Clinical trial NCT03020017
Conditions: Gliosarcoma Recurrent Glioblastoma
Sponsor: Northwestern University
Start date: 2017-05-25; Completion date: 2020-08-19
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this research study is to evaluate the safety of the study drug, NU-0129, based on Spherical Nucleic Acid (SNA) platform when infused in patients with recurrent glioblastoma multiforme or gliosarcoma. The SNA consists of nucleic acids arranged on the surface of a small spherical gold nanoparticle. This is a first-in-human trial to determine the safety of NU-0129. NU-0129 can cross the blood brain barrier (a filtering mechanism that carry blood to the brain). Once within the tumor, the nucleic acid component is able to target a gene called Bcl2L12 that is present in glioblastoma multiforme, and is associated with tumor growth. This gene prevents tumor cells from apoptosis, which is the process of programmed cell death, thus promoting tumor growth. Researchers think that targeting the Bcl2L12 gene with NU-0129 will help stop cancer cells from growing.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess the safety of intravenous NU-0129 in patients with recurrent glioblastoma multiforme (GBM) or gliosarcoma (GS).

SECONDARY OBJECTIVES:

I. To analyze drug concentration in serum at specific time points after drug administration.

II. To demonstrate intratumoral penetration of NU-0129. III. To assess the feasibility of giving NU-0129 as a standard treatment for recurrent GBM or GS.

TERTIARY OBJECTIVES:

I. To analyze tumor tissue for Bcl2L12 expression levels after NU-0129 administration.

II. Preliminary response (progression free survival \[PFS\] and overall survival \[OS\] at 6 months; overall response rate \[ORR\]).

OUTLINE:

Patients receive NU-0129 intravenously (IV) over 20-50 minutes and undergo standard of care tumor resection within 8-48 hours.

After completion of study treatment, patients are followed up at 7, 14, 21, and 28 days and then every 84 days for up to 2 years.

Arms: arm 1: Patients receive NU-0129 IV over 20-50 minutes and undergo standard of care tumor resection within 8-48 hours.
Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Pharmacological Study intervention 3: Targeted Molecular Therapy
Intervention descriptions: intervention 1: Correlative studies intervention 2: Correlative studies intervention 3: Given NU-0129 IV

Protocol documents:
Prot_SAP_000.pdf: 
NU Study Number: NU 16C01 
 
1 
 
 A Phase 0 first-in-human study using NU-0129: a spherical nucleic 
acid (SNA) gold nanoparticle targeting BCL2L12 in recurrent 
glioblastoma multiforme or gliosarcoma patients  
 
 
Principal Investigator:  
Priya Kumthekar, MD 
 
 
 
 
Northwestern University  
710 N. Lake Shore Drive, Suite 1123 
 
Chicago, IL 60611 
Phone: 312.503.1818 
Fax: 312.908.5073 
p-kumthekar@northwestern.edu 
 
 
Sub-Investigator(s): 
 
Karan Dixit, MD 
Sean Grimm, MD 
James Chandler, MD 
Orin Bloch, MD 
Matt Tate, MD, PhD 
Macej Lesniak, MD, PhD 
Margaret Schwartz, NP 
Lynnette Onuselogu, NP 
Valerie Nelson, MD, MBA 
 
 
 
 
 
Northwestern University, Department of Neurology  
 
 
Biostatistician: 
 
Borko Jovanovic, MS, PhD 
 
 
 
 
borko@northwestern.edu 
 
Study Intervention(s):  
NU-0129 
 
IND Number: 
 
 
IND #: 115876 
 
IND Holder: 
 
 
Priya Kumthekar, MD 
 
Funding Source:  
Northwestern University 
 
Version Date: 
 
 
12/19/2018 (Amendment 5) 
 
Coordinating Center:  
Clinical Research Office 
 
 
 
 
Robert H. Lurie Comprehensive Cancer Center  
Northwestern University 
676 N. St. Clair, Suite 1200 
Chicago, IL  60611 
 
 
 
 
http://cancer.northwestern.edu/CRO/index.cfm 
 
 
 
 
 
 
 
 
 
 
 
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Amendment 5: December 19, 2018 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ............................................................................................................. 5 
STUDY SCHEMA ............................................................................................................................ 7 
STUDY SUMMARY ......................................................................................................................... 8 
1.0 
Introduction – BACKGROUND & RATIONALE .............................................................. 10 
 
Disease Background ...................................................................................................... 10 
 
Intervention Background & Overview ............................................................................ 10 
 
Rationale for the Current Study ..................................................................................... 14 
 
Exploratory Studies ........................................................................................................ 14 
2.0 
OBJECTIVES & endpoints ............................................................................................... 14 
 
Primary Objective & Endpoint ........................................................................................ 14 
 
Secondary Objectives & Endpoints ............................................................................... 14 
 
Exploratory Objectives & Endpoints .............................................................................. 15 
3.0 
PATIENT ELIGIBILITY ...................................................................................................... 15 
 
Inclusion Criteria ............................................................................................................ 15 
 
Exclusion Criteria ........................................................................................................... 16 
4.0 
TREATMENT PLAN .......................................................................................................... 17 
 
Overview ........................................................................................................................ 17 
 
NU-0129 Administration................................................................................................. 17 
 
Toxicity Management & Dose Delays/Modifications ..................................................... 18 
 
Concomitant Medications/Treatments ........................................................................... 18 
 
Other Modalities or Procedures ..................................................................................... 19 
 
Duration of Therapy ....................................................................................................... 19 
 
Duration of Follow Up .................................................................................................... 19 
 
Removal of Subjects from Study Treatment and/or Study as a Whole ......................... 19 
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Amendment 5: December 19, 2018 
 
Patient Replacement ..................................................................................................... 19 
5.0 
STUDY PROCEDURES ..................................................................................................... 20 
Table 5.1 – On-Study Procedures (**see table 5.2 for follow-up procedures) ........................... 20 
Table 5.2 – Follow-Up Procedures ............................................................................................. 21 
6.0 
Endpoint assessment ...................................................................................................... 22 
 
Definitions ...................................................................................................................... 22 
 
Primary Endpoint ........................................................................................................... 23 
 
Secondary Endpoints ..................................................................................................... 23 
 
Exploratory Endpoints .................................................................................................... 23 
7.0 
ADVERSE EVENTS .......................................................................................................... 24 
 
Adverse Event Monitoring ............................................................................................. 24 
 
Definitions & Descriptions .............................................................................................. 24 
 
Adverse Event Reporting ............................................................................................... 25 
8.0 
DRUG INFORMATION ...................................................................................................... 27 
 
Agent NU-0129 .............................................................................................................. 27 
9.0 
CORRELATIVES/SPECIAL STUDIES .............................................................................. 29 
 
Blood Sample Collection Guidelines ............................................................................. 29 
 
Fresh tumor samples ..................................................................................................... 29 
 
Archival tissue ................................................................................................................ 29 
 
Sample Processing, Storage, and Shipment ................................................................. 30 
 
Assay Methodology ....................................................................................................... 30 
 
Specimen Banking ......................................................................................................... 31 
10.0 
STATISTICAL CONSIDERATIONS .................................................................................. 31 
 
Study Design/Study Endpoints ...................................................................................... 31 
 
Sample Size and Accrual .............................................................................................. 31 
 
Data Analyses Plans ...................................................................................................... 31 
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Amendment 5: December 19, 2018 
11.0 
STUDY MANAGEMENT .................................................................................................... 31 
 
Institutional Review Board (IRB) Approval and Consent ............................................... 31 
 
Amendments .................................................................................................................. 32 
 
Registration Procedures ................................................................................................ 32 
 
Data Submission ............................................................................................................ 32 
 
Data Management and Monitoring/Auditing .................................................................. 32 
 
Adherence to the Protocol ............................................................................................. 33 
 
Investigator Obligations ................................................................................................. 33 
REFERENCES ............................................................................................................................... 40 
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5 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
AED 
Antiepileptic Drug 
ALT 
Alanine Aminotransferase 
ALC 
Absolute Lymphocyte Count 
API 
Active Pharmaceutical Ingredient 
AST 
Aspartate Aminotransferase 
BBB 
Blood Brain Barrier 
BTB 
Blood Tumor Barrier 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMB 
Data and Safety Monitoring Board 
GLP 
Good Laboratory Practices 
ECOG 
Eastern Cooperative Oncology Group 
EIAED 
Enzyme-inducing Antiepileptic Drug 
HED 
Human equivalent dose 
H&PE 
History & Physical Exam 
ICP-MS 
Inductively Coupled Plasma Mass Spectrometry 
IHC 
Immunohistochemistry 
IV (or iv) 
Intravenously 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NOAEL 
No-observed-adverse-effect level 
ORR 
Overall Response Rate or Objective Response Rate 
OS 
Overall Survival 
PBMCs 
Peripheral Blood Mononuclear Cells 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PO (or p.o.) 
Per os/by mouth/orally 
PR 
Partial Response 
RANO 
Response Assessment in Neuro-Oncology 
REMBRANDT Repository of Molecular Brain Neoplasia Data 
RT-qPCR 
Quantitative Reverse Transcription Polymerase Chain Reaction 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SPGT 
Serum Glutamic Pyruvic Transaminase 
SNA 
Spherical Nucleic Acid 
TUNEL 
Terminal deoxynucleotidyl transferase dUTP nick end labeling 
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ULN 
Upper Limit of Normal 
VSS 
Volume of distribution at steady state 
WBC 
White Blood Cells 
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7 
STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patients with recurrent glioblastoma 
multiforme (GBM) or gliosarcoma (GS) 
who have failed prior therapy  
NU-0129 will be administered inpatient one 
time at ~ 0.04mg/kg IV 8-48 hours prior to 
scheduled tumor resection 
Patients will be followed up to 2 years after study treatment by routine 
clinic visit at least every 84 days (12 weeks) until progression, and for 
survival thereafter  
PK blood draws will take place over 24 hours 
post-dose, and a tumor sample will be collected 
to analyze biodistribution of NU-0129, Bcl2L12 
expression, and other apoptotic markers 
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STUDY SUMMARY 
Title 
A Phase 0 first-in-human study using NU-0129: a spherical nucleic acid 
(SNA) gold nanoparticle targeting BCL2L12 in recurrent glioblastoma 
multiforme or GS patients 
Version 
December 19, 2018 (Amendment 5) 
Study Design 
This is a single-arm, open-label, phase 0 first-in-human trial to determine 
the safety of NU-0129.  
Study Center(s) 
Northwestern University 
Objectives 
Primary Objective: 
• 
To evaluate the safety of NU-0129 SNA gold nanoparticle 
infusion in patients with recurrent GBM or GS 
 
Secondary Objectives: 
• 
To evaluate the bio-distribution of NU-0129 in tumor tissue 
• 
To evaluate the pharmacokinetics of NU-0129 in blood samples 
collected at 1, 3, 5, 10, 30, 60 minutes and 4, 8, and 24 hours 
post-dose 
• 
To evaluate the feasibility of NU-0129 administration 
 
Exploratory Objectives 
• 
To evaluate the Bcl2L12 expression levels and apoptotic markers 
in the tumor tissue post-treatment 
• 
To evaluate preliminary response (Overall Survival and 
Progression Free Survival at 2 years, as well as Overall 
Response Rate) 
 
Sample Size 
6-8 patients will be enrolled 
Diagnosis & Key 
Eligibility Criteria 
• Patients should have a diagnosis of recurrent glioblastoma multiforme 
(GBM) or gliosarcoma (GS) after failing prior therapy.  
• Eligible patients must be surgical candidates where surgery is felt to 
be an appropriate treatment option.  
• Bone marrow and organ function must be adequate as defined below 
• WBC ≥ 3,000/µL 
• ANC ≥ 1,500/mm3 
• Platelet count of ≥ 100,000/mm3 
• Hemoglobin ≥8 g/dL 
• Bilirubin ≤ 2 x ULN 
• AST/ALT ≤ 2 x ULN 
• Creatinine ≤ 1.5 x ULN  
Patients must not have had prior cancer therapy (including biologic, 
cytotoxic, and experimental therapies and nitrosoureas) within 21 
days of registration.  
Treatment Plan 
Once registered, eligible patients will receive intravenous NU-0129 
nominal dose ~ 0.04mg/kg (based on dosing chart) one time. Patients 
will be monitored with telemetry, vital signs, and labs before, during and 
after the infusion as indicated in section 5.0. Treatment will be followed 
by a tumor resection 8-48 hours later. The tissue will be collected and 
analyzed for bio-distribution and exploratory studies.   
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Statistical Methodology 
All patients properly included in the study who undergo surgery for tumor 
removed will be included in the analysis. Thus, an incorrect treatment 
schedule or drug administration would result in exclusion from the 
analysis of the tumor accumulation study. All conclusions will be based 
on all eligible patients. Sub-analyses may then be performed on the 
basis of a subset of patients, excluding those for who major protocol 
deviations have been identified. However, these sub-analyses may not 
serve as the basis for drawing conclusions concerning treatment 
efficacy, and the reasons for excluding patients form the analysis should 
be clearly reported.  
 
