Clinical trial NCT02765165
Conditions: Solid Tumors (Phase 1) Relapsed/Recurrent GBM (Phase 2)
Keywords: Phase 1 Phase 2 Glioblastoma Multiforme Glioblastoma GBM Brain Tumor Brain Cancer Tumor Solid Tumor Tumour Lomustine CCNU CXCR4 Phase 1 Clinical Trial Phase 2 Clinical Trial
Sponsor: Proximagen, LLC
Start date: 2016-04-01; Completion date: 2020-07-01
Enrollment: 26 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This is a multicenter, open-label, Phase 1/2, dose-escalation and dose expansion study of a CXCR4 inhibitor, USL311, alone and in combination with lomustine in subjects with advanced solid tumors (Phase 1) and subjects with relapsed/recurrent GBM (Phase 2). The study is designed to explore the safety, tolerability, pharmacokinetics, and preliminary efficacy of USL311 alone and in combination with lomustine.

Detailed description:

Arms: arm 1: USL311, intravenous, once per week, starting at 60 mg/m˄2 arm 2: USL311, oral, daily, starting at 40 mg arm 3: USL311, oral, daily, starting at dose as determined in Part 1b, in combination with lomustine 90 mg/m˄2, oral, once every 6 weeks arm 4: USL311, oral, daily, starting at dose determined in Part 1b arm 5: USL311, oral, daily, in combination with lomustine, oral, once every 6 weeks, at dose(s) as determined in part 2
Interventions: intervention 1: USL311 intervention 2: USL311 intervention 3: USL311 intervention 4: Lomustine
Intervention descriptions: intervention 1: Administered once weekly in a 21-day cycle intervention 2: Administered once daily in a 21-day cycle intervention 3: Administered once daily in a 42-day cycle intervention 4: Administered once every 6 weeks in a 42-day cycle

Protocol documents:
Prot_000.pdf: 
ClinicalTrials.gov Cover Page 
 
NCT02765165 
 
 
Protocol Title: A Phase 1/2 Dose-escalation of USL311 as Single Agent and in Combination 
with Lomustine (CCNU) in Subjects with Advanced Solid Tumors, with Subsequent Single 
Agent and Combination Phase 2 Cohorts for Subjects with Relapsed/Recurrent Glioblastoma 
Multiforme (GBM) 
 
Protocol Number: P311-201 
 
Protocol Version: Amendment 4 
 
Issue Date: 02 Aug 2018 


 
Proximagen, LLC 
505 Waterford Park 
Hwy 169 N, Suite 850 
Plymouth, MN 55441 
CLINICAL STUDY PROTOCOL 
Protocol Title: 
A Phase 1/2 Dose-escalation of USL311 as Single 
Agent and in Combination with Lomustine (CCNU) in 
Subjects with Advanced Solid Tumors, with 
Subsequent Single Agent and Combination Phase 2 
Cohorts for Subjects with Relapsed/Recurrent 
Glioblastoma Multiforme (GBM) 
Protocol Number: 
P311-201 
Protocol Version: 
Amendment 4 
Issue Date: 
02 Aug 2018 
Clinical Phase: 
Phase 1/2 
US IND Number: 
127616 
EudraCT Number: 
2015-004214-14 
Active Investigational Product: 
USL311 
Study Population: 
 
Phase 1 Dose-escalation: Subjects with advanced solid 
tumors for which no standard-of-care treatment is 
recognized or who have failed or are intolerant to the 
standard-of-care treatment  
Phase 2 Dose-expansion: Subjects with 
relapsed/recurrent GBM who are candidates for 
re-resection having previously received definitive first 
line treatment  
 
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CONTACT INFORMATION 
Sponsor of Clinical Trial: 
Proximagen, LLC 
Sponsor’s Address: 
505 Waterford Park 
Hwy 169 N, Suite 850 
Plymouth, MN 55441 
Sponsor's Responsible 
Medical Monitor: 
 MD 
Proximagen, LLC 
Duration of Subject 
Participation: 
Until disease progression, unacceptable toxicity, no longer 
deriving clinical benefit (in the opinion of the 
Investigator), or other withdrawal criteria are met. 
Subjects who discontinue study treatment for reasons 
other than disease progression will be followed until 
disease progression or death, or until termination of the 
study 
USL311 IV Starting Dose: 
60 mg/m2 
USL311 Oral Starting Dose: 40 mg 
Lomustine Starting Dose: 
90 mg/m2 
 
 
 
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PROTOCOL SYNOPSIS 
SPONSOR: 
Proximagen, LLC 
NAME OF DEVELOPMENT PRODUCT: 
USL311 
TITLE OF STUDY:  
A Phase 1/2 Dose-Escalation of USL311 as Single Agent and in Combination with Lomustine (CCNU) 
in Subjects with Advanced Solid Tumors, with Subsequent Single Agent and Combination Phase 2 
Cohorts for Subjects with Relapsed/Recurrent Glioblastoma Multiforme (GBM) 
PROTOCOL NUMBER: 
P311-201 
STUDY SITES: 
Parts 1 and 2 (Phase 1 dose-escalation in advanced solid tumors): approximately 4 study sites. Additional 
sites may be added depending on study recruitment. 
Parts 3 a nd 4 (Phase 2 d ose-expansion in relapsed/recurrent GBM): approximately 10 s tudy sites. 
Additional sites may be added depending on study recruitment. 
PHASE OF DEVELOPMENT: 
Phase 1/2 
STUDY RATIONALE:  
USL311 is initially being evaluated in glioblastoma multiforme (GBM) based on the following: 
• 
Biologic relevance of the target: CXCR4 receptor and its chemokine ligand CXCL12 
(SDF-1) have roles in tumor growth and metastasis. CXCR4 is also expressed on most cancer 
stem cells. CXCR4 antagonism inhibits migration and self-renewal of cancer stem cells while 
also rendering these cells more sensitive to concurrent therapies.  
• 
Overexpression of CXCR4 appears to be a negative prognostic factor for survival of patients. 
• 
Preclinical data: USL311 and other CXCR4 antagonists inhibit the migration, invasion and 
proliferation of GBM cell lines, induce apoptosis, and are effective in in vivo orthotopic 
models. USL311 has demonstrated nonclinical efficacy in both in vitro and in vivo 
pharmacology models when administered in combination with cytotoxics. Due to its 
lysosomotropic nature, USL311 may also be an inhibitor of autophagy, and like other 
autophagy inhibitors is expected to sensitize tumor cells to the effects of cytotoxic agents 
such as lomustine. 
• 
In contrast to other known CXCR4 antagonists, USL311 crosses the blood-brain barrier. 
 
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Initial dose-escalation will be conducted in an advanced solid tumor population for whom no 
standard-of-care treatment is recognized or who have failed or are intolerant to the standard-of-care 
treatment. Dose-escalation will be conducted according to a modified continual reassessment method 
(mCRM) design. Subsequent dose-expansion will allow a more robust investigation of the safety, 
efficacy, and pharmacokinetics (PK)/pharmacodynamics (PD) of USL311 alone and in combination 
with lomustine in the target population of relapsed/recurrent GBM. During Phase 2 dose-expansion, 
subjects will undergo surgical re-resection, as part of their standard-of-care treatment, which will allow 
for tumor tissue collection and biomarker analysis. 
For Part 1a, USL311 will be administered as an intravenous (IV) infusion over 120 minutes (2 hours) 
once weekly. A weekly dosing schedule was selected because USL311 demonstrates extensive uptake 
in tissues, including the CNS. Elimination from the tissues is slow, and as the predicted elimination half-
life in humans is on the order of days to weeks, target USL311 concentrations may be achieved and 
maintained with a weekly dosing schedule. 
The first-in-human starting dose of weekly IV administration of USL311 will be 60 mg/m2. The Severely 
Toxic Dose in 10% of animals (STD 10) was determined as 100 mg/kg USL311 administered as a 
weekly 2-hour IV infusion in the rat. Based on scaling by body surface area (BSA), the human equivalent 
dose to the STD 10 is 600 mg/m2 and thus the starting dose is equivalent to 1/10th of the rat STD 10. 
This dose is lower than the projected first-in-human starting dose of 267 mg/m2, calculated as 1/6 of the 
Highest Non-Severely Toxic Dose (HNSTD) in dogs (80 mg/kg as a weekly 2-hr IV infusion). 
As of the date of this amendment, data from all 13 subjects who participated in the Part 1a IV Dose 
Escalation portion of this study have been collected at USL311 doses of 60, 120, 180, and 250 mg/m2 
via 2- or 4-hour IV infusion. Interim data from the first 8 subjects suggested a potential USL311-related 
increase in the QT interval, which was transient, resolved post-end of infusion, and exhibited an apparent 
correlation with plasma USL311 concentrations (i.e., Cmax). Based on these observations, the duration 
of USL311 infusion was increased from 120 minutes (2 hours) to 240 minutes (4 hours, i.e., slower 
infusion rate) and was expected to decrease the magnitude of QT-prolongation (Amendment #3). 
Dosing with the 4 hour infusion was initiated at the highest safe dose of USL311 as determined from 
subjects who received USL311 via a 2 hour infusion (viz., prior to Amendment #3). Subjects who were 
previously enrolled and were actively participating at the time Protocol Amendment #3 is activated 
continued study participation according to Protocol Amendment #2. 
After 13 subjects were evaluable (i.e., had completed Cycle 1 dosing, at minimum) in Part 1a IV Dose 
Escalation, the Dose Escalation Committee halted dose escalation, although no DLTs had occurred, due 
to continuing dose-related increases in QTcF prolongation that was not ameliorated by increasing the 
infusion duration. Part 1b of the study will resume under this amendment with dosing initiation of an 
oral formulation of USL311, at a starting dose of 40 mg once daily in 3-week (21-day) cycles. The 
selected 40 mg daily oral starting dose is comparable to the 30 mg daily starting dose based on 1/6 
HNSTD in dogs (5 mg/kg/day oral daily dose) and is lower than the ~60 mg daily dose calculated based 
on the maximum IV dose tested in humans (250 mg/m2 weekly, divided into daily doses). USL311 
plasma pharmacokinetics are dose-proportional and minimal to no plasma accumulation is expected for 
USL311 and its main metabolites after daily oral dosing. In addition, a fixed-dosing approach is 
considered to be appropriate for future studies given that USL311 pharmacokinetics are not influenced 
by body size. Daily oral dosing is anticipated to further mitigate the concentration-related QT effect, 
compared to IV bolus weekly dosing.As of the date of this amendment there were no active subjects 
 
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currently participating in Part 1a IV Dose Escalation. All subsequent Part 1 participants will be enrolled 
in Part 1b, Oral Dose Escalation. 
Oral USL311 will be used in combination with lomustine during Part 2 of Phase 1 and Part 4 of Phase 
2. Lomustine, a cytotoxic drug, is a nitrosourea used in the treatment of certain oncologic conditions 
and functions as an alkylating agent. Lomustine is commonly used in recurrent GBM and has also been 
used as the comparator in recent registration-directed trials in this setting. The lomustine starting dose 
during Part 2 will be 90 mg/m2. The starting dose was selected based on the anticipated tolerability of 
the dose based on doses typically used in clinical practice. The maximum lomustine dose allowed during 
dose-escalation is 130 mg/m2 which is the maximum dose allowed per the package insert. 
OBJECTIVES:  
Parts 1 and 2 (Phase 1 Dose-Escalation in Subjects with Advanced Solid Tumors) 
The primary objectives of the Phase 1 dose-escalation are to: 
• 
Determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of 
USL311 as a single agent in subjects with advanced solid tumors for whom no 
standard-of-care treatment is recognized or who have failed or are intolerant to the 
standard-of-care treatment (Part 1) 
• 
Determine the MTD and RP2D of USL311 in combination with lomustine in subjects with 
advanced solid tumors for whom no standard-of-care treatment is recognized or who have 
failed or are intolerant to the standard-of-care treatment (Part 2) 
The secondary objectives of the Phase 1 dose-escalation are to: 
• 
Assess the safety and tolerability of USL311 as a single agent and in combination with 
lomustine 
• 
Determine preliminary efficacy parameters such as 6-month progression-free survival rate 
(PFS-6m), objective response rate (ORR%), disease control rate (DCR), progression free 
survival (PFS) and overall survival (OS) of USL311 as a single agent and in combination 
with lomustine 
• 
Determine the PK profile of USL311 in plasma and whole blood and of lomustine in plasma 
(prior to and with concomitant USL311 administration) 
• 
Evaluate the drug interaction potential between USL311 and lomustine 
The exploratory objectives of the Phase 1 dose-escalation are to: 
• 
Determine effects of USL311 on s ystemic markers of CXCR4 inhibition, including 
measurement of CD34+ cells, and white blood cell (WBC) count 
• 
Measure effects of USL311 on a urine biomarker of phospholipidosis, di-docosahexaenoyl 
(22:6)-bis(monoacylglycerol) phosphate (BMP) 
• 
Investigate exposure-response relationships for USL311 as a single agent and in combination 
with lomustine 
Parts 3 and 4 (Phase 2 Dose-Expansion in Subjects with Relapsed/Recurrent GBM) 
The primary objectives of the Phase 2 dose-expansion are to: 
 
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• 
Determine the percentage PFS-6m of USL311 as a si ngle agent in subjects with 
relapsed/recurrent GBM who previously received standard-of-care treatment in the first-line 
setting and who are candidates for re-resection (Part 3) 
• 
Determine the percentage PFS-6m of USL311 in combination with lomustine in subjects 
with relapsed/recurrent GBM who previously received standard-of-care treatment in the 
first-line setting and who are candidates for re-resection (Part 4) 
The secondary objectives of the Phase 2 dose-expansion are to: 
• 
Assess the safety and tolerability of USL311 as a single agent and in combination with 
lomustine in subjects with relapsed/recurrent GBM 
• 
Assess ORR%, PFS, DCR and OS of USL311 as a single agent and in combination with 
lomustine in subjects with relapsed/recurrent GBM 
• 
Determine the PK profile of USL311 in plasma and whole blood and of lomustine in plasma 
The exploratory objectives of the Phase 2 dose-expansion are to: 
• 
Assess PD markers of CXCR4 inhibition in tumor samples following pre-surgical 
administration of USL311 for comparison with subjects randomized to receive no pr e-
surgical USL311 treatment. These markers may include, but are not limited to, the following: 
− 
Tumor pCXCR4 profile 
− 
Tumor markers of autophagy (e.g., LC3, Beclin-1) 
− 
Tumor markers of vasculogenesis (e.g., CD11b) and cancer stem cell survival and 
proliferation (e.g., nestin, CD133) 
• 
Determine biodistribution of USL311 to the brain/cerebrospinal fluid (CSF) in resected 
tissue samples and CSF samples following pre-surgical administration of USL311 to 
investigate CNS penetration and for correlation with clinical response and/or PD data 
• 
Assess exposure-response relationships for USL311 as a single agent and in combination 
with lomustine 
• 
Assess health-related quality of life (QOL) and subject reported outcomes (European 
Organization for Research and Treatment of Cancer quality-of-life questionnaire, 
supplemented with a brain-cancer module [EORTC QLQ-C30/BN20]) 
STUDY DESIGN: 
This is a Phase 1/2 open-label, multicenter study in four parts: Part 1: dose escalation of single-agent 
USL311 in subjects with advanced solid tumors; Part 2: dose escalation of USL311 in combination with 
lomustine in subjects with advanced solid tumors; Part 3: preliminary efficacy evaluation of single-agent 
USL311 in subjects with relapsed/recurrent GBM who are candidates for re-resection, and Part 4: 
preliminary efficacy evaluation of USL311 in combination with lomustine in subjects with 
relapsed/recurrent GBM who are candidates for re-resection. Subjects will only participate in one part 
of the study. 
 
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the study meaning that subjects can be enrolled as they become available for the study, however, 
generally, there may be no more than 3 subjects enrolled in the study (Part 1 and Part 2) with unknown 
DLT information at any time. 
In the dose-toxicity model, non-DLT toxicity events (i.e., grade 2 toxicities) will inform the probability 
of DLT at each dose level. To account for the increase in infusion duration from 120 minutes (2 hours) 
to 240 minutes (4 hours), an additional covariate for infusion duration was included in the dose-toxicity 
model for Part 1a. 
The DLT observation period, for the purpose of dose-escalation, is one cycle. Once a su bject has 
completed this first cycle DLT observation period, the subject will be considered to have complete DLT 
information for the purposes of making dose-escalation decisions for the next subject enrolling into the 
study (Part 1 and Part 2). However, DLTs may also appear in later cycles. If a DLT appears at any time 
through subsequent cycles of treatment, a subject’s DLT status and mCRM model will be updated to 
reflect the late-cycle DLT. 
At each dose-escalation point, the Dose Escalation Committee (DEC) will review all of the safety data, 
any available PK/PD data, and all other relevant subject data in order to recommend the subsequent dose 
level. Clinical judgment will always supersede the model-based recommendations for dose-escalation, 
meaning that clinical judgment can be applied to reduce the increment of dose escalation or elect not to 
dose escalate in favor of accruing more subjects at that dose level. 
The MTD will be determined by the DEC and Sponsor after considering all available safety, PK, and 
PD data. Additionally, the RP2D will be determined by the DEC and the Sponsor after considering the 
safety, PK/PD, and preliminary efficacy outcomes and may be equal to or lower than the MTD. 
Parts 3 and 4 – Dose Expansion in Relapsed/Recurrent GBM: 
Once the MTDs and RP2Ds of single agent USL311 (Part 1) and USL311 in combination with lomustine 
(Part 2) have been determined, Phase 2 will assess preliminary efficacy of USL311 (Part 3) and USL311 
in combination with lomustine (Part 4) in subjects with relapsed/recurrent GBM, and who are candidates 
for re-resection. Subjects may begin enrolling into Part 3 after the completion of enrollment in Part 1 
and determination of the RP2D for single agent USL311 and subjects may begin enrolling into Part 4 
after the completion of enrollment in Part 2 a nd the determination of the RP2D for USL311 in 
combination with lomustine. Subjects will be randomized to receive either once daily pre-surgical 
treatment with USL311 or no USL311 treatment prior to surgery. Subjects randomized to receive 
pre-surgical treatment with USL311 are required to receive at least one week of treatment prior to 
surgery, and may receive up to a maximum of three weeks of treatment prior to surgery at the RP2D 
defined in Parts 1 and 2. The length of treatment  will depend on the surgery date. Scheduling of the 
surgery, as part of standard-of-care, should not be delayed due to the pre-surgical treatment. Exploratory 
(translational) studies on resected tissue will be performed following surgical resection to determine 
biodistribution of USL311 in the tumor and to assess PD markers (e.g., pCXCR4 profile, autophagy 
markers, markers of vasculogenesis and cancer stem cell survival and proliferation). Archiving of tissue 
samples is recommended to facilitate future biomarker testing. Following surgery, all subjects will 
initiate treatment of USL311 (Part 3) or USL311 in combination with lomustine (Part 4) within 28 days 
post-surgery, although treatment delays may be considered based upon discussions between Sponsor or 
designee and Investigator. Subjects must have fully recovered from surgery, including surgical wound 
healing, prior to initiating therapy. 
 
