Clinical trial NCT03027388
Conditions: Astrocytoma, Grades II, III and IV Glioblastoma Multiforme Giant Cell Glioblastoma Glioma Oligodendrogliomas
Keywords: Brain Tumor Blood Brain Barrier Pharmacokinetics Pharmacodynamics
Sponsor: National Cancer Institute (NCI)
Start date: 2019-01-09; Completion date: 2022-08-31
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

The brain is separated from the rest of the blood stream by the blood-brain barrier. This is like a filter that protects the brain. But is also a challenge when medicines need to get into the brain. Researchers want to give the new drug LB100 to people before brain tumor surgery. They will measure how much LB100 is in the blood and how much gets into the brain. This may help with the use of LB100 to treat brain tumors in the future.

Objective:

To see if LB100 can pass into the brain.

Eligibility:

People at least 18 years old with a brain tumor that requires surgery.

Design:

Participants will be screened with:

Physical exam

Medical history

Blood tests

Neurosurgery evaluation

Scans

Heart tests

Tumor sample. This can be from a previous procedure.

Participants will have their brain surgery at the Clinical Center.

Participants will get a dose of the study drug through a plastic tube in a vein for 2 hours during surgery.

Participants will have blood taken 7 times in the 8 hours after getting the study drug.

Tumor samples will be taken during surgery.

Participants will have a heart test after getting the study drug. Sticky pads on the skin will measure electrical activity of the heart.

Two-three weeks after leaving the hospital, participants will have a follow-up visit. They will have a physical exam and blood tests.

One month after surgery, they will be contacted in person or by phone to see how they are doing.

Detailed description:
Background:

* Primary gliomas are an incurable disease in spite of aggressive multimodality therapy consisting of craniotomy, irradiation, and chemotherapy. Therapeutic options for patients with recurrent glioma are limited, and there is an unmet need to identify more effective agents.
* LB100, a water-soluble small molecule novel protein phosphatase 2A (PP2A) inhibitor, was commercially developed through a Cooperative Research and Development Agreement (CRADA) based on our previous intramural research. This compound has shown to be effective in a variety of cancer types in both in vitro and in vivo models. Preclinical studies indicate LB100 has in vitro and in vivo activity as a single agent as well as potentiating the effect of cytotoxic agents including temozolomide, docetaxel, doxorubicin, and ionizing radiation. LB100 is active in combination with temozolomide or doxorubicin against xenografts of glioblastoma, neuroblastoma, pheochromocytoma, breast cancer, fibrosarcoma, and melanoma.
* A complete phase I study of LB100 has established its safety and the recommended phase II dose (2.33 mg/m\^2, daily for three days every 3 weeks).
* Although it is a polar compound, rodent studies suggest LB100 has activity in the brain.
* Whether LB100 can across the human blood brain barrier (BBB), and at what concentration relative to the plasma level is not known. Characterizing these parameters is important because:

  * 1\) Our ongoing in vitro studies indicate that LB100 has distinct mechanisms of action at different drug concentrations (e.g., nM versus uM);
  * 2\) There are other brain tumors lacking effective medical therapies but without a BBB. Characterizing the LB100 BBB penetration profile will assist in defining its optimal clinical indication.

Objective:

-To determine the pharmacokinetic (PK) properties of LB100 in glioma tumor tissues.

Eligibility:

* Patients with histologically proven glioblastoma and grades II-III astrocytomas and oligodendrogliomas.
* A clear clinical indication for another surgical resection must be present.
* Subjects must be greater than or equal to 18 years old.
* Karnofsky performance status of greater than or equal to 60%.
* Patients must have adequate organ function.

Design:

* This is a two stage Phase II, open label, single institution study to determine the PK and pharmacodynamic (PD) profile of LB100.
* The dose (established from a Phase I study) will be 2.33 mg/m\^2 delivered intravenously over 2 hours.
* PK and PD effect of LB100 treated tissues will only be evaluated with pathologic confirmation of recurrent tumor. Resected material demonstrating chemoradiation treatment effect or inflammatory response will not be included in the analysis.
* PK will be determined by quantitating LB100 in tumor tissues removed at various time points.
* The primary endpoint is PK response, defined as a binary variable indicating the presence/absence of LB100 in tumor tissues.
* PD effect is defined as statistically significant elevation of phospho-proteins in treated tumor tissues compared to untreated glioma specimens. Untreated inter-patient baseline variance and standard deviation (SD) will be calculated. Post-treatment PD effect difference greater than 2.5 times the baseline SD is statistically significant at the .05 significance level. Due to relatively small sample size, t-distribution is to be used to calculate the cutoff defining the PD response.
* Up to 25 patients may be enrolled to obtain 8 evaluable subjects. A two-stage design will be used. Five patients will be initially treated. If at least one of five demonstrates PK activity, 3 additional subjects will be enrolled. PK effect will be declared to be significant if at least 2 of the 8 patients demonstrate a PK response (presence of LB100 in tumor tissue).

Arms: arm 1: Treatment with LB100
Interventions: intervention 1: LB-100
Intervention descriptions: intervention 1: LB-100 will be infused over 2 hours via intravenous (IV) infusion 2 to 4 hours before surgery. The dose established from a Phase I study will be 2.33 mg/m\^2.

Protocol documents:
Prot_SAP_000.pdf: 
1
Abbreviated Title: Phase II Study LB100 gliomas
Version Date:   06/02/2022
Abbreviated Title: Phase II Study LB100 gliomas
NIH Protocol #: 17C0037
Title: Phase II Trial of LB100, a Protein Phosphatase 2A Inhibitor, in Recurrent Gliomas
Version Date:    06/02/2022
NCT Number:  NCT03027388
Principal Investigator:
Eric Burton, MD, NOB, CCR, NCI 
9030 Old Georgetown Road, 82/243
Bethesda, MD 20892 
Tel:  240-760-6030  
Email: eric.burton@nih.gov
Investigational Agents:    
Drug Name:
LB100
IND Number:
132947
Sponsor:
Center for Cancer Research, National Cancer Institute
Manufacturer:
Lixte Biotechnology Holdings, Inc.
Supplier:
Lixte Biotechnology Holdings, Inc.


2
Abbreviated Title: Phase II Study LB100 gliomas
Version Date:   06/02/2022
PRÉCIS 
Background:

Primary gliomas are  an incurable disease  in spite of aggressive multimodality therapy 
consisting of craniotomy, irradiation, and chemotherapy.(1)  Therapeutic options for 
patients with recurrent glioma  are limited, and there is an unmet need to identify more 
effective agents.

LB100, a water soluble small molecule novel protein phosphatase 2A (PP2A) inhibitor, 
was commercially developed through a CRADA based on our previous intramural 
research.(2)  This compound has shown to be effective in a variety of cancer types in 
both in vitro and in vivo models.  Preclinical studies indicate LB100 has in vitro and in 
vivo activity as a single agent as well as potentiating the effect of cytotoxic agents 
including temozolomide, docetaxel, doxorubicin, and ionizing radiation.(3-6)  LB100 is 
active in combination with temozolomide or doxorubicin against xenografts of 
glioblastoma, neuroblastoma, pheochromocytoma, breast cancer, fibrosarcoma, and 
melanoma.(5, 7-9)

A complete phase I study of LB100 has established its safety and the recommended 
Phase II dose (2.33 mg/m2 daily for three days every 3 weeks). 

Although it is a polar compound, rodent studies suggest LB100 has activity in the 
brain.(10)

Whether LB100 can across the human blood brain barrier (BBB), and at what 
concentration relative to the plasma level is not known.  Characterizing these parameters 
is important because: 1) Our ongoing in vitro studies indicate that LB100 has distinct 
mechanisms of action at different drug concentrations (e.g. nM versus uM); 2) There are 
other brain tumors lacking effective medical therapies but without a BBB.  
Characterizing the LB100 BBB penetration profile will assist in defining its optimal 
clinical indication.
Objective:
To determine the pharmacokinetic (PK) properties of LB100 in glioma tumor tissues. 
Eligibility:

Patients with histologically proven glioblastoma and grades II-III astrocytomas and 
oligodendrogliomas. 

A clear clinical indication for another surgical resection must be present.

Subjects must be ≥ 18 years old.  

Karnofsky performance status of ≥ 60%.

Patients must have adequate organ function.


3
Abbreviated Title: Phase II Study LB100 gliomas
Version Date:   06/02/2022
Design:

This is a two stage Phase II, open label, single institution study to determine the PK and 
PD profile of LB100.

The dose (established from a Phase I study) will be 2.33 mg/m2 delivered intravenously 
over 2 hours.  

PK and PD effect of LB100 treated tissues will only be evaluated with pathologic 
confirmation of recurrent tumor.  Resected material demonstrating chemoradiation 
treatment effect or inflammatory response will not be included in the analysis.

PK will be determined by quantitating LB100 in tumor tissues removed at various time 
points.

The primary endpoint is PK response, defined as a binary variable indicating the 
presence/absence of LB100 in tumor tissues.

PD effect is defined as statistically significant elevation of phospho-proteins in treated 
tumor tissues compared to untreated glioma specimens.  Untreated inter-patient baseline 
variance and standard deviation (SD) will be calculated.  Post-treatment PD effect 
difference greater than 2.5 times the baseline SD is statistically significant at the .05 
significance level.   Due to relatively small sample size, t-distribution is to be used to 
calculate the cutoff defining the PD response.

Up to 25 patients may be enrolled to obtain 8 evaluable subjects.  A two-stage design will 
be used.  Five patients will be initially treated.  If at least one of five demonstrates PK 
activity, 3 additional subjects will be enrolled.  PK effect will be declared to be significant 
if at least 2 of the 8 patients demonstrate a PK response (presence of LB100 in tumor 
tissue).


4
Abbreviated Title: Phase II Study LB100 gliomas
Version Date:   06/02/2022
TABLE OF CONTENTS 
PRÉCIS............................................................................................................................................2
TABLE OF CONTENTS ................................................................................................................4
STATEMENT OF COMPLIANCE ................................................................................................8
1.
INTRODUCTION ...................................................................................................................9
1.1
Study Objectives ...............................................................................................................9
1.1.1
Primary Objective......................................................................................................9
1.1.2
Secondary Objectives ................................................................................................9
1.2
Background and Rationale................................................................................................9
1.2.1
Glioblastoma..............................................................................................................9
1.2.2
Agent to be Studied, LB100 ....................................................................................10
1.2.3
LB100 Preclinical Studies .......................................................................................10
1.2.4
LB100 Phase I Study ...............................................................................................12
1.2.5
Rationale for a Phase II Study of LB100 in Gliomas ..............................................13
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT .......................................................14
2.1
Eligibility Criteria ...........................................................................................................14
2.1.1
Inclusion Criteria .....................................................................................................14
2.1.2
Exclusion Criteria ....................................................................................................14
2.1.3
Recruitment Strategies.............................................................................................15
2.2
Screening Evaluation ......................................................................................................15
2.2.1
Screening activities performed prior to obtaining informed consent ......................15
2.2.2
Screening activities performed after a consent for screening has been signed........16
2.3
Participant Registration and Status Update Procedures..................................................16
2.3.1
Screen Failures.........................................................................................................16
2.3.2
Treatment Assignment Procedures..........................................................................17
2.4
Baseline Evaluation.........................................................................................................17
3
STUDY IMPLEMENTATION .............................................................................................17
3.1
Study Design...................................................................................................................17
3.1.1
Design/Schema ........................................................................................................19
3.2
Drug Administration .......................................................................................................19
3.3
Follow-up........................................................................................................................20


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Abbreviated Title: Phase II Study LB100 gliomas
Version Date:   06/02/2022
3.4
Study Calendar................................................................................................................20
3.5
Surgical Guidelines.........................................................................................................21
3.6
Cost and Compensation ..................................................................................................21
3.6.1
Costs ........................................................................................................................21
3.6.2
Compensation ..........................................................................................................21
3.6.3
Reimbursement........................................................................................................21
3.7
Criteria for Removal from Protocol Therapy and Off Study Criteria.............................22
3.7.1
Criteria for removal from protocol therapy .............................................................22
3.7.2
Off-Study Criteria....................................................................................................22
4
CONCOMITANT MEDICATIONS/MEASURES...............................................................22
5
CORRELATIVE STUDIES FOR RESEARCH/PHARMACOKINETIC STUDIES ..........22
5.1
Biospecimen Collection ..................................................................................................22
5.1.1
Pharmacokinetic/Pharmacodynamic Studies...........................................................22
5.1.2
Detailed PK Analysis...............................................................................................23
5.1.3
Handling and Processing of Specimens...................................................................33
5.2
Sample Storage, Tracking and Disposition.....................................................................34
5.2.1
Tissue blocks ...........................................................................................................34
5.2.2
Pharmacokinetic samples.........................................................................................35
5.2.3
Sample Storage and Destruction..............................................................................35
6
DATA COLLECTION AND EVALUATION .....................................................................36
6.1
Data Collection ...............................................................................................................36
6.2
Data Sharing Plans..........................................................................................................37
6.2.1
Human Data Sharing Plan .......................................................................................37
6.3
Response Criteria ............................................................................................................37
6.4
Toxicity Criteria..............................................................................................................37
7
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN.....37
7.1
Definitions.......................................................................................................................37
7.2
OHSRP Office of Compliance and Training /IRB Reporting.........................................38
7.2.1
Expedited Reporting ................................................................................................38
7.2.2
IRB Requirements for PI Reporting at Continuing Review ....................................38
7.3
NCI Clinical Director Reporting.....................................................................................38


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Abbreviated Title: Phase II Study LB100 gliomas
Version Date:   06/02/2022
7.4
NIH Required Data and Safety Monitoring Plan............................................................38
7.4.1
Principal Investigator/Research Team.....................................................................38
7.4.2
Safety Monitoring Committee (SMC).....................................................................38
8
SPONSOR PROTOCOL/SAFETY REPORTING................................................................39
8.1
Definitions.......................................................................................................................39
8.1.1
Adverse Event..........................................................................................................39
8.1.2
Serious Adverse Event (SAE) .................................................................................39
8.1.3
Life-threatening .......................................................................................................40
8.1.4
Severity....................................................................................................................40
8.1.5
Relationship to Study Product .................................................................................40
8.2
Assessment of Safety Events ..........................................................................................40
8.3
Reporting of Serious Adverse Events .............................................................................41
8.4
Safety Reporting Criteria to the Pharmaceutical Collaborator .......................................41
8.5
Reporting Pregnancy.......................................................................................................41
8.5.1
Maternal exposure ...................................................................................................41
8.5.2
Paternal exposure.....................................................................................................41
8.6
Regulatory Reporting For Studies Conducted Under CCR Sponsored IND ..................42
8.7
Sponsor Protocol Deviation Reporting ...........................................................................42
9
CLINICAL MONITORING..................................................................................................42
10
STATISTICAL CONSIDERATIONS ..................................................................................43
11
COLLABORATIVE AGREEMENTS..................................................................................44
11.1
Agreement Type – CRADA........................................................................................44
12
HUMAN SUBJECTS PROTECTIONS................................................................................44
12.1
Rationale For Subject Selection ..................................................................................44
12.2
Participation of Children .............................................................................................44
12.3
Participation of Subjects Unable to Consent...............................................................44
12.4
Evaluation of Benefits and Risks/Discomforts ...........................................................44
12.4.1
Risks ........................................................................................................................44
12.4.2
Benefits....................................................................................................................46
12.4.3
Alternative Approaches or Treatments....................................................................46
12.4.4
Procedure for Protecting Against or Minimizing any Potential Risks ....................46


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Abbreviated Title: Phase II Study LB100 gliomas
Version Date:   06/02/2022
12.5
Consent Process and Documentation ..........................................................................46
12.5.1
Request for Waiver of Consent for Screening Activities ........................................47
13
REGULATORY AND OPERATIONAL CONSIDERATIONS..........................................47
13.1
Study Discontinuation and Closure.............................................................................47
13.2
Quality Assurance And Quality Control .....................................................................48
13.3
Conflict Of Interest Policy ..........................................................................................48
13.4
Confidentiality And Privacy........................................................................................49
14
PHARMACEUTICAL INFORMATION .............................................................................49
14.1
LB100 (IND# 132947) ................................................................................................49
14.1.1
Source ......................................................................................................................49
14.1.2
Toxicity....................................................................................................................50
14.1.3
Formulation and preparation....................................................................................58
14.1.4
Stability and Storage................................................................................................58
14.1.5
Administration procedures.......................................................................................58
14.1.6
Incompatibilities ......................................................................................................58
15
REFERENCES ......................................................................................................................59
16
APPENDICES .......................................................................................................................61
16.1
Performance Status Criteria.........................................................................................61
16.2
PK Worksheet..............................................................................................................62
16.3
PK Assay Validation ...................................................................................................64
16.3.1
LB-100 Plasma ........................................................................................................64
16.3.2
LB-100 Tissue .........................................................................................................71


8
Abbreviated Title: Phase II Study LB100 gliomas
Version Date:   06/02/2022
STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.