 
 
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10 
1.0 
INTRODUCTION – BACKGROUND & RATIONALE 
 
 
Disease Background 
Glioblastoma (GBM) is a neurologically debilitating disease, which culminates in death 
16-18 months after diagnosis. An incomplete understanding of genetic aberrations 
leading to tumor growth, invasion and anti-apoptosis, mechanisms of resistance, 
combined with the lack of effective drugs have conspired to make GBM an incurable 
disease. In addition to issues noted, drug delivery has long been an issue in treating 
brain tumors that is not an issue for most other solid tumors. 
Glioblastoma (GBM) is a highly malignant brain tumor of astrocytic origin which 
accounts for over 50% of all gliomas. GBM has an annual incidence rate of 3 to 4 
cases per 100,000 people resulting in 240,000 newly diagnosed cases worldwide 
each year [1,2]; . 
The current standard treatment for GBM is surgical resection followed by radiotherapy 
with concurrent and adjuvant temozolomide (TMZ). For newly diagnosed GBM, the 
addition of TMZ to surgery and radiation therapy prolongs median survival (from 12.1 
to 14.6 months) and increases the five-year survival rate (from 2% to 10%; hazard 
ratio 0.63; 95% CI 0.53-0.75; p<0.0001) [3]. 
Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), 
was approved in the US for the treatment of recurrent GBM based on a clinically 
meaningful and durable objective tumor response rate (ORR 28%-38%, median duration 
of response 4.2 months). The 6-month-PFS rate in the multiple studies ranged from 
approximately 29% to 50% and represented a significant improvement over the historical 
10-20% 6-month-PFS rate. Despite the improvement in response provided by 
bevacizumab, most patients with GBM experience relapse within months [4,5] and 
options for salvage remain extremely limited. 
Genetically, GBM is characterized by complex chromosomal abnormalities and 
extensive intratumor cytogenetic and histological heterogeneity displaying the genetic 
alterations that govern the processes of cellular proliferation, survival, invasion and 
angiogenesis [6,7,8].  Common mutations found in GBM include: EGFR overexpression 
(70%) [9]; TP53, RB, INK4a, PDGF-R, VEGF-R, C- Met and HGF and PTEN [10]. 
Besides GBM, which features the highest grade of malignancy among glioma (grade 
IV), lower grade glioma which include grade II and grade III are a heterogeneous group 
of tumors in which specific molecular features are associated with divergent clinical 
outcome. 
Currently approved therapy for a newly diagnosed GBM patient in the United States 
includes maximal surgical resection followed by radiation and temozolomide [11]. Upon 
recurrence there are few approved options and these include surgical implantation of 
chemotherapy bearing wafers[12] (polifeprosan 20 with carmustine implant, Gliadel® 
Wafer) and systemic administration of the anti-angiogenic agent bevacizumab, which has 
shown a partial response rate of 20% in one trial, and 26% in another [13, 14]. Each of 
these therapies has shown modest improvement in survival of recurrent GBM patients, 
with notable treatment related toxicities including wound breakdown after surgical 
resection [15]. 
 
 
Intervention Background & Overview 
NU-0129 is an investigational spherical nucleic acid (SNA) designed to target the 
silencing of Bcl2L12 gene expression, an overexpressed protein that plays an important 
role in driving the pathogenesis of glioblastoma multiforme (GBM) and mediating 
therapeutic resistance [16]. SNAs are three dimensional conjugates consisting of densely 
functionalized and highly oriented nucleic acids covalently attached to the surface of 
nanoparticles [17]. NU-0129 is composed of 13nm gold nanoparticles surrounded by 
siRNAs tailored to recognize Bcl2l12 sequence. Gene silencing using siRNAs conjugated 
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to these SNAs represents a promising new approach for systemic RNA interference 
(RNAi)-based therapy of this aggressive malignant brain tumor in humans. This 
nanoconjugate is one of the first to report stable and robust RNAi delivery to intracranial 
tumors in rodent GBM models, as they have the capacity to cross both intact and tumor-
compromised blood brain barrier (BBB), and has helped develop SNAs as a platform for 
biotherapeutic gene silencing. Non-human primate and non-primate toxicology studies 
were completed with NU-0129, with no significant clinical observations. 
 
The impact of NU-0129 on tumor progression in xenogeneic grafts in mice show 
intravenous administration of NU-0129 at a total injection of 7 mg/kg of the active 
pharmaceutical ingredient (API) resulted in intraglioma protein down-regulation and 
impaired tumorigenicity as measured by decreased tumor weight and prolonged survival 
of xenogeneic mice. Increased intratumoral apoptosis was evidenced by enhanced levels 
of DNA strand breaks as assessed by Terminal deoxynucleotidyl transferase dUTP nick 
end labeling (TUNEL) and active caspase-3 staining. Thus, blood-brain barrier/blood-
tumor barrier (BBB/BTB) penetration and intra-glioma dissemination of NU-0129 upon 
systemic administration resulted in increased survival of glioma-bearing animals. 
 
 
1.2.1 
Pre-clinical Pharmacokinetic studies 
 
Summary of finding from 126501 AD TK report Text 
NU-0129, in the vehicle (phosphate-buffered saline, pH 7.4), was administered 
by IV bolus once to 3 groups of male and female Cynomolgus monkeys.  A 
concurrent control group received the vehicle on the same regimen.  Table T1 
presents the study group assignment for the Toxicokinetic portion of the study.  
 
On the day of dosing, blood samples were collected from all animals prior to 
dosing and at approximately 3, 10, and 30 minutes, and 2, 8, and 24 hours post-
dose.  Plasma was analyzed for the concentration of NU-0129 using liquid 
chromatography with FLD.  The results of these analyses were used for 
toxicokinetic analysis. 
 
The toxicokinetic parameters for NU-0129 in plasma are summarized in Table 
 
T2.  
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Table T2. 
Toxicokinetic Parameters for NU-0129 in Male and Female Monkeys  
Males 
Females 
Dosage (mg/kg) 
1 
4 
8 
1 
4 
8 
 
Mean 
SD 
Mea
n 
SD 
Mea
n 
SD 
Mean 
SD 
Mea
n 
SD 
Mea
n 
SD 
AUClast 
(µg*h/mL) 
    
0.232†1 
NA 
2.37 
1.04 
9.82 
2.82 
    
0.321†3 
0.10
4 
3.62 
0.71
7 
14.2 1.90 
C0 (µg/mL) 
1.67 
0.879 34.0 
19.8 
131 
51.4 
3.90 
2.31 
68.9 
18.1 
174 
36.3 
T1/2 (h) 
NC 
NA 
0.06 
0.00 
0.08 
0.04     0.05†3 0.00 
0.05 
0.00 
0.07 0.01 
Cl (mL/h/kg) 
NC 
NA 
1980 
863 
863 
224 
    
3340†3 
1070 1140 
250 
570 
93.2 
Vss (mL/kg) 
NC 
NA 
158 
86.7 
72.6 
26.0 
    213†3 
75.3 
66.1 
22.4 
50.2 7.52 
 
N = 5, except where designated with †N 
 
Following a single IV bolus dose of NU-0129 to male and female monkeys, 
exposure increased with increasing dose.  The increase in AUClast was greater 
than dose proportional as NU-0129 dose increased from 1 mg/kg to 8 mg/kg.  
NU-0129 exposure, in terms of AUClast, was slightly higher in females than in 
males, but differences were <2-fold. 
 
Clearance, Vss, and terminal half-life were not calculable at 1 mg/kg for males.  
Mean Clearance, ranging from approximately 600 to 3000 mL/h/kg, was 
moderate to high (approximately 20% to 120% of hepatic blood flow in the 
monkey as reported by Davies and Morris, 1993) and decreased as dose 
increased.  Mean Vss was small, ranging from approximately 50 to 200 mL/kg 
(approximately 10% to 30% of total body water in the monkey as reported by 
Davies and Morris, 1993) and also decreased with increasing dose.  This 
resulted in a short terminal elimination halflife that ranged from approximately 2 
to 9 minutes for individual animals.  Clearance- and Vss values were 
approximately 1.4- to 2-fold higher for males than females, but half-life values 
were similar. 
 
1.2.2 
Pre-clinical toxicity studies 
The non-clinical toxicity studies for Bcl2l12-2-SNA in cynomolgus monkeys and 
rats showed no significant test article-related clinical observations. Purple and/or 
blue discoloration of various body surfaces (facial area, oral cavity, limbs and/or 
trunk) were noted in medium and high dose groups, along with macroscopic 
observations of blue discolorations in some tissues of high dose group. 
Consistently, microscopic findings indicated black pigment within macrophages 
and endothelium in corresponding tissues, i.e., adrenals, liver, lymph nodes, and 
spleen.  These pigments are likely attributed to the gold-nanoparticles. 
Importantly, toxicity was not observed at the cellular or tissue level in the 
presence of the gold-nanoparticles.   
 
 
  
Administration of Bcl2l12-2-SNA to male and female cynomolgus monkeys was 
well tolerated with all animals surviving to the scheduled primary (Day 2 post-
dose) or recovery (Day 14 post-dose) necropsies. Significantly, there were no 
clinical observations in hematology, coagulation, serum chemistry, or urinalysis 
parameters, or organ weight. Blue discoloration was noted in many of the tissues 
of the monkeys, more so at the higher dose levels, and this was correlated to the 
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presence of pigment within macrophages and endothelium in the various tissues. 
The pigment appeared black by light microscopy and is likely attributed to the 
gold-nanoparticles. There did not appear to be any cellular or tissue level toxicity 
to the presence of the gold-nanoparticles. Bcl2l12-2-SNA appears to be a 
promising, clinically-viable drug product. There is no significant toxicity 
associated with the chemistry or manufacturing of the drug product. All pre-
clinical studies were performed under conditions of Good Laboratory Practice 
(GLP). 
 
 
1.2.3 
More in-depth results and summary. 
The dose levels tested were 1mg/kg (low), 4mg/kg (medium) and 8mg/kg (high) 
via intravenous (bolus) injection to male and female cynomolgus monkeys. The 
dose levels correspond to the amount of siRNA, the actual test article 
component, in the neat powered material.  There was 0.025 grams of siRNA per 
1.00 gram of the neat, powered material.  
 