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60 
160 
400 
1040 
70 
180 
450 
1170 
80 
200 
510 
1310 
90 
220 
570 
1480 
100 
250 
650 
1660 
110 
280 
730 
 
Dose-escalation will begin in the single agent with enrollment of subjects to the 60 mg/m2 dose. Three 
subjects will be treated at the initial dose of 60 mg/m2 and evaluated by the DEC, after all three subjects 
have completed Cycle 1, before the dose is escalated/de-escalated. The 40 and 50 mg/m2 dose levels are 
de-escalation dose levels. For each dose-escalation, one (1) subject will be enrolled at the new dose level 
and will be treated and observed from Cycle 1-Day 1 through Cycle 1, Day 8 for tolerance to the dose 
before additional subjects may be treated at that dose level. 
Plan for Phase 1 oral dose escalation (Part 1b single agent oral USL311): 
Treatment will be administered once daily in 3-week (21-day) cycles. USL311 will be administered as 
an oral tablet once daily in the morning. It is recommended that subjects take their dose at the same time 
each day, except for visit days, when the dose will be held and taken during the clinic visit. If a dose is 
missed in the morning, and fewer than 12 hours have elapsed since the planned administration time, the 
subject should take the dose. If more than 12 hours have elapsed since the planned administration time, 
the dose should be skipped. 
There are a total of 27 possible dose levels specified between 20 mg and 1440 mg. Dose levels are 
defined to be in approximately 15% increments, and rounded to the nearest multiple of 20 in order to 
accommodate dosing with the available 20 mg and 100 mg strengths of the USL311 oral formulation. 
The dose levels, in mg, are shown below: 
USL311 Available Oral Doses for Dose-Escalation 
Available Oral Doses (mg) 
20 
180 
400 
1100 
40 
200 
460 
1260 
60 
220 
520 
1440 
80 
240 
580 
 
100 
260 
660 
 
120 
280 
740 
 
140 
320 
840 
 
160 
360 
960 
 
Dose escalation will begin in the single agent oral formulation with enrollment of subjects to the 40 mg 
dose. The 20 mg dose level is a de-escalation dose level. For each dose-escalation, one (1) subject will 
be enrolled at the new dose level and will be treated and observed from Cycle 1-Day 1 through Cycle 
1-Day 8 for tolerance to the dose before additional subjects may be treated at that dose level. 
 
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Treatment cycles will be repeated every 3 weeks (21 days) until disease progression, unacceptable 
toxicity, withdrawal of consent, Investigator decision to discontinue treatment, or Sponsor decision to 
terminate the study. The MTD will be determined for single agent USL311, and all available safety, PK, 
and PD data will be reviewed by the DEC and Sponsor prior to confirming the optimal starting dosage 
for USL311 oral administration in combination with lomustine and prior to determining the RP2D. The 
RP2D of single agent USL311 will be determined by the DEC and Sponsor after considering the safety, 
PK/PD, and preliminary efficacy outcomes and may be equal to or lower than the MTD. 
Plan for Phase 1 dose-escalation (Part 2 USL311 in combination with lomustine): 
Once the MTD is determined for oral single agent USL311, dose-escalation of USL311 in combination 
with lomustine may begin. Lomustine will be administered as a single oral dose every 7 weeks during 
Cycle 1 and every 6 weeks for subsequent cycles (Cycle 2+) and USL311 will be administered as an 
oral tablet every day during Cycle 1 starting on Day 8 or over the subsequent 6-week cycles (during 
Cycle 2+) starting on D ay 1. To evaluate drug-drug interaction potential between USL311 and 
lomustine, the first dose of lomustine in Cycle 1 will be administered on Cycle 1-Day 1, one week prior 
to the first dose of USL311 (Day 8). All remaining doses of lomustine (Cycle 2+) will be administered 
on Day 2 of the cycle. USL311 will be administered daily, continuously as of Cycle 1-Day 8, with no 
break between cycles. 
This dose escalation for USL311 in combination with lomustine will also be conducted according to a 
mCRM model similar to that for the single agent in Part 1; however, the dose range will be informed by 
results of USL311 as a single agent. The starting dose of USL311 when combined with lomustine will 
be at least two (2) evaluated dose levels below the MTD determined for USL311 as a single agent and 
the starting dose of lomustine will be 90 mg/m2. A dose de-escalation for lomustine to 80 mg/m2 may 
occur depending on the tolerability of the initial lomustine dose. If USL311 is escalated in combination 
with lomustine to the same dose as the single agent MTD, no further escalation of USL311 will be 
allowed. However, subsequent subjects may be enrolled to evaluate dose-escalation of lomustine up to 
a maximum of 130 mg/m2 in combination with USL311 (dosed at the MTD). 
For each dose-escalation, one (1) subject will be enrolled at the new dose level and will be treated and 
observed from Cycle 1-Day 1 through Cycle 1-Day 15 for tolerance to the combination dose before 
additional subjects may be treated at the dose level. 
Treatment cycles beyond Cycle 1 will be repeated every 6 weeks (42 days) until disease progression, 
unacceptable toxicity, withdrawal of consent, Investigator decision to discontinue treatment, or Sponsor 
decision to terminate the study. The MTD will be determined for USL311 in combination with 
lomustine, and all available safety, PK, and PD data will be reviewed by the DEC and Sponsor prior to 
determining the RP2D. The RP2D will be determined by the DEC and Sponsor after considering the 
safety, PK/PD, and preliminary efficacy outcomes and may be equal to or lower than the MTD. 
Plan for Phase 2 dose-expansion (Part 3 single agent USL311): 
Once the RP2D of single agent USL311 has been determined by the DEC and Sponsor, Phase 2 will 
assess preliminary efficacy of single agent USL311. Approximately 20 subjects with relapsed/recurrent 
GBM, who are candidates for re-resection, will be enrolled. Subjects will be randomized to receive once 
daily pre-surgical treatment with USL311 or no USL311 treatment prior to surgery. Subjects 
randomized to receive pre-surgical treatment with USL311 are required to receive at least one week of 
treatment prior to surgery and may receive up to a maximum of three weeks of treatment of USL311 (at 
 
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the single agent RP2D defined in Part 1) prior to surgery. The length of treatment will depend on the 
surgery date. Scheduling of the surgery, as part of standard-of-care, should not be delayed due to the 
pre-surgical treatment. Following surgery, all subjects (including those randomized to no pre-surgical 
treatment) will initiate treatment of USL311 within 28 days post-surgery, although treatment delays may 
be considered based upon discussions between Sponsor or designee and Investigator. Subjects must 
have fully recovered from surgery, including surgical wound healing, prior to initiating therapy. USL311 
will be administered daily during every 3-week (21-day) cycle, with no breaks between cycles. 
Treatment cycles will be repeated every 3 weeks (21 days) until disease progression, unacceptable 
toxicity, withdrawal of consent, Investigator decision to discontinue treatment, or Sponsor decision to 
terminate the study. 
Exploratory (translational) studies on resected tissue will be performed following surgery to determine 
biodistribution of USL311 in the tumor and assess PD markers (e.g., pCXCR4 profile, autophagy 
markers, markers of vasculogenesis and cancer stem cell survival and proliferation). 
Plan for Phase 2 dose-expansion (Part 4 USL311 in combination with lomustine): 
Once the RP2D of USL311 in combination with lomustine has been determined by the DEC and 
Sponsor, Phase 2 will assess preliminary efficacy of the combination. Approximately 20 subjects with 
relapsed/recurrent GBM, who are candidates for re-resection, will be enrolled. Subjects will be 
randomized to receive once daily oral pre-surgical treatment with USL311 or no USL311 treatment prior 
to surgery. Subjects randomized to receive pre-surgical treatment with USL311 are required to receive 
at least one week of treatment of USL311 (at the RP2D defined in Part 2) prior to surgery and may 
receive up to a maximum of three weeks of treatment prior to surgery. The length of treatment received 
will depend on the surgery date. Scheduling of the surgery, as part of standard-of-care, should not be 
delayed due to the pre-surgical treatment. Following surgery, all subjects (including those randomized 
to no pre-surgical treatment) will initiate treatment of USL311 in combination with lomustine within 28 
days post-surgery, although treatment delays may be considered based upon discussions between 
Sponsor or designee and Investigator. Subjects must have fully recovered from surgery, including 
surgical wound healing, prior to initiating therapy. USL311 will be administered daily during every 6-
week (42-day) cycle, with no breaks between cycles. Lomustine will be administered on Day 2 of every 
6-week (42-day) cycle. Treatment cycles will be repeated every 42 days until disease progression, 
unacceptable toxicity, withdrawal of consent, Investigator decision to discontinue treatment, or Sponsor 
decision to terminate the study. 
Exploratory (translational) studies on resected tissue will be performed following surgery to determine 
biodistribution of USL311 in the tumor and assess PD markers (e.g., pCXCR4 profile, autophagy 
markers, markers of vasculogenesis and cancer stem cell survival and proliferation).  
NUMBER OF SUBJECTS PLANNED:  
The total number of subjects will depend on the number of dose levels assessed in Phase 1 (Parts 1a/1b 
and Part 2). A total of 13 subjects were enrolled in Part 1a single agent IV dose-escalation. It is expected 
that approximately 6-40 subjects with advanced solid tumors will be enrolled for Part 1b single agent 
oral dose-escalation and approximately an additional 6-40 subjects with advanced solid tumors will be 
enrolled for Part 2 USL311 in combination with lomustine dose-escalation. It is expected that 
approximately 20 subjects with relapsed/recurrent GBM will be enrolled for each Phase 2 dose-
 
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expansion cohort (Parts 3 and 4), with a total of approximately 40 subjects. The total number of subjects 
for Phase 1 and 2 combined is expected to be approximately 65-133subjects. 
DIAGNOSIS AND ALL CRITERIA FOR INCLUSION AND EXCLUSION:  
Individuals eligible to participate in this study must meet all of the following criteria: 
Inclusion Criteria: 
Criteria for both Phase 1 dose-escalation and Phase 2 dose-expansion: 
1. Provide signed and dated informed consent prior to study-specific screening procedures  
2. ≥18 years old 
3. Karnofsky performance score (KPS) ≥ 70  
4. Must have adequate bone marrow and renal/hepatic function at the Screening Visit and at Baseline, 
defined as: 
a. Absolute neutrophil count (ANC) ≥ 1,500/mm3 without granulocyte colony-stimulating factor 
(G-CSF) support within 7 days preceding the lab assessment 
b. Platelet count ≥ 100,000/mm3, without transfusion within 7 days preceding the lab assessment 
c. Hemoglobin (Hgb) ≥ 9 g/dL, without transfusion support within 7 days preceding the lab 
assessment 
d. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 3 times upper limit of 
normal (ULN) 
e. Total serum bilirubin ≤ 1.5 times ULN, except in subjects with known Gilbert’s Syndrome 
≤ 3 times ULN  
f. Serum creatinine ≤ 1.5 times ULN with an estimated creatinine clearance of ≥ 60 mL/min 
(calculated by the Cockcroft-Gault equation), or creatinine clearance corrected for BSA ≥ 60 
mL/min/1.73 m2 (determined from 24-hour urine collection) per Investigator discretion 
g. Activated partial thromboplastin time/partial thromboplastin time (aPTT/PTT) and 
prothrombin time (PT) ≤ 1.5 times ULN 
h. Baseline potassium, sodium, calcium (corrected for albumin) and magnesium levels within 
the normal range, or above the ULN if considered not clinically significant per the 
Investigator. Baseline potassium, sodium, calcium (corrected for albumin) and magnesium 
levels below lower limit of normal must be corrected to within the normal range, or above the 
ULN if considered not clinically significant per the Investigator, by supplementation prior to 
starting study drug(s). 
5. Disease-free period of > 2 years from any other previous malignancies, excluding curatively 
treated basal cell carcinoma, squamous cell carcinoma of the skin, or carcinoma in situ of the 
cervix. Subjects with prostate cancer Stage 1 that do not require treatment may also be included. 
6. Women of childbearing potential (WOCBP) must have two negative pregnancy tests, the first 
during Screening and the second within 24 hours prior to first administration of study drug(s) and 
must agree to use highly effective physician-approved contraception (see Appendix 2) from 
Screening to 90 days following the last study drug administration. Male subjects must be surgically 
sterile or must agree to use highly effective physician-approved contraception from Screening to 
90 days following the last study drug administration (a barrier method of contraception must be 
employed by all subjects [male and female], when having sexual intercourse, regardless of other 
methods). 
a. Females are considered not of childbearing potential if they meet any of the following criteria: 
• Postmenopausal with > 1 year since last menses and: 
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− 
If younger than 65 years old, with a follicle-stimulating hormone (FSH) > 40 mIU/mL 
− 
If ≥ 65 years old and not on hor mone replacement therapy (HRT), with a FSH 
> 30 mIU/mL 
− 
If ≥ 65 years old and on HRT, the FSH requirement in not applicable. Postmenopausal 
females on HRT will be allowed if the treatment is stable for at least 6 months prior 
to dosing of study drug(s) 
• Written medical documentation of being sterilized (e.g. hysterectomy, double 
oophorectomy, bilateral salpingectomy). Note: Tubal ligation is not considered a form of 
permanent sterilization. 
7. 
Must be able and willing to comply with the study visit schedule and study procedures 
8. 
Must be able to take oral medications 
9. 
Must have available archived tumor tissue and be willing and able to provide consent for study 
access to such tissue 
10. For subjects with seizures, must be adequately controlled on a stable regimen of anti-epileptic 
drugs 
Criteria for Phase 1 only, dose-escalation in advanced solid tumors: 
11. Histologically or cytologically documented diagnosis of a solid tumor for which no standard 
therapy is recognized or have failed or are intolerant to the standard-of-care treatment 
12. Inoperable metastatic or locally advanced, unresectable disease 
13. Subjects must have either evaluable or measurable disease 
14. Subjects with treated (surgically excised or irradiated) and stable brain metastases are eligible 
as long as the subject has adequately recovered from treatment and the treatment was ≥ 28 days 
prior to initiation of study drug(s) and baseline brain computed tomography (CT) with contrast 
or magnetic resonance imaging (MRI) within 14 days of initiation of study drug(s) is negative 
for new brain metastases 
Criteria for Phase 2 only, dose-expansion in relapsed/recurrent GBM: 
15. Histologically confirmed diagnosis of GBM 
16. Subjects must have documented recurrence after first-line treatment 
17. Prior first-line treatment must have included radiation and temozolomide 
18. Subject is suitable for surgical re-resection, per Investigator discretion, as a component of their 
clinical care 
19. Not more than one prior resection (Note: biopsy does not count as prior resection) 
Exclusion Criteria: 
1. Subjects who have had recent systemic anticancer therapies, interventional device treatment 
and/or radiotherapy either within 14 days prior to first dose of study drug(s) or have not 
recovered (to grade ≤ 1) from all clinically significant toxicities related to prior therapies 
2. Subjects who have had any major surgery (not including re-resection surgery required in Phase 
2) within 28 days prior to first dose of study drug(s), or minor surgery within 14 days prior to 
first dose of study drug(s) 
3. For 14 days prior to first dose of study drugs(s) treatment, administration of any strong 
cytochrome P450 3A4 (CYP3A4) inducers including, but not limited to, the following: 
 
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carbamazepine, ethotoin, mephenytoin, phenobarbital, phenytoin, primidone, rifabutin, 
rifampin, and St. John’s Wort 
4. For 14 days prior to first dose of study drug(s) treatment, administration of any strong 
cytochrome P450 3A4 (CYP3A4) inhibitors including, but not limited to, the following: 
amprenavir, ataznavir, boceprevir, clarithromycin, conivaptan, fosamprenavir, indinavir, 
itraconazole, ketoconazole, lopinavir, nefazodone, posaconazole, ritonavir, saquinavir, 
telaprevir, telithromycin, and voriconazole 
5. For 14 days prior to first dose of study drug(s) treatment, administration of any agent with 
moderate-to-high risk to prolong the QTc interval or to cause Torsades de Pointes (see Appendix 
3) 
6. Subjects who have been treated with an investigational agent or investigational interventional 
device within 21 days prior to the first dose of study drug(s) 
7. Subject is growth factor dependent or transfusion dependent, or has received growth factor 
support or transfusion support within 14 days prior to the first dose of study drug(s) 
8. History of significant cardiac disease. Significant cardiac disease includes the following: 
a. Second/third degree heart block 
b. Significant ischemic heart disease (e.g. myocardial infarction, unstable angina, 
Grade 3 or 4 [Canadian Cardiovascular Society] angina, hospitalization for ischemic 
heart disease) within 2 years of first dose of study drug(s) 
c. Family history of long QT syndrome; mean Fridericia corrected QT interval (QTcF) 
> 450 msec on at least two separate ECGs prior to study start 
d. Poorly controlled hypertension per Investigator opinion  
e. Congestive heart failure of New York Heart Association (NYHA) Class II or worse (slight 
limitation of physical activity; comfortable at rest, but ordinary physical activity results in 
fatigue, palpitation, or dyspnea) 
9. Episode of status epilepticus within 1 year prior to the first dose of study drug(s) 
10. Pregnant or breastfeeding 
11. Any other significant co-morbid conditions that in the opinion of the Investigator would impair 
study participation or cooperation, including known or suspected history of significant allergic 
reaction or hypersensitivity to any components of the USL311 formulation 
Criteria for Phase 1 only, dose-escalation in advanced solid tumors 
12. Subjects with lymphoma as primary cancer 
Criteria for Phase 2 only, dose-expansion in relapsed/recurrent GBM: 
13. Subjects unable or unwilling to consent to the provision of resected tissue after surgery 
14. Prior treatment with plerixafor or another CXCR4 inhibitor 
15. Prior treatment with bevacizumab 
16. Prior treatment with lomustine and/or carmustine 
Criteria for all cohorts receiving oral USL311: 
17. Participants with any active medical condition or previous major abdominal surgery or 
procedure that might, in the investigator’s opinion, have a significant effect on USL311 
absorption 
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INVESTIGATIONAL PRODUCT(S), DOSE, ROUTE AND REGIMEN:  
The study drug, USL311, is supplied as a sterile, refrigerated citrate buffered solution, pH 3.5, 
containing 50 mg/ml of USL311 for IV administration, or as a tablet in 20 mg and 100 mg strengths for 
oral administration. 
The supplied IV solution will be admixed with 250 mL infusion bag of 0.9% Sodium Chloride Injection, 
USP prior to administration.In Part 1a, USL311 will be administered IV once weekly over a time period 
of four (4) hours (240 minutes). 
In Parts 1b, 2, 3 and 4, USL311 will be administered as oral tablets once daily in the morning under 
fasted conditions for 2 hours before and 2 hours after the dose on Cycle 1-Days 1, 2, 8, and 15 and on 
Cycle 2-Day 1.  For all other outpatient dosing days, the subject should be instructed to make an effort 
to take the oral tablets at least 1 hour before or at least 1 hour after their meal, and they will be instructed 
to document in their diary the time of any food eaten prior to dosing and for 1 hour after dosing.  It is 
recommended that subjects take their dose at the same time each day, except for visit days when the 
dose will be held and taken during the clinic visit.  If a dose is missed in the morning, and fewer than 12 
hours have elapsed since the planned administration time, the subject should take the missed dose.  If 
more than 12 hours have elapsed since the planned administration time, the missed dose should be 
skipped. On clinic visits where PK will be obtained, the dose will be administered at least 2 hours after 
the last meal consumed and the subject should not eat for at least 2 hours.  
Lomustine will be administered orally once every 6 weeks for all doses, with the exception of Cycle 1 
in Part 2, which will be 7 weeks. Lomustine will only be administered during Part 2 and Part 4. 
Summary of USL311 dose modification criteria: 
Dosing of USL311 may be interrupted to allow for recovery from toxicity, with dosing held  for up to 
14 days. Thereafter, treatment at the same or a reduced USL311 dose can be considered, based upon 
discussions between Sponsor or designee and Investigator, if the subject has not developed progressive 
disease. Subjects with toxicities that require interruptions of greater than 14 days should be discontinued 
from the study. During Part 2 and Part 4, the combination of USL311 and lomustine will be considered 
and the most likely agent(s) responsible for the observed toxicity will be modified. Dose modifications 
should be made based on observed toxicity as follows: 
• 
Grade 1 or 2 toxicity: No requirement for dose interruption or dose reduction. If the toxicity 
persists at grade 2, a dose reduction to the next lower dose level may be implemented at the 
discretion of the Investigator. 
• 
Grade 3 toxicity: Dosing should be stopped. USL311 dosing may resume at the next lower 
dose level when toxicity resolves to grade 1 or returns to baseline. 
• 
Grade 4 toxicity: Dosing should be stopped. USL311 may resume at a lower dose level (1-2 
dose level decrease) with the approval of the medical monitor when toxicity resolves to grade 
1 or returns to baseline. 
Lomustine dose modification criteria per lomustine prescribing information: 
Lomustine dose modifications will be based on lomustine prescribing information (see Appendix 4). 
Doses subsequent to the initial dose should be adjusted according to the hematologic response of the 
subject to the preceding dose. The following schedule is suggested as a guide to dosage adjustment: 
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Lomustine Dose Adjustment Guide 
Nadir After Prior Dose 
Percentage of Prior 
Dose to be Given 
Leukocytes (/mm3) 
Platelets (/mm3) 
≥4000 
≥100,000 
100% 
3000 – 3999 
75,000 – 99,999 
100% 
2000 – 2999 
25,000 – 74,999 
70% 
<2000 
<25,000 
50% 
A repeat course of lomustine should not be given until circulating blood elements have returned to 
acceptable levels (platelets above 100,000/mm3; leukocytes above 4000/mm3), and this is usually in 
6 weeks. Blood counts should be monitored weekly and repeat courses should not be given before 
6 weeks because the hematologic toxicity is delayed and cumulative. The use of granulocyte growth 
factor support will be consistent with the American Society of Clinical Oncology (ASCO) guidelines. 
Subjects may be pre-medicated with anti-emetic therapy per ASCO guidelines. Anti-emetic 5-HT3 
antagonists with known QTc interval prolongation effects should not be used. Permitted antiemetics are 
the following: granisetron, palonosetron, aprepitant, fosaprepitant, dexamethasone, and lorazepam. 
DURATION OF TREATMENT: 
Subjects who tolerate Cycle 1 treatment and do not have progressive disease, treatment failure or relapse 
are eligible to continue to receive treatment until they experience unacceptable toxicity, disease 
progression, meet any of the withdrawal criteria, or the study is terminated by the Sponsor.  
REFERENCE THERAPIES, DOSE, ROUTE AND REGIMEN:  
No reference therapy will be evaluated in this study. 
 