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Abbreviated Title: Phase II Study LB100 gliomas
Version Date:   06/02/2022
1. INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Primary Objective
To determine the pharmacokinetic (PK) properties of LB100 in gliomas tumor tissues 
1.1.2
Secondary Objectives
1.1.2.1
To determine the concentration LB100 and its major metabolite, 7-oxabicyclo [2.2.1] 
heptanes-2,3-dicarboxylic acid (LB100M) in glioma tumor tissue when a known non-
toxic dose of LB100 is delivered intravenously over 2 hours.
1.1.2.2
To determine the PD effect of LB100 in glioma tumor tissue.
1.1.2.3
To determine the plasma concentration and calculated PK parameters of LB100 and 
LB100M (endothall).  
1.1.2.4
To determine changes in phospho-protein expression in circulating PBMC.
1.1.2.5
Intra-patient PD effect in PBMC and tumor tissue will be evaluated in all subjects for 
presence of correlation to identify potential predictive markers.
1.2
BACKGROUND AND RATIONALE
1.2.1
Glioblastoma
Glioblastoma (GB) is a primary brain tumor and the most common type of gliomas.  Although 
the incidence rate of 3 per 100,000 is relatively low compared to other cancer types, this disease 
accounts for disproportionately high cancer associated morbidity and mortality due to 
involvement of the central nervous system and lack of effective therapies(11).  The average 
overall survival of treated GB patients ranges from 8 to 14 months with only 9.8% alive 5 years 
after diagnosis(12, 13); these are figures that have not significantly changed over the past 
decades in spite of improvements witnessed in surgical and imaging techniques and considerable 
positive strides made in treatment of other cancers.  Median survival after tissue diagnosis 
without additional treatment is 3 months.
Optimal upfront treatment of GB consists of craniotomy to remove as much tumor tissue as 
possible, followed by concurrent temozolomide chemotherapy and ionizing radiation.  Even for 
patients exposed to multimodality therapy of craniotomy, chemotherapy, and irradiation, disease 
recurrence is inevitable; at such time, patients face very limited therapeutic options.  This dismal 
outlook for GB underscores the importance of identifying more effective treatment strategies.  
Often cited reasons for the refractory nature of GB include: 1) Intrinsic relative resistance of 
tumors cells to chemotherapy and irradiation; 2) Infiltrating growth pattern of tumor cells into 
surrounding normal brain that has two clinical consequences: a) precludes surgical removal of all 
tumor cells; b) tumor cells distant from the surgical margin are spared from exposure to 
cytotoxic dose of irradiation because radiation to the whole brain results in unacceptable toxicity; 
3) Presence of a “protective” blood-brain-barrier (BBB) that prevents efficient entry of 
exogenously administered polar drugs into the tumor bed.  It should be noted that although GB is 
the most common of the primary brain tumors called gliomas, other gliomas exist in the brain, 


10
Abbreviated Title: Phase II Study LB100 gliomas
Version Date:   06/02/2022
and as such are also protected blood brain barrier. The other gliomas of interest include grades 
II-III astrocytomas and oligodendrogliomas. These tumors are treated using the same modalities 
as GB and unfortunately are also refractory to treatment with limited options at recurrence. Since 
morphological differences exist in the BBB between these tumors which may possibly alter drug 
penetrance, the study will include these tumors in the analysis.
Formulation of more effective treatment strategies will require addressing these barriers.
1.2.2
Agent to be Studied, LB100
Protein phosphatase 2A (PP2A) is a ubiquitous heterotrimeric serine/threonine phosphatase 
involved in broad cellular functions such as signal transduction, cell differentiation, regulation of 
cell cycle, and DNA repair(14).  Naturally occurring small molecule inhibitors of PP2A such as 
cantharidin and okadaic acid have drawn considerable interest in preclinical stages due to potent 
anti-cancer properties.  However clinical utility has been limited by high toxicity.  LB100 (3-
[4methylpiperazine-carbonyl]-7-oxalobicyclo [2.2.1] heptane-2-carboxylic acid; NSC D753810) 
is a small polar molecule (MW 268), which inhibits PP2A about 80 fold more efficiently than 
protein phosphatase 1 (PP1)(8).  This compound was commercially synthesized to specifically 
inhibit PP2A(15).  LB100 has single agent activity in vitro and in vivo and potentiates the 
activity of cytotoxic agents and irradiation in vivo.  The mechanism of potentiation is believed to 
involve modulation of cell cycle and mitotic checkpoints induced by nonspecific DNA damaging 
agents, facilitating cancer cells to continue in mitosis despite acute DNA damage(5, 8).  LB100 
also appears to affect the vasculature inducing transient vessel “leakiness” at higher doses(16).
1.2.3
LB100 Preclinical Studies
A series of preclinical studies support the potential clinical utility of LB100 in various 
malignancies.  In addition to demonstrating single agent activity, LB100 potentiates the activity 
of cytotoxic agents and ionizing radiation in animal models.
Pancreatic cancer: Two cell lines exposed to LB100 demonstrated aberrant activation of CDK1, 
attenuation of radiation-induced Rad51 focus formation and subsequent loss of homologous 
recombination repair activity; these effects were not seen in normal small intestine cells.  In a 
mouse xenograft model, LB100 resulted in significant radiosensitization with minimal weight 
loss(4).
Ovarian cancer: In vitro and in vivo (intraperitoneal metastatic mouse model) studies showed 
LB100 to sensitize ovarian carcinoma lines to cisplatin-mediated cell death.  The mechanism of 
action was determined to be loss of cisplatin-induced cell cycle arrest(7).
Medulloblastoma: LB100 enhanced the cisplatin-mediated cytotoxic effects in vitro and in 
vivo(16).
Nasopharyngeal carcinoma: Combination of LB100 with radiation treatment led to significant 
regression of xenografted tumor cells compared to radiation or LB100 alone.  Investigators 
observed reduction in p53 expression along with impaired DNA repair functions(6).
Osteosarcoma: LB100 prevented repair of cisplatin-induced DNA damage in both in vitro and in 
vivo models leading to mitotic catastrophe and tumor cell death(9).


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Abbreviated Title: Phase II Study LB100 gliomas
Version Date:   06/02/2022
GB (with chemotherapy): LB1.2 (earlier generation of LB100) abrogated cell cycle arrest and 
enhanced the cytotoxic effects of temozolomide and doxorubicin in both in vitro and in vivo 
models of neuroblastoma and GB(15).
GB (with irradiation): LB100 in combination with irradiation increased expression of γ-H2AX 
indicative of DNA double-strand breaks, decreased p53 expression, and delayed tumor growth in 
a subcutaneous in vivo model of GB (Figure 1)(5). 
Figure 1
Additional preclinical studies performed in our laboratory further supports the use of LB100 as a 
single agent and in combination with ionizing radiation.  Meningioma is the most common 
primary brain tumor without effective medical therapy.  Current treatment options consist only of 
surgery followed irradiation.  We investigated three malignant meningioma cell lines (IOMM-
LEE, GAR, CH-157) and found that LB100 alone at clinically achievable concentrations (5-6 
µM) can exhibit antitumor effect (Figure 2).  Cells were treated once with LB100 and viability 
assessed 48 hours later; x-axis represents LB100 drug concentration in uM.  As seen with 
pancreatic and GB cells, LB100 in combination with irradiation increased γ-H2AX foci (Figure 
3).


12
Abbreviated Title: Phase II Study LB100 gliomas
Version Date:   06/02/2022
Figure 2
Figure 3
          
1.2.4
LB100 Phase I Study
A phase I, open label, single center, two-part, dose-escalation study of LB100 administered 
intravenously in patients with advanced solid tumors was conducted at City of Hope National 
Medical Center.  The objectives of the study were to determine the: 1) Safety and tolerability; 2) 
Maximum tolerated dose (MTD); 3) Pharmacokinetics (PK).  Study reached its accrual goal and 
closed to further patient enrollment on 5/20/2016.  Dose limiting toxicity (DLT) was reversible 
decrease in creatinine clearance at the maximum administered dose of 3.1 mg/m2; no other 
toxicities were reported.  Additional patients were enrolled at a lower dose of 2.33 mg/m2.  This 
dose was well tolerated without creatinine elevation, and determined to be the recommended 


13
Abbreviated Title: Phase II Study LB100 gliomas
Version Date:   06/02/2022
phase II dose.  On-going PK evaluation on the first cohort of subjects suggest a LB100 half-life 
of ~1.3 hours.
1.2.5
Rationale for a Phase II Study of LB100 in Gliomas
Preclinical studies performed in a variety of different cancer models including GB suggest that 
LB100 may possess anti-cancer properties as a single agent, and also potentiate cytotoxic effects 
of chemotherapy and ionizing radiation.  However, given that LB100 is a polar molecule, a 
limitation of the two completed GB in vivo animal studies was the use of a subcutaneous rather 
than an orthotopic intracranial model.  The intracranial model more closely recapitulates the 
native environmental conditions of human disease, including presence of at least a partial BBB.  
How efficiently, and to what extent LB100 is able to cross an intact BBB is unclear, although 
there are suggestions that LB100 can do this to a certain degree in rodents.  First, administration 
of LB100 was shown to significantly decrease PP2A enzymatic activity in the lateral habenula 
(region of brain with an intact BBB) of mice.  Second, we established intracranial GB models in 
mice.  Animals were treated with one-time administration of LB100 at 1.5 mg/kg, a dose slightly 
higher than the human MTD; human MTD dose roughly translates to plasma concentration of 4-
6 µM and this animal dose translates to a similar range (6-8 µM).  Animals were sacrificed 3 
hours after treatment.  Liver, intracranial tumor, normal brain (animals without tumor implants) 
were collected and assayed by Dr. William Figg’s Laboratory for presence of LB100 in these 
tissues.  Low levels of LB100 were detected in the normal brain and liver from 2 of 3 treated 
animals and from the implanted tumor in 1 of 3 animals.  These are encouraging results 
considering that the plasma half-life of LB100 in human is approximately 1.3 hours, it is 
therefore possible that a higher drug concentration may be detected at an earlier time point 
depending on exact PK parameters of LB100.  Nevertheless, all of these studies were performed 
in rodent brains and how this may translate to human is not known.
Whether LB100 can cross the human BBB and at what concentration relative to the plasma level 
is not known.  Even if LB100 can penetrate the human BBB, it is critically important to elucidate 
the specific LB100 PK properties of the brain compartment and determine pharmacodynamic 
(PD) effects of LB100 on glioma tissue to confirm target modulation.  Even a negative study 
showing that LB100 is incapable of crossing the BBB is important in order to establish its 
clinical utility.  This is because there are other brain tumors lacking effective medical therapies 
but without an intact BBB, where LB100 may potentially play a therapeutic role.  Therefore, 
defining the LB100 BBB penetration profile will assist in defining its optimal clinical indication.
Additionally, morphologic differences exist in the BBB between grades of glioma that may 
potentially affect the penetrance of LB100. Therefore, it would be important to determine the 
PK/PD in these histological types in order to assess the possible therapeutic value of LB100 in a 
broader range of central nervous system tumors.


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Abbreviated Title: Phase II Study LB100 gliomas
Version Date:   06/02/2022
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1
ELIGIBILITY CRITERIA
2.1.1
Inclusion Criteria
2.1.1.1
Patients must have histologically confirmed glioblastoma/gliosarcoma, grades II-III 
astrocytoma and oligodendroglioma .
2.1.1.2
Patients must have recurrent disease for which there is a clinical indication for 
resection.
2.1.1.3
Age >18 years.
2.1.1.4
Karnofsky >60%, see 16.1.
2.1.1.5
Patients must have adequate bone marrow function (WBC ≥ 3,000/uL ANC ≥ 
1,500/mm3, platelet count of ≥ 100,000/mm3, and hemoglobin ≥ 10 gm/dL), adequate 
liver function (SGOT and bilirubin < 2 times ULN), These tests must be performed 
within 28 days prior to receiving drug.  Eligibility level for hemoglobin may be reached 
by transfusion.
2.1.1.6
Patients must have a serum creatinine of <1.7 mg/dL. If the serum creatinine is greater 
than 1.7 mg/dl, a 24-hour urine creatinine clearance will be obtained and if the result of 
this study is within normal limits*, the patient would be eligible to enroll onto study. 
This test must be performed within 28 days prior to receiving drug. (*Normal 
Creatinine Clearance Range: Male: 90 – 130 ml/min; Female: 80 – 125 ml/min) 
2.1.1.7
Patients must be in adequate general medical health to safely tolerate a craniotomy.
2.1.1.8
At the time of registration, all subjects must be removed ≥ 28 days from any 
investigational agents.
2.1.1.9
The effects of LB100 on the developing human fetus are unknown.  For this reason, 
women of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and for the 
duration of study participation.  Should a woman become pregnant or suspect she is 
pregnant while she or her partner is participating in this study, she should inform her 
treating physician immediately.  
2.1.1.10 Ability of subject to understand and the willingness to sign a written informed consent 
document indicating that they are aware of the investigational nature of this study, and 
that this is not a therapeutic clinical trial.
2.1.2
Exclusion Criteria
2.1.2.1
Patients who are receiving any other investigational agents.
2.1.2.2
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 


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Abbreviated Title: Phase II Study LB100 gliomas
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arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements.
2.1.2.3
Patients unwilling to undergo craniotomy.
2.1.2.4
Pregnant women are excluded from this study because the safety of PP2A inhibition on 
a developing fetus has not been established.  Because there is an unknown but potential 
risk for adverse events in nursing infants secondary to treatment of the mother with 
LB100, breastfeeding should be discontinued if the mother is treated with LB100.
2.1.2.5
Patients may not have had prior chemotherapy or biologic therapy in the 4 weeks prior 
to study entry.  For patients who have been treated with targeted therapy, 5 half-lives of 
that therapy (or 28 days, whichever is shorter) must have passed prior to enrollment in 
the study.
2.1.2.6
Known HIV-positive patients on combination antiretroviral therapy are ineligible 
because of the potential for pharmacokinetic interactions with LB100.  Appropriate 
studies will be undertaken in patients receiving combination antiretroviral therapy when 
indicated.
2.1.2.7
Patients who are receiving strong CYP450 inducers or inhibitors are ineligible
2.1.3
Recruitment Strategies
Patients with recurrent disease will be identified by the Neuro-Oncology Branch, Clinical Center.  
This study will be posted on NIH websites and on NIH Social media forums.
2.2
SCREENING EVALUATION
2.2.1
Screening activities performed prior to obtaining informed consent
Minimal risk activities that may be performed before the subject has signed a consent include the 
following: 

Email, written, in person or telephone communications with prospective subjects 

Review of existing medical records to include H&P, laboratory studies, etc.  

Review of existing MRI, x-ray, or CT images

Review of existing photographs or videos

Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes

Patients will be evaluated by the Neurosurgical Team (Surgical Neurology Branch, 
NINDS) prior to enrollment.  Patients must be in adequate health to tolerate a major 
operation (craniotomy).  The evaluation will consist of a discussion with the patient and 
the neurosurgical team will review the imaging and will discuss with the patient.
Documentation/ confirmation of tumor diagnosis  is required prior to enrollment.  Slides from 
the most recent pre-registration biopsy or resection will  be requested  for review if the previous 
surgery was not performed at NIH.  


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Abbreviated Title: Phase II Study LB100 gliomas
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A waiver of consent for these activities has been requested in section 12.5.1.
2.2.2
Screening activities performed after a consent for screening has been signed
The following activities will be performed only after the subject has signed the study consent OR 
the consent for study 01-C-0129 (provided the procedure is permitted on that study) on which 
screening activities may also be performed.  Assessments performed at outside facilities or on 
another NIH protocol within the timeframes below may also be used to determine eligibility once 
a patient has signed the consent.
Within 28 days prior to receiving study drug the following assessments are required:

A complete history and neurological examination (to include documentation of 
the patients’ Karnofsky Performance Status).

Neuro-imaging confirming tumor progression shall be performed on all patients.  
MRI is preferred over CT scan.  

12-lead EKG

Laboratory Evaluation:  
o
CBC with differential, platelets, PT, PTT, INR
o
Total protein, albumin, calcium, phosphorus, magnesium, glucose, BUN, 
creatinine, sodium, potassium, alkaline phosphatase, ALT, AST, total 
bilirubin, direct bilirubin), LDH and uric acid
o
24-hour urine collection for Creatinine Clearance (if required per section 
2.1.1.6)
o
Urine or serum β-HCG
2.3
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES
Registration and status updates (e.g. when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration & Status Updates found at 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825
2.3.1
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse event 
(SAE).
Individuals who do not meet the criteria for participation in this trial (screen failure) because of a 
potentially reversable conditions (i.e., lab abnormality) may be rescreened..


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Abbreviated Title: Phase II Study LB100 gliomas
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2.3.2
Treatment Assignment Procedures
Cohorts
Number
Name
Description
1
Phase 2
Phase 2 subjects
Arms
Number
Name
Description
1
LB100
Treatment with LB100
Stratifications
Name
Distinct Options
Notes
None
Arm Assignment:
Patients in cohort 1 will be directly assigned to arm 1.
2.4
BASELINE EVALUATION
All baseline evaluation procedures should be done prior to the study treatments.  They do not 
need to be repeated if performed within 28 days prior to study drug initiation.

A complete history and physical (including baseline blood pressure measurement) and 
neurological examination (include documentation of the patients’ height, weight, and 
Karnofsky Performance Status).

A baseline standard NOB Gd-DPTA enhanced MRI should be performed.
3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN
This is a two stage Phase II, open label, single institution study to determine the PK and PD profile 
of LB100 in the setting of gliomas. Patients who are planned for craniotomy will be enrolled if 
they meet the inclusion criteria.  Patients will be admitted to the Clinical Center for the surgery.  
Tumor tissue will be sampled as part of neurosurgical procedure.  LB-100 will be infused over 2 
hours (+/- 15 minutes) via IV infusion 2 to 4 hours before surgery. The dose established from a 
Phase I study will be 2.33 mg/m2.  Because the tumor resection phase of the craniotomy for 


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Abbreviated Title: Phase II Study LB100 gliomas
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recurrent gliomas typically lasts from one to 5 hours, tumor tissue will be sampled at multiple time 
points as clinically indicated.  The exact time points of tissue removal from LB100 infusion will 
be recorded by a member of the study team in the OR. Plasma sampling for PK measurements of 
LB100 will be performed on all participating subjects.  (See section 5.1). 
Up to 25 patients may be enrolled to obtain 8 evaluable patients. Five patients will be initially 
treated.  If one of five demonstrates a PK response, 3 additional subjects will be enrolled.  PK 
effect will be declared to be significant if at least 2 of the 8 patients demonstrate a PK response 
(Presence of LB100 in tumor tissue).   Participants whose pathology demonstrates treatment effect 
or not active tumor will be replaced.


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Abbreviated Title: Phase II Study LB100 gliomas
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3.1.1
Design/Schema
3.2
DRUG ADMINISTRATION
LB-100 will be infused over 2 hours (+/- 15 minutes) via IV infusion. The dose established from 
a Phase I study will be 2.33 mg/m2.   At the end of infusion, each subject will have an EKG 
(within 30 minutes of the end of infusion).
 Glioma patient with MRI 
suggestive of disease relapse.
1)
Confirmation of diagnosis 
2)
Clinical indication for surgical resection.
3)
Patient willing to participate in study.
4)
Meet all other eligibility requirements.  If any are no, discontinue 
enrollment process.
1)
Enroll and proceed with study.
2)
Collect blood at prescribed time points.
3)
Craniotomy: Begin tumor resection as clinical indicated
4)
Tumor Tissue will be sampled as part of neurosurgical procedure.
Pathologic confirmation of viable tumor tissue.
No: Discontinue.
Yes: Proceed with PK/PD 
Evaluation


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Abbreviated Title: Phase II Study LB100 gliomas
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3.3
FOLLOW-UP
All patients will be evaluated in person 1-3 days following craniotomy and followed for at least 
30 days after infusion of LB-100 for toxicity assessment. During the first week after infusion 
with LB-100, renal function tests and liver function tests will be performed.   Two to 3 weeks 
following discharge from the hospital, all patients will return to the clinic or be seen by their 
local physician for a physical exam and bloodwork. Given that the methodologies utilized are 
similar across all laboratories, no significant variability is expected and there is no anticipation 
that study data will be affected.   Patients will be contacted by phone (or seen in clinic) at 
approximately 30 days post craniotomy and will be asked a non-leading question to determine 
whether any new AEs have occurred and to follow up on any ongoing AEs. 
3.4
STUDY CALENDAR
STUDIES TO 
BE 
OBTAINED
PRE-
TREATMEN
T
AT 
CRANIOTOMY
3 DAY 
FOLLOW 
UP 
(+/- 2 Days)
2-3 WEEK 
FOLLOW 
UP
30 DAY 
FOLLOW- UP
Informed 
Consent
X
Medical 
History
X
Physical 
Examination
X
X
Tumor Imaging 
-MRI 
(preferred) or 
CT scan
X
Documentation 
of tumor 
diagnosis
X
Laboratory 
Evaluation1
X
X 
X
24 hour 
Creatinine 
clearance (if 
required per 
section  
2.1.1.6)
X
12-lead EKG
X
X5
LB100
X
PK/PD2, 3
X
X


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Abbreviated Title: Phase II Study LB100 gliomas
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STUDIES TO 
BE 
OBTAINED
PRE-
TREATMEN
T
AT 
CRANIOTOMY
3 DAY 
FOLLOW 
UP 
(+/- 2 Days)
2-3 WEEK 
FOLLOW 
UP
30 DAY 
FOLLOW- UP
Adverse Events 
Notation
X
X
X
X4
Pre-treatment studies should be performed within 28 days of receiving study drug.
1 Laboratory Evaluation: CBC, differential, platelets, PT, PTT, INR, total protein, albumin, 
calcium, phosphorus, magnesium, glucose, BUN, creatinine, sodium, potassium, uric acid, total 
bilirubin, alkaline phosphatase, LDH, ALT, AST.  The pregnancy test for women of child bearing 
age will be done at screening only.
2 Plasma PK: see section 5.1.1.1
3 Tissue PK: see section 5.1.1.2
4 Follow- up: see section 3.3
5EKG within 30 minutes of the end of infusion.
3.5
SURGICAL GUIDELINES 
Craniotomy will be performed on all subjects participating in this protocol.  The surgical 
procedure is necessary component of clinical management.  Patients will be under the care of the 
operating neurosurgeon of the Surgical Neurology Branch, NINDS.
3.6
COST AND COMPENSATION
3.6.1
Costs
NIH does not bill health insurance companies or participants for any research or related clinical 
care that participants receive at the NIH Clinical Center.  If some tests and procedures performed 
outside the NIH Clinical Center, participants may have to pay for these costs if they are not 
covered by insurance company.  Medicines that are not part of the study treatment will not 
generally be provided or paid for by the NIH Clinical Center.    
3.6.2
Compensation
Participants will not be compensated on this study.
3.6.3
Reimbursement
The NCI will cover the costs of some expenses associated with protocol participation.  Some of 
these costs may be paid directly by the NIH and some may be reimbursed to the 
participant/guardian as appropriate.  The amount and form of these payments are determined by 
the NCI Travel and Lodging Reimbursement Policy.   