All toxicology and cardiovascular animals survived to the end of the study. There 
were no test article-related effects on body weights, hematology, coagulation, 
serum chemistry, urinalysis, or organ weights. In addition, administration of a 
single dose of NU-0129 at high dose (8 mg/kg) via intravenous (bolus) injection 
to male and female cynomolgus monkeys resulted in moderately decreased 
blood pressure (systolic, diastolic, and mean blood pressure); this effect was only 
detected in the test article formulation group and not the control group.  NU-0129 
at 8 mg/kg had no effect on heart rate, pulse pressure, body temperature, ECG 
intervals (PR, QRS, RR, QT, or QTcB), or ECG waveform morphology. 
 
Test article-related clinical observations of purple and/or blue discoloration of 
various body surfaces (facial area, gums, forelimb[s], hindlimb[s], oral cavity, 
and/or trunk [dorsal and ventral]) were noted in the 4 and 8 mg/kg toxicology 
group males and females and in the 8 mg/kg cardiovascular group males and 
females throughout the study, and in a single 1 mg/kg toxicology group male on 
study days 4 and 5.  In general, purple discoloration was noted only on the day of 
dose administration and blue discoloration was noted for the remainder of the 
recovery period. 
 
Test article-related macroscopic observations of blue discoloration were noted in 
many tissues (adrenals, gastrointestinal tissues [esophagus, stomach, 
duodenum, jejunum, ileum, cecum, colon, and rectum], epididymis, lymphoid 
tissues [spleen, lymph nodes, and thymus], skin, liver, tongue, urogenital tissues 
[seminal vesicles, testes, vagina, and urinary bladder]) of most males and 
females at 8 mg/kg on study days 2 and 14.  Blue discoloration of the liver, 
spleen, lymph nodes, skin, tongue, and scattered other tissues was also noted in 
the 4 mg/kg/day group males and females on study days 2 and 14.  In the 1 
mg/kg/day group males and/or females, blue discoloration was noted only in the 
liver, adrenals, epididymis, testes, and spleen.  In addition, blue discoloration of 
the bone was noted in the 4 and 8 mg/kg group males and females on study day 
14.  Procedurerelated- macroscopic findings of dark red area(s) at the injection 
site were noted in all animals, including the control group, on study days 2 and 
14. 
 
Test article-related microscopic findings of pigment in the adrenals, bone marrow 
(femur and sternum), Kupffer cells in the liver, lymph nodes (axillary, mandibular, 
and/or mesenteric), and spleen were noted in all test article-treated male and 
female groups on study day 2 and in all test articletreated male groups as well as 
4 mg/kg and 8 mg/kg group females on study day 14.  In addition, pigment was 
noted in the skin and tongue in the 4 and 8 mg/kg group males and females on 
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study days 2 and 14.  Injection site findings of acute perivascular hemorrhage 
were noted in all groups, including the control group on study days 2 and 
14.  -Procedurerelated- injection site findings of perivascular acute inflammation 
(neutrophils, edema, and fibrin exudation) was noted at all dose levels on study 
day 2, and subacute inflammation was noted in the 4 and 8 mg/kg group males 
on study day 14. 
 
Since the neat test article is comprised of spherical nucleic acids in the presence 
of gold nanoparticles and the dosing formulation was described as being an 
opaque dark red liquid, it is hypothesized that it is the gold nanoparticles that are 
responsible for the blue discoloration of the tissues. 
 
Based on the results of this study, a single intravenous (bolus) injection of NU-
0129 to cynomolgus monkeys resulted in a no-observed-adverse-effect level 
(NOAEL) of 8 mg/kg for both systemic and local assessments. 
 
 
Rationale for the Current Study 
NU-0129 has undergone extensive pre-clinical testing and appears to be a viable, safe, 
and potentially efficacious drug product in GBM. The NOAEL determined for non-human 
primates is 8mg/kg (nucleic acid dose concentration). One fiftieth of the human 
equivalent dose (HED) is around 0.04 mg/kg.  Being that this is a Phase 0 first in human 
trial, micro-dosing will be utilized with a target dose of 0.04 mg/kg.   
 
NU-0129 is an ideal potential agent for the treatment of GBM for its ability to cross the 
blood brain barrier giving it potential bioavailability within the tumor bed.  Additionally, 
targeting the tumorigenic Bcl-2 could promote apoptosis and tumor kill for patients treated 
with NU-0129.  Given the preclinical data as well as data from animal studies in rats, 
mice and non-human primates, it has been shown that NU-0129 successfully crosses the 
blood brain barrier, successfully induces apoptosis and in the mouse model leads to 
improved survival in animal models with GBM.  
 
 
Exploratory Studies 
An exploratory objective will be to assess the level of Bcl2L12 expression in the primary 
tumor. Expression of Bcl2L12 is upregulated in most GBM patients as higher expression 
results in resistance to apoptosis. A survival analysis in 343 GBM patients with different 
levels of Bcl2L12 demonstrated a decreased survival rate correlating with increased 
expression of Bcl2L12.  
 
  
2.0 
OBJECTIVES & ENDPOINTS 
 
 
Primary Objective & Endpoint 
• The primary objective is to assess the safety of intravenous NU-0129 in patients with 
recurrent GBM or GS. 
• The total incidence of adverse events will be evaluated using CTCAE v4.03 from the 
time of informed consent to 21 days after study drug administration. Adverse events 
will be monitored during and immediately after the infusion as well as weekly for 21 
days after treatment administration. 
 
 
Secondary Objectives & Endpoints 
 
• To analyze drug concentration in serum at specific time points after drug 
administration.  
• PK blood samples will be collected post-infusion at 1, 3, 5, 10, 30, and 60 
minutes, and 4, 8, and 24 hours post infusion. 
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15 
 
Bio-distribution 
• To demonstrate intratumoral penetration of NU-0129  
• Tissue will be collected during the scheduled surgery and analyzed using ICP-
MS 
 
 
• To assess the feasibility of giving NU-0129 as a standard treatment for 
recurrent GBM or GS. 
• Feasibility will be calculated as the rate of successful production, delivery, and 
administration of the investigational product and subsequent resection.  
 
 
Exploratory Objectives & Endpoints 
 
To analyze tumor tissue for Bcl2L12 expression levels after NU-0129 
administration.  
Tissue collected during surgery will be analyzed using RNA analysis techniques. 
A comparison will be drawn with archival tissue collected at screening for any 
patients where it is available.  
 
 
Preliminary response will be measured as an exploratory outcome. Progression 
Free Survival (PFS) and Overall Survival (OS) will be measured at 6 months after 
treatment. 
Overall Response Rate will also be measured by brain MRI at least every 12 
weeks after treatment using RANO criteria 
 
3.0 
PATIENT ELIGIBILITY 
The target population for this study is patients with recurrent glioblastoma multiforme or 
gliosarcoma. This will be a single-center trial conducted at Northwestern Medicine.  
 
A total of 6-8 subjects will be needed for this trial. Approximately 8 potentially eligible patients are 
seen per month, and it is anticipated that at least 1 per month will be accrued. Potential patients 
may be referred to the Principal Investigator (PI) at Northwestern University, Dr. Priya Kumthekar, 
at (312) 503-1818. 
 
Eligibility will be evaluated by the study team according to the following criteria. Eligibility waivers 
are not permitted. Subjects must meet all of the inclusion and none of the exclusion criteria to be 
registered to the study. Study treatment may not begin until a subject is registered. Please refer 
to Section 11 for complete instructions regarding registration procedures. 
 
 
Inclusion Criteria 
3.1.1 Patients must have histologically proven glioblastoma multiforme (GBM) or 
Gliosarcoma (GS). 
 
3.1.2 Patients must have measurable disease by RANO 2010 criteria at the time of 
registration (pre-operative). 
 
3.1.3 Patients must have failed at least one regimen of chemo or radiation therapy. 
NOTE: There is no limit to the number or types of prior therapy.  
 
3.1.4 The patient must be a candidate for surgical debulking (either subtotal or gross 
total resection). Biopsy-only candidates will not be eligible.  
 
3.1.5 All patients must be capable to voluntarily sign an informed consent indicating that 
they are aware of the investigational nature of this study prior to registration.   
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16 
 
3.1.6 Patients must be > 18 years old. 
 
3.1.7 Patients must have a Karnofsky performance status of > 70. 
 
3.1.8 Patients must have adequate bone marrow, liver, coagulation and renal function 
within 7days prior to study registration, as defined below: 
• 
WBC > 3,000/µL 
• 
ANC > 1,500/mm3 
• 
Platelet count of > 100,000/mm3 (Note: Transfusion or growth factor may be 
used for eligibility outside of 7 days) 
• 
Hemoglobin > 8 g/dL (Note: Transfusion may be used for eligibility outside of 
7 days) 
• 
Bilirubin ≤2 x ULN 
• 
AST/ALT ≤2 x ULN 
• 
Creatinine ≤1.5 x ULN  
• 
Urine protein ≤ 30 mg/dL  
• 
Cholesterol ≤ 300 mg/dL  
• 
INR ≤ 1.5 x ULN 
• 
PT/PTT ≤ 1.5 x ULN 
 
3.1.9 Any patient who has had a recent surgery should have recovered from all effects 
of the surgery and be cleared by their surgeon. 
 
3.1.10 Females of child-bearing potential (FOCBP) and males must agree to use 
adequate contraception (e.g. hormonal or barrier method of birth control; 
abstinence) prior to study entry, for the duration of study participation, and for 21 
days following completion of therapy. Should a female patient, or a male patient’s 
partner, become pregnant or suspect she is pregnant while participating in this 
study, the patient should inform her or his treating physician immediately. 
 
NOTE: A FOCBP is any woman (regardless of sexual orientation, having 
undergone a tubal ligation, or remaining celibate by choice) who meets the  
following criteria: 
• Has not undergone a hysterectomy or bilateral oophorectomy 
• Has had menses at any time in the preceding 12 consecutive months (and 
therefore has not been naturally postmenopausal for > 12 months) 
 
3.1.11 FOCBP must have a negative pregnancy test (either urine or serum) within 14 
days prior to registration. 
 
 
Exclusion Criteria 
 Patients must not have any significant infections or medical illnesses that in the 
investigator’s opinion cannot be adequately controlled with appropriate therapy or 
would compromise the patient’s ability to tolerate NU-0129. 
 
 Patients must not have a history of any other cancer unless they are in complete 
remission and off of all therapy for that disease for a minimum of 3 years. 
 
NOTE: Non-melanoma skin cancer or carcinoma in-situ of the cervix are 
exceptions and may be permitted after discussion with study QAM. 
 
 Patients must not have had radiation therapy ≤12 weeks prior to starting study 
treatment. 
 
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NU Study Number: NU 16C01 
 
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17 
 
 
NOTE: Patients must not have had Novocure within 24 hours of registration 
 
3.2.5 Hormonal tumor therapies should not be administered within 14 days of 
registration. Exceptions may be discussed with the PI.  
 
 
 
3.2.7 Patients with known human immunodeficiency virus (HIV) infection or chronic or 
acute Hepatitis B or C are not eligible. 
Note: Patients do not need to have HIV, Hepatitis B, or Hepatitis C testing at 
screening. 
 