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CRITERIA FOR EVALUATION:  
DLT: 
A DLT will be defined as one or more of the following toxicities occurring during treatment during 
Phase 1 ( Parts 1 a nd 2) dose-escalation. All toxicities are considered related to study drug (either 
USL311 and/or lomustine) unless the event is clearly and incontrovertibly due to another cause (e.g., a 
subject’s underlying disease). Toxicities will be graded according to National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. 
Hematologic Toxicity: 
• 
Grade 4 neutropenia lasting > 7 days in the absence of growth factor support 
• 
Grade 3 neutropenia of any duration associated with fever ≥ 38.5°C 
• 
Grade 3 thrombocytopenia with bleeding 
• 
Any other grade 4 hematologic toxicity 
Non-hematologic Toxicity: 
• 
Grade 3 nausea, vomiting, and/or diarrhea that lasts > 48 hours despite maximum medical 
support 
• 
Grade 3 electrolyte imbalance that does not correct within 48 hours to < grade 2 despite 
maximal medical intervention 
• 
Grade 3 fatigue that does not improve to ≤ grade 2 within 5 days 
• 
Grade 3 QTcF interval prolongation with a ≥ 60 ms change from baseline 
− 
For DLT assessment based on safety ECGs, baseline is defined as the last ECG 
collected prior to the first dose of study drug.  For DLT assessment based on extracted 
ECGs, baseline is defined as the closest time-matched extracted ECG (triplicate 
average) from Cycle 1-Day -1 for Part 1 or the average of the Cycle 1-Day 1 ECG 
extractions for Part 2 
• 
Any other grade ≥ 3 adverse event (AE) considered at least possibly related to study drug(s), 
except: 
− 
Non-hematologic laboratory grade 3 AE that is asymptomatic and/or rapidly reversible 
(returned to baseline or to grade ≤ 1 within 7 days) unless identified as clinically 
relevant by the Investigator 
Other Toxicities: 
• 
Any IV dose(s) or 7 consecutive oral doses missed within Cycle 1 due to a possible study 
drug(s)-related toxicity 
• 
Inability to administer scheduled cycle of treatment within 21 days of the scheduled start of 
Cycle 2 due to a possible study drug(s)-related toxicity 
Dose-Escalation Decisions: 
A subject must meet one of the following criteria to be evaluable for cohort DLT/MTD/dose-escalation 
decisions: 
 
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• 
Received all 3 scheduled infusions or missed ≥ 16 of 21 daily oral doses of single agent 
USL311 during Cycle 1, completed Cycle 1-Day 21, and has not experienced a DLT (Part 
1)  
• 
Received all of the 6 scheduled infusions or ≥ 32 of 42 daily oral doses of USL311, as well 
as the Cycle 1 lomustine dose, has completed Cycle 1-Day 49, and has not experienced a 
DLT (Part 2) 
• 
Experienced a DLT 
• 
Withdrew from the study prior to completing Cycle 1 due to an AE considered by the 
investigator to be at least possibly related to study drug(s)  
If a subject does not meet any of these criteria, the subject is not evaluable for dose-escalation decisions 
and will be replaced in that cohort. 
Safety: 
The following safety outcome measurements will be assessed: 
• 
Incidence of treatment emergent AEs (TEAEs), including DLTs and serious AEs (SAEs)  
• 
Change in clinical laboratory tests (serum chemistry, hematology, and coagulation 
assessments) 
• 
Change in vital signs 
• 
Change in ECGs (including Holter monitor extractions and real-time wave form, available 
bedside on provided equipment ) 
• 
Change in physical examination  
• 
Change in neurological examination 
• 
Change in concomitant medication use 
• 
Change in BMP levels (Part 1 and Part 2) 
Pharmacokinetics: 
In Phases 1 and 2, blood samples will be collected to evaluate the PK of USL311 and its metabolites, as 
well as lomustine (parent drug and/or active metabolite) PK. 
In Phase 2 (and possibly in Phase 1 sub-study), CSF samples will be collected to evaluate the distribution 
of USL311 to the CNS. 
Plasma Sample Collection: 
PK samples will be collected according to the schedules in Table  8 – Table  12 and analyzed using a 
validated liquid chromatography – mass spectrometry (LC-MS) based method. As PK data become 
available, some samples may become optional if warranted based on ongoing PK data analysis during 
the study conduct; specific samples and the rationale for making them optional will be documented. 
Approximately 4 mL of blood will be collected at each nominal time point for the analysis of whole 
blood (2 mL) and plasma (2 mL) USL311, M10 and 4-AP concentrations. Approximately 4 mL of blood 
will be collected at each nominal time point for the analysis of plasma lomustine and/or its metabolites 
concentrations (Parts 2 and 4 only). 
CSF Sample Collection: 
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In Phase 1 (Parts 1 and 2), CSF sample collection is not required. However, if determined to be feasible 
and appropriate, CSF may be collected as part of a sub-study at select sites and in a subset of subjects. 
In that sub-study, CSF samples would be collected by lumbar puncture with approximately 1 mL of CSF 
collected from each subject. Subjects with lumbar puncture contraindications, as determined by the 
Investigator, would not be eligible for the potential collection of CSF during Parts 1 and 2. 
In Phase 2 (Parts 3 and 4), all subjects will have a CSF sample collected during the re-resection surgical 
procedure. The CSF sample will be collected from the operative field at time of resection. 
Approximately 1 mL of CSF will be collected from each subject. 
Pharmacokinetic Parameters: 
Plasma and whole blood PK parameters will be calculated from plasma and whole blood study drug 
levels, respectively, for USL311, its metabolites, and lomustine and/or its metabolites using non-
compartmental and/or compartmental-based methods and will include the following if supported by the 
available data: 
Dose Number 
Pharmacokinetic Parameters 
First Dose 
Cmax, tmax, tlast, AUC0-t, AUC0-tau, AUC0-∞, AUC % Extrapolated, *CL/F, λz, Terminal t1/2 
Subsequent 
Doses 
Cmax, tmax, Cmin, tmin, Cavg, Fluctuation Index (FI), AUC0-tau, *CLss/F, λz, Terminal t1/2,  
Vss (IV only), *Vz/F; Accumulation Ratio and AUC Ratio 
* Calculated for USL311 and lomustine (parent drug) only 
Additional PK parameters (i.e., area under the moment curve [AUMC], Mean Residence Time, etc.) 
may be calculated as warranted. 
Backup samples may be used for exploratory metabolite profiling of USL311. If conducted, this analysis 
will be performed independent of the clinical study and described in a separate analysis report. 
Biomarker samples: 
In Phase 1 (Parts 1 and 2), blood and urine samples will be collected to evaluate biomarkers of target 
engagement (WBC with differential [neutrophils, lymphocytes, monocytes, eosinophils, and basophils], 
CD34+ cell counts, and SDF-1 plasma concentration [Part 1a only]) and phospholipidosis (BMP), 
respectively. Approximately 3 mL 4 mL, and 2 mL of blood will be collected at each nominal time point 
for WBC count with differential samples, CD34+ count samples, and SDF-1 plasma samples, 
respectively. 
Samples will be collected according to the schedules in Table  8 – Table  12 and analyzed using 
appropriately validated and/or qualified methods. As data become available, some samples may become 
optional if warranted based on ongoing analysis during the study conduct; specific samples and the 
rationale for making them optional will be documented. 
In both Phase 1 and Phase 2, optional blood samples may be collected and stored for pharmacogenomics 
analyses. Samples will only be collected after obtaining consent from the subject with a separate 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved informed consent 
form (ICF). 
Efficacy: 
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The efficacy outcome of interest will be analysis of PFS-6m following the start of therapy in Part 1 and 
Part 2 and following the start of therapy post-surgery in Part 3 and Part 4. Secondary efficacy outcomes 
will also include overall response and overall survival. Progression/response will be determined by the 
Response Assessment in Neuro-Oncology (RANO) criteria for subjects with primary brain tumors, 
whereas Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 criteria will be used to determine 
response for all other subjects. 
Exploratory: 
The exploratory objectives are as follows: 
Phase 1: 
• 
Determine effects of USL311 on s ystemic markers of CXCR4 inhibition, including 
measurement of CD34+ cells, and WBC count 
• 
Measure effects of USL311 on a urine biomarker of phospholipidosis BMP 
• 
Investigate exposure-response relationships for USL311 as a single agent and in combination 
with lomustine 
Phase 2:  
• 
Assess PD markers of CXCR4 inhibition in tumor samples following pre-surgical 
administration of USL311 for comparison with subjects randomized to receive no pr e-
surgical USL311 treatment. These markers may include, but are not limited to, the following: 
− 
Tumor pCXCR4 profile 
− 
Tumor markers of autophagy (e.g., LC3, Beclin-1) 
− 
Tumor markers of vasculogenesis (e.g., CD11b) and cancer stem cell survival and 
proliferation (e.g., nestin, CD133) 
• 
Determine biodistribution of USL311 to the brain/CSF in resection tissue sample and CSF 
sample following pre-surgical administration of USL311 for correlation with clinical 
response or PD data 
• 
Assess exposure-response relationships for USL311 as a single agent and in combination 
with lomustine. 
• 
Assess health-related QOL and subject reported outcomes using the EORTC 
QLQ-C30/BN20 
Tissue samples collected for assessment of the exploratory objectives will be analysed using 
appropriately qualified and/or validated assay methods (i.e., LC-MS/MS, flow cytometry, ELISA). 
STATISTICAL METHODS: 
Efficacy, safety, PK, PD and QOL assessments will be summarized separately for Phase 1 (Parts 1 and 
2; the “dose-escalation cohorts”) and Phase 2 (Parts 3 and 4; the “dose-expansion cohorts”) of the study. 
Additional summaries and analyses of pooled Phase 1 and 2 data may also be generated. Descriptive 
and summary statistics will be presented by dose group and overall as appropriate. Statistics will include 
number of observations, mean, standard deviation, median, range, and inter-quartile range for 
continuous variables, and the number and percent for categorical variables; 95% or 90% confidence 
 
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intervals will be presented where appropriate. Additional statistics such as geometric mean and 
coefficient of variation (CV%) may be calculated as warranted. 
Analysis Sets: 
• 
Full Analysis Set will include all subjects who received at least one dose of USL311 or 
lomustine 
• 
Safety Analysis Set will include all subjects who received at least one dose of the USL311 
or lomustine and have at least one post-baseline safety evaluation. 
• 
MTD-Evaluable Set will include all subjects in Phase 1 (dose-escalation) who complete one 
cycle of treatment and assessment or who discontinue before completing the first cycle 
because of an AE considered by the investigator to be at least possibly related to study 
drug(s). 
• 
Pharmacokinetic Analysis Set will include all subjects who have received at least one dose 
of USL311 or lomustine and have at least one quantifiable post-dose blood or plasma 
concentration of either drug. 
• 
Pharmacodynamic Analysis Sets will include all subjects who have received at least one dose 
of USL311 or lomustine and have at least one evaluable post treatment assessment for the 
given PD measure. 
• 
Response-Evaluable Analysis Set will consist of those subjects who have received at least 
one dose of USL311 or lomustine and have evaluable disease at baseline. 
− 
In Parts 3 and 4, subjects must have received at least one dose of USL311 or lomustine 
post-surgery and have at least one non-missing efficacy assessment (i.e., imaging or 
survival assessment) 
• 
Exposure-Response Analysis Sets will be constructed for each PD or response endpoint to 
be evaluated for correlation with PK data. The exposure-response analysis sets will consist 
of all subjects in the PK Analysis Set that also have an evaluable PD/response pretreatment 
assessment and at least one post-treatment PD/response assessment. 
Safety Analyses: 
Safety and tolerability will be evaluated in both Phase 1 and Phase 2 components. The Phase 1 primary 
analyses will include determination of the MTD and RP2D for USL311 as a  single agent and in 
combination with lomustine. All available safety, tolerability, PK and PD data will be considered by the 
Sponsor in dose-escalation decisions. 
In both Phase 1 and Phase 2, the incidence and duration of toxicities will be graded according to the 
NCI CTCAE version 4.03. 
Efficacy Analyses: 
Efficacy will be evaluated in both Phase 1 and Phase 2 components. In Phase 1, preliminary efficacy 
parameters such as PFS-6m, ORR%, DCR, and as defined by RECIST v.1.1 or RANO criteria as 
appropriate. The Phase 2 analyses will characterize efficacy in subjects in the dose-expansion cohorts 
treated at the RP2D for USL311 as a single agent and in combination with lomustine as determined by 
% PFS-6m, PFS, OS, ORR%, DCR, and as defined by RANO criteria. 
There is no formal hypothesis testing in this trial for efficacy endpoints. Approximately 20 evaluable 
subjects will be studied in each of the two Phase 2 dose-expansion groups to provide a preliminary 
 
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estimate of efficacy in relapsed/recurrent GBM. The primary objective, PFS-6m, will be calculated with 
two-sided 90% confidence interval (CI) using Kaplan-Meier (K-M) product-limit estimate of PFS. This 
will be performed based on both the full analysis set and response evaluable set. Median PFS will be 
calculated using K-M product-limit estimates and presented with two-sided 90% CIs. 
Handling of missing data, drop-outs, outliers and censoring rules will be described in the Statistical 
Analysis Plan(s) (SAP). Every effort will be made to ensure complete, accurate and timely data 
collection, and to avoid missing data. 
Pharmacodynamic Analyses: 
PD data obtained from the exploratory/translational analyses will be summarized using descriptive 
statistics as appropriate. Correlations between PD parameters and safety and/or efficacy metrics may be 
explored graphically, and if relationships are observed, exploratory analyses may be performed. 
Additional exploratory analyses may be conducted and will be described in detail in a separate analysis 
plan. 
Pharmacokinetic Analyses: 
PK parameters will be calculated using non-compartmental and/or compartmental methods (such as 
population PK analysis) as appropriate using actual sample collection times post-dose and will be 
summarized using descriptive statistics. Mean and individual subject plasma concentration-time profiles 
for USL311, its metabolites and lomustine and/or its metabolites will be presented on rectilinear and 
semi-logarithmic scales stratified by dose number and dose level. 
Assessments of dose proportionality will be performed using standard methods (i.e., power model 
approach, population PK analysis) and will be supported by graphical analysis. 
Assessment of a PK drug-drug interaction between USL311 and lomustine will be via comparison of 
USL311 and lomustine PK parameters (AUC, Cmax) when administered in combination to the PK 
parameters of each agent when administered individually. Statistical analysis will be performed using 
standard methods (i.e., ANOVA, non-linear mixed effect modeling) and will be supported by graphical 
analysis. 
Correlations between PK parameters and safety, efficacy and/or PD metrics may be explored graphically 
and if relationships are observed, exploratory analyses may be performed. Additional exploratory 
analyses may be conducted and will be described in detail in a separate analysis plan. 
Quality of Life/Patient Reported Outcome Measures 
In Phase 2, changes in health-related QOL and patient reported outcome measures will be assessed based 
on the EORTC QLQ-C30/BN20. The QLQ-C30 is a 30-item self-report questionnaire that measures 
several domains, including physical functioning, role functioning, emotional functioning, cognitive 
functioning, social functioning, fatigue, pain, nausea and vomiting, and several single items. The BN20 
consists of 4 scales comprising multiple items (future uncertainty, visual disorder, motor dysfunction, 
communication deficit) and 7 single items (headache, seizures, drowsiness, hair loss, itching, difficulty 
with bladder control, and weakness of both legs). 
 