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Abbreviated Title: Phase II Study LB100 gliomas
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3.7
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
Prior to removal from study, effort must be made to have all subjects complete a safety 
evaluation approximately 30 days following the last dose of study therapy.
3.7.1
Criteria for removal from protocol therapy

Completion of protocol therapy, craniotomy, PK and PD evaluations.

Unacceptable Toxicity

Investigator discretion

Positive Pregnancy Test
3.7.2
Off-Study Criteria

Screen failure

Pathological evaluation  demonstrates treatment effect (e.g. necrosis or inflammation 
as a result of therapy) rather than tumor recurrence, PK and PD evaluations will not be 
performed in these subjects. However, given presurgical exposure to LB100 patient will 
still be followed for AEs as noted in section 6.1.

Completed study follow-up period

Participant requests to be withdrawn from study

Loss of capacity to provide consent

Investigator Discretion
4
CONCOMITANT MEDICATIONS/MEASURES
All participating subjects will undergo a craniotomy for resection of recurrent tumor.  
Concomitant medications/measures as clinically indicated will be delivered.  The surgical team 
will provide routine care as needed.  Participation in this study will not limit any routine care.
Only those medications that the patient is taking at baseline on a routine basis or medications that 
cause an AE will be captured in database. Thus one time medications and PRN medications will 
not be captured in database except those used to treat adverse events.]
5
CORRELATIVE STUDIES FOR RESEARCH/PHARMACOKINETIC STUDIES
5.1
BIOSPECIMEN COLLECTION
5.1.1
Pharmacokinetic/Pharmacodynamic Studies
Please note that tubes and media may be substituted based on availability with the permission of 
the PI or laboratory investigator.


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Abbreviated Title: Phase II Study LB100 gliomas
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5.1.1.1
Blood
Plasma PK: Plasma sampling for PK measurements of LB100 will be performed on all 
participating subjects.  Blood samples for the determination of plasma levels of LB-100 and its 
metabolite LB100 M (endothall) will be obtained from each patient via 6mL chilled sodium 
heparin tube (BD, Franklin Lakes, NJ). At each time point, 6 mL will be drawn into a chilled 
heparin collection tube and kept on ice.  Blood should be processed into plasma within 30 minutes 
of collection.  Once plasma is aliquoted, 5N sodium hydroxide (NaOH) will be added at a ratio of 
1:100 relative to plasma (e.g., 0.02 mL of 5N NaOH added to 2 mL plasma); the final NaOH 
concentration will be 50 mM in plasma. The fortified plasma will then be aliquoted into equal 
volumes in cryovials and frozen at -70° C until the time of analysis.  Plasma PK evaluation will 
be performed in the Figg Laboratory as described in 5.1.3
Blood samples will be collected at the following time points: 1*) Pre-dose; 2*) End of infusion (2 
hours post-start); 3*) 30 minutes post LB100 infusion completion; 4*) 1 hour post LB-100 infusion 
completion; 5*) 2 hours post LB100 infusion completion; 6) 4 hours post LB100 infusion 
completion; 7) 8 hours post LB100 infusion completion; 8) Other blood samplings will take place 
at the time post-infusion tissues are retrieved.  Note: * indicates that the sample may be obtained 
during the operative procedure.  Later time points are after leaving the OR.  All blood collection 
specified within time is allowed for +/- 15 minutes windows, with the exception of the pre-dose 
sample.  The pre-dose blood sample may be collected any time within 48 hours prior to drug 
administration.  Also, blood PK is at physician discretion.   The primary purpose of the study is to 
determine the tissue PK (brain tumor).
Bioanalytical measurements will be conducted on an ultra HPLC-MSMS system using an assay 
developed and validated by the Clinical Pharmacology Program.
5.1.1.2
Tissue
Tissue PK: Glioma tissue sampling to detect and quantify LB100 will be performed post-dose in 
each patient as clinically indicated (time points from end of LB100 infusion will be recorded).  
The removed tissues will be rinsed with saline immediately (to remove blood that contains 
LB100 to avoid falsely high measurements) then divided, flash frozen, and placed in a cryo tube.  
Majority of the tissue will be used for PK analysis.  A small aliquot (~100 ug) will be saved in 
cryo tube for PD evaluation.  PK samples will be transported to the Laboratory of Dr. Doug Figg 
(Molecular Pharmacology Section, Genitourinary Malignancies Branch) to quantitate LB100 
tissue concentration.
5.1.2
Detailed PK Analysis
5.1.2.1
Overview:
LC-MS-MS assay that can measure LB-100 in human plasma treated with 50 mM NaOH.  
Briefly, 50 l of NaOH-treated plasma is extracted using a protein precipitation. Assay range is 
2.0- 1000 ng/mL.  


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Abbreviated Title: Phase II Study LB100 gliomas
Version Date:   06/02/2022
5.1.2.2
Analyte:   LB-100 (Provided by the Pharmaceutical Collaborator)
 
Molecular Weight: 268.1 g/mol 
5.1.2.3
Internal Standard:  LB-105 (Provided by the Pharmaceutical Collaborator)
Molecular Weight: 282.2 g/mol 
5.1.2.4
Conditions:
HPLC: Acquity UPLC (Waters Corp, Beverly, MA)
Binary Pump
Mobile Phase A1: 5 mM Ammonium Bicarbonate (aq)
Mobile Phase B1: Methanol
Mobile Phase A2: (90/10, v/v) Water/ACN
Mobile Phase B2: ACN
Strong Needle Wash: ACN
Weak Needle Wash: 5 mM Ammonium Bicarbonate (aq)
Seal Wash: (90/10, v/v) Water/ACN
Total run time: 3 mins 
Gradient elution: 
Time
Flow Rate 
(mL/min)
%B2
Initial
0.500
2.0


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Abbreviated Title: Phase II Study LB100 gliomas
Version Date:   06/02/2022
1.50
0.500
12.0
1.51
0.500
95.0
1.52
1.000
95.0
2.70
1.000
95.0
2.71
1.000
2.0
3.00
0.500
2.0
LB-100 and LB-105 retention time: 1.08 and 1.34 mins
5.1.2.5
Sample Manager
Injection volume: 5 l
Sample temperature: 4 C
5.1.2.6
Column Compartment
Column: Waters Acquity UPLC BEH C18 2.1x50mm, 1.7-um particle-size
Temperature: 50 C
5.1.2.7
Mass Spectrometer: AB Sciex Q-Trap2 5500
Source Parameters 
Mode: Electrospray Positive
Curtain gas: 30
5.1.2.8
CAD: Medium
5.1.2.9
IS: 5000
GS-1: 60
GS-2: 60
Source Temperature: 650 C
MS Tune Parameters
Compound 
Name
Parent 
(m/z)
Daughter 
(m/z)
DP
EP
CE
CXP
LB-100
269.1
101.0
60
10
25
12
LB-105
283.2
115.1
60
10
25
12


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Abbreviated Title: Phase II Study LB100 gliomas
Version Date:   06/02/2022
5.1.2.10 Master Stock Solutions
5.1.2.10.1 Master Stock Preparation – LB-100 (1 mg/mL) from the Pharmaceutical Collaborator
a.
Accurately weigh ~1-2 mg of LB-100 in a 5-mL glass centrifuge tube on the 
analytical balance.
b. Add 1 mL of 10mM NaOH (aq) for each mg of LB-100.
c.
Vortex for 20 seconds.
d. Sonicate for 15 minutes at 35 C, to ensure all drug is dissolved. 
e.
Transfer to an amber glass Waters HPLC vial and store at –80 C. 
5.1.2.10.2 Master Stock Preparation – IS (LB-105) – 1.00 mg/mL from the Pharmaceutical 
Collaborator
a.
Accurately weigh ~1-2 mg of LB-105 in a 5-mL glass centrifuge tube on the 
analytical balance.
b. Add 1 mL of 10mM NaOH (aq) for each mg of LB-105.
c.
Vortex for 20 seconds.
d. Sonicate for 15 minutes at 35 C, to ensure all drug is dissolved.
e.
Transfer to an amber glass Waters HPLC vial and store at –80 C. 


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Abbreviated Title: Phase II Study LB100 gliomas
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5.1.2.10.3 Solution Preparation
a.
Mobile phase preparation
i. A1: 5 mM Ammonium Bicarbonate (aq) – Dissolve 0.395 g of ammonium 
bicarbonate in 1L of Milli-Q water
ii. A2 (Weak Wash/Seal Wash): 90:10 (v/v) Milli-Q H2O:ACN
iii. B2 and Strong Wash: 100% ACN
b. 5 N NaOH
i. Weigh out 20 grams of NaOH (pellets)
ii. Dissolve in 80 mL of H2O (initially…) with a stir bar on a stir plate
iii. Once pellets dissolve and solution cools, then add 20 mL more (100 mL 
total volume)
c.
50 mM NaOH in human plasma preparation
i. Transfer 25 mL of sodium heparin human plasma to a 50mL Falcon tube. 
Add 250 uL of 5 N NaOH using pipette. Mix thoroughly. Store at -20C; 
the expiration date is that of the plasma
d. 10 mM NaOH (aq), master stock diluent, preparation
i. Add 0.100 mL of 5N NaOH to 50 mL of DI water.
e.
10 mM TEA (aq) stock diluent preparation
i. 0.5 M TEA (aq)
1. Combine 1.4 mL of TEA and 18.6 mL of Milli-Q water in a falcon 
tube. Stir to mix and store the solution at room temperature. 
Expiration date is 1 month from preparation. 
ii. 10 mM TEA (aq)
1. Combine 2 mL of 0.5 M TEA (aq) and 100 mL in an 
approximately sized storage bottle. Stir to mix and store the 
solution at room temperature. The expiration date is when the 0.5 
M TEA expires. 
f.
0.5% TEA in ACN, precipitation solution, preparation
i. Add 0.250 mL of TEA to 50 mL of ACN.
g. 5 mM Ammonium Bicarbonate, reconstitution solution preparation
i. Dissolve 0.395 g of ammonium bicarbonate in 1 L of Milli-Q water. Store 
at room temperature. The expiration date is 1 month from preparation.
h. Internal Standard – 200 ng/mL LB-105 in 10 mM TEA (aq)
i. Add 100 uL of 1 mg/mL LB-105 to 900 uL 10 mM TEA to make a 100 
ug/mL solution
ii. Add 10 uL of 100 mg/mL LB-105 to 5 mL of 10 mM TEA (aq) to make a 
200 ng/mL IS-10mM TEA (aq) solution.  
iii. Discard solution after use.


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Abbreviated Title: Phase II Study LB100 gliomas
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5.1.2.10.4 Serial Dilutions and QC preparation
a.
Pipette specified amount of stock into glass centrifuge tube. Add specified volume of 
diluent, 10 mM TEA (aq), by piston pipette. Vortex mix. Each stock is utilized to prepare 
the next dilution. Store at -20C.
Stock 
Solution
Add X 
uL
of Stock: Volume 10 mM 
TEA (aq)
(uL)
Final volume 
(uL)
Working Stock 
Conc 
(ng/mL)
Final Conc 
(ng/ml)
X
100
Master
900
1,000
100,000
-
A
200
X
800
1,000
20,000
1,000
B
180
X
820
1,000
18,000
900
C
400
B
500
900
8,000
400
D
500
C
500
1000
4,000
200
E
200
D
800
1000
800
40
F
500
E
500
1000
400
20
G
250
F
750
1000
100
5
H
400
G
600
1000
40
2
5.1.2.10.5 Standard Curve


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Abbreviated Title: Phase II Study LB100 gliomas
Version Date:   06/02/2022
Concentration 
(ng/mL)
Add x l
Of stock:
to 50 mM NaOH treated 
plasma l:
1,000
10
A
190
900
10
B
190
400
10
C
190
200
10
D
190
40
10
E
190
20
10
F
190
5
10
G
190
2
10
H
190
* Prepare curve in duplicate (50 uL each), plus 50 uL of blank human plasma for “Blank” and 
“IS-only” samples (in duplicate)


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Abbreviated Title: Phase II Study LB100 gliomas
Version Date:   06/02/2022
5.1.2.10.6   QC preparation
Prepare each QC batch by pipetting designated volume of stock solution into a 5 mL 
volumetric flask. Add blank human plasma until final volume is 5 mL. Mix well and aliquot 
0.30 mL into clean, color-coded minifuge tubes (labeled with the date made) and store at –80 
C.  (5 mL = 15 aliquots).  Discard QCs older than 2 months.
QC Conc (ng/ml)
Stock
Volume 
Added
Actual Drug
Plasma up 
to-
6 (LQC; green)
F (400 ng/ml)
9 uL
3.6 ng
0.6 mL
40 (MQC; orange)
D (4,000 ng/ml)
5.0 uL
20 ng
0.5 mL
800 (HQC; red)
X (100,000 
ng/ml)
4.0 uL
400 ng
0.5 mL
5,000 (DQC; blue)
X (100,000 
ug/mL)
5.0 uL
500 ng
0.1 mL
* Prepare QCs in quintuplet (50 uL each).  For the dilution (10-fold), add 5 uL of DQC to 
45 uL of blank human plasma (in quintuplet).
5.1.2.10.7   Sample preparation
a.
Pipette 50 μl of human plasma (standards, QCs, patient samples) into a labeled Eppendorf 
mini-centrifuge tube.   
-
Curve in duplicate; QCs in quintuplet 
b. For patient samples and DQC samples, first add 45 uL blank plasma, then 5 uL of sample
c.
Add 50 ul of 100 ng/mL LB-105 in 10 mM TEA (aq) to each calibration, QC, blank with 
IS, and experimental sample.   *Blanks get pure 10 mM TEA
d. Add 400 μl of 0.5% TEA in ACN to precipitate proteins. 
e.
Vortex for 30 sec to mix well.
f.
Transfer ~450 uL into a clean, labeled 96-well Ostro plate.   


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g. Push supernatent through wells using Positive Pressure Manifold at ~12-15psi for 10 
min.
h. Dry down under desiccated air in the TurboVap 96 (plate temp 40C; gas flow ~30) 
-
Once volume gets to ~100 uL remaining, add 300 uL more ACN to expedite 
evaporation
i.
Reconstitute with 100 L of 5 mM Ammonium Bicarbonate (aq) directly into collection 
plate.
j.
Cover plate with parafilm and vortex for 20-30 sec.
k. Centrifuge plate for 10 min at 2,000 rpm at 4 C in big centrifuge.
l.
Run on UPLC-MS/MS
5.1.2.11 Assay Validation
See Appendix 16.3
Tissue PD effect of LB100 will be performed by assaying phospho-protein expression in glioma 
tissue resected prior to and after infusion of LB100. 
 LB100 is a serine/threonine phosphatase inhibitor.  Exposure to LB100 results in increased 
expression of phospho-serine/threonine residues.  The antibody we chose to mark LB100 activity 
detects variety of proteins and peptides phosphorylated at the threonine residues in a manner 
independent of the surrounding amino acid sequence (Cell Signaling Technology, Phospho-
Threonine Antibody (P-Thr-Polyclonal), #9381).  Our preclinical studies indicate that expression 
of phospho-protein (phospho-threonine antibody was used) upon treatment with LB100 is seen at 
the earliest by 4 hours (Left panel below).  By 8-hours expression is reliable, and maintained for 
approximately 40 hours (Right panel below).  Okadaic acid (OA), well-established PP2A inhibitor, 
was used as positive control.


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5.1.2.11.1 Planned analysis

PK evaluations of both blood and tumor tissues will be performed in Dr. Figg’s Laboratory, 
and PD analyses of blood and tumor tissues in NOB Laboratory.

A portion of blood collected for PK will be used to determine changes in phospho-protein 
expression in circulating PBMC.  

Intra-patient PD effect in PBMC (from above) and tumor tissue will be evaluated in all 
subjects for presence of correlation to identify potential predictive markers; this analysis 
consists of comparing PD effect in PBMC and tumor tissue to evaluate if PBMC changes 
predict effect in tumor tissue.  Phospho-protein analyses (PD effect) of PBMC and tumor 
tissue will be performed in the NOB Laboratory.

PD effect from LB100 treated tissues will only be evaluated with pathologic confirmation 
of recurrent tumor.  Resected material demonstrating chemoradiation treatment effect or 
inflammatory response (pseudoprogression) will not be included in the analysis.  This is 
because the compromised architecture of the BBB in necrotic tumor tissue may lead to 
falsely high penetration of LB100.  These tissue PK/ PD and plasma PK specimens will be 
destroyed and the patient will be removed from the study.

PK and PD specimens will be batched and performed retrospectively. The assays (both 
plasma and tissue) to quantitate LB100 and its major metabolite, LB100M (endothall) 
were developed in Dr. Figg’s Laboratory.  This data will be used to monitor LB-100 and 
its metabolite endothall plasma and tissue concentrations in order to correlate to 
pharmacodynamic endpoints, clinical response, and toxicity.

No cell lines will be established.
5.1.3
Handling and Processing of Specimens
PK: The blood samples will be placed immediately on wet ice and refrigerated. The date and 
exact time of each blood draw should be recorded on the sample tube and the PK sheet. Tumor 
samples for PK and PD evaluations will be picked up from the Laboratory of Pathology by the 
NOB staff and transported to NOB Laboratory in Building 37.  Tissues procured at various time 
points will be divided.  Material for PD studies will be frozen in NOB Laboratory and remaining 
tissue for PK evaluation will be sent to the Figg Laboratory.  
Please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the 
Friday before is preferred).
For sample pickup, page 102-11964.
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number).
For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov.  