3.2.8 Female patients who are pregnant or breast feeding are not eligible. 
 
3.2.9 Patients are not eligible if they are unwilling or unable to comply with the protocol. 
 
4.0 
TREATMENT PLAN 
 
Overview 
The phase 0 trial will evaluate the safety, pharmacokinetics, and bio-distribution of a 
systemically (IV) administered SNA gold nanoparticle, NU-0129. Once registered, eligible 
patients will receive intravenous NU-0129 one time as an inpatient followed by tumor 
resection within 8-48 hours post-infusion. Patients will be monitored with telemetry, vital 
signs and labs before and after the infusion as indicated in section 5.0. Bio-distribution 
will be analyzed with PK blood draws over 24 hours and collection of tissue during the 
scheduled surgery. 
 
 
NU-0129 Administration 
Patients will be admitted for a one-time administration of IV NU-0129 at a nominal dose 
of 0.04mg/kg (approximately 0.03 to 0.05mg/kg), based on the patient’s weight at 
screening. Patients will be dosed based on total body weight and the resulting dose will 
be rounded to one of the 5 dose groups as shown in dosing chart below. 
 
 
 
The infusion rate will be 5.0-8.0 mL/minute over approximately 20 - 50 minutes.  The flow 
rate will be monitored closely and the tissue surrounding the catheter examined 
frequently for any signs of extravasation. Patients will be monitored with telemetry from 
the beginning of the infusion for at least 8 hours post-infusion. Thereafter, vitals will be 
monitored at least every 4 hours for a total of 24 hours from the end of infusion. 
 
Immediately after the infusion is completed, PK blood draws will take place at 1, 3, 5, 10, 
30, and 60 minutes (± 1 minute) post-dose as well as 4, 8 and 24 hours (± 5 minutes) 
Patient’s weight in kg 
Dose in mg 
(Oligonucleotide component) 
Corresponding dose  
(mg/kg) 
Up to 37.0 kg 
0.987 mg 
Up to 0.027  
≥  37.0 to < 61.7 kg 
1.974 mg 
0.053 to 0.032  
≥  61.7 to < 86.4 kg 
2.96 mg 
0.048 to 0.034  
≥  86.4 to < 111.0 kg 
3.95 mg 
0.046 to 0.036  
≥  111.0 to 135.7 kg 
4.94 mg 
0.045 to 0.036  
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NU Study Number: NU 16C01 
 
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18 
post-dose. If necessary, blood draws may take place during the patient’s resection 
surgery, however this should be avoided when possible. 
 
Patients will remain inpatient for a tumor resection, occurring 8-48 hours after treatment 
with NU-0129. Vitals will be measured continuously throughout the surgery. Standard of 
care post-operative procedures will take place per institutional guidelines, including a 
brain MRI within 48 hours after the resection. Physician determined response will be 
determined using RANO (Response assessment in neurology-oncology) criteria. (NOTE: 
patient response is not expected based on a single sub-therapeutic dosing. In addition, 
the surgery may confound response assessment.) 
 
 
 
 
 
 
Toxicity Management & Dose Delays/Modifications 
Each patient will be assessed for the development of toxicity from the time of consent to 
21 days post-dose. Toxicity will be assessed according to CTCAE v4.03. Any patient who 
receives at least one dose of study therapy will be evaluable for toxicity endpoints. 
 
Patients should be closely observed for infusion-related reactions and any other form of 
toxicity.  Treatment for infusion reactions, and all events, will be based on institutional 
guidelines. Grading and resolution of the event will be reported using CTCAE v4.03. For 
example, if a severe infusion reaction occurs, the infusion rate should be cut in half to 
2.0-5.0mL/minute. 
 
During the surgical resection, the resected tumor sample should be observed for potential 
discoloration. The locations and degree of discoloration must be carefully recorded and 
assessed for relationship to treatment with NU-0129. 
 
There will be no dose delays or modifications as this is a single-dose therapy. However, 
each patient will be closely monitored for toxicities during the first 21 days after receiving 
study treatment. Any adverse event that is reported as a Grade 2 toxicity or higher, that is 
at least possibly related to NU-0129, will be referred to the external DSMB (Data Safety 
Monitoring Board) for review. The DSMB will review the event within 24 hours of 
notification to determine a plan for dosing future patients and immediate action if 
necessary. In addition, each patient’s safety data will be reviewed at the end of the 21-
day period post therapy and the DSMB will provide a recommendation for future dosing. 
No additional patients will be registered until the DSMB provides their analysis. 
 
 
Concomitant Medications/Treatments 
All concomitant therapies must be recorded in the appropriate eCRF and source 
documents throughout the study, beginning with the time of written informed consent up 
to 21 days after NU-0129 administration. 
 
 
• 
Standard supportive care therapies needed for the management of 
symptoms are permitted, as clinically indicated.  
• 
Hormonal birth control is permitted.  
 
 
Prohibited Medications 
The following medications are prohibited during the study:  
• 
Any chemotherapy  
• 
Anticancer immunotherapy  
• 
Experimental therapy  
• 
Radiation therapy 
 
 
 
 
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NU Study Number: NU 16C01 
 
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19 
 
Patients often receive adjuvant treatment post resection as standard of care for 
GBM or GS. Patients should not receive such adjuvant treatment until at least 21 
days after receiving NU-0129. After 21 days, patients may receive “physician’s 
best choice” treatment. 
 
 
Other Modalities or Procedures 
Tumor resection surgery is a standard of care procedure that will follow Northwestern 
Medicine institutional guidelines. The tissue collected during surgery will undergo testing 
for research purposes, however any other procedures related to surgery are standard of 
care. 
 
 
Duration of Therapy 
Within 14 days of study registration, patients will receive intravenous NU-0129 one time 
at nominal dose 0.04mg/kg. Patients will be admitted the morning of the planned NU-
0129 infusion, and a tumor resection will occur 8-48 hours after administration. Patients 
will remain inpatient for standard of care post-operative procedures, including an MRI of 
the brain. Discharge will take place when clinically appropriate.    
 
 
Duration of Follow Up 
Patients will have a routine follow-up visit 7, 14, and 21 days after NU-0129 
administration and then at least every 84 days (± 10 days) until disease progression or 
patient withdrawal for up to 2 years from treatment administration. They will be monitored 
for toxicities by physical exam and laboratory results as outlined in Table 5.0.  They will 
also undergo a brain MRI at least every 84 days (± 10 days). 
 
 
Removal of Subjects from Study Treatment and/or Study as a Whole 
Patients can be taken off the study treatment and/or study as a whole at any time at their 
own request, or they may be withdrawn at the discretion of the investigator for safety, 
behavioral or administrative reasons. The reason(s) for discontinuation must be clearly 
documented on the appropriate eCRF and may include: 
• 
Patient voluntarily withdraws from follow-up or prior to treatment  
• 
Patient withdraws consent (no follow-up permitted) 
• 
Patient is unable to comply with protocol requirements 
 
Patient Replacement 
If a patient withdraws for any reason after consent or registration but before receiving 
investigational product, he or she may be replaced.  
 
If a patient receives study drug and does not have a post-treatment surgical resection, or 
the surgery is delayed beyond 48 hours of treatment for any reason, the patient will be 
evaluable for toxicity, but will be inevaluable for all other study endpoints; another patient 
may be added to accrual.  
 
 
 
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NU Study Number: NU 16C01 
 
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20 
5.0 
STUDY PROCEDURES 
Table 5.1 – On-Study Procedures (**see table 5.2 for follow-up procedures) 
 
 
Inpatient  
Time Period 
Screening1 
Treatment 
Administration  
Surgery 
Post-op12 
Informed Consent1 
X 
 
 
 
Medical history  
X 
 
 
 
Physical exam2 
X 
 
 
X 
Karnofsky PS 
X 
 
 
X 
Vitals 
X 
X3 
X 
 
Toxicity assessment 
X 
X 
 
X13 
Conmeds 
X 
X 
 
X 
MRI4 
X 
 
 
X 
CBC with diff5 
X 
X5 
 
X 
Chemistry panel5 
X 
 
 
X 
Phosphorus + Mg5 
X 
X 
 
X 
PT/PTT/INR5 
X 
 
 
X 
Cholesterol panel5 
X 
 
 
X 
Urinalysis 
X 
 
 
 
Pregnancy test6 
X 
 
 
 
ECG 
X 
 
 
X7 
NU-0129 Infusion8 
 
X 
 
 
Tumor Resection 
 
 
X11 
 
PK blood samples 
 
X9 
 
 
Tissue collection 
X10 
 
 
X11 
 
1 All screening procedures must be completed within 14 days of registration unless otherwise noted 
(Labs and pregnancy test must be within 14 days of registration).  Informed consent can be within 
28 days prior to registration. 
2 Includes complete neurologic exam and weight. Height will be recorded at screening.  
3 Vital signs should include pulse and blood pressure. On the day of treatment administration, vitals 
will be measured using continuous telemetry immediately prior to, during, and for at least 8 hours 
post infusion. Vital signs will then be measured at least every 4 hours for a total of 24 hours post-
infusion. Vital signs will also be assessed continuously throughout the patient’s surgical resection. 
4 A brain MRI with and without contrast will be performed at baseline (within 21 days of registration) 
and after surgery as part of standard of care post-op procedures, likely within 48 hours of surgical 
resection. 
5 Laboratory tests (including, CBC, Chemistry, PT/PTT/INR, Phosphorus, Mg, and Cholesterol 
panel) must be drawn within 7 days of registration and treatment. If treatment occurs more than 7 
days after the indicated labs, they should be repeated. CBC w/ differential should include WBC, 
ANC, ALC, and Platelets. A complete chemistry panel will be drawn including Sodium, Potassium, 
Chloride, Bicarbonate, BUN/Creatinine, AST, ALT, Total Bilirubin, Calcium, and Albumin. CBC with 
diff will be repeated pre-dose on the day of study treatment. 
6 A pregnancy test will be performed for females of child-bearing potential at screening (serum or 
unine) within 14 days of registration.  
7 An ECG will be performed at screening and only as needed for standard of care toxicity 
management during post-operative observation. 
8 NU-0129 will be administered once at 0.04mg/kg IV. The infusion will take place as an inpatient 
8-48 hours prior to a planned tumor resection.  
9 Blood samples will be collected for PK analysis at 1, 3, 5, 10, 30, and 60 minutes (± 1 minute), 
and 4, 8, and  24 hours (± 5 minutes) post infusion. See section 9.1 for further details. 
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21 
10 Archival tissue will be collected at baseline if the patient has tissue available. See section 9.0 for 
details. 
11 The patient will have a tumor resection surgery, following institutional procedures, 8-48 hours 
after NU-0129 infusion. Tumor tissue collected during this surgery will be processed for research 
analysis as outlined in section 9.0 and the lab manual (provided as a separate document).  
12 Standard-of-care post-operative procedures will take place inpatient, including a brain MRI, 
physical exam, and KPS after surgery, likely within 48 hours of surgery. All other procedures 
indicated in Table 5.1, including labs, must be completed post-operatively. Patient should be 
monitored closely for late onset toxicities and discharged only when clinically appropriate. See table 
5.2 for study follow-up procedures. 
13 The tumor should be closely observed for potential discoloration. If discoloration is observed in 
the tissue, the location, color, and degree of color should be recorded.  
 