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c During Cycle 1, the Baseline (Day -1), Day 1 and Day 2 visits will occur on consecutive days; Day 3 and Day 5 PK/PD assessments will be collected according to acceptable 
PK/PD windows specified in Table  8. Remaining Cycle 1 visits will occur within ≤ 3 days post scheduled study day. All remaining visits (Cycle 2+ up to but not including EOT 
visit), visits will occur a minimum of 7 days and a maximum of 14 days (unless treatment is on hold for safety reasons) from the previous dose of IV USL311. 
d The IRB/IEC-approved ICF must be signed before any study-specific procedures or examinations are performed. 
e New or clinically significant changes in subject’s medical and/or oncologic history from ICF signing until first dose of study drug will be recorded as an AE. 
f Oncologic history includes disease course and prior cancer treatments including radiotherapy, surgery and systemic therapies. For each systemic therapy, the date of last therapy 
and best response to therapy should be documented, if possible. Any residual toxicity related to prior treatments should be documented. 
g Physical exams at Screening, Baseline (Day -1), Day 1 of Cycle 2+, and at Follow-up should be complete assessments. Other physical exams may be abbreviated, at  Investigator’s 
discretion, to identify changes from baseline or evaluate changes in clinical symptoms. Weight, BMI, and BSA to be reported at each visit; height at Screening only. 
h Neurological exams at Screening and Follow-up will be complete assessments. At Cycle 1-Day 1, complete neurological exams will be performed pre-dose and prior to clinic 
discharge (between 5 hr nominaltime point and discharge); abbreviated neurological exams will be performed at 2 hr and EOI. On Cycle 1-Day 8 and Day 15, neurological exams 
will be performed pre-dose and at EOI and may be abbreviated exams. Other scheduled neurological exams will be performed pre-dose only, if applicable, and may be abbreviated 
exams, at the Investigator’s discretion, to identify changes from baseline or evaluate changes in clinical symptoms. Neurological exams will be performed within 0.5 hr (mid-
infusion) and ≤ 1 hr (EOI) after the nominal time point unless otherwise stated. 
i On visits without study drug administration, vital signs will be collected once. On days of study drug administration during all cycles, vital signs (pulse, systolic and diastolic blood 
pressure, temperature, and respiration rate) will be collected prior to dosing and prior to clinic discharge.  Additionally, at Cycle 1 only, vital signs will be collected 2 hr post start 
of infusion and EOI. Subjects should be in semi-recumbent position for ≥ 5 mins prior to collection. Vital signs will be collected ± 10 mins relative to nominal time point; when 
multiple assessments are scheduled at the same nominal time point, collect vital signs following ECG extraction period (see footnote j), prior to PK sample collection. Additional 
vital signs assessments should be performed if clinically indicated. 
j Holter-extracted 12-lead ECGs to be performed on Day -1 and Cycle 1-Day 1 for approximately 8.5 hours occurring at equivalent time points (± 30 mins) on both days. On Cycle 1-
Day 1, ECG extractions will occur at the followingnominal time points: 30 mins predose, and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, and 8 hours post-start of infusion. ECGs will also be 
extracted on Cycle 1-Day 2 at 24 hours post start of Day 1 infusion; on Cycle 1-Day 8 pre-dose, and 0.5, 1.5, 3, and 4 hours post start of infusion; and on Cycle 1-Day 15 pre-dose, 
2 and 4 hours post start of infusion. Subjects will rest in semi-recumbent position for at least 20 minutes per timepoint: from ≥ 5 minutes prior to ECG collection period which 
spans from -15 to -5 minutes prior to the nominal time point No other assessments will be performed during ECG collection period except for safety ECG collections. Frequency 
of ECGs may be increased, and/or included at subsequent cycles if clinically indicated. 
k Safety ECGs will be collected (via ECG printouts) by clinic staff at Screening and EOT visits in triplicate with replicates at least 2 minutes apart. Single (i.e., non-triplicate) safety 
ECGs will also be collected during Cycle 1 on Days 1, 8 and 15 at the following nominaltime points: Predose, and 0.5, 1, 1.5, 2, 3 and 4 hours post start of infusion. Subjects will 
rest in semi-recumbent position for ≥ 5 minutes prior to safety ECG collection and will remain in this position throughout ECG collection.  When safety ECGs are to be collected 
at the same nominal time as an ECG extraction, the safety ECGs should be collected during the ECG extraction period which spans from -15 minutes to -5 minutes prior to the 
nominal time point (refer to footnote j).  Additional safety ECGs may be collected per Investigator discretion and should be collected for clinically significant changes from 
baseline. Frequency of safety ECGs may be increased and/or included at subsequent cycles if clinically indicated.  
l Real-time bedside ECGs and heart rate monitoring will be performed on provided equipment during Cycle 1 on Days 1, 8 and 15 from start of infusion through clinic discharge 
(approximately 6 hours post start of infusion). Printouts may be collected per Investigator discretion and should be collected for clinically significant changes from baseline. Real-
time bedside monitoring will be performed at subsequent cycles as clinically indicated. 
m For women of childbearing potential, serum pregnancy test is required at Screening. Serum or urine pregnancy test to be performed at Baseline (Day -1) of Cycle 1 and pre-dose 
on Day 1 of every even-numbered cycle (i.e., Cycle 2-Day 1; Cycle 4-Day 1; Cycle 6-Day 1, etc.), and at the EOT visit. If treatment with study drug is stopped for ≥14 days, 
subject should have a negative pregnancy test prior to restarting study drug. 
n Hematology performed weekly by local laboratory: red blood cell (RBC) count, Hgb, hematocrit (Hct), mean corpuscular volume (MCV), platelets, WBC count with differential 
(neutrophils, lymphocytes, monocytes, eosinophils, and basophils), absolute lymphocyte count (ALC), and ANC. If weekly hematology demonstrates CTCAE grade 3/4 cytopenias, 
increase to daily monitoring as clinically appropriate. Hematology assessments scheduled for day of dosing must be available and assessed for toxicity before dosing. Hematology 
sample can be drawn ≤ 24 hours prior to dosing. 
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o Coagulation assessments performed weekly by local laboratory: prothrombin time (PT), activated partial thromboplastin time (aPTT)/PTT, and international normalized ratio 
(INR). Coagulation assessments scheduled for day dosing must be available and assessed for toxicity before dosing. Coagulation sample can be drawn ≤ 24 hours prior to dosing. 
p Serum chemistry performed weekly by local laboratory: sodium, potassium, calcium, chloride, phosphorus or phosphate, magnesium, serum creatinine, total bilirubin, total protein, 
albumin, alkaline phosphatase (ALP), lactic dehydrogenase (LDH), AST, ALT, glucose, bicarbonate, blood urea nitrogen (BUN), uric acid, creatine phosphokinase (CPK) and 
gamma-glutamyltransferase (GGT). Baseline potassium, sodium, calcium (corrected for albumin) and magnesium levels below lower limit of normal (LLN) must be corrected to 
within normal range, or above the ULN if deemed not clinically significant by the Investigator, prior to study drug dosing. Serum chemistry assessments scheduled for day of 
dosing must be available and assessed for toxicity before dosing. Serum chemistry sample can be drawn ≤ 24 hours prior to dosing. 
q Urine dipstick must include pH, sp gravity, protein, glucose, ketones, bilirubin, blood, nitrite, and leukocyte esterase. Microscopy is required only to follow-up on clinically 
significant urine dipstick findings, as determined by the investiag. 
r A blood sample for cytochrome P450 genotyping will be collected on Baseline (Day -1). An optional blood sample for future pharmacogenomics analyses may also be collected 
on Day -1 (or at a later visit if determined appropriate per the clinical site) after appropriate separate consent is obtained. 
s Tumor assessments to be performed at Screening, Cycle 3-Day 1, then every 6 weeks (± 7 days) thereafter and at EOT visit. Baseline and subsequent radiographs/scans  to assess 
response should be performed using same techniques. RECIST v.1.1 will be used to determine response, with exception of RANO criteria for primary brain tumor assessment. 
t It is recommended that, when possible, subjects should remain in semi-recumbent position throughout the duration of USL311 infusion. 
u The AE/SAE collection period is from ICF signing through the Follow-up Visit. AEs/SAEs must be reported as described in Section 9.3 of the protocol. Any AEs/SAEs ongoing 
at the Follow-up Visit should be followed to resolution, until the Investigator considers them chronic or stable, or judges them to be no longer clinically significant. 
v All concomitant medications (including over-the-counter and herbal treatments) will be recorded from 28 days before the first dose until the Follow-up Visit. For primary brain 
tumor and GBM subjects, corticosteroid use, including any changes in dose and/or frequency will be documented for RANO criteria assessment. 
w Blood samples (approximately 4 mL) for PK analysis (USL311) will be collected on Cycle 1-Day 1, Day 2, Day 3, Day 5, Day 8, and Day 15 and a pre-dose sample prior to the 
first dose of Cycle 2. 
x In the event of a possible study drug-related SAE or DLT throughout the study, attempts will be made to collect additional PK blood samples as close to the event as possible to 
help characterize any possible relationships between drug exposure and the clinical event. 
y Blood samples (approximately 2 or 6 mL each) for PD analyses (CD34+ [6 mL], SDF-1 [2 mL], and WBC count with differential [neutrophils, lymphocytes, monocytes, 
eosinophils, and basophils] [2 mL]) will be collected on Cycle 1-Day 1 at predose, 0.5, 1, 2, 3, 4, 5, 6, 7 and 8 hours post-dose, on Day 2 at 24 hours post the Day 1 dose, Day 3, 
Day 5, Day 8 at predose, 0.5, 1.5, 3, and 4 hours post-dose, and Day 15 at predose and 2 and 4 hours post-dose and on Cycle 2-Day 1 a pre-dose sample prior to the first dose of 
Cycle 2 as described in Table  8. 
z BMP urine sample collection to occur on Baseline (Day -1) and prior to Day 1 dosing on even-numbered cycles (i.e., Cycle 2-Day 1; Cycle 4-Day 1; Cycle 6-Day 1; etc.). 
aa Confirmation of archival tumor tissue availability is required prior to enrollment. 
bb The EOT visit will occur within ≤ 14 days of the decision to discontinue study treatment; the Follow-up Visit will occur within ≤ 28 days of the last USL311 dose. The EOT visit 
may be the same as the Follow-up Visit; however, the Follow-up Visit should occur as close as possible to 28 days after the last USL311 dose. Any TEAEs ongoing at the EOT 
Visit should be followed to resolution or until the Investigator considers them chronic or stable. 
cc Subjects will be followed for survival information quarterly as defined in Section 7.4. Survival follow-up information will be collected via telephone calls and/or clinic visits. 
 
 
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c During Cycle 1, the Baseline (Day -1), Day 1 and Day 2 visits will occur on consecutive days; Day 3 and Day 5 PK/PD assessments will be collected according to the acceptable 
windows specified in Table  9. Remaining Cycle 1 visits will occur within ≤ 3 days post scheduled study day. All remaining visits (Cycle 2+ up to but not including EOT visit), 
will occur within ± 3 days of scheduled visit.  
d IRB/IEC-approved ICF must be signed before any study-specific procedures or examinations are performed. 
e New or clinically significant changes in subject’s medical and/or oncologic history from ICF signing until first dose of study drug will be recorded as an AE. 
f Oncologic history includes disease course and prior cancer treatments including radiotherapy, surgery and systemic therapies. For each systemic therapy, the date of last therapy 
and best response to therapy should be documented, if possible. Any residual toxicity related to prior treatments should be documented. 
g Physical exams at Screening, Baseline (Day -1), Day 1 of Cycle 2+, and Follow-up should be complete assessments. Other physical exams may be abbreviated, at Investigator’s 
discretion, to identify changes from baseline or evaluate changes in clinical symptoms. Weight, BMI, and BSA to be reported at each visit; height at Screening only. 
h Neurological exams at Screening and Follow-up will be complete assessments. At Cycle 1-Day 1, complete neurologic exams will be performed pre-dose and > 4 hours after 
dosing, prior to discharge. At Cycle 1-Day 8 and Day 15, neurological exams will be performed pre-dose and may be abbreviated exams. Other scheduled neurological exams will 
be performed pre-dose, if applicable, and may be abbreviated exams, at Investigator’s discretion, to identify changes from baseline or evaluate changes in clinical symptoms.  
i Vital signs (pulse, systolic and diastolic blood pressure, temperature, and respiration rate) will be collected prior to in-clinic dosing, and prior to clinic discharge.  If PK collection 
is prior to vitals, wait ≥ 5 minutes before obtaining vitals.  Subjects should be in semi-recumbent position for ≥ 5 mins prior to collection. Perform additional vital signs if indicated.  
j Holter-extracted 12-lead ECGs will be performed on Day -1 and Cycle 1-Day 1 for approximately 8.5 hours, occurring at equivalent time points (± 30 mins) on both days. On 
Cycle 1-Day 1, ECG extractions will occur at the following time points: Predose and 0.5, 1, 1.5, 2, 2.5, 3, 4, and 6 hours post-dose. ECGs will also be extracted on Cycle 1-Day 2 
at 24 hours post Cycle 1-Day 1 dose (prior to Day 2 dose); on Cycle 1-Day 8 pre-dose, and 0.5, 2, 3 and 4 hours post-dose; on Cycle 1-Day 15 pre-dose, and 2-4 hours post-dose 
(to be aligned with the PK collection time) and on Cycle 2-Day 1 pre-dose and 2-4 hours post-dose (to be aligned with the PK collection time.  The holter device will be placed at 
least 30 minutes prior to dosing and the subject will be placed in a resting, semi-recumbent position and will remain in a semi-recumbent position for at least 4 hours post-dose. 
No other assessments will be performed during each ECG collection period (i.e., from -15 to -5 minutes prior to the nominal time point) except for safety ECG collections. 
Frequency of ECGs may be increased and/or included at subsequent cycles if clinically indicated. All other electrical devices need to be removed from the bed/chair including cell 
phones. 
k Safety ECGs will be collected (via ECG printouts) by clinic staff at Screening and EOT visits in triplicate with replicates at least 2 minutes apart. Single (i.e., non-triplicate) safety 
ECGs will also be collected during Cycle 1-Day 1 predose and 0.5, 1, 1.5, 2, 2.5, 3, 4, and 6 hours post-dose; on Cycle 1-Day 2 at 24 hours post Cycle 1-Day 1 dose (prior to Day 
2 dose); on Cycle 1-Day 8 pre-dose, and 0.5, 2, 3 and 4 hours post-dose; on Cycle 1-Day 15 pre-dose, and 2-4 hours post-dose (to be aligned with the PK collection time) and on 
Cycle 2-Day 1 pre-dose and 2-4 hours post-dose (to be aligned with the PK collection time). Subjects will rest in semi-recumbent position for ≥ 5 minutes prior to safety ECG 
collection and will remain in this position throughout ECG collection.  When safety ECGs are to be collected at the same nominal time point as a Holter-extracted ECG, the safety 
ECGs should be collected during the Holter ECG extraction period, which spans from -15 minutes to -5 minutes prior to the nominal time point (refer to footnote j).  Additional 
safety ECGs may be collected per Investigator discretion and should be collected for clinically significant changes from baseline. Frequency of safety ECGs may be increased 
and/or included at subsequent cycles if clinically indicated.  
l Real-time bedside ECGs and heart rate monitoring will be performed on provided equipment during Cycle 1 on Days 1, 8 and 15 after in-clinic dosing. Printouts may be collected 
per Investigator discretion and should be collected for clinically significant changes from baseline. Real-time bedside monitoring will be performed at subsequent cycles as clinically 
indicated. 
m For women of childbearing potential, serum pregnancy test is required at Screening. Serum or urine pregnancy test to be performed Baseline (Day -1) of Cycle 1 and pre-dose on 
Day 1 of every even-numbered cycle (i.e., Cycle 2-Day 1; Cycle 4-Day 1; Cycle 6-Day 1, etc.), and at the EOT visit. If treatment with study drug is stopped for ≥14 days, subject 
should have a negative pregnancy test prior to restarting study drug.  
n Hematology performed weekly by local laboratory: RBC count, Hgb, Hct, MCV, platelets, WBC count with differential (neutrophils, lymphocytes, monocytes, eosinophils, and 
basophils), ALC, and ANC. If weekly hematology demonstrates CTCAE grade 3/4 cytopenias, increase to daily monitoring, as clinically appropriate.  Hematology sample can be 
drawn ≤ 24 hours prior to visit. 
o Coagulation performed weekly by local laboratory: PT, aPTT/PTT, and INR. Coagulation sample can be drawn ≤ 24 hours prior to visit. 
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p Serum chemistry performed weekly by local laboratory: sodium, potassium, calcium, chloride, phosphorus or phosphate, magnesium, serum creatinine, total bilirubin, total protein, 
albumin, ALP, LDH, AST, ALT, glucose, bicarbonate, BUN, uric acid, CPK and GGT. Baseline potassium, sodium, calcium (corrected for albumin) and magnesium levels below 
LLN must be corrected to within the normal range, or above the ULN if deemed not clinically significant by the Investigator, prior to dosing. Serum chemistry sample can be 
drawn ≤ 24 hours prior to dosing. 
q Urine dipstick must include pH, sp gravity, protein, glucose, ketones, bilirubin, blood, nitrite, and leukocyte esterase. Microscopy is required only to follow-up on clinically 
significant urine dipstick findings, which include a positive result for protein, blood, nitrite, and/or leukocyte esterase. 
r A blood sample for cytochrome P450 genotyping will be collected on Baseline (Day -1). An optional blood sample for future pharmacogenomics analyses may also be collected 
on Day -1 (or at a later visit if determined appropriate per the clinical site) after appropriate separate consent is obtained.  
s Tumor assessments to be performed at Screening, Cycle 3-Day 1, then every 6 weeks (± 7 days) thereafter and at EOT visit. Baseline and subsequent radiographs/scans to assess 
response should be performed using the same techniques. RECIST v.1.1 will be used to determine response, with exception of RANO criteria for primary brain tumor assessment. 
A confirmed objective response is defined as a response that persists on repeat imaging for two assessments with a time period of at least 4 weeks between the two assessments. 
In the event of a confirmed response, the timing of subsequent tumor assessment will be reset at the 6-week (± 7 days) interval from confirmatory scan. 
t Study drug will be held on the morning of clinic visits and will be administered in-clinic under fasted conditions for 2 hours before and 2 hours after the dose on Cycle 1-Days 1, 
2, 8 and 15 and on Cycle 2-Day 1, after pre-dose assessments have been completed.  
u The AE/SAE collection period is from ICF signing through the Follow-up visit. AEs/SAEs must be reported as described in Section 9.3 of the protocol. Any AEs/SAEs ongoing 
at the Follow-up visit should be followed to resolution, until the Investigator considers them chronic or stable, or judges them to be no longer clinically significant. 
v All concomitant medications (including over-the-counter and herbal treatments) will be recorded from 28 days before the first dose until the Follow-up visit. For primary brain 
tumor and GBM subjects, corticosteroid use, including any changes in dose and/or frequency will be documented for RANO criteria assessment. 
w Blood samples (approximately 4 mL) for PK analyses (USL311) will be collected on Cycle 1-Day 1, Day 2, Day 8, and Day 15, and on Cycle 2-Day 1. Collection schedule and 
acceptable PK sample collection windows are as defined in Table 9. 
x In the event of a possible study drug-related SAE or DLT throughout the study, attempts will be made to collect additional PK blood samples as close to the event as possible to 
help characterize any possible relationships between drug exposure and the clinical event. 
y Blood samples (approximately 2 or 6 mL each) for PD analyses (CD34+ [6 mL], and WBC count with differential [neutrophils, lymphocytes, monocytes, eosinophils, and basophils] 
[2 mL]) will be collected on Cycle 1-Day 1, Day 2, Day 8, and Day 15. Collection schedule and acceptable PD sample collection windows are defined in Table  9. 
z BMP urine sample collection to occur on Baseline (Day -1) and prior to dosing on Day 1 of every even-numbered cycle (i.e., Cycle 2-Day 1; Cycle 4-Day 1; Cycle 6-Day 1; etc.).   
aa Confirmation of archival tumor tissue availability is required prior to enrollment.  
bb The EOT visit will occur within ≤ 14 days of the decision to discontinue study treatment; the Follow-up visit will occur within ≤ 28 days of the last USL311 dose. The EOT visit 
may be the same as the Follow-up visit; however, the Follow-up visit should occur as close as possible to 28 days after the last USL311 dose. Any TEAEs ongoing at the EOT 
visit should be followed to resolution or until the Investigator considers them chronic or stable. 
cc Subjects will be followed for survival information quarterly as defined in Section 7.4. Survival follow-up information will be collected via telephone calls and/or clinic visits. 
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c During Cycle 1, the Day 8 and Day 9 visits will occur on consecutive days. All remaining Cycle 1 visits will occur on the scheduled study day or ≤ 3 days post scheduled study 
day. During Cycle 2-Day 1 and Day 2 visits will occur on consecutive days. All remaining visits (Cycle 2+ up to but not including the EOT visit) will occur within ± 3 days of 
scheduled visit.  
d In Cycle 1 only, the cycle duration is 7 weeks (Day 1 – Day 49); lomustine will be administered on Cycle 1-Day 1 and the first dose of USL311 will be administered on Cycle 1-
Day 8. In all subsequent cycles, the cycle duration is 6 weeks (Day 1 – Day 42); USL311 will be administered beginning on Day 1 and lomustine will be administered on Day 2 of 
each cycle. 
e The IRB/IEC-approved ICF must be signed before any study-specific procedures or examinations are performed. 
f New or clinically significant changes in subject’s medical and/or oncologic history from ICF signing until first dose of study drug will be recorded as an AE. 
g Oncologic history includes disease course and prior cancer treatments including radiotherapy, surgery and systemic therapies. For each systemic therapy, the date of last therapy 
and best response to therapy should be documented, if possible. Any residual toxicity related to prior treatments should be documented.  
h Physical exams at Screening, Day 1 of Cycle 2+, and Follow-up should be complete assessments. Other physical exams may be abbreviated, at Investigator’s discretion, to identify 
changes from baseline or evaluate changes in clinical symptoms. Weight, BMI, and BSA to be reported at each visit, height at Screening only. 
i Neurological exams at Screening and Follow-up will be complete assessments. At Cycle 1-Day 8, complete neurological exams will be performed pre-dose and > 4 hours after 
dosing, prior to clinic discharge.  At Cycle 1-Day 15, Day 22, Day 29, Day 36, and Day 43, neurological exams will be performed pre-dose and may be abbreviated exams. Other 
scheduled neurological exams will be performed prior to in-clinic dosing only, and may be abbreviated exams, at Investigator’s discretion, to identify changes from baseline or 
evaluate changes in clinical symptoms.  
j Vital signs (pulse, systolic and diastolic blood pressure, temperature, and respiration rate) will be collected prior to in-clinic USL311 dosing, and prior to clinic discharge.  If PK 
collection is prior to vitals, wait ≥ 5 minutes before obtaining vitals. Subjects should be in a semi-recumbent position for ≥ 5 mins prior to collection. Perform additional vital signs 
if clinically indicated. 
k Holter-extracted 12-lead ECGs will be performed on Cycle 1-Day 1 at -60 min, -45 min, and -30 min prior to lomustine dosing; on Cycle 1-Day 8 pre-dose and 0.5, 1, 1.5, 2, 2.5, 
3, 4, and 6 hours post-dose. ECGs will also be extracted on Cycle 1-Day 9 at 24 hours post Cycle 1-Day 1 dose (prior to Day 2 dose); on Cycle 1-Day 15 pre-dose, and 0.5, 2, 3 
and 4 hours post-dose; on Cycle 1-Day 22 pre-dose, and 2-4 hours post-dose (to be aligned with the PK collection time) and on Cycle 1-Days 29, 36, and 43 prior to in-clinic 
dosing with USL311 and 2 hours post-dose. ECGs will also be extracted on Cycle 2-Day 1 pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4 and 6 hours post-dose and on Cycle 2-Day 2 at 24 hours 
post Cycle 2-Day 1 dose (prior to Day 2 dose), and 1, 2, 3, 4, 5, 8 and 12 hours post-dose. On Cycle 1-Day 1, subjects will rest in a semi-recumbent position from -80 min (i.e., 20 
minutes prior to the -60 min time point) through -20 min prior to lomustine administration. On all other days, the holter device will be placed at least 30 minutes prior to dosing 
and the subject will be placed in a resting, semi-recumbent position and will remain in a semi-recumbent position for at least 4 hours post-dose. No other assessments will be 
performed during each ECG collection period (i.e., from -15 to -5 minutes prior to the nominal time point) except for safety ECG collections.  Frequency of ECGs may be increased 
and/or included at subsequent cycles if clinically indicated. All other electrical devices need to be removed from the bed/chair including cell phones. 
l Safety ECGs will be collected (via ECG printouts) by clinic staff at Screening and EOT visits in triplicate with replicates at least 2 minutes apart. Single (i.e., non-triplicate) safety 
ECGs will also be collected during Cycle 1 as follows: on Cycle 1-Day 8 predose and 0.5, 1, 1.5, 2, 2.5, 3, 4 and 6 hours post-dose; Day 9 at 24 hours post-dose (prior to in-clinic 
dosing); Day 15 pre-dose and 0.5, 2, 3, and 4 hours post-dose; Day 22 pre-dose and 2-4 hours post-dose (to be aligned with the PK collection time) and Cycle 1-Day 29, Day 36 
and Day 43 pre-dose and 2 hours post-dose.  Subjects will rest in semi-recumbent position for ≥ 5 minutes prior to safety ECG collection and will remain in this position throughout 
ECG collection.  When safety ECGs are to be collected at the same nominal time as a Holter-extracted ECG, the safety ECGs should be collected during the Holter ECG extraction 
period, which spans from -15 minutes to -5 minutes prior to the nominal time point (refer to footnote k).  Additional safety ECGs may be collected per Investigator discretion and 
should be collected for clinically significant changes from baseline. Frequency of safety ECGs may be increased and/or included at subsequent cycles if clinically indicated. 
m Real-time bedside ECGs and heart rate monitoring will be performed on provided equipment during Cycle 1 on Days 8, 15, 22, 29, 36 and 43 in-clinic dosing. Printouts may be 
collected per Investigator discretion and should be collected for clinically significant changes from baseline. Real-tine bedside monitoring will be performed at subsequent cycles 
as clinically indicated. 
n For women of childbearing potential, serum pregnancy test is required at Screening. Serum or urine pregnancy test to be performed prior to dosing with lomustine on Cycle 1-
Day 1, prior to USL311 dosing on Day 1 of every cycle thereafter, and at the EOT visit. If treatment with study drug is stopped for ≥14 days, subject should have a negative 
pregnancy test prior to restarting study drug. 
 