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Upon arrival in the Clinical Pharmacology Program, samples will be centrifuged and the plasma 
transferred into cryovials for storage at -80 C until the time of analysis. In addition, samples will 
be barcoded as described in Section 5.2.2.1.
5.1.3.1
PD: Tumor tissues will be frozen in a -80 freezer in the NOB Laboratory until time of 
analysis.  For PD studies on blood, PBMC will be retrieved from the Figg Laboratory.
5.1.3.2
Tissue blocks can be shipped to Department of Pathology at NCI at the following 
address:
Laboratory of Pathology
Center for Cancer Research
National Cancer Institute 
Building 10, Room 2S235
Bethesda, MD 20892-1500
Ph: 301-480-5010 
5.2
SAMPLE STORAGE, TRACKING AND DISPOSITION
5.2.1
Tissue blocks
5.2.1.1
Laboratory of Pathology
Paraffin embedded tissue block will be stored at Laboratory of Pathology located at building 10. 
Tissues designated for clinical diagnostics are transported to the Laboratory of Pathology (LP) 
where they are examined grossly and relevant portions are fixed, embedded in paraffin and 
sectioned and stained for diagnostic interpretation.  Unutilized excess tissues are stored for up to 
three months, in accordance with College of American Pathologists/Joint Commission on 
Accreditation of Healthcare Organizations (CAP/JCAHO) guidelines, and then 
discarded.  Following completion of the diagnostic workup, the slides and tissue blocks are 
stored indefinitely in the LP’s clinical archives.  All specimens are catalogued and retrieved 
utilizing the clinical laboratory information systems, in accordance with CAP/JCAHO 
regulations.  The use of any stored specimens for research purposes is only allowed when the 
appropriate IRB approval has been obtained.  In some cases, this approval has been obtained via 
the original protocol on which the patient was enrolled. 
5.2.1.2
NOB Laboratory (PD Studies)
Samples will be ordered in CRIS and tracked through the Clinical Trial Data Management 
system.  Should a CRIS screen not be available, the CRIS downtime procedures will be 
followed.   Samples will not be sent outside NIH appropriate approvals and/or agreements, if 
required. 
All samples sent to the Neuro-Oncology, Pathology Laboratory or the Brain Tumor Tissue Bank 
will be barcoded with data entered and stored in the Labmatrix system utilized by the CCR, NCI. 
This is a secure system with access limited to defined personnel. 
Labmatrix creates a unique barcode ID for every sample which cannot be traced back to patients 
without Labmatrix access. The data recorded for each sample includes the patient ID, name, trial 
name/protocol number, date/time drawn, as well as box and freezer location. Patient 
demographics associated with the Clinical Center patient number are provided in the system. For 


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each sample, there are notes associated with the processing method (delay in sample processing, 
storage conditions on the ward, etc.).
These freezers are located onsite located in Room 1135, building 37. The freezer remains locked 
and access to stored clinical samples is restricted. Samples will be stored at -80o C in freezers 
with electronic monitoring.  Samples will be stored until requested by a researcher named on the 
protocol. All requests are monitored and tracked in the Labmatrix System. All researchers are 
required to sign a form stating that the samples are only to be used for research purposes 
associated with an IRB approved protocol and that any unused samples must be returned to the 
NCI. It is the responsibility of the NCI Principal Investigator to ensure that the samples requested 
are being used in a manner consistent with IRB approval.
5.2.2
Pharmacokinetic samples
Samples for this study will be collected and stored by the Sample Processing Core.  Bioanalytical 
measurements will be conducted on an ultra HPLC-MSMS system using an assay developed and 
validated by the Clinical Pharmacology Program.
Clinical Pharmacology Contact for Processing:   NCIBloodcore@mail.nih.gov
5.2.2.1
Sample Data Collection
All samples sent to the Blood Processing Core (BPC) will be barcoded, with data entered and 
stored in Labmatrix utilized by the BPC. This is a secure program, with access to Labmatrix 
limited to defined Figg lab personnel, who are issued individual user accounts. Installation of 
Labmatrix is limited to computers specified by Dr. Figg. These computers all have a password 
restricted login screen. 
Labmatrix creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to patients without Labmatrix access. The data recorded for each sample includes the 
patient ID, name, trial name/protocol number; time drawn, cycle time point, dose, material type, 
as well as box and freezer location. Patient demographics associated with the clinical center 
patient number are provided in the system. For each sample, there are notes associated with the 
processing method (delay in sample processing, storage conditions on the ward, etc.).
Following completion of this study, samples will remain in storage as detailed above. Access to 
these samples will only be granted following OHSRP/IRB approval of an additional protocol, 
granting the rights to use the material or if the use is not considered to be human subjects 
research.
5.2.3
Sample Storage and Destruction
All specimens obtained in the protocol are used as defined in the protocol. Any specimens that 
are remaining at the completion of the protocol will be stored in the conditions described above. 
The study will remain open so long as sample or data analysis continues.  Samples from 
consenting subjects will be stored until they are no longer of scientific value or if a subject 
withdraws consent for their continued use, at which time they will be destroyed. 


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If the patient withdraws consent the participant’s data will be excluded from future distributions, 
but data that have already been distributed for approved research use will not be able to be 
retrieved.
The PI will record any loss or unanticipated destruction of samples as a deviation. Reporting will 
be per the requirements of section 7.2.
6
DATA COLLECTION AND EVALUATION 
6.1
DATA COLLECTION
The PI will be responsible for overseeing entry of data into a 21 CFR Part 11-compliant  data 
capture system provided by the NCI CCR and ensuring data accuracy, consistency and 
timeliness. The principal investigator, associate investigators/research nurses and/or a contracted 
data manager will assist with the data management efforts. Primary and final analyzed data will 
have identifiers so that research data can be attributed to an individual human subject participant.
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event. 
Document adverse events from the first study intervention, Study Day 1 through Study Day 30 
(safety visit).  Beyond 30 days after the last intervention, only adverse events which are serious 
and related to the study intervention need to be recorded.
For patients whose pathological evaluation at craniotomy demonstrates treatment effect (e.g. 
necrosis or inflammation as a result of therapy) rather than tumor recurrence, adverse events will 
still be monitored from the first study intervention, Study Day 1 through Study Day 30 (safety 
visit).
Grade 1 events need not be captured, collected, or reported.
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following:

Results in discontinuation from the study

Is associated with clinical signs or symptoms 

Requires treatment or any other therapeutic intervention

Is associated with death or another serious adverse event, including hospitalization. 

Is judged by the Investigator to be of significant clinical impact

If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome.
End of study procedures: Data will be stored according to HHS, FDA regulations and NIH 
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Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in section 7.2.1. 
6.2
DATA SHARING PLANS
6.2.1
Human Data Sharing Plan
What data will be shared?
I will share human data generated in this research for future research as follows: 

Coded, linked data in BTRIS (automatic for activities in the Clinical Center)

Identified or coded, linked data with approved outside collaborators under appropriate 
agreements.
How and where will the data be shared? 
Data will be shared through:

BTRIS (automatic for activities in the Clinical Center)

Approved outside collaborators under appropriate individual agreements.

Publication and/or public presentations.
When will the data be shared? 

Before publication.

At the time of publication or shortly thereafter.
6.3
RESPONSE CRITERIA
This is not a therapeutic protocol.  Response will not be monitored.
6.4
TOXICITY CRITERIA
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study.  The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 
5.0.  A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
7
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN
7.1
DEFINITIONS
Please refer to definitions provided in Policy 801: Reporting Research Events found at:
 https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. 


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7.2
OHSRP OFFICE OF COMPLIANCE AND TRAINING /IRB REPORTING 
7.2.1
Expedited Reporting
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. 
Note: Only IND Safety Reports that meet the definition of an unanticipated problem will need to 
be reported per these policies.
7.2.2
IRB Requirements for PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. 
7.3
NCI CLINICAL DIRECTOR REPORTING
Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI Clinical 
Director.  A separate submission is not necessary as reports in iRIS will be available to the 
Clinical Director.
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email to the Clinical Director unless they are due to 
progressive disease.  
To report these deaths, please send an email describing the circumstances of the death to the 
Clinical Director/designee at NCICCRQA@mail.nih.gov within one business day of learning of 
the death.
7.4
NIH REQUIRED DATA AND SAFETY MONITORING PLAN
7.4.1
Principal Investigator/Research Team 
The clinical research team will meet on a regular basis when patients are being actively treated 
on the trial to discuss each patient. 
All data will be collected in a timely manner and reviewed by the principal investigator or 
associate investigators. Events meeting requirements for expedited reporting as described in 
section 7.2.1 will be submitted within the appropriate timelines.   
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff. 
7.4.2
Safety Monitoring Committee (SMC)
This protocol will require oversight from the Safety Monitoring Committee (SMC).  Initial 
review will occur as soon as possible after the annual NIH Intramural IRB continuing review 
date.   Subsequently, each protocol will be reviewed as close to annually as the quarterly meeting 
schedule permits or more frequently as may be required by the SMC.   For initial and subsequent 


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reviews, protocols will not be reviewed if there is no accrual within the review period. Written 
outcome letters will be generated in response to the monitoring activities and submitted to the 
Principal investigator and Clinical Director or Deputy Clinical Director, CCR, NCI.
8
SPONSOR PROTOCOL/SAFETY REPORTING
8.1
DEFINITIONS
8.1.1
Adverse Event 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product (ICH E6 (R2))
8.1.2
Serious Adverse Event (SAE)
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following:

Death,

A life-threatening adverse event (see 8.1.3)

Inpatient hospitalization or prolongation of existing hospitalization
o
A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing 
condition, or a procedure required by the protocol, without a serious deterioration 
in health, is not considered a serious adverse event.
o
A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for patient convenience) is not considered a serious adverse event. 
o
Emergency room visits or stays in observation units that do not result in 
admission to the hospital would not be considered a serious adverse event. The 
reason for seeking medical care should be evaluated for meeting one of the other 
serious criteria.

Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions

A congenital anomaly/birth defect.

Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.


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8.1.3
Life-threatening 
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. (21CFR312.32)
8.1.4
Severity
The severity of each Adverse Event will be assessed utilizing the CTCAE version 5.0.
8.1.5
Relationship to Study Product
All AEs will have their relationship to study product assessed using the terms:  related or not 
related.  

Related – There is a reasonable possibility that the study product caused the adverse 
event. Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event.

Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event.
8.2
ASSESSMENT OF SAFETY EVENTS
AE information collected will include event description, date of onset, assessment of severity 
and relationship to study product and alternate etiology (if not related to study product), date of 
resolution of the event, seriousness and outcome. The assessment of severity and relationship to 
the study product will be done only by those with the training and authority to make a diagnosis 
and listed on the Form FDA 1572 as the site principal investigator or sub-investigator.  AEs 
occurring during the collection and reporting period will be documented appropriately regardless 
of relationship.  AEs will be followed through resolution.
SAEs will be:

Assessed for severity and relationship to study product and alternate etiology (if not 
related to study product) by a licensed study physician listed on the Form FDA 1572 as 
the site principal investigator or sub-investigator.

Recorded on the appropriate SAE report form, the medical record and captured in the 
clinical database.

Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site principal investigator or sub-investigator.
For timeframe of recording adverse events, please refer to section 6.1. All serious adverse events 
recorded from the time of first investigational product administration must be reported to the 
sponsor.


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8.3
REPORTING OF SERIOUS ADVERSE EVENTS
Any AE that meets protocol-defined serious criteria or meets the definition of Adverse Event of 
Special Interest that require expedited reporting must be submitted immediately (within 24 hours 
of awareness) to OSRO Safety using the CCR SAE report form.
All SAE reporting must include the elements described in 8.2
SAE reports will be submitted to the Center for Cancer Research (CCR) at: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  CCR SAE report form 
and instructions can be found at: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions 
Following the assessment of the SAE by OSRO, other supporting documentation of the event 
may be requested by the OSRO Safety and should be provided as soon as possible.
8.4
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATOR
Reporting will be per the collaborative agreement. 
Reports should be sent to:
John Kovach, MD
Lixte
Email: jkovach@lixte.com
8.5
REPORTING PREGNANCY
All required pregnancy reports/follow-up to OSRO will be submitted to: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  Forms and instructions 
can be found here: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions
8.5.1
Maternal exposure
If a patient becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 hours of 
when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later 
than 24 hours of when the outcome of the pregnancy become known.
Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects 
and spontaneous miscarriages that meet serious criteria (8.1.2) should be reported as SAEs. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth, or congenital abnormality) should be followed up and documented.
8.5.2
Paternal exposure
Male patients should refrain from fathering a child or donating sperm during the study and for 30 
days after the last dose of LB100.
Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 


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congenital abnormality) occurring from the date of the first dose until 30 days after the last dose 
should, if possible, be followed up and documented.
8.6
REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR SPONSORED IND
Following notification from the investigator, CCR, the IND sponsor, will report any suspected 
adverse reaction that is both serious and unexpected.  CCR will report an AE as a suspected 
adverse reaction only if there is evidence to suggest a causal relationship between the study 
product and the adverse event.  CCR will notify FDA and all participating investigators (i.e., all 
investigators to whom the sponsor is providing drug under its INDs or under any investigator’s 
IND) in an IND safety report of potential serious risks from clinical trials or any other source, as 
soon as possible, in accordance to 21 CFR Part 312.32. 
All serious events will be reported to the FDA at least annually in a summary format.
8.7
SPONSOR PROTOCOL DEVIATION REPORTING
A Protocol Deviation is defined as any non-compliance with the clinical trial Protocol, Manual 
of Operational Procedures (MOP) and other Sponsor approved study related documents, GCP, or 
protocol-specific procedural requirements on the part of the participant, the Investigator, or the 
study site staff inclusive of site personnel performing procedures or providing services in support 
of the clinical trial.
It is the responsibility of the study Staff to document any protocol deviation identified by the 
Staff or the site Monitor in the CCR Protocol Deviation Tracking System (PDTS) online 
application. The entries into the PDTS online application should be timely, complete, and 
maintained per CCR PDTS user requirements. 
In addition, any deviation to the protocol should be documented in the participant’s source 
records and reported to the reviewing IRB per their guidelines. OSRO required protocol 
deviation reporting is consistent with E6(R2) GCP: Integrated Addendum to ICH E6(R1): 4.5 
Compliance with Protocol; 5.18.3 (a), and 5.20 Noncompliance; and ICH E3 16.2.2 Protocol 
deviations.
9
CLINICAL MONITORING
Clinical site monitoring is conducted to ensure:

that the rights of the participants are protected; 

that the study is implemented per the approved protocol, Good Clinical Practice and 
standard operating procedures; and 

the quality and integrity of study data and data collection methods are maintained.  
Monitoring for this study will be performed by NCI CCR Office of Sponsor and Regulatory 
Oversight (OSRO) Sponsor and Regulatory Oversight Support (SROS) Services contractor. 
Clinical site monitoring activities will be based on OSRO standards, FDA Guidance E6(R2) 
Good Clinical Practice: Integrated Addendum to ICH E6(R1) March 2018, and applicable 
regulatory requirements.
Details of clinical site monitoring will be documented in a Clinical Monitoring Plan (CMP) 
developed by OSRO. CMPs will be protocol-specific, risk-based and tailored to address human 


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subject protections and integrity of the study data. OSRO will determine the intensity and 
frequency of monitoring based on several factors, including study type, phase, risk, complexity, 
expected enrollment rate, and any unique attributes of the study and the site. The Sponsor will 
conduct a periodic review of the CMP to confirm the plan's continued appropriateness. A change 
to the protocol, significant or pervasive non-compliance with GCP, or the protocol may trigger 
CMP updates.
OSRO SROS Monitoring visits and related activities will be conducted throughout the life cycle 
of each protocol. The first activity is before the study starts to conduct a Site Assessment Visit 
(SAV) (as warranted), followed by a Site Initiation Visit (SIV), Interim Monitoring Visit(s) 
(IMVs), and a study Close-Out Visit (COV).
Some monitoring activities may be performed remotely, while others will occur at the study site(s). 
Monitoring visit reports will describe visit activities, observations, and associated action items or 
follow-up required for resolution of any issues, discrepancies, or deviations. Monitoring reports 
will be distributed to the study PI, NCI CCR QA, CCR Protocol Support Office, coordinating 
center (if applicable), and the Sponsor regulatory file.
The site Monitor will inform the study team of any deviations observed during monitoring visits. 
If unresolved, the Monitor will request that the site Staff enter the deviations in the CCR Protocol 
Deviation Tracking System (PDTS) for deviation reporting to the Sponsor and as applicable per 
institutional and IRB guidance.
10 STATISTICAL CONSIDERATIONS  
The primary objective of this study is to determine the PK response of LB100 in glioma tissue. 
The PK response is defined as a binary endpoint indicating the presence/absence of LB100, and 
will be established by measuring the level of LB100 in resected tumor tissues. This two-stage 
study is designed to define a significant PK effect with an expected target PK response rate of 
40% across patients.  The expected 40% response rate is based on preliminary in vitro and 
animal studies. 
Up to 25 patients may be enrolled to obtain 8 evaluable patients.  Five patients will be initially 
treated.  If one of five demonstrates a PK response, three additional subjects will be enrolled.  PK 
effect will be declared to be significant if at least 2 of the 8 patients demonstrate a PK response.  
This yields 87% power to detect a 40% PK response rate across patients, with an overall 10% 
false positive rate under the null hypothesis that the agent has no biologic effect(17).
The PK parameters, including Cmax, AUC and elimination half-life time t1/2, will be estimated 
based on standard PK modeling. 
PD response is defined as statistically significant elevation of phospho-protein expression in 
treated tumor tissues compared to untreated glioma specimens.  Tissue samples obtained with the 
initial surgical exposure of the tumor OR material obtained prior to LB100 infusion will be used 
as control.  Untreated inter-patient baseline variance of phospho-protein expression and standard 
deviation (SD) will be calculated.  Post-treatment PD effect (as measured by increase in tumor 
tissue phospho-protein expression) difference greater than 2.5 times the baseline SD is 
statistically significant at the .05 significance level. Due to relatively small sample size, t-


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distribution is to be used to calculate the cutoff defining the PD response. The frequency of PD 
response and its 95% confidence interval will be estimated. 
11 COLLABORATIVE AGREEMENTS
11.1
AGREEMENT TYPE – CRADA
The study agent, LB100 is provided by Lixte Biotechnology Holdings under a Cooperative 
Research and Development Agreement (CRADA), No. 03152.  Results or study data will be 
communicated to CRADA partner, Lixte Biotechnology, according to the terms of the CRADA.  
12 HUMAN SUBJECTS PROTECTIONS 
12.1
RATIONALE FOR SUBJECT SELECTION
This study was designed to include women and minorities, but was not designed to measure 
differences of intervention effects.  Males and females will be recruited with no preference to 
gender.  No exclusion to this study will be based on race.  Minorities will actively be recruited to 
participate.
12.2
PARTICIPATION OF CHILDREN
Because no dosing or adverse event data are currently available on the use of LB100 in subjects 
<18 years of age, children are excluded from this study.
12.3
PARTICIPATION OF SUBJECTS UNABLE TO CONSENT
Adults unable to give consent are excluded from enrolling in the protocol. However, re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. In such cases, subjects would be removed from the study as there is no 
prospect of direct benefit from research participation.
12.4
EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS
12.4.1 Risks
12.4.1.1 LB100
The primary risk to patients participating in this research study is from toxicity of the LB100 as 
described in the protocol. This is a Phase II clinical study to determine the PK/PD of LB100 in 
subjects with gliomas.  Although safety of LB100 has been established from a Phase I study, 
LB100 has not been given to patients with gliomas.  Potential risks include unexpected toxicity 
from LB100 infusion not seen during the phase I study.  All patients will be carefully monitored 
during the post-operative period to identify potential toxicity.  If patients experience unexpected 
toxicity, immediate medical treatment is available at the Clinical Center of NIH.  LB100 may 
involve unpredictable risks to the participants.


