium T1-weighted volumetric images: this high-resolution (3-dimensional 1 
mm isotropic) acquisition is used to define the spatial extent of the enhancing volume 
and for registration between examinations. We recommend 3-dimensional isotropic T1-
weighted images using a gradient-recalled echo (GRE) acquisition with inversion 
preparation (IR).
8.
Post-gadolinium T1-weighted images: these should match the pre-gadolinium images 
are used to define the extent of the enhancing lesion. For consistency in contrast 
enhancement we recommend that these images be acquired after volumetric post-
gadolinium T1-weighted images.
Any of the above sequences or a combination thereof may be used for quantitative analysis of 
disease response and/or treatment effect. Decisions regarding which sequences will be utilized 
will be determined as based on the specific study intervention and anticipated imaging findings 
that accompany the intervention (e.g. immunotherapy vs. targeted small molecules), as well as 
individual characteristics of tumor subtypes. In addition to assessing disease response and 
treatment effect, sequences may be used for pre-surgery exams, clinical evaluation of the 
patient, and volumetric analysis of regions of interest. 
De-Identification and Labeling
It is the responsibility of the PNOC sites to de-identify images according to HIPAA, Institutional 
Review Board (IRB) guidelines, GCPs and local regulatory requirements, with the following 
considerations:

Do not remove the date of the exam or the technical information (eg, slice location, kVP, 
echo time, etc).

Do not modify time or date information before or during the de-identification process.
Labeling of Digital Images
Use the patient ID, the date (ddmmyy) and scan number (01 or 02 for the two advanced imaging 
exams) to label the data as follows: PatientID_date_xx
Checklist for Media Submission

Completed Exam Data Sheet. 

De-identified DICOM images. 
Sending Digital Images via FedEx:

PNOC sites should batch ship all images pertaining to each patient at the time the 
patient comes off treatment. 

All MRIs should be de-identified prior to shipment.

All shipping materials should be provided by the site.

All shipments require signature for delivery.


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
Include checklist items and address packages sent to the PNOC Operations Office as 
outlined in the Imaging SOP on the PNOC SharePoint website.
Example of Data Analysis Performed by PNOC Central Review
The anatomic images will be used to manually define the contrast enhancing lesion (CEL) and 
the T2 lesion (T2L), as well as T2/FLAIR changes. The T1 weighted pre-contrast image will be 
used to define a brain mask so that intensity values can be normalized. The diffusion images 
are processed to generate maps of apparent diffusion coefficient (ADC) and fractional 
anisotropy (FA). The perfusion data are processed to calculate maps of relative cerebral blood 
volume (rCBV), peak height (PH) and percentage recovery (RECOV).