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o Hematology performed weekly by local laboratory: RBC count, Hgb, Hct, MCV, platelets, WBC count with differential (neutrophils, lymphocytes, monocytes, eosinophils, and 
basophils), ALC, and ANC. If weekly hematology demonstrates CTCAE grade 3/4 cytopenias, increase to daily monitoring, as clinically appropriate. Hematology sample can be 
drawn ≤ 24 hours prior to visit. 
p Coagulation assessments performed weekly by local laboratory: PT, aPTT/PTT, and INR. Coagulation sample can be drawn ≤ 24 hours prior to dosing. 
q Serum chemistry performed weekly by local laboratory: sodium, potassium, calcium, chloride, phosphorus or phosphate, magnesium, serum creatinine, total bilirubin, total protein, 
albumin, ALP, LDH, AST, ALT, glucose, bicarbonate, BUN, uric acid, CPK, and GGT. Baseline potassium, sodium, calcium (corrected for albumin) and magnesium levels below 
LLN must be corrected to within the normal range, or above the ULN if deemed not clinically significant by the Investigator The serum chemistry sample can be drawn ≤ 24 hours 
prior to dosing. 
r Urine dipstick must include pH, sp gravity, protein, glucose, ketones, bilirubin, blood, nitrite, and leukocyte esterase. Microscopy is required only to follow-up on clinically 
significant urine dipstick findings, which include a positive test for protein, blood, nitrite and/or leukocyte esterase.  
s  A blood sample for cytochrome P450 genotyping will be collected on Cycle 1-Day 1. An optional blood sample for future pharmacogenomics analyses may also be collected on 
Cycle 1-Day 1 (or at a later visit if determined appropriate per the clinical site) after appropriate separate consent is obtained. 
t Tumor assessments to be performed at Screening, Cycle 2-Day 1, then every 6 weeks (± 7 days) thereafter and at EOT visit. Baseline and subsequent radiographs/scans to assess 
response should be performed using same techniques. RECIST v1.1 will be used to determine response with exception of RANO criteria for primary brain tumor assessment.  A 
confirmed objective response is defined as a response that persists on repeat imaging for two assessments with a time period of at least 4 weeks between the two assessments. In 
the event of a confirmed response, the timing of subsequent tumor assessment will be reset at the 6-week (± 7 days) interval from confirmatory scan. 
u Study drug will be held on the morning of clinic visits and will be administered in-clinic under fasted conditions for 2 hours before and 2 hours after the dose on Cycle 1-Days 8, 
9, 15 and 22 and on Cycle 2-Days 1 and 2, after pre-dose assessments have been completed. v 
The AE/SAE collection period is from ICF signing through the Follow-up visit. 
AEs/SAEs must be reported as described in Section 9.3 of the protocol. Any AEs/SAEs ongoing at the Follow-up visit should be followed to resolution or until the Investigator 
considers them chronic or stable, or judges them to be no longer clinically significant. 
w All concomitant medications (including over-the-counter and herbal treatments) will be recorded from 28 days before the first dose of lomustine until the Follow-up visit. For 
primary brain tumor subjects, corticosteroid use including any changes in dose and/or frequency will be documented for RANO criteria assessment. 
x Blood samples (approximately 4 mL) for PK analyses (USL311 and/or lomustine) will be collected on Cycle 1-Day 1, Day 8, Day 9, Day 15 and Day 22, and on Cycle 2-Day 1 
and Day 2. Collection schedule and acceptable PK sample collection windows are as defined in Table  10. 
y In the event of a possible study drug-related SAE or DLT throughout the study, attempts will be made to collect additional PK blood samples as close to the event as possible to 
help characterize any possible relationships between drug exposure and the clinical event. 
z Blood samples (approximately 2 or 6 mL each) for PD analyses (CD34+ [6 mL], and WBC count with differential [neutrophils, lymphocytes, monocytes, eosinophils, and basophils] 
[2mL]) will be collected on Cycle 1-Day 8, Day 9, Day 15, and Day 22, and Cycle 2-Day 1. Collection schedule and acceptable PD sample collection windows are defined in 
Table  10. 
aa BMP urine sample collection to occur prior to dosing with lomustine on Cycle 1-Day 1 and prior to in-clinic USL311 dosing on Day 1 of every cycle thereafter.   
bb Confirmation of archival tumor tissue availability is required prior to enrollment. 
cc The EOT visit will occur within ≤ 14 days of the decision to discontinue study treatment; the Follow-up visit will occur within ≤ 28 days of the last USL311 dose. The EOT visit 
may be the same as the Follow-up visit; however, the Follow-up visit should occur as close as possible to 28 days after the last USL311 dose. Any TEAEs ongoing at the EOT 
visit should be followed to resolution or until the Investigator considers them chronic or stable, or judges them to be no longer clinically significant. 
dd Subjects will be followed for survival information quarterly as defined in Section 7.4. Survival follow-up information will be collected via telephone calls and/or clinic visits.
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b The following Screening safety assessments are required to be repeated at Pre-surgical Dosing-Day 1 (baseline) if Screening assessments were performed > 3 days before 
Pre-surgical Dosing-Day 1 (1st dose of USL311): inclusion/exclusion criteria, physical exam, neurological exam, UA, hematology, coagulation and serum chemistry). If collected 
≤ 3 days prior to Pre-surgical Dosing-Day 1, these assessments do not need to be repeated. 
c The assessments within the Pre-surgical Dosing period only apply to subjects randomized to receive pre-surgical treatment with USL311. Subjects randomized to receive no 
USL311 treatment prior to surgery will not participate in any of the assessments within the Pre-surgical Dosing period and will not visit the clinic for these visits. 
d For subjects randomized to pre-surgical treatment with USL311, surgical re-resection may occur at any time from Day 2 onwards; USL311 will be administered daily until surgery. 
Assessments within the Pre-surgical Dosing period that are pending at the time of surgery will no longer be required and will not be performed post-surgery. Subjects will continue 
with assessments as defined per Post-surgical Cycle 1. 
e During the Pre-surgical Dosing period, the Day 1 and Day 2 visits will occur on consecutive days. The windows for Day 3, Day 5, and Day 8 visits (PK samples) are described in 
Table 11 All remaining Pre-surgical Dosing visits are dependent on the length of treatment with pre-surgical USL311 and will occur weekly within ± 3 days of the scheduled visit. 
Cycle 1-Day 1 and Day 2 Post-surgery visits will occur on consecutive days. All remaining visits (up to but not including the EOT visit), will occur within ± 3 days of scheduled 
visit. 
f For subjects randomized to receive pre-surgical treatment with USL311, daily dosing will continue until surgery; the dose will be held on the day of surgery. Cycle 1-Day 1 Post-
surgery will be initiated within ≤ 28 days of surgery.   
g The IRB/IEC-approved ICF must be signed before any study-specific procedures or exams are performed. 
h New or clinically significant changes in subject’s medical and/or oncologic history from ICF signing until first dose of study drug will be recorded as an AE. 
i Oncologic history includes disease course and prior cancer treatments including radiotherapy, surgery and systemic therapies. For each systemic therapy, the date of last therapy 
and best response to therapy should be documented, if possible. Any residual toxicity related to prior treatments should be documented. 
j Physical exams at Screening, Day 1 of each cycle post-surgery, and Follow-up are complete assessments. Other physical exams, including Day 1 of Pre-surgical Dosing, may be 
abbreviated, at Investigator’s discretion, to identify changes from baseline or evaluate changes in clinical symptoms. Weight, BMI, and BSA to be reported at each visit, height at 
Screening only. 
k Neurological exams at Screening, Day 1 of each cycle post-surgery, and Follow-up are complete assessments. At Pre-surgical Dosing Day 1, complete neurological exams will be 
performed pre-dose and > 4 hours after dosing, prior to clinic discharge. At Pre-surgical Dosing-Day 8, Day 15, at each subsequent weekly Pre-Surgical visit, and at Post-surgery 
Cycle 1-Day 8 and Day 15, neurological exams will be performed prior to in-clinic dosing and may be abbreviated. Other scheduled neurological exams will be performed prior 
to in-clinic dosing only, and may be abbreviated exams, at the Investigator’s discretion, to identify changes from baseline or evaluate changes in clinical symptoms.  
l Vital signs (pulse, systolic and diastolic blood pressure, temperature, and respiration rate) will be collected prior to in-clinic USL311 dosing, and prior to clinic discharge. If PK 
collection is prior to vitals, wait ≥ 5 minutes before obtaining vitals.  Subjects should be in a semi-recumbent position for ≥ 5 mins prior to collection. Collect additional vital signs 
if clinically indicated.  
m Holter-extracted 12-lead ECGs will be performed at Screening, during the Pre-surgical Dosing period on Day 1 pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4 and 6 hours post-dose, on Day 
2 at 24 hours post the Pre-surgical Dosing-Day 1 dose (prior to Day 2 dose), on Day 3 (60 hours post-Day 1 dose), Day 5 (108 hours post-Day 1 dose) and Day 8 pre-dose.  ECGs 
will also be extracted on the Day of Surgery (prior to surgery), and on Cycle 1-Day 1 pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, and 7 hours post-dose, on Cycle 1-Day 2 at 24 hours 
post the Cycle 1-Day 1 dose (prior to Day 2 dose), and pre-dose on Cycle 1-Day 8, Day 15, on Cycle 2-Day 1 and at the EOT visit. The holter device will be placed at least 30 
minutes prior to dosing and the subject will be placed in a resting, semi-recumbent position and will remain in a semi-recumbent position for at least 4 hours post-dose.  No other 
assessments will be performed during each ECG collection period (i.e., from -15 to -5 minutes prior to the nominal time point). Frequency of ECGs may be increased and/or 
included at subsequent cycles if clinically indicated. All other electrical devices need to be removed from the bed/chair including cell phones. 
n Real-time bedside ECGs and heart rate monitoring will be performed on provided equipment during Pre-surgical Dosing visits and on Cycle 1-Day 1 Post-surgery visit after in-
clinic dosing. Printouts may be collected per Investigator discretion and should be collected for clinically significant changes from baseline. Real-tine bedside monitoring will be 
performed at subsequent cycles as clinically indicated. 
o For women of childbearing potential, serum pregnancy test is required at Screening. Serum or urine pregnancy test to be performed prior to dosing on Day 1 of the Pre-surgical 
Dosing period, prior to in-clinic dosing on Cycle 1-Day 1 Post-surgery, prior to dosing on Day 1 of every even numbered cycle (i.e., Cycle 2-Day 1; Cycle 4-Day 1; Cycle 6-Day 
1; etc.), and at the EOT visit. If treatment with study drug is stopped for ≥ 14 days, subject should have a negative pregnancy test prior to restarting study drug.  
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p Hematology performed weekly by local laboratory: RBC count, Hgb, Hct, MCV, platelets, WBC count with differential (neutrophils, lymphocytes, monocytes, eosinophils, and 
basophils), ALC, and ANC. If weekly hematology demonstrates CTCAE grade 3/4 cytopenias, increase to daily monitoring, as clinically appropriate. Hematology sample can be 
drawn ≤ 24 hours prior to visit.  
q Coagulation assessments performed weekly by local laboratory: PT, aPTT/PTT, and INR. Coagulation sample can be drawn ≤ 24 hours prior to visit. 
r Serum chemistry performed weekly by local laboratory: sodium, potassium, calcium, chloride, phosphorus or phosphate, magnesium, serum creatinine, total bilirubin, total protein, 
albumin, ALP, LDH, AST, ALT, glucose, bicarbonate, BUN, uric acid, CPK, and GGT. Baseline potassium, sodium, calcium (corrected for albumin) and magnesium levels below 
LLN must be corrected to within the normal range, or above the ULN if deemed not clinically significant by the Investigator, prior to dosing.  The serum chemistry sample can be 
drawn ≤ 24 hours prior to dosing. 
s Urine dipstick must include pH, sp gravity, protein, glucose, ketones, bilirubin, blood, nitrite, and leukocyte esterase.  Microscopy is required only to follow-up on clinically 
significant urine dipstick findings, which include a positive test for protein, blood, nitrite and/or leukocyte esterase. 
t  A blood sample for cytochrome P450 genotyping will be collected on Cycle 1-Day 1. An optional blood sample for future pharmacogenomics analyses may also be collected on 
Cycle 1-Day 1 (or at a later visit if determined appropriate per the clinical site) after appropriate separate consent is obtained. 
u Tumor assessments to be peformed at Screening, between Surgery and Cycle 1-Day 1 Post-surgery, at Cycle 3-Day 1 Post-surgery, then every 6 weeks (± 7 days) thereafter, at 6 
months (± 7 days), and at the EOT visit. Baseline and subsequent radiographs/scans to assess response should be performed using same techniques. RANO criteria will be used to 
establish post-surgical baseline status (i.e., radiographic assessment occurring between Surgery and Day 1 of Cycle 1 Post-surgery) and to determine response.  A confirmed 
objective response is defined as a response that persists on repeat imaging for two assessments with a time period of at least 4 weeks between the two assessments. In the event of 
a confirmed response, the timing of subsequent tumor assessment will be reset at the 6-week (± 7 days) interval from confirmatory scan. 
v Study drug will be held on the morning of clinic visits and will be administered in-clinic under fasted conditions for 2 hours before and 2 hours after the dose on Pre-surgical 
Dosing-Day 1, Day 2, Day 3, Day 5 and Day 8 and on Cycle 1-Days 1, 2, 8 and 15 and on Cycle 2-Day 1, after pre-dose assessments have been completed. 
w Only subjects randomized to receive USL311 prior to surgery will receive USL311 treatment during the Pre-surgical Dosing period. Subjects randomized to no USL311 treatment 
prior to surgery will receive their first dose of USL311 on Cycle 1-Day 1 Post-surgery. 
x The AE/SAE collection period is from ICF signing through the Follow-up visit. AEs/SAEs must be reported as described in Section 9.3 of the protocol. Any AEs/SAEs ongoing 
at the Follow-up visit should be followed to resolution or until the Investigator considers them chronic or stable or judges them to be no longer clinically significant. 
y All concomitant medications (including over-the-counter and herbal treatments) will be recorded from 28 days before the first dose of USL311 until the Follow-up visit. For 
primary brain tumor subjects, corticosteroid use, including any changes in dose and/or frequency will be documented for RANO criteria assessment. 
z Blood samples (approximately 4 mL) for PK analyses (USL311) will be collected during Pre-surgical Dosing on Day 1, Day 2, Day 3, Day 5, and Day 8, on the Day of Surgery, 
and Post-surgery on Cycle 1-Day 1, Day 2, Day 8, and Day 15, and on Cycle 2-Day 1. Collection schedule and acceptable PK sample collection windows are as defined in 
Table  11 and Table  12. 
aa In the event of a possible study drug-related SAE or DLT throughout the study, attempts will be made to collect additional PK blood samples as close to the event as possible to 
help characterize any possible relationships between drug exposure and the clinical event. 
bb Confirmation of archival tumor tissue availability is required prior to enrollment. 
cc The health-related QOL questionnaire will be completed at Screening, between Surgery and Post-surgery Cycle 1-Day 1, at the end of Post-surgery Cycle 2, every 6 weeks (± 7 
days), at 6 months (± 7 days), and at the EOT visit. Note that these assessments should coincide with the schedule of tumor assessments, but the questionnaire should be 
administered prior to completing any other assessments for that visit. 
dd The EOT visit will occur within ≤ 14 days of the decision to discontinue study treatment; the Follow-up visit will occur within ≤ 28 days of the last USL311 dose. The EOT visit 
may be the same as the Follow-up visit; however, the Follow-up visit should occur as close as possible to 28 days after the last USL311 dose . Any TEAEs ongoing at EOT visit 
should be followed to resolution or until the Investigator considers them chronic or stable or judges them to be no longer clinically significant. 
ee Subjects will be followed for survival information quarterly as defined in Section 7.4. Survival information will be collected via telephone calls and/or clinic visits. If a subject 
discontinues treatment for non-progression reasons and has not initiated any new oncology treatment, a 6-month visit for response assessment using RANO criteria and for 
collecting the EORTC QLQ-C30/BN20 health-related QOL questionnaire will occur. 
 