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12.4.1.2 Gd-DPTA enhanced MRI
There are no long-term risks of MRI scans, however, there is a risk of injury for persons who 
have metal in their bodies.  Per Clinical Center practice, participants will be screened to 
determine whether they are at risk.
The MRIs to be done in this study will involve contrast.  The risks associated with MRIs and 
contrast are discussed in the consent form.
The risks of an IV catheter include bleeding, infection, or inflammation of the skin and vein with 
pain and swelling.  
Mild symptoms from gadolinium infusion occur in fewer than 1% of those who receive it and 
usually go   away quickly.  Mild symptoms may include coldness in the arm during the    
injection, a metallic taste, headache, and    nausea.  In an extremely small number, fewer than 
one in 300,000 people, more severe symptoms have been reported including shortness of   
breath, wheezing, hives, and lowering of blood pressure. Study participants should not receive 
gadolinium if they previously had an allergic reaction to   it.  Study participants will be asked 
about such allergic reactions before gadolinium is given.   People with kidney disease are at risk 
for a serious reaction to gadolinium contrast called “nephrogenic systemic fibrosis (NSF)”.  This 
condition always involves the skin and can also involve the muscles, joints and internal organs.  
NSF has resulted in a very small number of deaths.  A blood test of their kidney function may be 
done within the month before an MRI scan with gadolinium contrast. Study participants will not 
receive gadolinium for a research MRI scan if their kidney function is below the safe level. Most 
of the gadolinium contrast leaves the body in the urine.  However, the FDA has issued a safety 
alert that indicates small amounts of gadolinium may remain in the body for months to years.  
The effects of the retained gadolinium are not clear. At this time, retained gadolinium has not 
been linked to health risks in people whose kidneys work well.  Some types of gadolinium 
contrast drugs are less likely to remain in the body than others.  
Additionally, the gadolinium contrast drugs that are used are less likely to remain in the body, 
whenever possible.  The study participant will also be given additional information called a 
“Medication Guide.”  Upon request, the study participant will be given individual information 
about retained gadolinium we see on your studies.
Although MR imaging with gadolinium has been used as part of the standard care for patients 
with high grade gliomas, long term toxicities of gadolinium as a consequence of gadolinium 
accumulation in the body have been reported. All investigators will ascertain the MR imaging 
history of all prospective study participants to determine the extent of prior exposure to 
gadolinium contrast.  Radiology will be consulted if there is a history of repeated gadolinium 
exposure.
12.4.1.3 CT scan
The risk of CT scan includes radiation risk which is listed in 12.4.1.4.  As noted in Section 2.2.2, 
an MRI is preferred over CT Scan.


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12.4.1.4 Radiation
The amount of radiation received from the CT Scan of the cerebrum in this study is 0.1 rem of 
radiation per year. The amount of radiation received in this study does not exceed the dose 
guideline established by the NIH Radiation Safety Committee for research subjects. The 
guideline is an effective dose of 5 rems (or 5,000 mrem) received per year. More information 
about radiation is available in the pamphlet, An Introduction to Radiation for NIH Research 
Subjects. 
12.4.1.5 Blood collection
The risks of taking blood may include fainting, pain and/or bruising. Rarely, subjects may 
experience clotting or infection at the puncture site.
12.4.1.6 EKG
Other than the minor skin irritation from the electrodes there are no expected risks related to the 
EKG.
12.4.2 Benefits
There are no direct benefits to participating subjects.
12.4.3 Alternative Approaches or Treatments
Patients may have their planned craniotomy while not participating in this trial.  
12.4.4 Procedure for Protecting Against or Minimizing any Potential Risks
All care will be taken to minimize side effects, but they can be unpredictable in nature and 
severity. This study may involve risks to patients, which are currently unforeseeable. All patients 
will have blood tests, examinations and scans as described in the study calendar (Section 3.4).  
Patients will also be required to have a local physician to provide long-term care and to monitor 
for complications.  If patients suffer any physical injury as a result of the participation in this 
study, immediate medical treatment is available at the Clinical Center, National Cancer Institute, 
Bethesda, Maryland. Although no compensation is available, any injury will be evaluated and 
treated in keeping with the benefits or care to which patients are entitled under applicable 
regulations.
12.5
CONSENT PROCESS AND DOCUMENTATION
The informed consent document will be provided as a physical or electronic document to the 
participant for review prior to consenting.  A designated study investigator will carefully explain 
the procedures and tests involved in this study, and the associated risks, discomforts and benefits. 
In order to minimize potential coercion, as much time as is needed to review the document will 
be given, including an opportunity to discuss it with friends, family members and/or other 
advisors, and to ask questions of any designated study investigator. A signed informed consent 
document will be obtained prior to entry onto the study.
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms) per discretion of the 
designated study investigator and with the agreement of the participant.  Whether in person or 


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remote, the privacy of the subject will be maintained. Consenting investigators (and participant, 
when in person) will be located in a private area (e.g., clinic consult room). When consent is 
conducted remotely, the participant will be informed of the private nature of the discussion and 
will be encouraged to relocate to a more private setting if needed.
Consent will be documented with required signatures on the physical document (which includes 
the printout of an electronic document sent to participant) or as described below, with a manual 
(non-electronic) signature on the electronic document.  When required, witness signature will be 
obtained similarly as described for the investigator and participant.
Manual (non-electronic) signature on electronic document:
When a manual signature on an electronic document is used for the documentation of consent at 
the NIH Clinical Center, this study will use the following to obtain the required signatures:

Adobe platform (which is not 21 CFR Part 11 compliant); or,  

iMedConsent platform (which is 21 CFR Part 11 compliant)
During the consent process, participants and investigators will view individual copies of the 
approved consent document on screens at their respective locations (if remote consent); the same 
screen may be used when in the same location but is not required.  
Both the investigator and the participant will sign the document using a finger, stylus or mouse. 
Note: Refer to the CCR SOP PM-2, Obtaining and Documenting the Informed Consent Process 
for additional information (e.g., verification of participant identity when obtaining consent 
remotely) found at:   
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825.
12.5.1 Request for Waiver of Consent for Screening Activities
Prior to the subject signing the consent for this study pre-screening activities listed in section 
2.2.1 may be performed. 
We request a waiver of consent for these activities as they involve only minimal risk to the 
subjects.  A waiver will not adversely affect the rights and welfare of the subjects given that the 
activities are only intended to determine suitability for screening for participation in research 
protocols.  These activities could not practicably be carried out without the wavier as central 
recruiting services, utilized in the NIH Clinical Center, perform pre-screening activities for 
multiple studies and obtaining consent for each one is beyond their resources.  The subjects will 
be provided with additional pertinent information after participation as they will be informed 
whether or not they are eligible to sign a consent for additional screening.
13 REGULATORY AND OPERATIONAL CONSIDERATIONS  
13.1
STUDY DISCONTINUATION AND CLOSURE
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 


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termination, will be provided by the suspending or terminating party to study participants, 
investigator, funding agency, the Investigational New Drug (IND) and regulatory authorities.  If 
the study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly 
inform study participants, the Institutional Review Board (IRB), and sponsor and will provide 
the reason(s) for the termination or suspension.  Study participants will be contacted, as 
applicable, and be informed of changes to study visit schedule.
 Circumstances that may warrant termination or suspension include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to participants

Demonstration of efficacy that would warrant stopping   

Insufficient compliance to protocol requirements

Data that are not sufficiently complete and/or evaluable

Determination that the primary endpoint has been met

Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and as applicable, Food and Drug Administration (FDA).
13.2
QUALITY ASSURANCE AND QUALITY CONTROL
The clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management 
plan will be developed to describe a site’s quality management.
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted, and data are generated, and biological specimens are collected, 
documented (recorded), and reported in compliance with the protocol, International Conference 
on Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements 
(e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local 
and regulatory authorities.
13.3
CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be 
required to have such conflicts managed in a way that is appropriate to their participation in the 
design and conduct of this trial.  The study leadership in conjunction with the National Cancer 
Institute has established policies and procedures for all study group members to disclose all 


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conflicts of interest and will establish a mechanism for the management of all reported dualities 
of interest.
13.4
CONFIDENTIALITY AND PRIVACY
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the participants in this study. The 
clinical study site will permit access to such records.
The study participant’s contact information will be securely stored at the clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor 
requirements.
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be stored at the NCI CCR. This will not include the participant’s contact or 
identifying information. Rather, individual participants and their research data will be identified 
by a unique study identification number. The study data entry and study management systems 
used by the clinical site(s) and by NCI CCR research staff will be secured and password 
protected. At the end of the study, all study databases will be archived at the NIH.
To further protect the privacy of study participants, a Certificate of Confidentiality has been 
issued by the National Institutes of Health (NIH).  This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any 
civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or 
local level. By protecting researchers and institutions from being compelled to disclose 
information that would identify research participants, Certificates of Confidentiality help achieve 
the research objectives and promote participation in studies by helping assure confidentiality and 
privacy to participants.
14 PHARMACEUTICAL INFORMATION  
14.1
LB100 (IND# 132947)
14.1.1 Source 
Lixte Biotechnology Holdings, Inc.


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14.1.2 Toxicity 
Mice: In the mouse, 1.5 mg/kg (~4.3 mg/m2) was tolerated IP daily for up to 20 days without 
observable toxicity.  Doses of 2.0 mg/kg IP daily for 5 days, were also explored, but although 
this dose was tolerated, the animals were lethargic and appeared ill.  Therefore, for activity 
studies, the standard regimen used in numerous studies was no more than 1.5 mg/kg daily for 5 
days.  Although LB100 at 1.5 mg/kg IP daily for 5 days was well tolerated as a single agent, 
when given in combination with temozolomide in xenograft studies, mortality was observed in 1 
of 10 mice.
Dose Ranging Study in Rats: A dose ranging study of single dose of LB100 was conducted in 
rats (12 male and 12 female) to examine systemic toxicity and to determine the maximum 
tolerated dose following a single intravenous (IV) dose of LB100.  No toxicity was observed and 
no change in body weight related to drug treatment occurred.
Dose levels explored were 0.375, 0.75, 1.25, and 1.5 mg/kg.  On Day 1, animals (n=3/sex/group) 
received LB100 prepared in phosphate buffered saline and deionized water (PBS/DI-Water) at 
the listed dose levels.  Doses were delivered into a tail vein using a dose volume of 1 mL/kg.  
Body weights were collected on Days 1 (prior to dosing), 4, and 8 (prior to euthanasia).  
Mortality and moribundity checks were conducted twice daily, and detailed clinical observations 
were collected daily on Days 1 (prior to dosing and approximately two hours after dosing) 
through 8 (prior to euthanasia).  Following collection of final body weight and detailed clinical 
observations, animals were euthanized without further observation.  Over the course of the study, 
no clinical signs of toxicity, including changes in body weight, were observed in any treatment 
group.  Thus, under the conditions of this study, LB100 treatment did not result in systemic 
toxicity, and a maximum tolerated dose was not determined.
Non-GLP Toxicity Study in Rats: A non-GLP dose ranging study of LB100 toxicity in the rat 
was conducted by the National Cancer Institute as part of the NExT Program.  The study 
evaluated the toxicity of four consecutive daily IV infusions of LB100 in male Fischer rats.  
Twenty-four rats (6/group) were assigned to four treatment groups: vehicle control of phosphate 
buffered saline, 0.5, 0.75, and 1.5 mg/kg/day of LB100.  Animals were weighed daily prior to 
dose administration.  Clinical observations were recorded for all animals twice daily and again 
prior to termination.
Blood samples were collected in 3 of the 6 rats per dose group to evaluate hematology and 
clinical chemistry at 1 hour after the end of the infusion on day 2 and day 4 of treatment.  On day 
4, the rats were sacrificed approximately 1 to 2 hours after the last infusion by humane 
euthanasia and necropsied.  Microscopic evaluation was performed on limited tissues. 
There were no unscheduled deaths in any of the treatment groups. There were no effects on body 
weight and no clinical signs of toxicity in rats receiving 0.5 mg/kg/day. At 0.75 mg/kg/day, no 
clinical signs of toxicity were observed, however, a minimal decrease (1.6%) in body weight in 
comparison to day 1 was observed in 2 of 3 rats at termination of the study. At 1.5 mg/kg/day, 
clinical observations included blood in urine, lethargy and hind limb paresis. Lethargy was 
observed in all three rats on days 3 and 4, hind limb paresis was observed on day 4, and blood in 
the urine was observed in 2 of 3 rats on day 4. In addition, mean body weight was statistically 
significantly decreased between days 3 and 4 in comparison to the control group for the 1.5 


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mg/kg/day group. A mean decrease (23%) in body weight in the 1.5 mg/kg/day dose group was 
also observed on day 4 when compared to day 1 body weights. 
Daily administration of LB-100 at 1.5 mg/kg/day for four consecutive days caused adverse 
effects in kidney (nephrosis) in the distal convoluted tubules in 3 of 3 rats; in the 0.75 mg/kg/day 
group, nephrosis was mild, and in the 0.5 mg/kg/day group, nephrosis was minimal.  
Heart toxicity (epicardial hyperplasia with inflammation primarily on the epicardium of the atria) 
was observed in the 0.75 and 1.5 mg/kg/day groups. The hyperplasia was accompanied by 
subepicardial accumulation of mononuclear cells and eosinophils.  One rat in the 1.5 mg/kg/day 
group had a large focus of inflammation with eosinophils associated with the aorta.   
Rats in the 1.5 mg/kg/day group had compound-related lesions in femoral bone (necrosis), liver 
(mesothelial hyperplasia in 3 of 3 rats) and urinary bladder (mucosal erosion with transmural 
hemorrhage). Blood in the urine was also noted in 2 of 3 rats in the 1.5 mg/kg/day group.  
Primary clinical signs of blood in the urine and clinical chemistry findings of increased blood 
urea nitrogen and creatinine supported kidney and urinary bladder as target organs of toxicity. 
Hind leg paresis was observed in rats at the 1.5 mg/kg/day dose level; there were no 
histopathology correlates that would explain the paresis. Other changes observed in the 1.5 
mg/kg/day group included significant weight loss, higher total white blood cell count, and 
eosinophil, basophil, lymphocyte, and monocyte counts, and a decrease in the percent of 
reticulocytes and platelet counts (day 4).  
A NOAEL was not established for this 4-day intravenous toxicity study in male Fischer rats.  
The MTD for LB-100 in this study was 0.75 mg/kg/day.  Kidney, heart, femoral bone, liver, and 
urinary bladder toxicity appeared to be dose-limiting toxicities in rats treated with LB-100 when 
administered intravenously once per day for four consecutive days. 
GLP Repeat-Dose Toxicity Study in Rats: The objective of this study was to assess the potential 
toxicities of the test article, LB-100, when administered as a slow bolus intravenous injection to 
Sprague Dawley rats daily for 5 consecutive days, as well as to determine the reversibility of any 
potentially adverse findings during a minimum 23-day recovery period. 
LB-100 in a 4.2% sterile sodium bicarbonate vehicle was administered by intravenous slow 
bolus push via infusion pump over an approximate 2-minute period once daily for 5 consecutive 
days to 3 toxicology groups (Groups 2-4) and 3 toxicokinetic groups (Groups 2A-4A) of 
Crl:CD(SD) rats.  Dose levels were 0.5, 0.75, and 1.25 mg/kg/day for Groups 2/2A, 3/3A, and 
4/4A, respectively.  Concurrent control groups (Groups 1 and 1A) received the vehicle on a 
comparable regimen.  The dose volume was 1.25 mL/kg for all groups.  Groups 1-4 each 
consisted of 15 animals/sex.  Group 1A consisted of 3 animals/sex, and Groups 2A-4A each 
consisted of 9 animals/sex.  Following 5 days of dose administration, 10 rats/sex per toxicology 
group were euthanized; the remaining 5 rats/sex per toxicology group were euthanized following 
a minimum 23-day non-dosing (recovery) period.   
All animals were observed twice daily for mortality and moribundity.  Clinical examinations 
were performed daily, and detailed physical examinations were performed approximately 
weekly.  Individual body weights were recorded daily during the dosing period and 
approximately weekly during the recovery period.  Individual food consumption was recorded 
approximately weekly (with the exception of study weeks 3 and 4).  Ophthalmic examinations 


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were performed on study days -2, 4, and 23 for males and -3, 4, and 22 for females.  Clinical 
pathology parameters (hematology, coagulation, serum chemistry, and urinalysis) were analyzed 
for rats assigned to the primary (study day 5) and recovery (study days 29 and 28 for males and 
females, respectively) necropsies.  Complete necropsies were conducted on all animals, and 
selected organs were weighed at the scheduled necropsies.  Selected tissues were examined 
microscopically from all animals.  For toxicokinetic evaluation, blood samples were collected 
from 3 animals/sex/group approximately 30 minutes following dose administration (Group 1A) 
and prior to dose administration, approximately 15 and 30 minutes following dose 
administration, and approximately 1, 4, and 12 hours following dose administration (Groups 2A-
4A) on study days 0 and 4.  All animals were euthanized and discarded on study day 6 (males) or 
5 (females). 
There were no test article-related effects on survival, clinical observations, or ophthalmic 
parameters.  Test article-related lower cumulative body weight gains and food consumption 
values were noted during the dosing period for the 1.25 mg/kg/day group males and/or females 
when compared with the control group but were reversible following a minimum 23-day non-
dosing (recovery) period.  Changes in laboratory parameters were observed in the 1.25 
mg/kg/day group. Hematological changes included test article-related higher lymphocyte counts 
in males and females on study day 5 versus control animals. Also observed in the 1.25 
mg/kg/day group were minimally higher basophil counts, which were thought to be possibly test 
article-related, though not biologically meaningful, in males and females.  Slightly higher counts 
of large unstained cell (LUC) counts were observed in the females on study day 5.  Slightly 
lower reticulocyte counts, considered to be likely related to the test article, occurred in males and 
females of the 1.25 mg/kg/day group. In general, the hematologic changes resolved during the 
recovery period, with the exception of partially resolved higher lymphocyte and leukocyte counts 
in females. 
The following abnormalities in clinical chemistry parameters were observed in the 1.25 mg/kg 
group: test article-related higher urea nitrogen, creatinine, phosphorus, and globulin values in 
males and/or females on study day 5.  Test article-related minimally lower albumin levels and 
lower A/G ratio values occurred in females.  These effects resolved during the recovery period.  
Slightly higher cholesterol values were also noted in the males on study day 5.  The higher 
cholesterol values may have been test article-related.  Higher gamma glutamyltransferase (GGT) 
values were noted in some males and females of the 1.25 mg/kg/day group, but it was not 
determined if the change was test article-related. 
Test article-related effects on urinalysis parameters were observed in all treatment groups and 
included an increase in incidence and severity of: urine occult blood in 0.5 mg/kg/day group 
males and 0.75 and 1.25 mg/kg/day group males and females, urine protein in 1.25 mg/kg/day 
females, and increase in microscopic observations of leukocytes in males and females of the 1.25 
mg/kg/day group, and in one female in both the 0.5 and 0.75 mg/kg/day group on study day 5.  
These changes were reversible. 
The following macroscopic pathology findings were reported in the 1.25 mg/kg/day group: test 
article-related pale kidneys in males at the primary necropsy, as well as test article-related higher 
kidneys weights in males and females.  At the recovery necropsy, kidney weights remained 
higher in 1.25 mg/kg/day group males.  