 
Table 5.2 – Follow-Up Procedures 
Follow-Up 
Time from Study 
Treatment 
Day 7  
(± 3 days) 
Day 14 
(± 3 days) 
Day 21 
(± 3 days) 
q 84 days3 
(± 10 days) 
Physical exam 
X 
X 
X 
X 
Karnofsky PS 
X 
X 
X 
X 
Vitals 
X 
X 
X 
X 
Toxicity assessment 
X 
X 
X 
X5 
Conmeds1 
X 
X 
X 
X 
Tumor 
Measurements2 
 
 
X2 
X 
CBC with diff 
X 
X 
X 
 
Complete Chemistry 
panel 
X 
X 
X 
 
Phosphorus + Mg 
X 
X 
X 
 
PT/PTT/INR 
X 
X 
 
 
Cholesterol panel 
X 
X 
 
 
Survival status 
 
 
 
X4 
 
1 Concomitant medications will be collected from consent up to 21 days after study drug 
administration. After 21 days, patients may begin adjuvant treatment for GBM/GS, and such 
therapies should also be recorded in the patient’s study chart. 
2 Patients will have a brain MRI 21 days (± 10 days) after study drug administration (prior to 
adjuvant therapy, if applicable) and at least every 84 days (12 weeks) thereafter until disease 
progression for up to 2 years. If a response is suspected (CR or PR), it should be confirmed with 
a repeat scan four weeks later per RANO criteria 2011 (see section 6.1). 
3 Patients will be followed by routine clinic visit at least every 84 days (12 weeks) for up to 2 years 
until radiologic disease progression or withdrawal of consent. Post-treatment therapies for 
GBM/GS during this time should be collected for data purposes.  
4 After progression, patients will be followed for survival, including subsequent therapies for 
GBM/GS, for up to 2 years post-treatment. OS and PFS will be analyzed at 6 months post-
treatment for all patients. 
5 If a patient has a continuing adverse event at 21-days post-treatment, the AE should be followed 
until resolution to ≤ Grade 2 or baseline 
 
 
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NU Study Number: NU 16C01 
 
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22 
6.0 
ENDPOINT ASSESSMENT 
 
Definitions  
 
 
Table 6.1. Criteria for Response Assessment Incorporating MRI and Clinical Factors 
Response  
Criteria 
Complete 
response 
Requires all of the following: complete disappearance of all enhancing 
measurable and nonmeasurable disease sustained for at least 4 weeks; 
no new lesions; stable or improved nonenhancing (T2/FLAIR) lesions; 
patients must be off corticosteroids (or on physiologic replacement 
doses only); and stable or improved clinically. Note: Patients with 
nonmeasurable disease only cannot have a complete response; the 
best response possible is stable disease. 
Partial 
response 
Requires all of the following: ≥ 50% decrease compared with baseline in 
the sum of products of perpendicular diameters of all measurable 
enhancing lesions sustained for at least 4 weeks; no progression of 
nonmeasurable disease; no new lesions; stable or improved 
nonenhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared with baseline scan; the corticosteroid dose at 
the time of the scan evaluation should be no greater than the dose at 
time of baseline scan; and stable or improved clinically. Note: Patients 
with nonmeasurable disease only cannot have a partial response; the 
best response possible is stable disease. 
Stable 
disease 
Requires all of the following: does not qualify for complete response, 
partial response, or progression; stable nonenhancing (T2/FLAIR) 
lesions on same or lower dose of corticosteroids compared with 
baseline scan. In the event that the corticosteroid dose was increased 
for new symptoms and signs without confirmation of disease 
progression on neuroimaging, and subsequent follow-up imaging shows 
that this increase in corticosteroids was required because of disease 
progression, the last scan considered to show stable disease will be the 
scan obtained when the corticosteroid dose was equivalent to the 
baseline dose. 
Progression 
Defined by any of the following: ≥ 25% increase in sum of the products 
of perpendicular diameters of enhancing lesions compared with the 
smallest tumor measurement obtained either at baseline (if no 
decrease) or best response, on stable or increasing doses of 
corticosteroids* ; significant increase in T2/FLAIR nonenhancing lesion 
on stable or increasing doses of corticosteroids compared with baseline 
scan or best response after initiation of therapy* not caused by comorbid 
events (eg, radiation therapy, demyelination, ischemic injury, infection, 
seizures, postoperative changes, or other treatment effects); any new 
lesion; clear clinical deterioration not attributable to other causes apart 
from the tumor (eg, seizures, medication adverse effects, complications 
of therapy, cerebrovascular events, infection, and so on) or changes in 
corticosteroid dose; failure to return for evaluation as a result of death or 
deteriorating condition; or clear progression of nonmeasurable disease. 
NOTE. All measurable and nonmeasurable lesions must be assessed using the same 
techniques as at baseline.  
Abbreviations: MRI, magnetic resonance imaging; FLAIR, fluid-attenuated inversion 
recovery.   
*Stable doses of corticosteroids include patients not on corticosteroids. 
 
 
 
 
These RANO Criteria are also summarized in Table 6.2: 
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23 
 
Table 6.2 
Summary of the RANO Criteria 
 
 
CR 
PR 
SD 
PD# 
T1-Gd + 
None 
≥50% decrease 
<50% decrease but 
≤ 25% increase 
≥25% increase* 
T2/FLAIR 
Stable or decrease Stable or decrease Stable or decrease 
Increase* 
New Lesion 
None 
None 
None 
Present* 
Corticosteroids 
None 
Stable or decrease Stable or decrease 
NA** 
Clinical Status 
Stable or improve 
Stable or improve 
Stable or improve 
Deterioration* 
Requirement for Response 
All 
All 
All 
Any* 
CR=complete response; PR=partial response; SD=stable disease; PD=progressive disease 
 
*: Progression when this criterion is met **: Increase in corticosteroids alone will not be taken into account in 
determining progression in the absence of persistent clinical deterioration 
 
 
Primary Endpoint 
Safety will be measured by recording adverse events using CTCAE v4.03 from the time a 
patient signs consent to 21 days after study drug administration. Any patient who has 
received at least a partial dose of NU-0129 will be evaluable for this endpoint. If a patient 
has a continuing adverse event at 21 days which is related to treatment, it will be followed 
until resolution to baseline or Grade ≤ 2. 
 
 
Secondary Endpoints 
 
Pharmacokinetics  
PK blood samples will be collected post-infusion at 1, 3, 5, 10, 30, and 60 
minutes (+/- 1 minute), and 4, 8, and 24 hours (+/- 5 minutes). 
 
 
Bio-distribution / Tumoral Penetration 
A fresh tumor sample will be collected at the time of the patient’s tumor resection 
surgery. It will be assayed with Inductively Coupled Plasma Mass Spectrometry 
(ICP-MS) to determine accumulated dose.   
 
 
Feasibility 
To assess feasibility, the rate of successful production, delivery, and 
administration of the investigational product and subsequent resection will be 
calculated.  
 
 
Exploratory Endpoints 
 
An exploratory objective will assess for Bcl2L12 levels in tumor tissue collected 
post administration of NU-0129 using IHC/IF as well as RT-qPCR. Other 
apoptotic markers will be analyzed as well using IHC. 
 
 
Preliminary Response will be measured by Overall Survival and Progression 
Free Survival at 6 months post treatment as well as Overall Response Rate. 
Brain MRI’s will be performed at least every 12 weeks during follow-up. 
 
 
 
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NU Study Number: NU 16C01 
 
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24 
7.0 
ADVERSE EVENTS 
This study will be conducted in compliance with the study-specific standard operating procedure 
(SOP) and per the DSMP guidelines of the Robert H. Lurie Comprehensive Cancer Center of 
Northwestern University for in-house research. The level of risk attributed to this study requires 
High Risk Monitoring as outlined in the SOP. In addition, the study will abide by all safety 
reporting regulations, as set forth in the Code of Federal Regulations.   
 
 
Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those 
who will enroll in future studies using similar agents. Adverse events are reported in a 
routine manner at scheduled times during a trial (see Section 5 for time points). In 
addition, certain adverse events must be reported in an expedited manner to allow for 
optimal monitoring and patient safety and care.  
 
All patients experiencing an adverse event, regardless of its relationship to study drug, 
will be followed until:  
• 
the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline;  
• 
any abnormal laboratory values have returned to baseline;  
• 
there is a satisfactory explanation other than the study drug for the changes 
observed; or 
• 
death. 
 
 
Definitions & Descriptions 
 
An adverse event (AE) is any untoward medical occurrence in a patient receiving 
study treatment and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an experimental intervention, whether or not related to 
the intervention.  
 
Recording of AEs should be done in a concise manner using standard, 
acceptable medical terms. In general, AEs are not procedures or measurements, 
but should reflect the reason for the procedure or the diagnosis based on the 
abnormal measurement. Preexisting conditions that worsen in severity or 
frequency during the study should also be recorded (a preexisting condition that 
does not worsen is not an AE). Further, a procedure or surgery is not an AE; 
rather, the event leading to the procedure or surgery is considered an AE. 
 
If a specific medical diagnosis has been made, that diagnosis or syndrome 
should be recorded as the AE whenever possible.  However, a complete 
description of the signs, symptoms and investigations which led to the diagnosis 
should be provided. For example, if clinically significant elevations of liver 
function tests are known to be secondary to hepatitis, “hepatitis” and not 
“elevated liver function tests” should be recorded. If the cause is not known, the 
abnormal test or finding should be recorded as an AE, using appropriate medical 
terminology (e/g/ thrombocytopenia, peripheral edema, QT prolongation). 
 
 
All adverse events will be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03. The CTCAE v4.03 is available 
at http://ctep.cancer.gov/reporting/ctc.html 
 
IRB #: STU00203790-MOD0013 Approved by NU IRB for use on or after 4/2/2019 through 10/28/2019.


NU Study Number: NU 16C01 
 
Initial Version Date: August 19, 2016 
Amendment 5: December 19, 2018 
 
25 
If no CTCAE grading is available, the severity of an AE is graded as follows: 
• 
Mild (grade 1): the event causes discomfort without disruption of normal daily 
activities. 
• 
Moderate (grade 2): the event causes discomfort that affects normal daily 
activities. 
• 
Severe (grade 3): the event makes the patient unable to perform normal daily 
activities or significantly affects his/her clinical status. 
• 
Life-threatening (grade 4): the patient was at risk of death at the time of the 
event. 
• 
Fatal (grade 5): the event caused death. 
 
All SAEs, regardless of attribution, occurring from time of signed informed 
consent, through 21 days after the administration of study drug, must be reported 
upon discovery or occurrence. 
An SAE is defined in regulatory terminology as any untoward medical occurrence 
that: 
• 
Results in death. 
If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself. 
• 
Is life-threatening. 
The patient was at risk of death at the time of the event; it does not refer to 
an event that hypothetically might have caused death if it were more severe. 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours. 
• 
Results in persistent or significant disability or incapacity. 
• 
Is a congenital anomaly/birth defect. 
• 
Is an important medical event. 
Any event that does not meet the above criteria, but that in the judgment of 
the investigator jeopardizes the patient, may be considered for reporting as a 
serious adverse event. The event may require medical or surgical 
intervention to prevent one of the outcomes listed in the definition of “Serious 
Adverse Event“.  
For example: allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; convulsions that may not result in 
hospitalization; development of drug abuse or drug dependency. 
 
 
A UPIRSO is a type of SAE that includes events that meet ALL of the following 
criteria: 
• 
Is unanticipated in terms of nature, severity, or frequency 
• 
Places the research subject or others at a different or greater risk of harm 
• 
Is deemed to be at least possibly related to participation in the study.    
 
 
Adverse Event Reporting 
 
All routine adverse events, such as those that are expected, or are unlikely or 
definitely not related to study participation, are to be reported on the appropriate 
eCRF. Routine AEs will be reviewed by the external Data Safety Monitoring 
Board (DSMB) according to the study’s phase and risk level, as outlined in the 
DSMP. NU’s Data Monitoring Committee (DMC) will also be informed.  
IRB #: STU00203790-MOD0013 Approved by NU IRB for use on or after 4/2/2019 through 10/28/2019.


NU Study Number: NU 16C01 
 
Initial Version Date: August 19, 2016 
Amendment 5: December 19, 2018 
 
26 
 
 
This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of 
treatment and is attributed (possibly, probably, or definitely) to the agent(s) must 
also be reported accordingly. 
 