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d For subjects randomized to receive no USL311 treatment prior to surgery, surgical re-resection will occur following Screening, with the Screening Day -28 to Day -1 window 
calculated relative to day of Surgery. The Cycle 1-Day 1 Post-surgery visit will be initiated ≤ 28 days of surgery. These subjects will not participate in any of the assessments 
within the Pre-surgical Dosing period and will not visit the clinic for these visits. 
e The IRB/IEC-approved ICF must be signed before any study-specific procedures or exams are performed. 
f New or clinically significant changes in subject’s medical and/or oncologic history from ICF signing until first dose of study drug will be recorded as an AE. 
g Oncologic history includes disease course and prior cancer treatments including radiotherapy, surgery and systemic therapies. For each systemic therapy, the date of last therapy 
and best response to therapy should be documented, if possible. Any residual toxicity related to prior treatments should be documented. 
h Physical exams at Screening, Day 1 of each cycle Post-surgery, and at Follow-up should be complete assessments. Other physical exams may be abbreviated, at Investigator’s 
discretion, to identify changes from baseline or evaluate changes in clinical symptoms. Weight, BMI, and BSA to be reported at each visit, height at Screening only. 
i Neurological exams at Screening, Day 1 of each cycle Post-surgery, and Follow-up will be complete assessments. At Cycle 1-Day 1, complete neurological exams will be 
performed pre-dose and >4 hours after dosing, prior to clinic discharge. At Post-surgery Cycle 1-Day 8 and Day 15, neurological exams will be performed prior to in-clinic dosing 
and may be abbreviated. Other scheduled neurological exams will be performed prior to in-clinic dosing only, and may be abbreviated exams, at the Investigator’s discretion to 
identify changes from baseline or evaluate changes in clinical symptoms. 
j Vital signs (pulse, systolic and diastolic blood pressure, temperature, and respiration rate) will be collected prior to in-clinic dosing with USL311 and prior to clinic discharge.  If 
PK collection is prior to vitals, wait ≥ 5 minutes before obtaining vitals.  Subjects should be in a semi-recumbent position for at least 5 mins prior to collection. Perform additional 
vital signs if clinically indicated.  
k Holter-extracted 12-lead ECGs will be performed at Screening, on the Day of Surgery (prior to surgery), on Cycle 1-Day 1 pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, and 7 hours 
post-dose, on Cycle 1-Day 2 at 24 hours post Cycle 1-Day 1 dose (prior to the Cycle 1-Day 2 dose), and predose on Cycle 1-Day 8, Cycle 1-Day 15, and Cycle 2-Day 1, and at 
the EOT visit. The holter device will be placed at least 30 minutes prior to dosing and the subject will be placed in a resting, semi-recumbent position and will remain in a semi-
recumbent position for at least 4 hours post-dose.   No other assessments will be performed during each ECG collection period (i.e., from -15 to -5 minutes prior to the nominal 
time point). Frequency of ECGs may be increased and/or included at subsequent cycles if clinically indicated. All other electrical devices need to be removed from the bed/chair 
including cell phones. 
l Real-time bedside ECGs and heart rate monitoring will be performed on provided equipment on Cycle 1-Day 1 Post-surgery after in-clinic dosing. Printouts may be collected per 
Investigator discretion and should be collected for clinically significant changes from baseline. Real-time bedside monitoring will be performed at subsequent cycles as clinically 
indicated. 
m For women of childbearing potential, serum pregnancy test is required at Screening. Serum or urine pregnancy test to be performed on the day of Surgery, prior to dosing on 
Cycle 1-Day 1 Post-surgery, prior to dosing on Day 1 of every even numbered cycle (i.e., Cycle 2-Day 1; Cycle 4-Day 1; Cycle 6-Day 1; etc.), and at EOT visit. If treatment with 
study drug is stopped for ≥ 14 days, subject should have a negative pregnancy test prior to restarting drug. 
n Hematology performed weekly by local laboratory: RBC count, Hgb, Hct, MCV, platelets, WBC count with differential (neutrophils, lymphocytes, monocytes, eosinophils, and 
basophils), ALC, and ANC. If weekly hematology demonstrates CTCAE grade 3/4 cytopenias, increase to daily monitoring, as clinically appropriate. Hematology sample can be 
drawn ≤ 24 hours prior to visit.  
o Coagulation performed weekly by local laboratory: PT, aPTT/PTT, and INR. Coagulation sample can be drawn ≤ 24 hours prior to dosing. 
p Serum chemistry performed weekly by local laboratory: sodium, potassium, calcium, chloride, phosphorus or phosphate, magnesium, serum creatinine, total bilirubin, total protein, 
albumin, ALP, LDH, AST, ALT, glucose, bicarbonate, BUN, uric acid, CPK, and GGT. Baseline potassium, sodium, calcium (corrected for albumin) and magnesium levels below 
LLN must be corrected to within the normal range, or above the ULN if deemed not clinically significant by the Investigator, prior to dosing. Serum chemistry sample can be 
drawn ≤ 24 hours prior to dosing. 
q Urine dipstick must include pH, sp gravity, protein, glucose, ketones, bilirubin, blood, nitrite, and leukocyte esterase.  Microscopy is required only to follow-up clinically significant 
urine dipstick findings, which include a positive test for protein, blood, nitrite and/or leukocyte esterase. 
r  A blood sample for cytochrome P450 genotyping will be collected on Cycle 1-Day 1. An optional blood sample for future pharmacogenomics analyses may also be collected on 
Cycle 1-Day 1 (or at a later visit if determined appropriate per the clinical site) after appropriate separate consent is obtained. 
 
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s Tumor assessments to be performed at Screening, between Surgery and Cycle 1-Day 1 Post-surgery, at Cycle 3-Day 1 Post-surgery, then every 6 weeks (± 7 days) thereafter, at 6 
months (± 7 days), and at EOT visit. Baseline and subsequent radiographs/scans to assess response should be performed using the same techniques. RANO criteria will be used to 
determine response.  A confirmed objective response is defined as a response that persists on repeat imaging for two assessments with a time period of at least 4 weeks between 
the two assessments. In the event of a confirmed response, the timing of subsequent tumor assessment will be reset at the 6-week (± 7 days) interval from confirmatory scan. 
t Study drug will be held on the morning of clinic visits and will be administered in-clinic under fasted conditions for 2 hours before and 2 hours after the dose on Cycle 1-Days 1, 
2, 8 and 15 and on Cycle 2-Day 1, after pre-dose assessments have been completed.  
u The AE/SAE collection period is from the ICF signing through the Follow-up visit. AEs/SAEs must be reported as described in Section 9.3 of the protocol. Any AEs/SAEs 
ongoing at the Follow-up visit should be followed to resolution, until the Investigator considers them chronic or stable, or judges them to be no longer clinically significant. 
v All concomitant medications (including over-the-counter and herbal treatments) will be recorded from 28 days before the first dose of USL311 until the Follow-up visit.  For 
primary brain tumor and GBM subjects, corticosteroid use, including any changes in dose and/or frequency will be documented for RANO criteria assessment. 
w Blood samples (approximately 4 mL) for PK analyses (USL311) will be collected on the Day of Surgery and Post-surgery on Cycle 1-Day 1, Day 2, Day 8, and Day 15 and on 
Cycle 2-Day 1. Collection schedule and acceptable PK sample collection windows are as defined in Table  12. 
x In the event of a possible study drug-related SAE or DLT throughout the study, attempts will be made to collect additional PK blood samples as close to the event as possible to 
help characterize any possible relationships between drug exposure and the clinical event. 
y Confirmation of archival tumor tissue availability is required prior to enrollment. 
z The health-related QOL questionnaire will be completed at Screening, between Surgery and  Post-surgery Cycle 1-Day 1, at the end of Post-surgery Cycle 2, every 6 weeks (± 7 
days), at 6 months (± 7 days), and at the EOT Visit. Note that these assessments should coincide with the schedule of tumor assessments but the questionnaire should be administered 
prior to completing any other assessments for that visit. 
aa The EOT Visit will occur ≤ 14 days of the decision to discontinue study treatment; the Follow-up visit will occur within ≤ 28 days of the last USL311 dose. The EOT visit may 
be the same as the Follow-up visit; however, the Follow-up visit should occur as close as possible to 28 days after the last USL311 dose. Any TEAEs ongoing at EOT visit should 
be followed to resolution or until the Investigator considers them chronic or stable, or judges them to be no longer clinically significant. 
bb Subjects will be followed for survival information quarterly as defined in Section 7.4. Survival information will be collected via telephone calls and/or clinic visits. If a subject 
discontinues treatment for non-progression reasons and has not initiated any new oncology treatment, a 6-month visit for response assessment using RANO criteria and for 
collecting the EORTC QLQ-C30/BN20 health-related QOL questionnaire will occur. 
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Footnotes: 
a All procedures and examinations will be performed before the administration of study drug, except as indicated below. When multiple assessments are planned at the same time 
point, ECG assessment (including semi-recumbent positioning which is to occur at least 20 minutes prior to the nominal time point) will be completed first, and remaining 
assessments will be collected after the ECGs, with the PK sample being collected at the nominal time point. 
b The following Screening safety assessments are required to be repeated at Pre-surgical Dosing-Day 1 (baseline) if Screening assessments were performed > 3 days before Pre-
surgical Dosing-Day 1 (1st dose of USL311): inclusion/exclusion criteria, physical exam, neurological exam, UA, hematology, coagulation and serum chemistry). If collected ≤ 
3 days prior to Pre-surgical Dosing-Day 1, these assessments do not need to be repeated.  
c The assessments within the Pre-surgical Dosing period only apply to subjects randomized to receive pre-surgical treatment with USL311. Subjects randomized to receive no 
USL311 treatment prior to surgery will not participate in any of the assessments within the Pre-surgical Dosing period and will not visit the clinic for these visits. 
d For subjects randomized to pre-surgical treatment with USL311, surgical re-resection may occur at any time from Day 2 onwards; USL311 will be administered daily until surgery. 
Assessments within the Pre-surgical Dosing period  that are pending at the time of surgery will no longer be required and will not be performed post-surgery. Subjects will continue 
with assessments as defined per Post-surgical Cycle 1. 
e During the Pre-Surgical Dosing period, the Day 1 and Day 2 visits will occur on consecutive days. The windows for Day 3, Day 5, and Day 8 visits (PK samples) are described in 
Table  11. All remaining Pre-surgical Dosing visits are dependent on the length of treatment with pre-surgical USL311 and will occur weekly after Day 8 (e.g., Day 15, 22, etc.) 
a minimum of 7 days and a maximum of 14 days from the previous visit. Cycle 1-Day 1 and Day 2 Post-surgery visits will occur on consecutive days All remaining visits (up to 
but not including the EOT visit),  will occur within ± 3 days of scheduled visit.  
f For subjects randomized to receive pre-surgical treatment with USL311, daily dosing will continue until surgery; the dose will be held on the day of surgery. Cycle 1-Day 1 Post-
surgery will be initiated within ≤ 28 days of surgery. 
g The IRB/IEC-approved ICF must be signed before any study-specific procedures or exams are performed. 
h New or clinically significant changes in subject’s medical and/or oncologic history from ICF signing until the first dose of study drug will be recorded as an AE . 
i Oncologic history includes disease course and prior cancer treatments including radiotherapy, surgery and systemic therapies. For each systemic therapy, the date of last therapy 
and best response to therapy should be documented, if possible. Any residual toxicity related to prior treatments should be documented. 
j Physical exams at Screening, Day 1 of each cycle post-surgery, and at Follow-up are complete assessments.  Other physical exams, including Day 1 of Pre-surgical Dosing, may 
be abbreviated at Investigator’s discretion, to identify changes from baseline or evaluate changes in clinical symptoms. Weight, BMI, and BSA to be reported at each visit, height 
at Screening only. 
k Neurological exams at Screening, Day 1 of each cycle post-surgery, and Follow-up are complete assessments. At Pre-surgical Dosing Day 1, complete neurological exam will be 
performed pre-dose and > 4 hours after dosing, prior to clinic discharge. At Pre-surgical Dosing-Day 8, Day 15 and at each subsequent weekly Pre-Surgical visit, and at Post-surgery 
Cycle 1-Day 8, Day 15, Day 22, Day 29, and Day 36, neurological exams will be performed prior to in-clinic dosing and may be abbreviated. Other scheduled neurological exams 
will be performed prior to in-clinic dosing only, and may be abbreviated exams at the Investigator’s discretion, to identify changes from baseline or evaluate changes in clinical 
symptoms.  
l Vital signs (pulse, systolic and diastolic blood pressure, temperature, and respiration rate) will be collected prior to in-clinic USL311 dosing, and prior to clinic discharge.    If PK 
collection is prior to vitals, wait ≥ 5 minutes before obtaining vitals.  Subjects should be in a semi-recumbent position for ≥ 5 mins prior to collection.  Collect additional vital 
signs if clinically indicated. 
m Holter-extracted 12-lead ECGs will be performed at Screening, during the Pre-surgical Dosing period on Day 1 pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4 and 6 hours post-dose, on Day 
2 at 24 hours post the Pre-surgical Dosing-Day 1 dose (prior to Day 2 dose), on Day 3 (60 hours post-Day 1 dose), Day 5 (108 hours post-Day 1 dose) and Day 8 pre-dose.  ECGs 
will also be extracted on the day of Surgery (prior to surgery), on Cycle 1-Day 1 pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, and 7 hours post-dose, on Cycle 1-Day 2 at 24 hours post 
the Cycle 1-Day 1 dose (prior to the Cycle 1-Day 2 dose), and pre-dose on Cycle 1-Day 8, Cycle 1-Day 15, Cycle 2-Day 1 and at the EOT visit. The holter device will be placed 
at least 30 minutes prior to dosing and the subject will be placed in a resting, semi-recumbent position and will remain in a semi-recumbent position for at least 4 hours post-dose.  
No other assessments will be performed during each ECG collection period (i.e., from -15 to -5 minutes prior to the nominal time point). Frequency of ECGs may be increased 
and/or included at subsequent cycles if clinically indicated. All other electrical devices need to be removed from the bed/chair including cell phones. 
46 of 272


 
n Real-time bedside ECGs and heart rate monitoring will be performed on provided equipment during the Pre-surgical Dosing visits and on Cycle 1-Day 1 Post-surgery visit after 
in-clinic dosing. Printouts may be collected per Investigator discretion and should be collected for clinically significant changes from baseline. Real-tine bedside monitoring will 
be performed at subsequent cycles as clinically indicated. 
o For women of childbearing potential, serum pregnancy test is required at Screening. Serum or urine pregnancy test to be performed prior to dosing on Day 1 of the Pre-surgical 
Dosing period, prior to in-clinic USL311 dosing on Day 1 of every cycle thereafter, and at the EOT visit. If treatment with study drug is stopped for ≥ 14 days, subject should have 
a negative pregnancy test prior to restarting drug.  
p Hematology performed weekly by local laboratory: RBC count, Hgb, Hct, MCV, platelets, WBC count, WBC differential (neutrophils, lymphocytes, monocytes, eosinophils, and 
basophils), ALC, and ANC. If weekly hematology demonstrates CTCAE grade 3/4 cytopenias, increase to daily monitoring, as clinically appropriate. Hematology sample can be 
drawn ≤ 24 hours prior to visit.  
q Coagulation performed weekly by local laboratory: PT, aPTT/PTT and INR. Coagulation sample can be drawn ≤ 24 hours prior to visit. 
r Serum chemistry performed weekly by local laboratory: sodium, potassium, calcium, chloride, phosphorus or phosphate, magnesium, serum creatinine, total bilirubin, total protein, 
albumin, ALP, LDH, AST, ALT, glucose, bicarbonate, BUN, uric acid, CPK, and GGT. Baseline sodium, potassium, calcium (corrected for albumin) and magnesium levels below 
LLT must be corrected to within the normal range, or above the ULN if deemed not clinically significant by the Investigator, prior to dosing.  Serum chemistry sample can be 
drawn ≤ 24 hours prior to dosing. 
s Urine dipstick must include pH, sp gravity, protein, glucose, ketones, bilirubin, blood, nitrite, and leukocyte esterase.  Microscopy is required only to follow-up on clinically 
significant urine dipstick findings, which include a positive test for protein, blood, nitrite and/or leukocyte esterase.  
t  A blood sample for cytochrome P450 genotyping will be collected on Cycle 1-Day 1. An optional blood sample for future pharmacogenomics analyses may also be collected on 
Cycle 1-Day 1 (or at a later visit if determined appropriate per the clinical site) after appropriate separate consent is obtained. 
u Tumor assessments to be performed at Screening, between Surgery and Cycle 1-Day 1 Post-surgery, at Cycle 2-Day 1 Post-surgery, then every 6 weeks (± 7 days) thereafter, at 6 
months (± 7 days), and at the EOT visit. Baseline and subsequent radiographs/scans to assess response should be performed using same techniques. RANO criteria will be used to 
establish post-surgical baseline status (i.e., radiographic assessment occurring between Surgery and Cycle 1-Day 1 Post-surgery) and to determine response. A confirmed objective 
response is defined as a response that persists on repeat imaging for two assessments with a time period of at least 4 weeks between the two assessments. In the event of a confirmed 
response, the timing of subsequent tumor assessment will be reset at the 6-week (± 7 days) interval from confirmatory scan. 
v Study drug will be held on the morning of clinic visits and will be administered in-clinic under fasted conditions for 2 hours before and 2 hours after the dose on Pre-surgical 
Dosing-Day 1, Day 2, Day 3, Day 5 and Day 8 and on Cycle 1-Days 1, 2, 8 and 15 and on Cycle 2-Day 1, after pre-dose assessments have been completed. 
w Only subjects randomized to receive USL311 prior to surgery will receive USL311 treatment during the Pre-surgical period. Subjects randomized to no USL311 treatment prior 
to surgery will receive their first dose of USL311 on Cycle 1-Day 1 Post-surgery. 
x Lomustine will be given every 6 weeks and will be administered on Day 2 of each cycle Post-surgery. 
y The AE/SAE collection period is from ICF signing through the Follow-up visit. AEs/SAEs must be reported as described in Section 9.3 of the protocol. Any AEs/SAEs ongoing 
at the Follow-up visit should be followed to resolution or until the Investigator considers them chronic or stable or judges them to be no longer clinically significant. 
z All concomitant medications (including over-the-counter and herbal treatments) will be recorded from 28 days before the first dose of USL311 until the Follow-up visit.  For 
primary brain tumor subjects, corticosteroid use, including any changes in dose and/or frequency will be documented for RANO criteria assessment. 
aa Blood samples (approximately 4 ml) for PK analyses will be collected during Pre-surgical Dosing on Day 1, Day 2, Day 3, Day 5, and Day 8, on the Day of Surgery,and Post-
surgery on Cycle 1-Day 1, Day 2, Day 8, and Day 15, and on Cycle 2-Day 1. Collection schedule and acceptable PK sample collection windows are as defined in Table 11 and 
Table 12. 
bb In the event of a possible study drug-related SAE or DLT throughout the study, attempts will be made to collect additional PK blood samples as close to the event as possible to 
help characterize any possible relationships between drug exposure and the clinical event. 
cc Confirmation of archival tumor tissue availability is required prior to enrollment. 
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dd The health-related QOL questionnaire will be completed at Screening, between Surgery and Post-Surgery Cycle 1-Day 1, at the end of Post-Surgery Cycle 2, every 6 weeks (± 7 
days), at 6 months (± 7 days), and at the EOT visit. Note that these assessments should coincide with the schedule of tumor assessments but the questionnaire should be administered 
prior to completing any other assessments for that visit.  
ee The EOT visit will occur within ≤ 14 days of the decision to discontinue study treatment; the Follow-up visit will occur within ≤ 28 days of the last USL311 dose. The EOT visit 
may be the same as the Follow-up visit; however, the Follow-up visit should occur as close as possible to 28 days after the last USL311 dose. Any TEAEs ongoing at EOT visit 
should be followed to resolution or until the Investigator considers them chronic or stable, or judges them to be no longer clinically significant. 
ff Subjects will be followed for survival information quarterly as defined in Section 7.4. Survival information will be collected via telephone calls and/or clinic visits. If a subject 
discontinues treatment for non-progression reasons and has not initiated any new oncology treatment, a 6-month visit for response assessment using RANO criteria and for 
collecting the EORTC QLQ-C30/BN20 health-related QOL questionnaire will occur. 
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d For subjects randomized to receive no USL311 treatment prior to surgery, Surgery (re-resection) will occur following Screening, with the Screening Day -28 to Day -1 window 
calculated relative to day of Surgery. The Cycle 1-Day 1 Post-surgery visit will be initiated ≤ 28 days of surgery. These subjects will not participate in any of the assessments 
within the Pre-surgical Dosing period and will not visit the clinic for these visits. 
e The IRB/IEC-approved ICF must be signed before any study-specific procedures or exams are performed. 
f New or clinically significant changes in subject’s medical and/or oncologic history from ICF signing until first dose of study drug will be recorded as an AE . 
g Oncologic history includes disease course and prior cancer treatments including radiotherapy, surgery and systemic therapies. For each systemic therapy, the date of last therapy 
and best response to therapy should be documented, if possible. Any residual toxicity related to prior treatments should be documented. 
h Physical exams at Screening, Day 1 of each cycle Post-surgery, and at Follow-up should be complete assessments. Other physical exams may be abbreviated, at the Investigator’s 
discretion, to identify changes from baseline or evaluate changes in clinical symptoms. Weight, BMI, and BSA to be reported at each visit, height at Screening only. 
i Neurological exams at Screening, Day 1 of each cycle Post-surgery, and Follow-up will be complete assessments. During Cycle 1-Day 1, a complete neurological exam will be 
performed pre-doseand >4 hours after dosing, prior to clinic discharge.  At Post-surgery Cycle 1-Day 8, Day 15, Day 22, Day 29 and Day 36, neurological exams will be performed 
prior to in-clinic dosing and may be abbreviated. Other scheduled neurological exams will be performed prior to in-clinic dosing only, and may be abbreviated exams, at the 
Investigator’s discretion, to identify changes from baseline or evaluate changes in clinical symptoms.  
j Vital signs (pulse, systolic and diastolic blood pressure, temperature, and respiration rate) will be collected prior to in-clinic dosing with USL311, and prior to clinic discharge.  If 
PK collection is prior to vitals, wait ≥ 5 minutes before obtaining vitals. Subjects should be in a semi-recumbent position for at least 5 mins prior to collectionPerform additional 
vital signs assessments if clinically indicated. 
k Holter-extracted 12-lead ECGs will be performed at Screening, on the day of Surgery (prior to surgery), on Cycle 1-Day 1 pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5 and 7 hours post-
dose, on Cycle 1-Day 2, 24 hours post the Cycle 1-Day 1 dose (prior to the Cycle 1-Day 2 dose), on Cycle 1-Day 8, Cycle 1-Day 15, Cycle 2-Day 1 and at the EOT visit. The 
holter device will be placed at least 30 minutes prior to dosing and the subject will be placed in a resting, semi-recumbent position and will remain in a semi-recumbent position 
for at least 4 hours post-dose.   No other assessments will be performed during each ECG collection period (i.e., from -15 to -5 minutes prior to the nominal time point). Frequency 
of ECGs may be increased and/or included at subsequent cycles if clinically indicated. All other electrical devices need to be removed from the bed/chair including cell phones. 
l Real-time bedside ECGs and heart rate monitoring will be performed on the provided equipment during the Cycle 1-Day 1 Post-surgery visit after in-clinic dosing. Printouts may 
be collected per Investigator discretion and should be collected for clinically significant changes from baseline. Real-tine bedside monitoring will be performed at subsequent 
cycles as clinically indicated. 
m For women of childbearing potential, serum pregnancy test is required at Screening. Serum or urine pregnancy test to be performed on the day of Surgery, prior to dosing on Day 
1 of every cycle thereafter, and at the EOT visit. If treatment with study drug is stopped for ≥ 14 days, subject should have a negative pregnancy test prior to restarting drug.  
n Hematology performed weekly by local laboratory: RBC count, Hgb, Hct, MCV, platelets, WBC count with differential (neutrophils, lymphocytes, monocytes, eosinophils, and 
basophils), ALC, and ANC. If weekly hematology demonstrates CTCAE grade 3/4 cytopenias, increase to daily monitoring as clinically appropriate. Hematology sample can be 
drawn ≤ 24 hours prior to visit.  
o Coagulation performed weekly by local laboratory: PT, aPTT/PTT, INR. Coagulation sample can be drawn ≤ 24 hours prior to dosing. 
p Serum chemistry performed weekly by local laboratory: sodium, potassium, calcium, chloride, phosphorus or phosphate, magnesium, serum creatinine, total bilirubin, total protein, 
albumin, ALP, LDH, AST, ALT, glucose, bicarbonate, BUN, uric acid, CPK, and GGT. Baseline sodium, potassium, calcium (corrected for albumin) and magnesium levels below 
LLN must be corrected to within the normal range, or above the ULN if determined not clinically significant by the Investigator, prior to dosing. Serum chemistry sample can be 
drawn ≤ 24 hours prior to dosing. 
q Urine dipstick must include pH, sp gravity, protein, glucose, ketones, bilirubin, blood, nitrite, and leukocyte esterase.  Microscopy is required only to follow-up clinically significant 
urine dipstick findings, which include a positive test for protein, blood, nitrite and/or leukocyte esterase.  
r  A blood sample for cytochrome P450 genotyping will be collected on Cycle 1-Day 1. An optional blood sample for future pharmacogenomics analyses may also be collected on 
Cycle 1-Day 1 (or at a later visit if determined appropriate per the clinical site) after appropriate separate consent is obtained. 
 