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Evaluation of microscopic pathology revealed adverse, test article-related nephrosis of the 
kidneys in the 0.75 and 1.25 mg/kg/day group males and females, which persisted or progressed 
in the males at the recovery necropsy.  Minimal to severe nephrosis was observed in the kidney 
and was characterized by tubular degeneration and regeneration in the cortex and/or medulla.  
Minimal to mild nephrosis was most often observed in the medulla and/or occasionally the 
cortex.  The 0.75 and 1.25 mg/kg/day group males had minimal to mild dilatation of the renal 
pelvis. The nephrosis correlated to pale kidneys in the males; higher kidney weights in the 1.25 
mg/kg/day group males and females; higher serum urea nitrogen, phosphorous, and creatinine 
levels, and higher incidence of urine occult blood, protein, and leukocytes in the 1.25 mg/kg/day 
group males and/or females.  Moderate nephrosis in the cortex and medulla persisted in the 0.75 
and 1.25 mg/kg/day males and was accompanied by moderate interstitial fibrosis at the recovery 
necropsy and was associated with higher kidney weights in the 1.25 mg/kg/day group males at 
the recovery necropsy.  Neither nephrosis nor interstitial fibrosis was observed in the females at 
the recovery necropsy. 
LB-100 administration resulted in subacute subepicardial inflammation and/or mesothelial 
hypertrophy in the atria of males at ≥ 0.5 mg/kg/day and at 1.25 mg/kg/day in the females at the 
primary necropsy and was considered adverse in one 1.25 mg/kg/day group male.  Minimal to 
mild subacute inflammation was observed in the epicardium and subepicardium of the left and/or 
right atrium of the heart in the 0.5, 0.75, and 1.25 mg/kg/day group males and the 1.25 
mg/kg/day group females.  One male in the 1.25 mg/kg/day group had mild subacute 
inflammation that was accompanied by minimal fibroplasia (plump fibroblasts) in the right 
atrium.  Inflammation was often accompanied by mesothelial hypertrophy.  There was a higher 
incidence of mesothelial hypertrophy in the 1.25 mg/kg/day group females when compared to the 
control group.  Mesothelial hypertrophy was observed in control and test article-treated males 
and did not show a dose response. 
Based on these findings, the severely toxic dose in 10% of the animals (STD 10) for this study 
was determined as 0.75 mg/kg/day.  This dose corresponds to AUClast values of 596 and 691 
ng∙h/mL and C0 values of 1804 and 2347 ng/mL for males and females, respectively, on study 
day 4.
Dose Ranging Toxicity Studies in Dogs: The objectives of this study were to evaluate the 
tolerability and potential toxic effects of LB-100 when administered by intravenous (slow bolus) 
injection to beagle dogs in an escalating dose design. LB-100, in 4.2% sterile sodium 
bicarbonate, pH 8.4, was administered by intravenous injection (slow bolus push) to beagle dogs 
at dose levels of 0.1, 0.25, 0.5, and 1.0 mg/kg administered on study days 0, 4, 8, and 12, 
respectively, to Groups 1, 2, 3, and 4, respectively.  The dose volume was 0.5 mL/kg for all 
groups. Each group consisted of 2 animals/sex.  Each dose administration was followed by a 3-
day washout period.   
The animals were observed twice daily for mortality and morbidity.  Clinical examinations were 
performed daily, and detailed physical examinations were performed approximately weekly 
during the pretest period, at the time of animal selection for randomization, and on the days of 
dosing, prior to each dose.  Individual body weights and food consumption were recorded daily.   


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There were no LB-100-related effects on survival.  A possible test article-related clinical 
observation of intermittent tremors was noted in one female on study day 13 following 
administration of LB-100 at 1.0 mg/kg.  Lower body weight gains and food consumption were 
noted in one or both females during study days 8-16, following test article administration at 0.5 
and 1.0 mg/kg. Based on the results of this study, LB-100 administered intravenously (slow 
bolus push) to beagle dogs at dose levels of 0.1, 0.25, 0.5, and 1.0 mg/kg every 4 days x 4 doses, 
resulted in a no-observed-effect level (NOEL) of 0.25 mg/kg.  At dose levels of 0.5 and 1.0 
mg/kg, lower body weight gains and food consumption were noted in females.   
GLP Repeat-Dose Dog Toxicity Study: The objective of this study was to assess the potential 
toxicities of the test article, LB-100, when administered as a slow bolus intravenous injection to 
beagle dogs, daily for 5 consecutive days, as well as to determine the reversibility of any 
potentially adverse findings during a minimum 23-day recovery period. 
LB-100, in 4.2% sterile sodium bicarbonate, pH 8.4, was administered via intravenous (slow 
bolus) push.   Dose levels of 0.15, 0.30, and 0.75 mg/kg/day were administered on study days 1 
to 5, to groups comprised of 10 dogs, 5 females and 5 males.  The intent was to sacrifice 3 
animals of each sex in each group the day following the fifth dose and 2 animals of each sex 23 
days after the fifth dose. One male and one female were found dead the morning following the 
third injection at the highest dose, 0.75 mg/kg.  As a result, the protocol was amended to 
decrease the highest dose level from 0.75 to 0.5 mg/kg for each of the remaining eight animals in 
the highest dose group. There were no further deaths. Note that a dose of 0.75 mg/kg in the dog 
(average weight of 9 kg and BSA of 0.5 m2) is about 13.8 mg/m2 or more than twice the MTD in 
the rat. This highest dose was selected because the dose range study in the dog revealed almost 
no signs of toxicity following a single dose of 1.0 mg/kg (approximately 18 mg/m2) in the dose 
ranging study.  
All animals were observed twice daily for mortality and moribundity.  Clinical examinations 
were performed daily, and detailed physical examinations were performed approximately 
weekly.  Individual body weights were recorded daily on the days of dosing and approximately 
weekly during the recovery period.  Food consumption was recorded daily.  Clinical pathology 
parameters (hematology, coagulation, serum chemistry, and urinalysis) were analyzed for all 
animals prior to randomization (study day -3) and for all surviving animals prior to the scheduled 
primary (study day 5) and recovery (study day 29) necropsies.  Blood samples for toxicokinetic 
evaluation were collected from all animals prior to dosing, approximately 15 and 30 minutes 
following dose administration, and approximately 1, 4, and 12 hours following dose 
administration on study days 0 and 4.  Ophthalmic examinations were performed on study days -
3, 3, and 28.  Electrocardiograms, heart rate, waveform intervals (PR, QRS, RR, QT, and QTcV), 
and blood pressure were recorded on study days -8, 4 (approximately 2 to 4 hours following dose 
administration), and 27.  Complete necropsies were performed on all animals, and selected 
organs were weighed at the scheduled necropsies.  Selected tissues were examined 
microscopically from all animals.   
Test article-related clinical observations for the animals that died early in the 0.75 mg/kg/day 
group included intermittent tremors, swollen forelimb(s), and/or emesis containing white 
material.  Necropsy of the two animals revealed both animals had similar test article-related 
macroscopic and microscopic findings affecting the gastrointestinal tract, kidneys, injection sites, 


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spleen, larynx, lungs and/or liver.  Test article-related macroscopic findings consisted of dark red 
discoloration of the kidneys, small spleens, and red discoloration (reddened mucosa or dark red 
areas) of various segments of the gastrointestinal tract in males and females.  Although the most 
noteworthy findings (mitotic figures and single cell necrosis of the renal tubular epithelial cells 
from the outer medulla and cortex) would be associated with altered renal function, these 
findings were not considered fatal lesions; therefore, the cause of death for each animal was 
considered undetermined but directly attributed to test article administration.  All other animals 
survived to the scheduled primary (study day 5) and recovery (study day 29) necropsies. 
There were no ophthalmic findings or changes in electrocardiography parameters and blood 
pressures associated with test article administration in any treatment groups. 
Animals in the 0.30 mg/kg/day group had the following clinical observations during the dosing 
period: reduced body weights and food consumption, intermittent tremors, hypoactivity, 
vocalization, thin body condition, labored respiration, clear material around mouth, abnormal 
excreta (decreased defecation, mucoid feces, and/or yellow or red mucoid feces), emesis 
(containing food or white material), pale gums, and/or swollen forelimb(s).  Most of these 
clinical findings were more prevalent towards the end of the dosing period. Macroscopic 
examination revealed lower thymus weights in the 0.30 mg/kg/day group females.  Also reported 
in the 0.30 mg/kg/day group were lower chloride and sodium levels and the presence of blood in 
the urine. 
Test article-related histological changes at the study day 5 primary necropsy consisted of 
congestion, basophilic tubules, and nephrosis of the kidney in the 0.15 (females only) and 0.30, 
and/or 0.75/0.50 mg/kg/day group and inflammation of the vagina and cervix in the 0.30 and 
group females.  Persistent test article-related changes in the kidneys were seen in the 0.30 
mg/kg/day group males and females at the study day 29 recovery necropsy.   
The surviving animals of the 0.75/0.5 mg/kg/day group exhibited test article-related clinical 
signs that included: reduced body weights and food consumption; also observed were impaired 
muscle coordination, intermittent tremors, hypoactivity, thin body condition, body and/or ear(s) 
cool to touch, increased respiration rate, green and red nasal discharge, clear and/or red material 
around nose or mouth and/or on ear(s), abnormal excreta (decreased defecation, mucoid feces, 
yellow and red mucoid feces, and diarrhea containing red material), emesis (containing food, 
white material, and/or yellow material), pale gums, and/or swollen forelimb(s).   
During the recovery period, all surviving animals had body weight gains indicative of recovery, 
and the majority of the other observed clinical signs resolved within the first few days of the 
recovery period.   
At the primary necropsy (study day 5), test article-related macroscopic findings consisted of dark 
red discoloration of the kidneys, small spleens, and red discoloration (reddened mucosa or dark 
red areas) of various segments of the gastrointestinal tract in the 0.75/0.50 mg/kg/day group 
males and females.  At the recovery necropsy (study day 29), no test article-related macroscopic 
findings were observed.   
Test article-related changes in organ weights at the study day 5 primary necropsy included the 
following: higher adrenal gland and kidney weights and lower spleen and thymus weights in the 


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0.75/0.50 mg/kg/day group males and females. At the recovery necropsy (study day 29), higher 
kidney weights were noted in the surviving male from the 0.75/0.50 mg/kg/day group.   
Test article-related effects on hematology and coagulation parameters at the study day 5 
evaluation included higher red blood cell mass (red blood cell count, hemoglobin, and 
hematocrit), lower platelet counts, and prolonged activated partial thromboplastin time values in 
the animals of the 0.75/0.50 mg/kg/day group.  At the study day 29 evaluation, there were no 
residual effects of test article administration on hematology or coagulation parameters.   
At the study day 5 evaluation, test article-related changes in serum chemistry parameters 
included higher urea nitrogen, creatinine, cholesterol, phosphorus, triglycerides, total bilirubin, 
alanine aminotransferase, aspartate aminotransferase, sorbitol dehydrogenase, and lower chloride 
and sodium levels in the 0.75/0.50 mg/kg/day group.  At study day 29, higher cholesterol and 
triglycerides values were noted for the surviving male in the 0.75/0.50 mg/kg/day group 
compared to the control group; however, a decrease from the study day 5 values was present 
suggestive of recovery.   
Test article-related changes in urinalysis parameters observed at the study day 5 evaluation 
included lower specific gravity, higher urine volume, and increased presence of blood in the 
0.75/0.50 mg/kg/day groups.  At study day 29, no test article-related changes in urinalysis 
parameters were present.  
Test article-related histological changes at the study day 5 primary necropsy in the 0.75/0.50 
mg/kg/day group consisted of: congestion, basophilic tubules, and nephrosis of the kidney; 
increased mitoses of the liver in males; lymphoid depletion or single cell necrosis of the lymph 
nodes, Peyer’s patches, and thymus; hypocellular bone marrow; erosion and hemorrhage within 
the gastrointestinal tract; and inflammation of the vagina and cervix in the females.  Persistent 
test article-related changes in the kidneys were seen in males and females at the study day 29 
recovery necropsy.   
In conclusion, administration of LB-100 via daily intravenous (slow bolus) injection for 5 days to 
male and female beagle dogs was well tolerated at the dosage level of 0.15 mg/kg/day.  At 
dosage levels of 0.30 and 0.75/0.50 mg/kg/day, administration of LB-100 resulted in adverse 
clinical observations, lower body weights, and histological findings (congestion and nephrosis in 
kidneys, increased mitoses and single cell necrosis in liver, lymphoid depletion and single cell 
necrosis in thymus, and/or erosion and/or hemorrhage in stomach or intestines) correlating with 
effects on clinical pathology, organ weight, and/or macroscopic findings during the dosing 
period.  Persistent adverse test article-related histological changes in the kidneys were observed 
in the 0.30 and 0.75/0.50 mg/kg/day group males and females at the day 29 recovery necropsy.  
These changes were more indicative of a progression towards chronicity rather than recovery.  In 
addition, lethality was observed at 0.75 mg/kg/day.  Therefore, the Highest Non-Severely Toxic 
Dose (HNSTD) was 0.15 mg/kg, which corresponded to an AUClast for LB-100 of 267 and 335 
ng•h/mL on study day 4 for males and females, respectively.  
Summary of Results of Toxicity Studies: Results indicate that in the mouse, 1.5 mg/kg 
(approximately 4.7 mg/m2) can be administered daily for 5 days (up to 20 days) without 
observable toxicity.  


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The results of the rat toxicity studies varied somewhat according to strain.  In Fischer rats, the 
MTD was 0.75 mg/kg (about 4.5 mg/m2) iv daily for 4 days.  Administration of 1.5 mg/kg/day 
for 4 days caused renal and bladder toxicity and transient hind limb paresis with no gross or 
microscopic evidence of neurological tissue damage.   
Administration of LB-100 via daily intravenous (slow bolus) injection for 5 days to male and 
female Sprague Dawley rats at dose levels of 0.5, 0.75, and 1.25 mg/kg/day resulted in adverse, 
test article-related nephrosis of the kidneys in the 0.75 and 1.25 mg/kg/day group males and 
females, which persisted or progressed in the 0.75 and 1.25 mg/kg/day group males at the 
recovery necropsy.  LB-100 administration resulted in subacute subepicardial inflammation 
and/or mesothelial hypertrophy in the atria of males at ≥ 0.5 mg/kg/day and at 1.25 mg/kg/day in 
the females at the primary necropsy and was considered adverse in one 1.25 mg/kg/day group 
male.   Based on these findings, the severely toxic dose in 10% of the animals (STD 10) for this 
study was determined as 0.75 mg/kg/day.  This dose corresponds to AUClast values of 596 and 
691 ng∙h/mL and C0 values of 1804 and 2347 ng/mL for males and females, respectively, on 
study day 4. 
Test article-related laboratory abnormalities were observed in rats administered LB-100 at the 
1.25 mg/kg dose level in the GLP toxicity study.  Hematologic changes included higher 
lymphocytes and leukocytes on day 5 that partially resolved in the recovery period.  Blood 
chemistry changes included increased urea nitrogen, creatinine, phosphorus, globulin, and 
cholesterol on day 5; most of these parameters resolved in the recovery period. Urinalysis 
showed blood, protein, and leukocytes in urine on day 5, but these changes were reversible 
during recovery. 
Administration of LB-100 via daily intravenous (slow bolus) injection for 5 days to male and 
female beagle dogs was well tolerated at the dosage level of 0.15 mg/kg/day.  At dosage levels of 
0.30 and 0.75/0.50 mg/kg/day, administration of LB-100 resulted in adverse clinical 
observations, lower body weights, and histological findings (congestion and nephrosis in 
kidneys, increased mitoses and single cell necrosis in liver, lymphoid depletion and single cell 
necrosis in thymus, and/or erosion and/or hemorrhage in stomach or intestines) correlating with 
effects on clinical pathology, organ weight, and/or macroscopic findings during the dosing 
period.  Persistent adverse test article-related histological changes in the kidneys were observed 
in the 0.30 and 0.75/0.50 mg/kg/day group males and females at the day 29 recovery necropsy.  
These changes were more indicative of a progression towards chronicity rather than recovery.  In 
addition, lethality was observed at 0.75 mg/kg/day.  Therefore, the Highest Non-Severely Toxic 
Dose (HNSTD) was 0.15 mg/kg, which corresponded to an AUClast for LB-100 of 267 and 335 
ng•h/mL on study day 4 for males and females, respectively.  
Test article-related laboratory abnormalities were observed in dogs administered LB-100 at the 
0.75/0.5 mg/kg dose level in the GLP toxicity study.  Hematologic changes included higher red 
blood cell mass (red blood cell count, hemoglobin, and hematocrit) and prolonged activated 
partial thromboplastin time (aPTT).  Blood chemistry changes included increased urea nitrogen, 
creatinine, cholesterol, phosphorus, triglycerides and some hepatic enzymes on day 5; the 
changes showed evidence of resolving during recovery.  Urinalysis on day 5 showed increased 


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presence of blood in urine, higher urine volume and lower specific gravity; these changes were 
not present at recovery. 
14.1.3 Formulation and preparation 
LB-100 for Injection is supplied as a sterile solution for intravenous administration.  Each vial 
contains 10 mL of a 1.0 mg/mL solution of LB100 in monosodium glutamate, pH 10.5.  
The appropriate dose of LB100 is to be drawn from the vial using a sterile syringe and added to 
normal saline (0.9%) before infusing intravenously.  Dilution in saline was done to reduce the 
pH so that the infusate is non-irritating (but extravasation is to be avoided).  However, 
intravenous infusion of LB100 diluted in 50-500 mL of normal saline and infused over 15 
minutes to 120 minutes, respectively, produced no local irritation (unpublished data of Lixte)
14.1.4 Stability and Storage 
LB100 is stored frozen at MRIGlobal, Kansas City, MO. Stability analysis is done annually and 
will be kept in the study/pharmacy records with the drug supply. Drug is shipped frozen and will 
be stored in the Clinical Center Pharmacy.
14.1.5 Administration procedures
The recommended dose of LB-100 for Phase 2 trials is based on the documented MTD dose of 
2.33 mg/m2 diluted in 500 mL normal sterile saline and infused over 2 hours daily for 3 
consecutive days repeated every three weeks.  In this Phase II study, we will administer a single 
dose of 2.33 mg/m2 in 500 mL normal sterile saline infused over 2 hours (+/- 15 minutes).
14.1.6 Incompatibilities  
None identified.


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15 REFERENCES 
References
1.
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. 
Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. The New England 
journal of medicine. 2005;352(10):987-96.
2.
Park DM, Li J, Okamoto H, Akeju O, Kim SH, Lubensky I, et al. N-CoR pathway 
targeting induces glioblastoma derived cancer stem cell differentiation. Cell cycle. 
2007;6(4):467-70.
3.
Lu J, Zhuang Z, Song DK, Mehta GU, Ikejiri B, Mushlin H, et al. The effect of a PP2A 
inhibitor on the nuclear receptor corepressor pathway in glioma. Journal of neurosurgery. 
2010;113(2):225-33.
4.
Wei D, Parsels LA, Karnak D, Davis MA, Parsels JD, Marsh AC, et al. Inhibition of 
protein phosphatase 2A radiosensitizes pancreatic cancers by modulating CDC25C/CDK1 and 
homologous recombination repair. Clin Cancer Res. 2013;19(16):4422-32.
5.
Gordon IK, Lu J, Graves CA, Huntoon K, Frerich JM, Hanson RH, et al. Protein 
Phosphatase 2A Inhibition with LB100 Enhances Radiation-Induced Mitotic Catastrophe and 
Tumor Growth Delay in Glioblastoma. Mol Cancer Ther. 2015;14(7):1540-7.
6.
Lv P, Wang Y, Ma J, Wang Z, Li JL, Hong CS, et al. Inhibition of protein phosphatase 
2A with a small molecule LB100 radiosensitizes nasopharyngeal carcinoma xenografts by 
inducing mitotic catastrophe and blocking DNA damage repair. Oncotarget. 2014;5(17):7512-24.
7.
Chang KE, Wei BR, Madigan JP, Hall MD, Simpson RM, Zhuang Z, et al. The protein 
phosphatase 2A inhibitor LB100 sensitizes ovarian carcinoma cells to cisplatin-mediated 
cytotoxicity. Mol Cancer Ther. 2015;14(1):90-100.
8.
Hong CS, Ho W, Zhang C, Yang C, Elder JB, Zhuang Z. LB100, a small molecule 
inhibitor of PP2A with potent chemo- and radio-sensitizing potential. Cancer Biol Ther. 
2015;16(6):821-33.
9.
Zhang C, Hong CS, Hu X, Yang C, Wang H, Zhu D, et al. Inhibition of protein 
phosphatase 2A with the small molecule LB100 overcomes cell cycle arrest in osteosarcoma 
after cisplatin treatment. Cell cycle. 2015;14(13):2100-8.
10.
Lecca S, Pelosi A, Tchenio A, Moutkine I, Lujan R, Herve D, et al. Rescue of GABAB 
and GIRK function in the lateral habenula by protein phosphatase 2A inhibition ameliorates 
depression-like phenotypes in mice. Nat Med. 2016;22(3):254-61.
11.
Ostrom QT, Gittleman H, Liao P, Rouse C, Chen Y, Dowling J, et al. CBTRUS statistical 
report: primary brain and central nervous system tumors diagnosed in the United States in 2007-
2011. Neuro Oncol. 2014;16 Suppl 4:iv1-63.
12.
Johnson DR, O'Neill BP. Glioblastoma survival in the United States before and during 
the temozolomide era. Journal of neuro-oncology. 2012;107(2):359-64.
13.
Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al. Effects 
of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on 
survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC 
trial. The Lancet Oncology. 2009;10(5):459-66.
14.
Lambrecht C, Haesen D, Sents W, Ivanova E, Janssens V. Structure, regulation, and 
pharmacological modulation of PP2A phosphatases. Methods Mol Biol. 2013;1053:283-305.