 
1) 
Identify the type of adverse event using the NCI CTCAE v 4.03. 
 
 
2) 
Grade the adverse event using the NCI CTCAE v 4.03. 
 
 
3) 
Determine whether the adverse event is related to the protocol therapy.   
 
 
 
Attribution categories are as follows: 
• 
Definite: AE is clearly related to the study treatment. 
• 
Probable: AE is likely related to the study treatment. 
• 
Possible: AE may be related to the study treatment. 
• 
Unlikely: AE not likely to be related to the study treatment. 
• 
Unrelated: AE is clearly NOT related to the study treatment. 
 
 
4) 
Determine the prior experience of the adverse event. 
Expected events are those that have been previously identified as 
resulting from administration of the agent. An adverse event is 
considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is not listed in: 
• 
the current protocol 
• 
the drug package insert 
• 
the current Investigator’s Brochure 
 
 
All SAEs must be reported to the DSMB within 24 hours of becoming 
aware of the event. The study coordinator must complete the Medwatch 
and NU SAE Forms, provided as a separate documents, and submit to 
the appropriate QAM at croqualityassurance@northwestern.edu. The 
QAM will distribute to the DSMB appropriately. 
 
The completed form should assess whether or not the event qualifies as 
a UPIRSO. The report should also include: 
• 
Protocol description and number(s) 
• 
The patient’s identification number 
• 
A description of the event, severity, treatment, and outcome (if 
known) 
• 
Supportive laboratory results and diagnostics 
• 
The hospital discharge summary (if available/applicable) 
 
All SAEs will be reported to, and reviewed by, the external DSMB within 
24 hours, and will also be reviewed by the NU DMC at their next 
meeting. 
7.3.3.2 Reporting to the Northwestern University IRB 
The following information pertains to the responsibilities of the lead site 
(Northwestern University). Additional participating sites should follow 
their local IRB guidelines for reporting to their local IRBs. 
• 
Any death of an NU subject that is unanticipated in nature and at 
least possibly related to study participation will be promptly reported 
to the NU IRB within 24 hours of notification.  
• 
Any death of an NU subject that is actively on study treatment 
(regardless of whether or not the event is possibly related to study 
treatment) 
IRB #: STU00203790-MOD0013 Approved by NU IRB for use on or after 4/2/2019 through 10/28/2019.


NU Study Number: NU 16C01 
 
Initial Version Date: August 19, 2016 
Amendment 5: December 19, 2018 
 
27 
• 
Any death of a non-NU subject that is unanticipated and at least 
possibly related and any other UPIRSOs will be reported to the NU 
IRB within 5 working days of notification. 
• 
All other deaths of NU subjects not previously reported, other non-
NU subject deaths that were unanticipated and unrelated, and any 
other SAEs that were not previously reported as UPIRSOs will be 
reported to the NU IRB at the time of annual continuing review. 
 
7.3.3.3 Reporting to the FDA  
The FDA will be notified within 7 calendar days of any SAE that is 
associated with study treatment, is unexpected, and is fatal or life-
threatening. 
 
The FDA will be notified within 15 calendar days of any SAE that is 
associated with the study treatment, unexpected, and serious but not 
fatal or life-threatening. This includes any previous SAEs that were not 
initially deemed reportable, but are later determined to meet the criteria 
for reporting (i.e. by the DMC). 
 
All other SAEs will be reported on an annual basis as part of the annual 
FDA report. 
 
8.0 
DRUG INFORMATION 
 
Agent NU-0129 
 
 
 
n/a 
 
 
 
 
Bcl2L12-targeting Spherical Nucleic Acid (SNA) 
 
 
NU-0129 is spherical nucleic acid (SNA) designed to target the silencing of 
Bcl2L12 gene expression, an overexpressed protein that plays an important role 
in driving the pathogenesis of glioblastoma multiforme (GBM) and mediating 
therapeutic resistance. SNAs are three dimensional conjugates consisting of 
densely functionalized and highly oriented nucleic acids covalently attached to 
the surface of nanoparticles. NU-0129 is composed of 13nm gold nanoparticles 
surrounded by siRNAs tailored to recognize Bcl2l12 sequence. 
 
 
 
NU-0129 in powder form should be at -200C (±50C) freezer. Once prepared in 
liquid/solution form, if not used immediately, NU-0129 could be stored up to 8 
hours in room temperature (20-25 °C). Remaining or unused solution should be 
stored at 4ºC. Solution must NOT be frozen.  
 
 
Each patient’s dose will be based on his or her weight at screening. Patients will 
be dosed based on total body weight and the resulting dose will be rounded to 
one of the 5 dose groups as shown in dosing chart below.  Nominal dose will be 
0.04mg/kg (approximately 0.03 to 0.05 mg/kg).  
Patient’s weight in kg 
Dose in mg 
(Oligonucleotide component) 
Corresponding dose  
(mg/kg) 
Up to 37.0 kg 
0.987 mg 
Up to 0.027  
≥  37.0 to < 61.7 kg 
1.974 mg 
0.053 to 0.032  
IRB #: STU00203790-MOD0013 Approved by NU IRB for use on or after 4/2/2019 through 10/28/2019.


NU Study Number: NU 16C01 
 
Initial Version Date: August 19, 2016 
Amendment 5: December 19, 2018 
 
28 
 
 
• 
Prior to reconstitution, the vials should be equilibrated to room 
temperature to reach room temperature for 5-30 minutes. .  
• 
Vials can be stored at room temperature (20-25 °C) for up to 3 hours.  
This includes thawing time and reconstitution time. 
• 
Vials should not be refrozen after thawing.  
• 
Each NU-0129 manufactured clinical vial should be reconstituted in 1mL 
SWFI for final concentration approximately 0.987 mg/ml.  
• 
Mix the solution in the vial by gentle swirling or gentle shaking by 
benchtop sonicator, if available.  
• 
Visually inspect for particulate matter and discoloration prior to 
administration. Reconstituted solution should red or maroon color, free of 
visible particles. 
• 
Calculate the dose and the amount of vials required based on the dosing 
chart. 
• 
Withdraw the full content of the NU-0129 vials and inject into an 
appropriate size bag of normal saline (0.9% sodium chloride).  
• 
Reconstituted solution should be further diluted with normal saline (0.9% 
sodium chloride) to 1:50 dilution.  
• 
Preparation should take place immediately prior to administration, but, if 
needed, reconstituted vials and/or IV bags may be stored at room 
temperature (20-25 ºC) for up to 8 hours (including administration time).  
• 
Administer study drug using non-PVC/DEHP administration set with a 
sterile, non-pyrogenic, low-protein binding 0.22 µm filter.  
• 
Visually inspect final product for particulate matter and discoloration prior 
to administration. Do not use and discard the drug product vial if 
extraneous particulate matter is observed. 
 
 
 
 
Intravenous 
 
 
Given unknown compatibility data with PVC/DEHP materials, PVC/DEHP-free 
bags and administration set should be used for drug preparation. Refer to 
pharmacy manual for a full list of materials acceptable and required.  
 
 
NU-0129 is an investigational product, which will be manufactured and supplied 
by University of Iowa Pharmaceuticals. The drug product is supplied as 
approximately 0.987mg per vial lyophilized powder to be reconstituted with SWFI 
and further diluted with 0.9% sodium chloride by pharmacy  on the day of 
administration. . 
 
 
As this is a first-in-human trial, side effects in this population are not completely 
known.  In the primate and non-primate treatment trials, a few noted side 
effects were observed.  Gold nanoparticle accumulation in the liver has occurred 
in some pre-clinical studies as well as skin discoloration following the infusion 
have been seen with animal models displaying a purple hue to their baseline skin 
≥  61.7 to < 86.4 kg 
2.96 mg 
0.048 to 0.034  
≥  86.4 to < 111.0 kg 
3.95 mg 
0.046 to 0.036  
≥  111.0 to 135.7 kg 
4.94 mg 
0.045 to 0.036  
IRB #: STU00203790-MOD0013 Approved by NU IRB for use on or after 4/2/2019 through 10/28/2019.


NU Study Number: NU 16C01 
 
Initial Version Date: August 19, 2016 
Amendment 5: December 19, 2018 
 
29 
tone.  Hypercholesterolemia was also observed in the non-primate model (rat 
model).   
       
 
Possible side effects: 
   
 
Liver Damage  
      
Skin Discoloration  
      
Infusion Reaction  
      
Hypercholesterolemia 
 
 
Low blood pressure 
 
 
 
There is no significant toxicity associated with the chemistry or manufacturing of  
 
 
the drug product. 
 
 
The dose (based on dosing chart) will be based on the patient’s weight at 
baseline. The infusion rate will be 5.0-8.0 mL/minute.  A sterile, non-pyrogenic, 
low-protein binding 0.22 µm in-line filter must be used during administration to 
remove any adventitious particles. If the infusion set does not contain in-line filter, 
0.22 µm add-on filter should be used. The flow rate will be monitored closely and 
the tissue surrounding the catheter examined frequently for any signs of 
extravasation.  
Drug Administration Log should be completed by administering nurse and 
returned to study coordinator, documenting date and time of infusion start/ stop, 
interruptions (if any). Any staining or discoloration of the syringe, IV bag, delivery 
device, and /or administration set should be documented in the Administration 
Log. 
 
 
Drug accountability records will be maintained for all clinical trial supplies. 
Remaining or unused solution should be stored at 4ºC. Refer to pharmacy 
manual for management of all unused clinical trial supplies. . 
 
 
9.0 
CORRELATIVES/SPECIAL STUDIES 
All patients must provide blood samples for pharmacokinetic analysis as well as tumor tissue 
during their surgery to assess accumulated dose, expression of BcL2L12 levels, and other 
apoptotic markers. Archival tissue will be collected at baseline if available. 
 
 
Blood Sample Collection Guidelines 
Blood samples will be collected for PK analysis at 1, 3, 5, 10, 30, and 60 minutes (± 1 
minute), and 4 hours, 8 hours, and 24 hours (±5 minutes) post NU-0129 infusion. Each 
sample will contain 1mL of blood collected in pre-chilled 4mL K2EDTA tubes and 
maintained on wet ice throughout collection and processing. See separate lab manual for 
full collection and processing details.  
 
 
Fresh tumor samples 
Patients will undergo a tumor resection 8-48 hours after treatment with NU-0129. The mass 
that is removed during surgery will be collected and processed for the study as detailed in 
section 9.4.2 below.  
 
 
Archival tissue  
All patients must provide an archival tissue sample if it is available. This tissue will 
undergo histology testing for Bcl2L12 and other apoptotic markers as indicated in section 
9.4.2.1.  
 
IRB #: STU00203790-MOD0013 Approved by NU IRB for use on or after 4/2/2019 through 10/28/2019.


NU Study Number: NU 16C01 
 
Initial Version Date: August 19, 2016 
Amendment 5: December 19, 2018 
 
30 
 
Sample Processing, Storage, and Shipment 
 
PK blood samples should be drawn into pre-chilled 4mL K2EDTA tubes and must 
be immediately chilled on ice and transported to PCF-CTU (Pathcore Facility 
Clinical Trials Unit). Samples will be spun down within 15 minutes of collection in 
a temperature-controlled (4ºC) centrifuge. Samples should be immediately flash-
frozen on dry ice and stored frozen (-65ºC to -85ºC). The plasma samples will be 
shipped on dry ice to Covance. See separate lab manual for shipping 
instructions. 
Note: While the patient’s tumor resection surgery should ideally be planned 
around the timing of PK blood draws, it is acceptable for blood draws to take 
place during surgery. Such cases should be planned closely with the surgical 
team. 
 