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s Tumor assessments to be performed at Screening, between Surgery and Cycle 1-Day 1 Post-surgery, at Cycle 2-Day 1 Post-surgery, then every 6 weeks (± 7 days) thereafter, at 6 
months (± 7 days), and at the EOT visit. Baseline and subsequent radiographs/scans to assess response should be performed using same techniques. RANO criteria will be used to 
establish post-surgical baseline status (i.e., between Surgery and Cycle 1-Day 1 Post-surgery) and to determine response. A confirmed objective response is defined as a response 
that persists on repeat imaging for two assessments with a time period of at least 4 weeks between the two assessments. In the event of a confirmed response, the timing of 
subsequent tumor assessment will be reset at the 6-week (± 7 days) interval from confirmatory scan. 
t Study drug will be held on the morning of clinic visits and will be administered in-clinic under fasted conditions for 2 hours before and 2 hours after the dose on Cycle 1-Days 1, 
2, 8 and 15 and on Cycle 2-Day 1, after pre-dose assessments have been completed. 
u Lomustine will be given every 6 weeks and will be administered on Day 2 of each cycle Post-surgery. 
v The AE/SAE collection period is from ICF signing through the Follow-up visit. AEs/SAEs must be reported as described in Section 9.3 of the protocol. Any AEs/SAEs ongoing 
at the Follow-up visit should be followed to resolution or until the Investigator considers them chronic or stable or judges them to be no longer clinically significant. 
w All concomitant medications (including over-the-counter and herbal treatments) will be recorded from 28 days before the first dose of USL311 until the Follow-up visit.  For 
primary brain tumor subjects, corticosteroid use, including any changes in dose and/or frequency will be documented for RANO criteria assessment. 
x Blood samples (approximately 4 mL) for PK analyses will be collected on the Day of Surgery, and Post-surgery on Cycle 1-Day 1, Day 2, Day 8, and Day 15, and on Cycle 2-
Day 1. Collection schedule and acceptable PK sample collection windows are as defined in Table  12. 
y In the event of a possible study drug-related SAE or DLT throughout the study, attempts will be made to collect additional PK blood samples as close to the event as possible to 
help characterize any possible relationships between drug exposure and the clinical event. 
z Confirmation of archival tumor tissue availability is required prior to enrollment. 
aa The health-related QOL questionnaire will be completed at Screening, between Surgery and Cycle 1-Day 1 Post-surgery, at the end of Cycle 2 Post-surgery, every 6 weeks (± 7 
days), at 6 months (± 7 days), and at the EOT visit. Note that these assessments should coincide with the schedule of tumor assessments but the questionnaire should be administered 
prior to completing any other assessments for that visit. bb 
The EOT visit will occur ≤ 14 days of the decision to discontinue study treatment; the Follow-up visit will occur 
within ≤ 28 days of the last USL311 dose. The EOT visit may be the same as the Follow-up visit; however, the Follow-up visit should occur as close as possible to 28 days after 
the last USL311 dose. Any TEAEs ongoing at EOT visit should be followed to resolution or until the Investigator considers them chronic or stable or judges them to be no longer 
clinically significant. 
cc Subjects will be followed for survival information quarterly as defined in Section 7.4. Survival information will be collected via telephone calls and/or clinic visits. If a subject 
discontinues treatment for non-progression reasons and has not initiated any new oncology treatment, a 6-month visit for response assessment using RANO criteria and for 
collecting the EORTC QLQ-C30/BN20 health-related QOL questionnaire will occur. 
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Pharmacokinetic (PK) and Pharmacodynamic (PD) Sample Times 
Table  8: 
PK and PD Sample Times – Part 1a: IV USL311 Single Agent Dose 
Escalation 
Day 
Sample 
USL311 
PK 
WBC 
SDF-1 
CD34+ 
Nominal Timea 
Acceptable  
Collection 
Window 
Cycle 1, 
Day 1 
1 
X 
X 
X 
X 
Predose 
≤ 30 min prior to 
USL311 infusion  
2 
X 
X 
NS 
NS 
0.5 hr 
± 2 min 
3 
X 
X 
NS 
NS 
1 hr 
± 5 min 
4 
X 
X 
X 
X 
2 hr 
± 5 min 
5 
X 
X 
NS 
NS 
3 hr 
± 5 min 
6 
X 
X 
X 
X 
4 hr 
± 5 min 
7 
X 
X 
NS 
NS 
5 hr 
± 5 min 
8 
X 
X 
X 
X 
6 hr 
± 5 min 
9 
X 
X 
NS 
NS 
7 hr 
± 5 min 
10 
X 
X 
X 
X 
8 hr 
± 5 min 
Cycle 1, 
Day 2  
11 
X 
X 
X 
X 
24 hr 
± 60 min 
Cycle 1, 
Day 3 
12 
X 
X 
NS 
NS 
60 hr 
≥ 48 hr to < 72 hra,b 
Cycle 1, 
Day 5 
13 
X 
X 
NS 
NS 
108 hr 
≥ 96 hr to < 120 
hra,b 
Cycle 1, 
Day 8 
 
14 
X 
X 
NS 
NS 
Predose 
(Equivalent to 
Dose #1 trough) 
≤ 30 min prior to 
USL311 infusion  
(Dose #2) 
15 
X 
NS 
NS 
NS 
0.5 hr 
± 2 min 
16 
X 
NS 
NS 
NS 
1.5 hr 
± 5 min 
17 
X 
X 
NS 
NS 
3 hr 
± 5 min 
18 
X 
X 
NS 
NS 
4 hr 
± 5 min 
Cycle 1 
Day 15 
 
19 
X 
X 
NS 
NS 
Predose 
(Equivalent to 
Dose #2 trough) 
≤ 30 min prior to 
USL311 infusion  
(Dose #3) 
20 
X 
X 
NS 
NS 
2 hr 
± 5 min 
21 
X 
X 
NS 
NS 
4 hr 
± 5 min 
Cycle 2, 
Day 1 
22 
X 
X 
NS 
NS 
Predose 
(Equivalent to 
Dose #3 trough) 
≤ 30 min prior to 
USL311 infusion  
(Dose #4) 
 
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Table  9: 
PK and PD Sample Times – Part 1b: Oral USL311 Single Agent Dose 
Escalation 
Day 
Sample 
USL311 
PK 
WBC 
CD34+ 
Nominal Timea 
Acceptable  
Collection Window 
Cycle 1-
Day 1 
1 
X 
X 
X 
Predose 
≤ 30 min prior to 
USL311 dose 
2 
X 
X 
NS 
0.5 hr 
± 2 min 
3 
X 
X 
NS 
1 hr 
± 5 min 
4 
X 
X 
NS 
1.5 hr 
± 5 min 
5 
X 
X 
X 
2 hr 
± 5 min 
6 
X 
X 
NS 
2.5 hr 
± 5 min 
7 
X 
X 
NS 
3 hr 
± 5 min 
8 
X 
X 
X 
4 hr 
± 5 min 
9 
X 
X 
X 
6 hr 
± 5 min 
Cycle 1-
Day 2  
10 
X 
X 
X 
24 hr 
± 60 min 
Prior to Day 2 dose 
Cycle 1-
Day 8 
 
11 
X 
NS 
NS 
Predose 
≤ 30 min prior to 
USL311 dose  
12 
X 
NS 
NS 
0.5 hr 
± 5 min 
13 
X 
X 
NS 
2 hr 
± 5 min 
14 
X 
X 
NS 
3 hr 
± 5 min 
15 
X 
X 
NS 
4 hr  
± 5 min  
Cycle 1-
Day 15 
 
16 
X 
X 
NS 
Predose 
≤ 30 min prior to 
USL311 dose  
17 
X 
X 
NS 
2-4 hrc 
± 5 min 
Cycle 2-
Day 1 
18 
X 
X 
NS 
Predose 
≤ 30 min prior to 
USL311 dose 
19 
X 
X 
NS 
2-4 hrc 
± 5 min  
NS = No Sample Collected 
a All nominal times are relative to the start of USL311 infusion 
b One sample to be collected anytime within the specified time window 
b The exact collection time will be decided after reviewing the PK data obtained on Cycle 1-Day 1 
 
 
 
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Table  10: 
PK and PD Sample Times – Part 2: USL311 + Lomustine Dose Escalation 
Day 
Sample 
Lomustine 
PK 
USL311 
PK 
WBC 
CD34
+ 
Nominal 
Time 
Acceptable collection 
window 
Cycle 1-Day 1 
1 
X 
NS 
NS 
NS 
Predose 
≤ 24 hr prior to  
lomustine administration 
2 
 
X 
NS 
NS 
NS 
1 hr 
± 5 min 
(nominal time is relative  
to lomustine dose 
administration) 
3 
X 
NS 
NS 
NS 
2 hr 
4 
X 
NS 
NS 
NS 
3 hr 
5 
X 
NS 
NS 
NS 
4 hr 
6 
X 
NS 
NS 
NS 
5 hr 
7 
X 
NS 
NS 
NS 
8 hr 
8 
X 
NS 
NS 
NS 
12 hr 
Cycle 1-Day 8 
 
9 
NS 
X 
X 
X 
Predose 
≤ 30 min prior to  
USL311 administration 
10 
NS 
X 
X 
NS 
0.5 hr 
± 5 min 
(nominal time is relative  
to USL311 
administration) 
11 
NS 
X 
X 
X 
1 hr 
12 
NS 
X 
X 
NS 
1.5 hr 
13 
NS 
X 
X 
NS 
2 hr 
14 
NS 
X 
X 
NS 
2.5 hr 
15 
NS 
X 
X 
NS 
3 hr 
16 
NS 
X 
X 
X 
4 hr 
17 
NS 
X 
X 
NS 
6 hr 
Cycle 1-Day 9 
18 
NS 
X 
X 
X 
24 hr 
± 60 min 
 
Cycle 1-Day 
15 
19 
NS 
X 
X 
X 
Predose 
≤ 30 min prior to  
USL311 administration 
20 
NS 
X 
NS 
NS 
0.5 hr 
± 5 min 
(nominal time is relative 
to USL311 
administration) 
21 
NS 
X 
X 
NS 
2 hr 
22 
NS 
X 
NS 
NS 
3 hr 
23 
NS 
X 
X 
NS 
4 hr 
Cycle 1-Day 
22 
 
24 
NS 
X 
X 
X 
Predose 
≤ 30 min prior to  
USL311 administration 
25 
NS 
X 
X 
NS 
2-4 hra 
± 5 min 
(nominal time is relative 
to USL311 
administration)  
Cycle 2-Day 1 
26 
NS 
X 
X 
NS 
Predose 
≤ 30 min prior to  
USL311 administration 
27 
NS 
X 
NS 
NS 
0.5 hr 
± 5 min 
(nominal time is relative 
28 
NS 
X 
X 
NS 
1 hr 
 
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Day 
Sample 
Lomustine 
PK 
USL311 
PK 
WBC 
CD34
+ 
Nominal 
Time 
Acceptable collection 
window 
29 
NS 
X 
X 
NS 
1.5 hr 
to USL311 
administration) 
30 
NS 
X 
NS 
NS 
2 hr 
31 
NS 
X 
X 
NS 
2.5 hr 
32 
NS 
X 
X 
NS 
3 hr 
33 
NS 
X 
X 
NS 
4 hr 
34 
NS 
X 
X 
NS 
6 hr 
Cycle 2-Day 2 
35 
X 
X 
NS 
NS 
24 hr/ 
Predose 
≤ 30 min prior to  
lomustine administration 
36 
X 
NS 
NS 
NS 
1 hr 
± 5 min 
(nominal time is  
relative to lomustine dose 
administration or  
USL311 administration 
where applicable) 
 
37 
X 
NS 
NS 
NS 
2 hr 
38 
X 
NS 
NS 
NS 
3 hr 
39 
X 
NS 
NS 
NS 
4 hr 
40 
X 
NS 
NS 
NS 
5 hr 
41 
X 
NS 
NS 
NS 
8 hr 
42 
X 
NS 
NS 
NS 
12 hr 
NS = No Sample Collected 
a Exact collection time will be decided after reviewing the PK data obtained on Cycle 1-Day 8 
 
 
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Table  11: 
USL311 PK Sample Times –Parts 3 & 4: Pre-Surgical USL311 Dosing 
Day 
Sample 
Nominal Timea,b 
Acceptable Collection Window 
Pre-surgical Dosing, Day 1 
1 
Predose 
≤ 24 hr prior to USL311 administration 
2 
0.5 hr 
± 2 min 
3 
1 hr 
± 5 min 
4 
1.5 hr 
± 5 min 
5 
2 hr 
± 5 min 
6 
2.5 hr 
± 5 min 
7 
3 hr 
± 5 min 
8 
4 hr 
± 5 min 
9 
6 hr 
± 5 min 
Pre-surgical Dosing, Day 2 
10 
24 hr 
± 60 min 
Pre-surgical Dosing, Day 3d 
11 
60 hr 
≥ 48 hr to < 72 hrb,c 
Pre-surgical Dosing, Day 5d 
12 
108 hr 
≥ 96 hr to < 120 hrb,c 
Pre-surgical Dosing, Day 8d 
13 
Predose/Trough 
≤ 30 min prior to USL311 administration 
Day of Surgery 
14 
Pre-surgery 
≤ 2 hr prior to surgery 
a Pre-surgical Dosing PK samples are collected only for subjects randomized to receive USL311 prior to surgery. For subjects 
randomized to no USL311 treatment prior to surgery, PK samples will be collected starting at Cycle 1 post-surgery (see 
Table 12). 
b All nominal times are relative to the start of USL311 infusion 
c One sample to be collected anytime within the specified time window 
d Samples not required if surgery occurs prior to the day of collection 
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Table  12: 
USL311 and Lomustine PK Sample Times – Parts 3 & 4: Dose-Expansion 
Post-Surgery Cycle 1 
Day 
Sample 
Nominal Time  
(USL311, Parts 3 and 4)a,b 
Nominal Time  
(Lomustine, Part 4 only)c,d 
Acceptable  
Collection Window 
Cycle 1-
Day 1  
1 
Predose/Trough 
NS 
≤ 30 min prior to  
USL311 administration 
2 
0.5 hr 
NS 
± 5 min 
3 
1 hr 
NS 
4 
1.5 hr 
NS 
5 
2 hr 
NS 
6 
2.5 hr 
NS 
7 
3 hr 
NS 
8 
4 hr 
NS 
9 
5 hr 
NS 
10 
7 hr 
NS 
Cycle 1-
Day 2 
11 
24 hr 
Predose 
≤ 30 min prior to 
lomustine administration 
12 
NS 
1 hr 
± 5 min 
13 
NS 
2 hr 
14 
NS 
3 hr 
15 
NS 
4 hr 
16 
NS 
5 hr 
17 
NS 
8 hr 
18 
NS 
12 hr 
Cycle 1-
Day 8 
19 
Predose/Trough 
NS 
≤ 30 min prior to 
USL311 administration 
Cycle 1-
Day 15 
20 
Predose/Trough 
NS 
≤ 30 min prior to 
USL311 administration 
Cycle 2-
Day 1 
21 
Predose/Trough 
NS 
≤ 30 min prior to 
USL311 administration 
NS = No Sample Collected 
a Samples to be collected from all subjects in Parts 3 and 4 regardless of participation in Pre-surgical Cycle 
b Nominal times are relative to the start of USL311 infusion 
c Lomustine samples collected only for subjects in Part 4 (GBM Dose-Expansion USL311 + lomustine) 
d Nominal times are relative to lomustine dose administration 
 