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Abbreviated Title: Phase II Study LB100 gliomas
Version Date:   06/02/2022
15.
Lu J, Kovach JS, Johnson F, Chiang J, Hodes R, Lonser R, et al. Inhibition of 
serine/threonine phosphatase PP2A enhances cancer chemotherapy by blocking DNA damage 
induced defense mechanisms. Proc Natl Acad Sci U S A. 2009;106(28):11697-702.
16.
Ho WS, Feldman MJ, Maric D, Amable L, Hall MD, Feldman GM, et al. PP2A inhibition 
with LB100 enhances cisplatin cytotoxicity and overcomes cisplatin resistance in 
medulloblastoma cells. Oncotarget. 2016.
17.
Rubinstein LV, Steinberg SM, Kummar S, Kinders R, Parchment RE, Murgo AJ, et al. 
The statistics of phase 0 trials. Stat Med. 2010;29(10):1072-6.


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16 APPENDICES 
16.1
PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no 
evidence of disease.
0
Normal activity.  Fully active, 
able to carry on all pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of 
disease.
80
Normal activity with effort; 
some signs or symptoms of 
disease.
1
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work).
70
Cares for self, unable to carry on 
normal activity or to do active 
work.
60
Requires occasional assistance, 
but is able to care for most of 
his/her needs.
2
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and 
about more than 50% of waking 
hours.
50
Requires considerable assistance 
and frequent medical care.
40
Disabled, requires special care 
and assistance.
3
In bed >50% of the time.  
Capable of only limited self-care, 
confined to bed or chair more 
than 50% of waking hours.
30
Severely disabled, 
hospitalization indicated.  Death 
not imminent.
20
Very sick, hospitalization 
indicated. Death not imminent.
4
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.


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16.2
PK WORKSHEET
Cover Letter Form
PKs to Dr. Figg’s Lab
Page: 102-11964
Samples must be retrieved and processed within 30 minutes.
PLEASE clearly label the PIVs for PK’s/LB-100 infusion, respectively. 
Protocol # 17-C-0037, Drug: LB-100
Cycle 1 Day 1
LB-100 Dose:_____________
Staff Obtaining Samples: ______________________________(printed name)  
Signature/initials: _____________________________
Staff Obtaining Samples: ______________________________(printed name)  
Signature/initials: _____________________________
Staff Obtaining Samples: _______________________________(printed name)  
Signature/initials: ____________________________
Staff Obtaining Samples: _______________________________(printed name)  
Signature/initials: ____________________________
Staff Obtaining Samples: _______________________________(printed name)  
Signature/initials: _____________________________
When documenting in CRIS, please include the details in your note:
-
Pre-chilled 6 ml Sodium Heparin tube
-
Date and time sample obtained
-
If the collection time differs from the “scanned time,” please indicate this in your note 
with actual time sample obtained. 
-
If sample or EKG is obtained outside of the protocol-defined time window (+/- 15 min), 
please indicate reason


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-
Update Research Nurse via phone or email if sample outside of the defined window.


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16.3
PK ASSAY VALIDATION
16.3.1 LB-100 Plasma
Sample Name
Calculated Concentration
LB-100
Day 1
Day 2
Day 3
Day 4
H
1.041
1.989
1.885
1.87
G
4.458
4.873
5.084
5.448
F
20.07
20.78
20.66
20.69
E
40.68
40.99
41.20
42.32
D
202.50
210.30
192.60
213.00
C
402.90
401.70
379.60
404.10
B
814.60
875.50
885.90
828.10
A
957.40
968.20
938.90
962.70
LOQ
0.77
1.97
2.13
1.85
LQC
5.10
7.19
5.78
6.32
MQC
41.23
39.10
39.51
41.96
HQC
736.30
767.00
771.30
727.50
DQC
5121.00
5205.00
4954.00
4771.00
LOQ
2.06
1.94
1.76
1.90
LQC
5.06
8.02
6.20
6.41
MQC
39.66
40.16
39.30
40.93
HQC
754.20
780.20
770.00
730.60
DQC
4886.00
5244.00
4809.00
4810.00
LOQ
1.09
2.03
2.01
2.22
LQC
5.10
7.37
5.83
6.51


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MQC
40.00
40.39
39.98
38.36
HQC
718.90
791.20
763.20
709.60
DQC
4890.00
5239.00
4876.00
5054.00
LOQ
2.08
2.20
1.96
2.12
LQC
5.38
7.56
5.90
6.11
MQC
40.32
41.91
39.57
40.98
HQC
743.10
800.90
766.90
735.40
DQC
5104.00
5378.00
4840.00
4721.00
LOQ
1.36
2.11
1.97
2.05
LQC
5.22
7.60
6.07
5.86
MQC
41.02
41.37
39.13
40.58
HQC
762.80
775.40
793.70
775.40
DQC
5005.00
5277.00
4893.00
4802.00
H
1.93
2.02
2.07
2.00
G
5.85
5.08
5.05
5.27
F
21.47
18.98
21.08
19.71
E
41.27
37.18
42.51
41.61
D
208.20
212.80
202.40
199.80
C
414.90
414.20
404.30
399.70
B
848.70
866.70
885.90
821.80
A
943.50
1001.00
974.30
933.20
2/18/2016
2/19/2016
2/22/2016
2/23/2016
Linearity
AVG
SD


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Day 1
0.994049
0.99659875
0.001934316
Day 2
0.998141
Day 3
0.998061
Day 4
0.996144
Nomin
al 
(ng/mL
)
Day 
1-1
Da
y 
1-2
Day 
2-1
Day 
2-2
Day 
3-1
Day 3-
2
Da
y 4-
1
Day 4-
2
GM 
(ng/
mL)
SD 
(ng/
mL)
DEV 
(%)
R.S.D 
(%)
n
2
1.9
3
1.9
9
2.0
2
1.8
9
2.07
1.8
7
2.00
1.97
0.07
-
1.68
%
3.75
%
7
5.00
4.46
5.8
5
4.8
7
5.0
8
5.0
8
5.05
5.4
5
5.27
5.14
0.41
2.80
%
7.96
%
8
20.00
20.0
7
21.
47
20.
78
18.
98
20.
66
21.08
20.
69
19.71
20.43
0.80
2.15
%
3.92
%
8
40.00
40.6
8
41.
27
40.
99
37.
18
41.
20
42.51
42.
32
41.61
40.97
1.66
2.43
%
4.04
%
8
200.00
202.
50
20
8.2
0
210
.30
212
.80
192
.60
202.4
0
21
3.0
0
199.80
205.2
0
7.14
2.60
%
3.48
%
8
400.00
402.
90
41
4.9
0
401
.70
414
.20
379
.60
404.3
0
40
4.1
0
399.70
402.6
8
10.8
8
0.67
%
2.70
%
8
900.00
814.
60
84
8.7
0
875
.50
866
.70
885
.90
885.9
0
82
8.1
0
821.80
853.4
0
29.1
4
-
5.18
%
3.41
%
8
1000.0
0
957.
40
94
3.5
0
968
.20
100
1.0
0
938
.90
974.3
0
96
2.7
0
933.20
959.9
0
22.0
5
-
4.01
%
2.30
%
8


67
Abbreviated Title: Phase II Study LB100 gliomas
Version Date:   06/02/2022
LLOQ QC
Day 1
Day 2
Day 3
Day 4
GM
SD
DEV
2 ng/mL
0.77
1.97
2.13
1.85
1.88
0.377066079
-6.11%
 
2.06
1.94
1.76
1.90
 
 
 
1.09
2.03
2.01
2.22
 
 
 
2.08
2.20
1.96
2.12
 
 
 
1.36
2.11
1.97
2.05
 
 
ANOVA
Source of 
Variation
SS
df
MS
F
P-value
Between 
Groups
1.123
3
0.3744
F (3, 16) = 3.799
P = 0.0313
Within Groups
1.577
16
0.09855
Total
2.7
19
BRP
12.51
WRP
16.72
Low QC
Day 1
Day 2
Day 3
Day 4
GM
SD
DEV
6 ng/mL
5.10
7.19
5.78
6.32
6.23
0.90406471
3.84%
 
5.06
8.02
6.20
6.41
 
 
 
5.10
7.37
5.83
6.51
 
 
 
5.38
7.56
5.90
6.11
 
 
 
5.22
7.60
6.07
5.86
 
 


68
Abbreviated Title: Phase II Study LB100 gliomas
Version Date:   06/02/2022
ANOVA
Source of 
Variation
SS
df
MS
F
P-value
Between 
Groups
14.66
3
4.886
F (3, 16) = 92.41
P < 0.0001
Within Groups
0.846
16
0.05287
Total
15.5
19
BRP
15.78
WRP
3.69
Middle QC
Day 1
Day 2
Day 3
Day 4
GM
SD
DEV
40 ng/mL
41.23
39.10
39.51
41.96
40.27
0.977607714
0.68%
 
39.66
40.16
39.30
40.93
 
 
 
40.00
40.39
39.98
38.36
 
 
 
40.32
41.91
39.57
40.98
 
 
 
41.02
41.37
39.13
40.58
 
 
ANOVA
Source of 
Variation
SS
df
MS
F
P-value
Between Groups
4.06
3
1.353
F (3, 16) = 1.536
P = 0.2437
Within Groups
14.1
16
0.8811
Total
18.16
19
BRP
0.76


69
Abbreviated Title: Phase II Study LB100 gliomas
Version Date:   06/02/2022
WRP
2.33
High QC
Day 1
Day 2
Day 3
Day 4
GM
SD
DEV
800 ng/mL
736.30
767.00
771.30
727.50
758.68
25.75993625
-5.17%
 
754.20
780.20
770.00
730.60
 
 
 
718.90
791.20
763.20
709.60
 
 
 
743.10
800.90
766.90
735.40
 
 
 
762.80
775.40
793.70
775.40
 
 
ANOVA
Source of 
Variation
SS
df
MS
F
P-value
Between 
Groups
7831
3
2610
F (3, 16) = 8.744
P = 0.0012
Within Groups
4777
16
298.5
Total
12608
19
BRP
2.83
WRP
2.28
Dilution QC
Day 1
Day 2
Day 3
Day 4
GM
SD
DEV
5000 ng/mL
5121
5205
4954
4771
4993.95
195.6991448
-0.12%
 
4886
5244
4809
4810
 
 
 
4890
5239
4876
5054
 
 
 
5104
5378
4840
4721
 
 


70
Abbreviated Title: Phase II Study LB100 gliomas
Version Date:   06/02/2022
 
5005
5277
4893
4802
 
 
ANOVA
Source of 
Variation
SS
df
MS
F
P-value
Between Groups
7831
3
2610
F (3, 16) = 8.744
P = 0.0012
Within Groups
4777
16
298.5
Total
12608
19
BRP
2.83
WRP
2.28
Dilution QC
Day 1
Day 2
Day 3
Day 4
GM
SD
DEV
5000 ng/mL
5121
5205
4954
4771
4993.95
195.6991448
-0.12%
 
4886
5244
4809
4810
 
 
 
4890
5239
4876
5054
 
 
 
5104
5378
4840
4721
 
 
 
5005
5277
4893
4802
 
 
ANOVA
Source of 
Variation
SS
df
MS
F
P-value
Between 
Groups
580675
3
193558
F (3, 16) = 21.07
P < 0.0001
Within Groups
146990
16
9187
Total
727665
19


71
Abbreviated Title: Phase II Study LB100 gliomas
Version Date:   06/02/2022
BRP
3.85
WRP
1.92
16.3.2 LB-100 Tissue
Sample Name
Calculated Concentration
LB-100 tissue
Day 1
Day 2
Day 3
H
3.05
2.67
3.22
G
9.25
10.19
10.55
F
28.17
32.70
31.86
E
101.13
106.41
101.28
D
292.02
294.28
292.85
C
996.24
942.92
960.10
B
2905.33
2903.10
2879.97
A
10135.85
10350.06
9981.22
LOQ
2.89
3.21
2.66
LQC
7.03
8.17
7.00
MQC
1871.82
1876.91
1722.76
HQC
7756.64
7715.07
7816.03
LOQ
2.98
2.97
3.02
LQC
6.92
7.27
6.56
MQC
1849.08
1876.22
1816.34
HQC
8213.18
7792.95
7608.25
LOQ
1.80
3.57
2.64


72
Abbreviated Title: Phase II Study LB100 gliomas
Version Date:   06/02/2022
LQC
6.40
7.88
6.91
MQC
1906.27
1790.11
1838.19
HQC
8234.50
8057.81
7662.84
LOQ
1.04
2.66
3.63
LQC
6.92
8.00
7.32
MQC
1935.47
1846.60
1827.07
HQC
8129.39
7774.61
7650.04
LOQ
4.21
4.97
2.73
LQC
6.84
7.45
7.61
MQC
1967.56
1787.57
1882.56
HQC
8266.66
7652.88
7927.77
H
3.02
3.26
2.68
G
1.50
9.96
10.27
F
30.41
33.43
31.29
E
112.10
97.67
100.82
D
301.06
285.99
292.89
C
1014.10
931.49
953.40
B
1422.93
2804.38
2873.89
A
4232.95
10256.63
10519.78
4/27/2016
5/2/2016
5/3/2016
Linearity
AVG
SD
Day 1
0.997142045
0.996223902
0.001404329
Day 2
0.99460729


73
Abbreviated Title: Phase II Study LB100 gliomas
Version Date:   06/02/2022
Day 3
0.996922372
Nomina
l 
(pg/mg)
Day 
1-1
Day 
1-2
Day 
2-1
Day 
2-2
Day 
3-1
Day 3-
2
GM 
(ng/
mL)
SD 
(ng/mL)
DEV 
(%)
R.S.D 
(%)
n
3
3.05
3.02
2.67
3.26
3.22
2.68
2.98
0.26
-
0.56%
8.59
%
6
10.00
9.25
 
10.1
9
9.96
10.5
5
10.27
10.04
0.49
0.44%
4.89
%
5
30.00
28.1
7
30.4
1
32.7
0
33.4
3
31.8
6
31.29
31.31
1.87
4.37%
5.96
%
6
100.00
101.
13
112.
10
106.
41
97.6
7
101.
28
100.82
103.2
4
5.17
3.24%
5.01
%
6
300.00
292.
02
301.
06
294.
28
285.
99
292.
85
292.89
293.1
8
4.83
-
2.27%
1.65
%
6
1000.00
996.
24
1014
.10
942.
92
931.
49
960.
10
953.40
966.3
8
32.08
-
3.36%
3.32
%
6
3000.00
2905
.33
 
2903
.10
2804
.38
287
9.97
2873.8
9
2873.
33
40.95
-
4.22%
1.43
%
5
10000.0
0
1013
5.85
 
1035
0.06
1025
6.63
998
1.22
10519.
78
1024
8.71
205.00
2.49%
2.00
%
5
LLOQ QC
Day 1
Day 2
Day 3
GM
SD
DEV
3 pg/mg
2.89
3.21
2.66
3.00
0.91963
-0.04%
 
2.98
2.97
3.02
 
 
 
1.80
3.57
2.64
 
 
 
1.04
2.66
3.63
 
 
 
4.21
4.97
2.73
 
 


74
Abbreviated Title: Phase II Study LB100 gliomas
Version Date:   06/02/2022
ANOVA
Source of 
Variation
SS
df
MS
F
P-value
Between 
Groups
2.019
2
1.009
F (2, 12) = 1.233
P = 0.3258
Within Groups
9.821
12
0.8184
Total
11.84
14
BRP
6.51
WRP
30.17
Low QC
Day 1
Day 2
Day 3
GM
SD
DEV
8 pg/mg
7.03
8.17
7.00
7.22
0.51941
-9.77%
 
6.92
7.27
6.56
 
 
 
6.40
7.88
6.91
 
 
 
6.92
8.00
7.32
 
 
 
6.84
7.45
7.61
 
 
ANOVA
Source of 
Variation
SS
df
MS
F
P-value
Between 
Groups
2.316
2
1.158
F (2, 12) = 9.509
P = 0.0034
Within Groups
1.461
12
0.1218
Total
3.777
14
BRP
6.31


75
Abbreviated Title: Phase II Study LB100 gliomas
Version Date:   06/02/2022
WRP
4.83
Middle QC
Day 1
Day 2
Day 3
GM
SD
DEV
2000 pg/mg
1871.82
1876.91
1722.76
1852.97
61.2912
-7.35%
 
1849.08
1876.22
1816.34
 
 
 
1906.27
1790.11
1838.19
 
 
 
1935.47
1846.60
1827.07
 
 
 
1967.56
1787.57
1882.56
 
 
High QC
Day 1
Day 2
Day 3
GM
SD
DEV
8000 pg/mg
7756.64
7715.07
7816.03
7883.91
234.934
-1.45%
 
8213.18
7792.95
7608.25
 
 
 
8234.50
8057.81
7662.84
 
 
 
8129.39
7774.61
7650.04
 
 
 
8266.66
7652.88
7927.77
 
 
ANOVA
Source of 
Variation
SS
df
MS
F
P-value
Between 
Groups
429092
2
214546
F (2, 12) = 7.492
P = 0.0077
Within Groups
343626
12
28636
Total
772718
14
BRP
2.45