 
Tissue 
All patients will undergo a tissue resection 8-48 hours after NU-0129 
administration. The full tissue sample will be sent for pathology processing and 
samples will be processed and shipped for the study as described below. 
 
In addition, patients will provide an archival tissue sample at screening if it is 
available. 10 unstained slides will be processed for histological testing as in 
section 9.4.2.1. 
 
 Histology (apoptotic markers e.g. caspase) 
For both archival and fresh tissue samples, 10 unstained slides will be 
requested for Bcl2L12 Immunohistochemistry (IHC), 
Immunofluorescence (IF), TUNEL (Terminal deoxynucleotidyl 
transferase), and active caspase-3 staining. See separate lab manual 
for details of processing and analysis. 
 
 Bcl2L12 expression in tissue (RNA) 
 Tissue Bio-Distribution 
Any remaining tissue (whether necrotic or not) will be processed by 
PCF-CTU and shipped frozen to QBIC for bio-distribution studies. 
Please see lab manual for shipping and processing details.  
 
 
Assay Methodology 
 
 
See lab manual for details on PK assay methodology. 
 
 
Tissue samples will be processed for Bcl2L12 IHC, IF, TUNEL, and active 
caspase-3. See lab manual for details. 
 
 
Extracted RNA will be frozen and sent to NUSeq Core for RACE analysis.  
 
 
Remaining tissue will be sent to QBIC for ICP-MS of biodistribution. See lab 
manual for details. 
 
IRB #: STU00203790-MOD0013 Approved by NU IRB for use on or after 4/2/2019 through 10/28/2019.


NU Study Number: NU 16C01 
 
Initial Version Date: August 19, 2016 
Amendment 5: December 19, 2018 
 
31 
 
Specimen Banking 
Any excess tissue should be stored in Northwestern University’s biorepository for future 
unspecified use. Samples will be stored indefinitely until exhausted or the patient 
withdraws consent for storage. 
 
10.0 STATISTICAL CONSIDERATIONS 
 
Study Design/Study Endpoints 
This is a single group Phase 0 study. A small number n=6-8 of patients will be given the 
treatment and observed for a fixed period of time. 
 
 
Sample Size and Accrual 
The sample size n=6, 7, or 8 was determined on the basis of feasibility of recruitment and 
of conducting the study. This is the first study in humans or this treatment, and it was felt 
that both the primary and secondary outcomes can be estimated with sufficient precision 
with such n, while few patients would be put to risk. 
 
 
Data Analyses Plans 
 
 
 
To evaluate the pharmacokinetics of NU-0129 in blood samples collected at 1, 3, 
5, 10, 30, 60 minutes and 4, 8, and 24 hours post-dose, we will provide 
appropriate pharmacokinetic curves and parameters such as Cmax, Tmax etc.  
To evaluate the feasibility of NU-0129 administration, we will record a) 
successes/failures, b) number of attempts to administrate nanoparticles.  
 
 
To evaluate the Bcl2L12 expression levels and apoptotic markers in the tumor 
tissue post-treatment, and to evaluate preliminary response (Overall Survival and 
Progression Free Survival at 2 years, as well as Overall Response Rate) we will 
describe expression levels and PFS and OS Kaplan-Meier curves corresponding 
to in study time up to 24 months.  
 
In general, all patients properly included in the study who undergo surgery for tumor 
removed will be included in the analysis. Thus, an incorrect treatment schedule or drug 
administration would result in exclusion from the analysis of the tumor accumulation 
study. All conclusions will be based on all eligible patients. Subanalyses may then be 
performed on the basis of a subset of patients, excluding those for who major protocol 
deviations have been identified. However, these subanalyses may not serve as the basis 
for drawing conclusions concerning treatment efficacy, and the reasons for excluding 
patients form the analysis should be clearly reported.  
 
 
11.0 STUDY MANAGEMENT 
 
Institutional Review Board (IRB) Approval and Consent  
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB should approve the consent form and 
protocol. 
 
IRB #: STU00203790-MOD0013 Approved by NU IRB for use on or after 4/2/2019 through 10/28/2019.


NU Study Number: NU 16C01 
 
Initial Version Date: August 19, 2016 
Amendment 5: December 19, 2018 
 
32 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the patient and the investigator is assured that the patient understands the 
implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient and by the person who conducted the 
informed consent discussion. 
 
 
 
Amendments 
The Principal Investigator will formally initiate all amendments to the protocol and/or 
informed consent. All amendments will be subject to the review and approval of the 
appropriate local, institutional, and governmental regulatory bodies. Amendments will be 
distributed by the lead institution (Northwestern) to all affiliate sites upon approval by the 
Northwestern University IRB. 
 
 
Registration Procedures 
For potential patients, study teams are asked to inform the QAM of the date and time that 
the patient will need to be registered (croqualityassurance@northwestern.edu).   
 
BEFORE a patient can be treated on study, please complete and submit the following 
items to confirm eligibility and receive an identification number: 
• Patient’s signed and dated informed consent form (upload to NOTIS and keep original 
hard copy in a secure location/study chart) 
• Eligibility checklist (signed and dated by the treating physician – upload to NOTIS) 
• Eligibility eCRF (complete in NOTIS) 
• Copy of the pathology report (upload to NOTIS) 
 
The QAM will review all source documentation required to confirm eligibility that is readily 
available in the patient’s electronic medical record (EMR).  Any information that is not 
available in the EMR must be de-identified and emailed to the QAM. Once the QAM 
confirms the patient is eligible, he or she will register the patient, assign a subject 
identification number, provide a cohort assignment, and send a confirmation of 
registration to involved personnel. Registration will then be complete and the patient may 
begin study treatment.  
 
 
Data Submission 
Once a subject is confirmed and registered to the study, eCRFs should be submitted 
according to the detailed data submission guidelines (provided in a separate document in 
NOTIS).   
 
 
Data Management and Monitoring/Auditing 
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) 
of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University in-
house research (please refer to NOTIS for additional information). The level of risk 
attributed to this study requires High Risk Monitoring, as outlined in the DSMP. The 
assigned QAM, with oversight from the external DSMB and NU Data Monitoring 
Committee, will monitor this study in accordance with the study phase and risk level. 
Please refer to the NOTIS for additional data submission instructions. 
IRB #: STU00203790-MOD0013 Approved by NU IRB for use on or after 4/2/2019 through 10/28/2019.


NU Study Number: NU 16C01 
 
Initial Version Date: August 19, 2016 
Amendment 5: December 19, 2018 
 
33 
 
 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study patient requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol.  
 
 
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB approval.  
 
For any such emergency modification implemented, an IRB modification form 
must be completed within 5 business days of making the change, and the QAM 
must be notified within 24 hours of such change.  
 
 
All other deviations from the protocol must be reported to the assigned QAM 
using the appropriate form. 
 
A protocol deviation is any unplanned variance from an IRB approved protocol 
that:  
• 
Is generally noted or recognized after it occurs. 
• 
Has no substantive effect on the risks to research participants. 
• 
Has no substantive effect on the scientific integrity of the research plan or the 
value of the data collected. 
• 
Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
A protocol deviation may be considered an instance of Promptly Reportable Non-
Compliance (PRNC) if it: 
• 
Has harmed or increased the risk of harm to one or more research 
participants. 
• 
Has damaged the scientific integrity of the data collected for the study. 
• 
Results from willful or knowing misconduct on the part of the investigator(s). 
• 
Demonstrates serious or continuing noncompliance with federal regulations, 
State laws, or University policies. 
 
 
Investigator Obligations 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The PI is responsible for personally overseeing the treatment of all study 
patients. The PI must assure that all study site personnel, including sub-investigators and 
other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected, entered onto the appropriate eCRFs, and submitted 
within the study-specific timeframes. Periodically, monitoring visits may be conducted and 
the Principal Investigator will provide access to his/her original records to permit 
verification of proper entry of data. The study may also be subject to routine audits by the 
Audit Committee, as outlined in the DSMP.  
 
 
 
 
IRB #: STU00203790-MOD0013 Approved by NU IRB for use on or after 4/2/2019 through 10/28/2019.


NU Study Number: NU 16C01 
 
Initial Version Date: August 19, 2016 
Amendment 5: December 19, 2018 
 
34 
APPENDIX A  
 
Karnofsky Performance Status and Neurological Function 
 
Patient's performance status and Neurologic Functions will be graded according to the following 
scales: 
 
Karnofsky Performance Status 
 
KPS 100 
Normal; no complaints; no evidence of disease 
KPS   90 
Able to carry on normal activity; minor signs or symptoms of disease 
KPS   80 
Normal activity with effort; some sign or symptoms of disease 
KPS   70 
Cares for self; unable to carry on normal activity or do active work 
KPS   60 
Requires occasional assistance, but is able to care for most personal needs 
KPS   50 
Requires considerable assistance and frequent medical care 
KPS   40 
Disabled; requires special care and assistance 
KPS   30 
Severely disabled; hospitalization is indicated, although death no imminent 
KPS   20 
Very sick; hospitalization necessary; active support treatment is necessary 
KPS   10 
Moribund; fatal processes progressing rapidly 
KPS     0 
Dead 
 
 
IRB #: STU00203790-MOD0013 Approved by NU IRB for use on or after 4/2/2019 through 10/28/2019.


NU Study Number: NU 16C01 
 
Initial Version Date: August 19, 2016 
Amendment 5: December 19, 2018 
 
35 
APPENDIX B 
Summary of Changes 
Amendment 1 – February 2nd, 2017 
Approved by Scientific Review Committee: February 7th, 2017 
Sections Affected 
Original Version 
Amendment 1 
Rationale 
Study Summary;  
3.1.8 (Inclusion 
Criteria) 
Listed hemoglobin 
requirement in mg/dL 
Changes units to g/dL 
Correction for accuracy 
3.1.10 (Inclusion 
Criteria);  
9.3 (Archival tissue) 
Patient was required 
to have archival tissue 
available prior to study 
enrollment 
Removes requirement 
for archival tissue 
Clarification of 
discrepancy – archival 
tissue is only required if 
available at baseline 
3.2.4 (Exclusion 
Criteria) 
“NOTE: Patients must 
not have Novocure 
within 24 hours” 
“NOTE: Patients must 
not have had Novocure 
within 24 hour of 
registration” 
Clarification 
4.9 (Patient 
Replacement) 
If patient receives 
study drug but surgical 
resection is delayed or 
does not occur, patient 
is inevaluable for 
endpoints and will be 
replaced. 
Removes “and will be 
replaced” and states 
“another patient may be 
added to accrual”. 
Since such patients are 
still evaluable for toxicity 
endpoints, it is not 
appropriate to fully replace 
the patient. 
5.0 (Study 
Procedures, #3) 
Vitals were to include 
respirations 
Removes respirations as 
part of vitals requirement 
Not clinically relevant or 
part of standard care 
5.0 (Study 
Procedures, #10); 
9.4.2 (Tissue) 
Archival tissue 
collection is stated as 
being optional if the 
patient agrees 
Removes optional 
component of archival 
tissue collection 
Clarification - tissue is 
required if available, and 
patients do not need to 
sign consent 
7.3.3.1 (Reporting to 
the external DSMB) 
The Medwatch form 
was required for SAE 
reporting 
Both Medwatch and NU 
SAE forms will be 
required for SAE 
reporting 
Administrative – NU SAE 
form facilitates internal 
reports and monitoring 
9.0 
(Correlatives/Special 
Studies) 
n/a 
Adds sentence “Archival 
tissue will be collected at 
baseline if available.” 
Clarification for consistent 
listing of correlative 
requirements 
11.2 (Amendments) 
Protocol amendments 
were to be reviewed 
by Janssen Scientific 
Affairs 
Removes reference to 
Janssen Scientific 
Affairs 
Correction of typo, added 
inadvertently 
11.5 (Data 
Management and 
Auditing) 
Contained incorrect 
hyperlink for DSMP 
Updates hyperlink for 
DSMP  
Administrative 
Amendment 2 – August 1st, 2017 
Approved by Scientific Review Committee: August 17th, 2017 
Sections Affected 
Original Version 
Amendment 2 
Rationale 
Cover Page 
Listed “Pre-IND” 
number 
Changes to “IND 
Number” 
Administrative; IND 
number now available 
Study Summary 
Contained short title of 
study protocol 
Removes short title 
Short title is no longer a 
template requirement; 
avoids discrepancies on 
clinicaltrials.gov  
2.1 (Primary 
Objective & 
Endpoint); 3.1.10 
Immediate follow-up 
procedures were to 
take place for up to 28 
Immediate follow-up 
procedures will now take 
place up to 21 days after 
A shorter follow-up 
window is felt to be 
clinically appropriate and 
IRB #: STU00203790-MOD0013 Approved by NU IRB for use on or after 4/2/2019 through 10/28/2019.