76
Abbreviated Title: Phase II Study LB100 gliomas
Version Date:   06/02/2022
WRP
2.15

ICF_001.pdf: 
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date:   06-02-2022
Page 1 of 12
CC pre rCR ICF template v. 05.05.2020
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR:  Eric Burton, M.D.
STUDY TITLE:
Phase II Trial of LB100, a Protein Phosphatase 2A Inhibitor, in Recurrent 
Gliomas
STUDY SITE:
NIH Clinical Center
Cohort: Affected Study Patient
Consent Version: 06/02/2022 
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Principal Investigator: 
Eric Burton, MD
240-760-6030
eric.burton@nih.gov
This consent form describes a research study and is designed to help you decide if you would like 
to be a part of the research study.  
The remaining document will now describe the research study in more detail.  This information 
should be considered before you make your choice. Members of the study team will talk with you 
about the information described in this document. Some people have personal, religious, or ethical 
beliefs that may limit the kinds of medical or research interventions in which they would want to 
participate.  Take the time you need to ask any questions and discuss this study with NIH staff, 
and with your family, friends, and personal health care providers. 
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 
must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research.  
WHY IS THIS STUDY BEING DONE?
This study will test an investigational drug called LB100. The safety profile of LB100 is uncertain 
since only 29 people have been treated and most of those were not treated at the dose used in this 
study. An “investigational drug” is a drug that is being tested and is not approved for sale in the 
United States by the Food and Drug Administration (FDA). The purpose of this research study is 
to find out if LB100 can pass into your brain. Your brain is separated from the rest of your blood 
stream by a membrane called the “blood- brain barrier.” This is like a filter that protects your brain 
but is also a challenge when medications need to get into your brain. You have a brain tumor that 
IRB NUMBER: 17C0037
IRB APPROVAL DATE: 07/13/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date:   06-02-2022
Page 2 of 12
CC pre rCR ICF template v. 05.05.2020
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
requires surgery. We want to give you a dose of LB100 before your surgery and then take samples 
of your blood during and after surgery; and the tumor tissue that is being removed during surgery. 
We will then measure how much LB100 is in your blood and how much gets into your brain. This 
may help us use LB100 to treat brain tumors in the future.
WHY ARE YOU BEING ASKED TO TAKE PART IN THIS STUDY?
We are asking you to be in this study because you have a brain tumor that has recurred after your 
standard treatment and requires surgery.
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
Up to 25 participants will take part in this study. 
DESCRIPTION OF RESEARCH STUDY
What will happen if you take part in this research study?
If you agree to be in this study, we will ask you to do the following things:
Before you begin the study
Before you can start this protocol, we will do an evaluation to see if you are eligible to participate 
in this study. This will include a physical examination and blood laboratory studies. We may also 
need to collect all the urine you produce over 24 hours. You will need to see a neurosurgeon to be 
evaluated for surgery. You will also need to have an MRI of the brain if you have not had one in 
28 days.  If you are unable to have an MRI, you may have a CT Scan instead of an MRI.   Your 
healthcare provider will tell you which one you will have.  An EKG will be done. We must also 
be certain we have complete information about your history any past treatments, including 
surgeries. If available, we will request surgical tissue samples from prior surgeries. Women who 
are capable of having children will have a pregnancy test. You cannot take part in this study if you 
are pregnant. Also, you must not be taking certain medications or eating foods that strongly alter 
liver function.
These include cimetidine, ketoconazole, fluconazole, erythromycin, ciprofloxacin, omeprazole, 
phenytoin, phenobarbital, carbamazepine, or drinking a large volume of alcohol or any grapefruit 
juice. If you are unsure about the other medications that you are taking, please discuss them with 
the study team.
Any concerns you or your clinician may have can be further explored, and you may be referred to 
a specialist for further evaluation or treatment if necessary.
During the study
If you are found to be eligible to take part in this study, you will be scheduled for removal of your 
brain tumor in the operating room. You will be admitted to the Clinical Center for your surgery.
You will receive LB100 at a dose of 2.33 mg/m2 though a temporary plastic tube which is placed 
into a vein (IV) over 2 hours 2-4 hours prior to surgery.
Blood samples will be collected at the following time points: 1) Before LB100 infusion; 2) At the 
completion of LB100 infusion); 3) 30 minutes after LB100 infusion; 4) 1 hour after LB100 
IRB NUMBER: 17C0037
IRB APPROVAL DATE: 07/13/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date:   06-02-2022
Page 3 of 12
CC pre rCR ICF template v. 05.05.2020
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
infusion; 5) 2 hours after LB100 infusion; 6) 4 hours after LB100 infusion; and 7) 8 hours after 
LB100 infusion.
Glioma tissue sampling to measure LB100 will be performed in the operating room during your 
surgery. The number of tumor samples taken will depend on the length of your surgery.
You will receive an EKG at the end of the infusion. An electrocardiogram (EKG) is a test that 
gives us a measure of the heart’s electrical activity. You will be asked to lie flat on a table and 
several small electrode pads (like stickers) will be placed on the body. This test takes about 10 
minutes.
Study visits
During the first week after infusion with LB100, you will have routine blood tests to check your 
kidney and liver function.
Two to three weeks after you are discharged from the hospital after your surgery, you will come 
into the clinic or see your physician to have an exam and some routine blood tests performed. 
About a month after the surgery, you will be contacted either in person or by phone to discuss any 
problems or concerns you may have. After that contact, if you are doing fine, you will no longer 
be a participant of the study. A member of the study team will not contact you again unless you 
are experiencing problems when we talk to you.
BIRTH CONTROL
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
we don’t know how this medicine would affect your baby or your unborn child. If you are a woman 
who can become pregnant, or are the partner of a woman who can become pregnant, you will need 
to practice an effective form of birth control before starting study treatment, during study treatment 
and for 30 days after the last dose of study medication. If you think that you or your partner is 
pregnant, you should tell your study doctor or nurse at once.
Effective forms of birth control include:

abstinence

intrauterine device (IUD)

hormonal [birth control pills, injections, or implants]

tubal ligation

vasectomy
RISKS OR DISCOMFORTS OF PARTICIPATION
What side effects or risks can I expect from being in this study?
While on the study, you are at risk for these side effects. You should discuss these with your doctor. 
There also may be other side effects that we cannot predict. Other drugs will be given to make side 
effects less serious and uncomfortable.
IRB NUMBER: 17C0037
IRB APPROVAL DATE: 07/13/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date:   06-02-2022
Page 4 of 12
CC pre rCR ICF template v. 05.05.2020
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
LB100 risks
COMMON, SOME MAY BE SERIOUS
The following possibly related risks were reported for ≥ 25% of people receiving LB100:
•
Fatigue.
OCCASIONAL, SOME MAY BE SERIOUS
The following possible related risks were reported for ≥ 10% but ≤ 25% of people receiving LB100
•
Temporary elevation of blood measures of kidney function.
•
Temporary elevation of blood measures of liver function.
•
Headache
•
Increase blood concentration of sodium.
•
Decrease in a blood measure of liver function.
•
Nausea.
•
Fever.
•
Abdominal discomfort.
•
Abdominal distension.
•
Anemia.
•
Joint pain.
•
Yeast infections.
•
Chest pain.
•
Chills.
•
Constipation.
•
Decreased appetite.
Please tell the study doctor or study staff right away if you have any side effects. Please tell them 
if you have any other problems with your health or the way you feel during the study, whether or 
not you think they are related to the study drug.
You should inform the study doctor before you start any new medications, including prescription, 
over-the-counter, or herbal products. If you are having stomach upset, consult with your physician 
for recommended medications.
Other Risks
Blood draws may cause pain, bleeding, and/or bruising. You may faint and/or develop an infection 
with redness and irritation of the vein at the site where blood is drawn. Frequent blood collection 
may cause anemia (low red blood cell count), which may create a need for blood transfusions.
IRB NUMBER: 17C0037
IRB APPROVAL DATE: 07/13/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date:   06-02-2022
Page 5 of 12
CC pre rCR ICF template v. 05.05.2020
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
EKGs may cause some redness or itching where the pads are placed. Other than the minor skin 
irritation from the electrodes there are no expected risks related to the EKG.
LB100 may involve unpredictable risks to the study participants.
Risks for MRI
MRI scans cannot be done on people who have a cardiac pacemaker, neural pacemaker, surgical 
metal clips in the brain or on blood vessels, cochlear implants, or foreign metal objects within the 
eye. At the time of your MRI, you will be asked about these things. When you are in the scanning 
machine, a feeling of claustrophobia may come over you, and there will be a repetitive thumping 
noise. Cool air will surround you, and the room is lit so you will not feel like you are in a cave or 
underground. It is important to remain still during the MRI scan. If you are very claustrophobic in 
MRI scanners, you may ask your physician for a mild sedative for the procedure. If you do this, 
you must not drive a vehicle after the MRI. You can notify the MRI technologist of any discomfort 
you feel. The medicine that is used for the injection may rarely (1:2000) cause an allergic reaction 
such as hives, shortness of breath, or low blood pressure. The medical personnel in the MRI room 
are prepared to treat you for this kind of reaction. The MRI study will be stopped.
Risks for gadolinium enhanced MRI scans:
Procedure
During part of the MRI you will receive gadolinium, a contrast agent, through an intravenous (iv) 
catheter.   It will be done for research and medical purposes.
It is not known if MRI with contrast is completely safe for a developing fetus. Therefore, all 
women of childbearing potential will have a pregnancy test performed no more than 24 hours 
before each MRI scan with contrast. The scan will not be done if the pregnancy test is positive.
Risks
The risks of an IV catheter include bleeding, infection, or inflammation of the skin and vein with 
pain and swelling.  
Mild symptoms from gadolinium infusion occur in   fewer than 1% of those who receive it and 
usually go   away quickly.  Mild symptoms may include coldness in the arm during the    
injection, a metallic taste, headache, and    nausea.  In an extremely small number, fewer than 
one in 300,000 people, more severe symptoms have been reported including shortness of   
breath, wheezing, hives, and lowering of blood pressure. You should not receive gadolinium if   
you previously had an allergic reaction to   it.  You will be asked about such allergic reactions 
before gadolinium is given.   People with kidney disease are at risk for a serious reaction to   
gadolinium contrast called “nephrogenic systemic fibrosis (NSF)”.  This condition always 
involves the skin and can also involve the muscles, joints and internal organs.  NSF has    
resulted in   a very small number of deaths.  A blood test of your kidney function may be done 
within the month before an   MRI scan with gadolinium contrast. You will not receive 
IRB NUMBER: 17C0037
IRB APPROVAL DATE: 07/13/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date:   06-02-2022
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CC pre rCR ICF template v. 05.05.2020
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
gadolinium for a research MRI scan if your kidney function is below the safe level. Most of the    
gadolinium contrast leaves the body in the urine.  However, the FDA has issued a safety alert 
that indicates small amounts of gadolinium may remain in the body for months to years.  The 
effects of the retained gadolinium are not clear. At this time, retained gadolinium has not been 
linked to health risks in people whose kidneys work well.  Some types of gadolinium contrast 
drugs are less likely to remain in the body than others.  In this study, we will use the    
gadolinium contrast drugs that are less likely to remain in the body, whenever possible. We will 
also give you additional information called a “Medication Guide.”  Upon request, we will give 
you individual information about retained gadolinium we see on your studies.
CT Scans
In addition to the radiation risks from the scans, you may experience an allergic reaction to the dye 
we inject into your veins to help us view the scan better.  You might experience hives, itching, 
headache. More serious reactions that would include difficulty breathing, increased heartrate and 
swelling of your throat or other body parts. 
What are the risks of radiation from being in the study?
During your participation in this research study, you will be exposed to radiation from a CT 
Scan.   This is considered a low exposure. The risk of this exposure is too low to be reliably 
measured. Every day, people are exposed to   low levels of   radiation that come from the sun and 
the environment around them.  This type of radiation is called “background radiation”.  No one 
knows for sure whether exposure to these low amounts of radiation is harmful to your body.  The 
radiation you will get by participating in this study is less than the average yearly background 
radiation in the United States.
You may not participate in this study if you are pregnant. If you are able to become pregnant, we 
will perform a pregnancy test before exposing you to radiation. You must tell us if you may have 
become pregnant within the previous 14 days because the pregnancy test is unreliable during that 
time.
POTENTIAL BENEFITS OF PARTICIPATION
Are there benefits to taking part in this study?
The aim of this study is to determine if LB100 can cross the blood- brain barrier. We do not yet 
know whether LB100 can help treat brain tumors, or even whether it can cross the blood-brain 
barrier.Because there is not much information about the drug’s effect on your cancer, we do not 
know if you will benefit from taking part in this study, although the knowledge gained from this 
study may help others in the future who have cancer.
ALTERNATIVE APPROACHES OR TREATMENTS
What other choices do I have if I do not take part in this study?
Instead of being in this study, you have these options:

Instead of being in this study, you have could have a different treatment including surgery 
without LB100 for your relapsed brain tumor. You do not have to join this study.
IRB NUMBER: 17C0037
IRB APPROVAL DATE: 07/13/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date:   06-02-2022
Page 7 of 12
CC pre rCR ICF template v. 05.05.2020
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY

Taking part in another study

Getting comfort care, also called palliative care. This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer. It does not treat the 
cancer directly. Instead, it tries to improve how you feel. Comfort care tries to keep you as 
active and comfortable as possible.
Please talk to your doctor about these and other options.
STOPPING THERAPY
Your doctor may decide to stop your therapy for the following reasons:

if he/she believes that it is in your best interest

if during the time of surgery, it is confirmed that you do not have tumor tissue in your brain 
that can be sampled, you will not have the blood samples performed
In this case, you will be informed of the reason therapy is being stopped. Your participation in this 
study will end approximately one month after your surgery.
You can stop taking part in the study at any time. However, if you decide to stop taking part in the 
study, we would like you to talk to the study doctor and your regular doctor first.
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to Lixte Biotechnology 
Holdings, Inc. or designated representatives. If you withdraw your consent and leave the trial, any 
samples of yours that have been obtained for the study and stored at the NCI can be destroyed 
upon request. However, any samples and data generated from the samples that have already been 
distributed to other researchers or placed in the research databases cannot be recalled and 
destroyed.
CONFLICT OF INTEREST
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest. This process is detailed in a Protocol Review Guide.  You may ask your research team 
for a copy of the Protocol Review Guide or for more information. Members of the research team 
who do not work for NIH are expected to follow these guidelines but they do not need to report 
their personal finances to the NIH.
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study. This is allowed under federal rules and is not a 
conflict of interest.
The National Institutes of Health and the research team for this study have developed a drug being 
used in this study. This means it is possible that the results of this study could lead to payments to 
NIH scientists and to the NIH. By law, government scientists are required to receive such payments 
for their inventions. You will not receive any money from the development of LB100.
IRB NUMBER: 17C0037
IRB APPROVAL DATE: 07/13/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date:   06-02-2022
Page 8 of 12
CC pre rCR ICF template v. 05.05.2020
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
The National Institutes of Health and the research team for this study are using LB100 developed 
by Lixte Biotechnology through a joint study with your researchers and the company. The 
company also provides financial support for this study.
USE OF SPECIMENS AND DATA FOR FUTURE RESEARCH
To advance science, it is helpful for researchers to share information they get from studying human 
samples. They do this by putting it into one or more scientific databases, where it is stored along 
with information from other studies. A researcher who wants to study the information must apply 
to the database and be approved. Researchers use specimens and data stored in scientific databases 
to advance science and learn about health and disease.
We plan to keep some of your specimens and data that we collect and use them for future research 
and share them with other researchers. We will not contact you to ask about each of these future 
uses. These specimens and data will be stripped of identifiers such as name, address or account 
number, so that they may be used for future research on any topic and shared broadly for research 
purposes. Your specimens and data will be used for research purposes only and will not benefit 
you. It is also possible that the stored specimens and data may never be used.
Results of research done on your specimens and data will not be available to you or your doctor. 
It might help people who have cancer and other diseases in the future.
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data. Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers.
COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will you receive compensation for participation in the study?
Some NIH Clinical Center studies offer compensation for participation in research. The amount 
of compensation, if any, is guided by NIH policies and guidelines.
You will not receive compensation for participation in this study. 
Will you receive reimbursement or direct payment by NIH as part of your participation?
Some NIH Clinical Center studies offer reimbursement or payment for travel, lodging or meals 
while participating in the research. The amount, if any, is guided by NIH policies and guidelines.
On this study, the NCI will cover the cost for some of your expenses.  Some of these costs may be 
paid directly by the NIH and some may be reimbursed after you have paid. The amount and form 
of these payments are determined by the NCI Travel and Lodging Reimbursement Policy.   You 
will be given a summary of the policy which provides more information.
IRB NUMBER: 17C0037
IRB APPROVAL DATE: 07/13/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date:   06-02-2022
Page 9 of 12
CC pre rCR ICF template v. 05.05.2020
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. 
What are the costs of taking part in this study?
If you choose to take part in the study, the following will apply, in keeping with the NIH policy:

You will receive study treatment at no charge to you. This may include surgery, medicines, 
laboratory testing, x-rays or scans done at the Clinical Center, National Institutes of Health 
(NIH), or arranged for you by the research team to be done outside the Clinical Center, 
NIH if the study related treatment is not available at the NIH.

There are limited funds available to cover the cost of some tests and procedures performed 
outside the Clinical Center, NIH. You may have to pay for these costs if they are not 
covered by your insurance company.

Medicines that are not part of the study treatment will not be provided or paid for by the 
Clinical Center, NIH.
Once you have completed taking part in the study, medical care will no longer be provided by the 
Clinical Center, NIH.
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY  
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be kept 
private.  However, we cannot guarantee total privacy.  Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include:

The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people.

National Institutes of Health Intramural Institutional Review Board

The Study Sponsor, Center for Cancer Research, NCI or their agent(s)

Qualified representatives from Lixte Biotechnology Holdings, Inc., the pharmaceutical 
company who produces LB100
The researchers conducting this study and the NIH follow applicable laws and policies to keep 
your identifying information private to the extent possible.  However, there is always a chance 
that, despite our best efforts, your identity and/or information about your participation in this 
research may be inadvertently released or improperly accessed by unauthorized persons.
IRB NUMBER: 17C0037
IRB APPROVAL DATE: 07/13/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date:   06-02-2022
Page 10 of 12
CC pre rCR ICF template v. 05.05.2020
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
In most cases, the NIH will not release any identifiable information collected about you without 
your written permission. However, your information may be shared as described in the section of 
this document on sharing of specimens and data, and as further outlined in the following sections.  
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act. 
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.  
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.  
The Certificate does not protect your information when it:  
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
3. is for other research;
4. is disclosed with your consent. 
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent.
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical records we 
collect under the authority of the Public Health Service Act.  In some cases, the Privacy Act 
protections differ from the Certificate of Confidentiality.  For example, sometimes the Privacy Act 
allows release of information from your medical record without your permission, for example, if 
it is requested by Congress. Information may also be released for certain research purposes with 
due consideration and protection, to those engaged by the agency for research purposes, to certain 
federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting, to tumor registries, for quality assessment and medical audits, or when the NIH is 
involved in a lawsuit.  However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act.
POLICY REGARDING RESEARCH-RELATED INJURIES  
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation for 
IRB NUMBER: 17C0037
IRB APPROVAL DATE: 07/13/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date:   06-02-2022
Page 11 of 12
CC pre rCR ICF template v. 05.05.2020
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
PROBLEMS OR QUESTIONS
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Eric Burton, 
M.D., Bldg. 82, Room 243, Telephone: 240-760-6030.  You may also call the NIH Clinical Center 
Patient Representative at 301-496-2626, or the NIH Office of IRB Operations at 301-402-3713, if 
you have a research-related complaint or concern.
CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.
IRB NUMBER: 17C0037
IRB APPROVAL DATE: 07/13/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date:   06-02-2022
Page 12 of 12
CC pre rCR ICF template v. 05.05.2020
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness should sign below if either: 
1. A short form consent process has been used to enroll a non-English speaking subject or
2. An oral presentation of the full consent has been used to enroll a blind or illiterate subject
Witness:
Signature of Witness*
Print Name of Witness
Date
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.
IRB NUMBER: 17C0037
IRB APPROVAL DATE: 07/13/2022