NU Study Number: NU 16C01 
 
Initial Version Date: August 19, 2016 
Amendment 5: December 19, 2018 
 
36 
(Inclusion Criteria); 
4.3 (Toxicity 
Management & 
Dose Delays / 
Modifications); 4.4 
(Concomitant 
Medications / 
Treatments); 4.4.3 
(Adjuvant Treatment 
Post-Surgery); 4.7 
(Duration of Follow 
Up); 5.0 (Table 5.2); 
6.2 (Primary 
Endpoint); 7.2.3 
(SAE’s) 
days after dosing with 
NU-0129.  
dosing with NU-0129. 
These include: 
• Safety (AE’s, DLT’s 
and SAE’s)  
• birth control 
requirements   
• recording of 
concomitant therapies  
• weekly follow-up visits 
• initial follow-up brain 
MRI  
• permission to start 
adjuvant treatment 
post-surgery 
safe based on prior pre-
clinical and clinical data. 
Since patients with 
recurrent GBM are 
progressing at a rapid 
rate, it is important that the 
next line of therapy be 
started as soon as safely 
possible.   
3.2.3 (Exclusion 
Criteria)  
“Patients must not 
have had radiation 
therapy within 12 
weeks prior to 
registration” 
“Patients must not have 
had radiation therapy 
≤28 days prior to starting 
study treatment” 
Window for prior radiation 
therapy has been 
shortened to allow patients 
on study who are rapidly 
progressing and in need of 
more urgent resection. 
This will not affect the 
primary outcome of safety.   
5.0 (Study 
Procedures Table 
5.1, #2) 
Informed consent can 
be within 28 days “of 
registration” 
Informed consent can be 
within 28 days “prior to 
registration” 
Clarification  
5.0 (Study 
Procedures Table 
5.1, #5) 
CBC with diff was 
required at screening 
and post-operatively 
Adds CBC with diff on 
the day of treatment 
administration, pre-dose 
An additional CBC on the 
day of treatment allows 
the team to better 
determine whether any 
changes/ fluctuations are 
actually due to study drug 
Amendment 3 – November 1st, 2017 
Approved by Scientific Review Committee:  
Sections Affected 
Original Version 
Amendment 3 
Rationale 
5.0 (Study 
Procedures, Table 
5.1 & 5.2) 
• n/a 
• Magnesium was 
listed as part of the 
Chemistry panel 
• Footnote 12 indicated 
that post-operative 
procedures were to 
take place per 
standard of care. It 
was unclear whether 
labs were required. 
 
• Adds a phosphorus 
requirement at 
Screening, Treatment 
Administration, and 
Day 7, 15, and 21 of 
follow-up 
• Moves magnesium to 
its own line with 
phosphorus 
• Adds language that 
MRI, physical exam, 
and KPS will be done 
per SOC and all other 
procedures are 
required 
• DSMB recommendation 
to account for the 
possibility of toxicities 
related to phosphorus 
levels 
• Clarification; magnesium 
is a separate lab and 
was easily missed as 
previously listed 
• Clarification of 
ambiguous language 
3.2.3 (Exclusion 
Criteria) 
“Patients must not 
have had radiation 
“Patients must not have 
had radiation therapy 
Extends RT window back 
to original criteria. There 
IRB #: STU00203790-MOD0013 Approved by NU IRB for use on or after 4/2/2019 through 10/28/2019.


NU Study Number: NU 16C01 
 
Initial Version Date: August 19, 2016 
Amendment 5: December 19, 2018 
 
37 
therapy ≤28 days prior 
to starting study 
treatment” 
≤12 weeks prior to 
starting study therapy” 
was concern that 
shortening the window for 
RT might impact 
secondary efficacy 
endpoints from the original 
concept. 
4.2.3 (Toxicity 
Management & 
Dose Delays/ 
Modifications) 
Referred to DLT’s 
occurring within the 
first 21 days after 
therapy. 
Removes any reference 
to DLT’s and instead 
refers to just adverse 
events that are Grade 2 
or higher, which will be 
reported to the DSMB  
There are no dose 
adjustments given that this 
study involves micro-
dosing. Therefore, “DLT” is 
not felt to be an 
appropriate term for 
related toxicities. Toxicities 
will still be monitored with 
the same method and 
caution. 
Amendment 4 – March 1st, 2018 
Approved by Scientific Review Committee:  
 
Sections Affected 
Original Version 
Amendment 4 
Rationale 
3.1.8 (Inclusion 
Criteria) 
Urine protein was 
required to be ≤ 3x 
ULN 
Updates urine protein 
requirement to ≤ 30 mg/g 
Previous requirement did 
not make sense since the 
ULN is 0 or negative. 
Updates to clinically 
appropriate upper limit in 
the opinion of the PI. 
5.0 (Study 
Procedures, #5) 
n/a 
Adds Phosphorus and 
Magnesium to footnote 5 
Clarification; Phosphorus 
and Mg should be within 7 
days prior to registration 
6.0 (Endpoint 
Assessment) 
Contained inaccurate 
reference to Table 6.1 
Updates to reference 
Table 6.2 
Correction of discrepancy 
Amendment 5 – December 19, 2018 
Sections Affected 
Original Version 
Amendment 5 
Rationale 
2.3.1 (Exploratory 
Objectives & 
Endpoints); 9.4.2.2 
(Bcl2L12 expression 
in tissue (RNA)); 
9.5.3 (Tissue–RNA) 
Tissue collected was 
to be analyzed using 
qRT-PCR as part of 
RNA and Bcl2L12 
analysis 
 
Section 2.3.1: “Tissue 
collected during 
surgery will be 
analyzed using qRT-
PCR techniques.” 
 
Section 9.4.2.2: “A 
tissue sample (0.5cm 
x 05cm) will be sent to 
Pathcore’s Molecular 
Laboratory. Half of 
the sample will be 
used for RNA 
extraction, and the 
other half will be 
stored in -80ºC for 
Removes qRT-PCR and 
refers more vaguely to 
“RNA analysis” or 
“RACE” techniques 
 
 
Section 2.3.1: “Tissue 
collected during surgery 
will be analyzed using 
RNA analysis 
techniques.” 
 
Section 9.4.2.2: “A tissue 
sample (0.5cm x 05cm) 
will be collected and 
processed for RNA 
analysis as detailed in 
a separate lab manual. 
Half of the sample will be 
used for RNA extraction, 
and the other half will be 
Samples will have RNA 
analyzed using techniques 
which will no longer include 
qRT-PCR 
IRB #: STU00203790-MOD0013 Approved by NU IRB for use on or after 4/2/2019 through 10/28/2019.


NU Study Number: NU 16C01 
 
Initial Version Date: August 19, 2016 
Amendment 5: December 19, 2018 
 
38 
reserve use. 
Extracted RNA will 
be stored in -80ºC 
until PCF transfers it 
to NUSeq, who will 
then perform RT-
qPCR on the RNA 
samples.” 
 
Section 9.5.2: 
“Extracted RNA will be 
frozen and sent to 
NUSeq Core for RT-
qPCR analysis” 
stored in -80ºC for 
reserve use.” 
 
 
 
 
 
 
 
Section 9.5.2: “Extracted 
RNA will be frozen and 
sent to NUSeq Core for 
RACE analysis” 
3.1.8 (Inclusion 
Criteria) 
Urine protein cutoff 
was listed with units in 
mg/g  
Updates urine protein 
cutoff to reflect units in 
mg/dL 
Correction of error; md/dL 
is the standard unit for 
urine protein levels 
5.0 (Study 
Procedures) 
The window for 
baseline pregnancy 
test was inconsistent 
throughout the 
protocol 
Updates study 
procedures to match the 
eligibility criteria for 
pregnancy test window; 
pregnancy test is 
required within 14 days 
of registration 
Correction of discrepancy 
9.1 (Blood Sample 
Collection 
Guidelines) 
Specific details were 
included outlining tube 
types, processing 
instructions and 
locations 
 
“Blood samples will be 
collected for PK 
analysis at 1, 3, 5, 10, 
30, and 60 minutes (± 
1 minute), and 4 
hours, 8 hours, and 24 
hours (±5 minutes) 
post NU-0129 
infusion. Each sample 
will contain 1mL of 
blood collected in pre-
chilled 4mL K2EDTA 
tubes (additional 
5.4mg/mL of K2EDTA 
should be added) 
and maintained on wet 
ice throughout 
collection and 
processing. Samples 
are to be spun down 
within 15 minutes of 
blood collection in a 
temperature-
controlled (4ºC) 
centrifuge” 
Removes details on 
processing and location 
of analysis for correlative 
samples 
 
 
“Blood samples will be 
collected for PK analysis 
at 1, 3, 5, 10, 30, and 60 
minutes (± 1 minute), 
and 4 hours, 8 hours, 
and 24 hours (±5 
minutes) post NU-0129 
infusion. Each sample 
will contain 1mL of blood 
collected in pre-chilled 
4mL K2EDTA tubes and 
maintained on wet ice 
throughout collection and 
processing. See 
separate lab manual for 
full collection and 
processing details.” 
By removing specific 
information from the 
protocol and limiting it to 
the lab manual, we aim to 
avoid unnecessary 
protocol amendments / 
deviations in the case of 
changes to analysis 
methods. 
IRB #: STU00203790-MOD0013 Approved by NU IRB for use on or after 4/2/2019 through 10/28/2019.


NU Study Number: NU 16C01 
 
Initial Version Date: August 19, 2016 
Amendment 5: December 19, 2018 
 
39 
Section 9.4.2.1 
(Histology (apoptotic 
markers e.g. 
caspase); Section 
9.5.2 (Tissue - IHC) 
Protocol references 
NU Pathcore’s 
Histology IHC lab for 
where histology will be 
performed 
Removed specific details 
on location of analysis 
and refer to separate lab 
manual for details. 
By removing specific 
information from the 
protocol and limiting it to 
the lab manual, we aim to 
avoid unnecessary 
protocol amendments / 
deviations in the case of 
changes to analysis 
methods. 
 
 
 
IRB #: STU00203790-MOD0013 Approved by NU IRB for use on or after 4/2/2019 through 10/28/2019.


NU Study Number: NU 16C01 
 
Initial Version Date: August 19, 2016 
Amendment 5: December 19, 2018 
 
40 
 
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IRB #: STU00203790-MOD0013 Approved by NU IRB for use on or after 4/2/2019 through 10/28/2019.