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TABLE OF CONTENTS 
CONTACT INFORMATION ...................................................................................... 2 
PROTOCOL SYNOPSIS ............................................................................................ 3 
SCHEDULE OF VISITS AND ASSESSMENTS ..................................................... 24 
Part 1a Schedule of Events (Dose-Escalation Single Agent IV USL311) ................. 24 
Part 1b Schedule of Events (Dose-Escalation Single Agent Oral USL311) .............. 28 
Part 2 Schedule of Events (Dose-Escalation USL311 + Lomustine) ........................ 32 
Part 3 Schedules of Events (GBM Dose-Expansion Single Agent USL311) ............ 36 
Part 4 Schedules of Events (GBM Dose-Expansion USL311 + Lomustine)............. 44 
Pharmacokinetic (PK) and Pharmacodynamic (PD) Sample Times .......................... 53 
LIST OF ABBREVIATIONS .................................................................................... 67 
1. 
INTRODUCTION .................................................................................. 73 
1.1. 
Background Information ......................................................................... 73 
1.1.1. 
Disease Background ............................................................................... 73 
1.1.2. 
USL311 Background .............................................................................. 74 
1.2. 
Nonclinical Study Findings for USL311 ................................................ 75 
1.2.1. 
Primary Pharmacology (Efficacy) .......................................................... 75 
1.2.2. 
Secondary Pharmacology ....................................................................... 76 
1.2.3. 
USL311 Pharmacokinetics/Toxicokinetics ............................................ 77 
1.2.4. 
Toxicology and Safety Pharmacology .................................................... 80 
1.3. 
Clinical Study Findings for USL311 ...................................................... 83 
2. 
STUDY OBJECTIVES .......................................................................... 84 
2.1. 
Phase 1: Parts 1 and 2 Dose-Escalation in Subjects with Advanced Solid 
Tumors .................................................................................................... 84 
2.1.1. 
Primary Objectives ................................................................................. 84 
2.1.2. 
Secondary Objectives ............................................................................. 84 
2.1.3. 
Exploratory Objectives ........................................................................... 84 
2.2. 
Phase 2: Parts 3 and 4 Dose-Expansion in Subjects with 
Relapsed/Recurrent GBM ....................................................................... 84 
2.2.1. 
Primary Objectives ................................................................................. 84 
2.2.2. 
Secondary Objectives ............................................................................. 85 
2.2.3. 
Exploratory Objectives ........................................................................... 85 
3. 
INVESTIGATIONAL PLAN ................................................................. 86 
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3.1. 
Overview ................................................................................................. 86 
3.2. 
Phase 1 – Dose-Escalation in Subjects with Advanced Solid Tumors ... 86 
3.2.1. 
Part 1a – Dose-Escalation in Advanced Solid Tumors of Single Agent IV 
USL311 ................................................................................................... 87 
3.2.2. 
Part 1b – Dose-Escalation in Advanced Solid Tumors of Single Agent 
Oral USL311 ........................................................................................... 88 
3.2.3. 
Part 2 – Dose Escalation in Solid Tumors of Combination USL311 plus 
Lomustine ............................................................................................... 90 
3.2.4. 
Dose-Escalation Strategy ........................................................................ 91 
3.2.5. 
Dose-Limiting Toxicity .......................................................................... 92 
3.2.6. 
Dose Escalation Committee .................................................................... 93 
3.3. 
Phase 2 – Dose-Expansion in Relapsed/Recurrent GBM ....................... 93 
3.3.1. 
Part 3 – Dose-Expansion in GBM of Single Agent USL311 ................. 95 
3.3.2. 
Part 4 – Dose Expansion in GBM of USL311 in Combination with 
Lomustine ............................................................................................... 96 
3.3.3. 
Surgical Re-Resection ............................................................................ 97 
3.4. 
End of Study ........................................................................................... 97 
4. 
RATIONALE ......................................................................................... 98 
4.1. 
Rationale for Study ................................................................................. 98 
4.2. 
Rationale for Study Design ..................................................................... 98 
4.3. 
Rationale of Study Population ................................................................ 99 
4.4. 
Rationale for Study Treatment ................................................................ 99 
5. 
SUBJECT POPULATION ................................................................... 101 
5.1. 
Number of Subjects .............................................................................. 101 
5.2. 
Eligibility Criteria ................................................................................. 101 
5.2.1. 
Inclusion Criteria .................................................................................. 101 
5.2.2. 
Exclusion Criteria ................................................................................. 103 
5.3. 
Prior and Concomitant Medications ..................................................... 106 
5.3.1. 
Permitted Medications .......................................................................... 106 
5.3.2. 
Prohibited Medications ......................................................................... 107 
5.4. 
Dietary and Other Protocol Restrictions ............................................... 108 
5.5. 
Subject Withdrawal or Discontinuation................................................ 108 
5.6. 
Subject Identification and Replacement of Subjects ............................ 109 
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5.7. 
Duration of Subject Participation ......................................................... 110 
5.8. 
Informed Consent ................................................................................. 110 
5.9. 
Authorization to Use and Disclose Medical Information ..................... 111 
6. 
STUDY TREATMENT INFORMATION ........................................... 112 
6.1. 
Study Treatment Administration and Doses ......................................... 112 
6.1.1. 
Directions for Administration ............................................................... 112 
6.1.2. 
Selection of Treatment and Doses ........................................................ 114 
6.1.3. 
Risks and Toxicities .............................................................................. 116 
6.1.4. 
Monitoring and Toxicity Management ................................................. 117 
6.1.5. 
Dose Modifications ............................................................................... 117 
6.1.6. 
Duration of Treatment .......................................................................... 118 
6.1.7. 
Treatment Compliance .......................................................................... 119 
6.2. 
Treatment Randomization .................................................................... 119 
6.3. 
Treatment Blinding ............................................................................... 120 
6.4. 
Study Drug Identification and Supply .................................................. 120 
6.5. 
Packaging and Labeling ........................................................................ 120 
6.6. 
Handling, Storage and Accountability .................................................. 121 
6.6.1. 
Dispensing of Study Drug .................................................................... 122 
6.6.2. 
Return and Disposition of Clinical Supplies ........................................ 123 
7. 
STUDY VISIT SCHEDULE AND ASSESSMENTS ......................... 124 
7.1. 
Screening Phase .................................................................................... 124 
7.2. 
Treatment Phase .................................................................................... 126 
7.2.1. 
Part 1a Treatment .................................................................................. 126 
7.2.2. 
Part 1b Treatment ................................................................................. 128 
7.2.3. 
Part 2 Treatment ................................................................................... 131 
7.2.4. 
Part 3 Treatment ................................................................................... 134 
7.2.5. 
Part 4 Treatment ................................................................................... 140 
7.3. 
End of Treatment/Follow-up Visit........................................................ 147 
7.4. 
Long-term Follow-up Phase ................................................................. 148 
7.5. 
Unscheduled Visits ............................................................................... 149 
8. 
EFFICACY AND SAFETY ENDPOINTS AND ASSESSMENTS ... 150 
8.1. 
Efficacy Endpoints ................................................................................ 150 
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8.2. 
Efficacy Assessments ........................................................................... 150 
8.2.1. 
Evaluation of Response and Progression .............................................. 151 
8.2.2. 
Response Evaluation Criteria in Solid Tumors (RECIST) ................... 151 
8.2.3. 
Response Assessment in Neuro-Oncology Criteria (RANO) ............... 151 
8.3. 
Safety Endpoints ................................................................................... 151 
8.4. 
Safety and Screening Assessments ....................................................... 151 
8.4.1. 
Karnofsky Performance Status (KPS) Scale Criteria ........................... 151 
8.4.2. 
Medical History .................................................................................... 152 
8.4.3. 
Oncologic History ................................................................................. 152 
8.4.4. 
Concomitant Medications ..................................................................... 152 
8.4.5. 
Clinical Examinations ........................................................................... 153 
8.4.6. 
Vital Signs ............................................................................................ 154 
8.4.7. 
Electrocardiogram Monitoring ............................................................. 154 
8.4.8. 
Clinical Laboratory Assessments ......................................................... 156 
8.4.9. 
Pregnancy Testing ................................................................................ 158 
8.4.10. 
Archived Tumor Histology ................................................................... 159 
8.5. 
Pharmacokinetic Endpoints .................................................................. 159 
8.6. 
Pharmacokinetic Assessments .............................................................. 160 
8.6.1. 
Whole Blood and Plasma Sample Collection ....................................... 160 
8.6.2. 
Cerebrospinal Fluid Sample Collection ................................................ 161 
8.7. 
Exploratory Assessments ...................................................................... 161 
8.7.1. 
Quality of Life Assessment .................................................................. 161 
8.7.2. 
Resected Tissue Collection ................................................................... 162 
8.7.3. 
Collection of Other Biomarkers ............................................................ 162 
8.8. 
Appropriateness of Measures ............................................................... 163 
9. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ............ 165 
9.1. 
Definitions ............................................................................................ 165 
9.1.1. 
Adverse Events ..................................................................................... 165 
9.1.2. 
Serious Adverse Events and Serious Unexpected Adverse Events ...... 166 
9.1.3. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments 167 
9.2. 
Evaluation of Adverse Events and Serious Adverse Events ................ 167 
9.2.1. 
Classification of Adverse Event Intensity ............................................ 167 
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9.2.2. 
Classification of Adverse Event Causality ........................................... 168 
9.2.3. 
Classification of Adverse Event Outcome ............................................ 169 
9.3. 
Reporting Procedures ............................................................................ 169 
9.3.1. 
Serious Adverse Events and Serious Unexpected Adverse Events ...... 169 
9.3.2. 
Any Adverse Event ............................................................................... 170 
9.3.3. 
Pregnancy ............................................................................................. 171 
9.4. 
Follow-up of Adverse Events and Serious Adverse Events ................. 171 
9.5. 
Urgent Safety Measures ........................................................................ 171 
10. 
DATA ANALYSIS AND STATISTICAL PROCEDURES ............... 173 
10.1. 
General Statistical Considerations ........................................................ 173 
10.2. 
Interim Analysis .................................................................................... 173 
10.3. 
Missing Data ......................................................................................... 173 
10.4. 
Analysis Data Sets ................................................................................ 173 
10.5. 
Dispositions, Demographics, and Other Baseline Characteristics ........ 174 
10.6. 
Medical and Surgical History ............................................................... 174 
10.7. 
Efficacy Endpoints Analysis................................................................. 174 
10.8. 
Safety Endpoints Analysis .................................................................... 175 
10.9. 
Pharmacokinetic Endpoints Analyses ................................................... 175 
10.10. 
Pharmacodynamic Endpoints Analyses ................................................ 176 
10.11. 
Quality of Life/ Patient Reported Outcome Measures ......................... 176 
10.12. 
Sample Size Calculation ....................................................................... 176 
10.13. 
Data Collection and Electronic Data Capture ....................................... 176 
11. 
ADMINISTRATIVE PROCEDURES ................................................. 178 
11.1. 
Regulatory Approval ............................................................................ 178 
11.2. 
Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC) Approval ..................................................................................... 178 
11.3. 
Ethical Conduct of Study ...................................................................... 179 
11.4. 
Study Personnel .................................................................................... 179 
11.5. 
Ongoing Information for Institutional Review Board .......................... 180 
11.6. 
Data Handling and Record Keeping ..................................................... 180 
11.6.1. 
Case Report Forms ............................................................................... 180 
11.6.2. 
Source Documentation .......................................................................... 180 
11.7. 
Study Monitoring .................................................................................. 181 
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11.8. 
Quality Assurance and Auditing Procedures ........................................ 182 
11.8.1. 
Access to Source Documentation ......................................................... 182 
11.9. 
Policy on Research Misconduct in Clinical Research .......................... 183 
11.10. 
Use of Information and Publication Policy .......................................... 183 
11.11. 
Amendment to Protocol ........................................................................ 183 
11.12. 
Deviations from Protocol ...................................................................... 183 
11.13. 
Records of Study ................................................................................... 184 
11.14. 
Completion of Study ............................................................................. 185 
11.15. 
Study Funding ....................................................................................... 185 
11.16. 
Financial Disclosure ............................................................................. 185 
12. 
REFERENCES LIST ............................................................................ 186 
APPENDICES ......................................................................................................... 192 
PROTOCOL SIGNATURE PAGE ......................................................................... 191 
 
LIST OF TABLES 
Table  1: 
Dose-Escalation Single Agent IV USL311 ............................................ 24 
Table  2: 
Dose-Escalation Single Agent Oral USL311 ......................................... 28 
Table  3: 
Dose-Escalation Oral USL311 + Lomustine .......................................... 32 
Table  4: 
GBM Dose-Expansion Single Agent Oral USL311 – Pre-surgical Dosing 
Cohort ..................................................................................................... 36 
Table  5: 
GBM Dose-Expansion Single Agent USL311 – No Pre-surgical Dosing 
Cohort ..................................................................................................... 40 
Table  6: 
GBM Dose-Expansion USL311 + Lomustine – Pre-surgical Dosing 
Cohort ..................................................................................................... 44 
Table  7: 
GBM Dose-Expansion USL311 + Lomustine – No Pre-surgical Dosing 
Cohort ..................................................................................................... 49 
Table  8: 
PK and PD Sample Times – Part 1a: IV USL311 Single Agent Dose 
Escalation ................................................................................................ 53 
Table  9: 
PK and PD Sample Times – Part 1b: Oral USL311 Single Agent Dose 
Escalation ................................................................................................ 54 
Table  10: PK and PD Sample Times – Part 2: USL311 + Lomustine Dose 
Escalation ................................................................................................ 55 
Table  11: USL311 PK Sample Times –Parts 3 & 4: Pre-Surgical USL311 Dosing
 ................................................................................................................ 57 
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Table  12: USL311 and Lomustine PK Sample Times – Parts 3 & 4: Dose-
Expansion Post-Surgery Cycle 1 ............................................................ 58 
Table 13: Mean plasma USL311 TK parameters in rats and dogs (males and 
females combined) following weekly 2-hour IV infusions of USL311 . 79 
Table 14: Clinical Starting Dose Estimated from GLP Toxicology Studies .......... 82 
Table 15: USL311 Available IV Doses for Dose Escalation .................................. 87 
Table 16: USL311 Available Oral Doses for Dose-Escalation .............................. 89 
Table 17: Prohibited Cytochrome P450 Enzyme Interaction Medications .......... 107 
Table 18: Lomustine Dosage Adjustment Guide .................................................. 118 
Table 19: Clinical Laboratory Tests ..................................................................... 156 
Table 20: Pharmacokinetic Parameters ................................................................. 160 
Table 21: Classifications for Adverse Event Intensity/Grading ........................... 168 
Table 22: Relationship to Study Drug .................................................................. 168 
Table 23: Classifications for Adverse Event Outcomes ....................................... 169 
Table 24: SAE Reporting Information .................................................................. 170 
Appendix 3 – Table 1: Medications with QTc Prolongation Risk ........................ 218 
 
LIST OF FIGURES 
Figure 1: 
Phase 1/2 Study Components Flow Diagram ......................................... 86 
Figure 2: 
Study Schematic for Phase 2 .................................................................. 94 
Figure 3: 
Phase 2 Dose-Expansion in Relapsed/Recurrent GBM: Treatment 
Allocation ............................................................................................. 120 
 
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LIST OF APPENDICES 
APPENDIX 1A. ADAPTIVE DESIGN REPORT FOR THE PART 1 
DOSE-ESCALATION OF IV USL311 IN SUBJECTS WITH 
ADVANCED SOLID TUMORS ......................................................... 193 
APPENDIX 1B. ADAPTIVE DESIGN REPORT FOR THE PART 1B 
DOSE-ESCALATION OF ORAL USL311 IN SUBJECTS WITH 
ADVANCED SOLID TUMORS ......................................................... 205 
APPENDIX 2. HIGHLY EFFECTIVE CONTRACEPTIVE METHODS .......... 218 
APPENDIX 3. MEDICATIONS WITH QTC PROLONGATION RISK ............ 219 
APPENDIX 4. LOMUSTINE (GLEOSTINE®) PACKAGE INSERT ................ 222 
APPENDIX 5. RESPONSE ASSESSMENT USING RECIST V.1.1 CRITERIA
 
                                                                                                       233 
APPENDIX 6. RESPONSE ASSESSMENT USING RANO CRITERIA .......... 254 
APPENDIX 7. KARNOFSKY PERFORMANCE STATUS SCALE ................. 265 
APPENDIX 8. EUROPEAN ORGANIZATION FOR RESEARCH AND 
TREATMENT OF CANCER QUALITY-OF-LIFE QUESTIONNAIRE, 
WITH A BRAIN-CANCER MODULE (EORTC QLQ-C30/BN20) .. 266 
APPENDIX 9. PROTOCOL AMENDMENT CHANGES .................................. 269 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
4-AP 
4-aminopyridine 
ADL 
Activities of daily living 
ADME 
Absorption, distribution, metabolism and excretion 
AE 
Adverse event 
AMD3100 
Known antagonist of CXCR4, aka Plerixafor 
ALC 
Absolute lymphocyte count 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase  
ANC 
Absolute neutrophil count  
ANOVA 
Analysis of variance 
aPTT 
Activated partial thromboplastin time  
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase  
AUC 
Area under the concentration-time curve 
AUC0-t 
Area under the concentration-time curve from 0 to a specified time point 
AUC0-tau 
Area under the concentration-time curve over a dosing interval  
AUC0-∞ 
Area under the concentration-time curve from time 0 extrapolated to 
infinity 
AUC % Extrapolated 
Percent of AUC0-∞ due to extrapolation 
AUMC 
Area under the moment curve 
β-hCG 
Beta-human chorionic gonadotropin 
Beclin-1 
Protein which participates in the regulation of autophagy 
BICR 
Blinded independent central review 
BMI 
Body mass index 
BMP 
Di-docosahexaenoyl (22:6)-bis(monoacylglycerol) phosphate, biomarker 
of phospholipidosis 
BSA 
Body surface area 
BUN 
Blood urea nitrogen  
C0 
Estimated plasma concentration at time 0 
cAMP 
Cyclic adenosine monophosphate 
CCNU 
1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea; lomustine 
CD11b 
Leukocyte surface antigen CD11b 
 
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Abbreviation 
Definition 
CD133 
Cancer stem cell (as well as other cells) antigen CD133 
CD34+ 
Hematopoietic progenitor cell antigen CD34 
CDER 
Center for Drug Evaluation and Research 
CES 
Carboxylesterase 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CL 
Systemic clearance 
CLss 
Steady-state systemic clearance 
Cavg 
Average concentration over a steady state dosing interval 
Cmax 
Maximum plasma concentration 
Cmin 
Minimum observed plasma concentration, occurring at tmin 
CNS 
Central nervous system 
CPK 
Creatine phosphokinase 
CRA 
Clinical research associate 
CrCL 
Creatinine clearance 
CRO 
Contract research organization 
CSCs 
Cancer stem cells 
CSF 
Cerebrospinal fluid 
CSR 
Clinical study report  
CT 
Computed tomography  
CTCAE 
Common Terminology Criteria for Adverse Events  
CV% 
Coefficient of variation 
CXCL12 
C-X-C motif chemokine 12, ligand for CXCR4 (also known as SDF-1) 
CXCR4 
Chemokine (C-X-C Motif) receptor 4, an α-chemokine receptor in the 
GPCR gene family expressed by cells in the immune system and the 
central nervous system 
CYP2D6 
Cytochrome P450 2D6  
CYP3A4 
Cytochrome P450 3A4 
CYP450 
Cytochrome P450 
DCR 
Disease control rate 
DEC 
Dose Escalation Committee 
DIPL 
Drug-induced phospholipidosis 
DLT 
Dose-limiting toxicity 
DSMB 
Data Safety and Monitoring Board 
 
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Abbreviation 
Definition 
ECG 
Electrocardiogram  
EDC 
Electronic data capture 
EDTA 
Ethylenediaminetetraacetic acid 
EGFR 
Epidermal growth factor receptor 
EORTC QLQ-
C30/BN20 
European Organization for Research and Treatment of Cancer quality-of-
life questionnaire, supplemented with brain cancer module 
eCRF/CRF 
Electronic case report form/ case report form 
EIAED 
Enzyme-inducing anti-epileptic drug 
EU 
European Union 
EudraCT 
EU Drug Regulating Authorities Clinical Trials 
FDA 
Food and Drug Administration 
FLIPR 
Fluorescent imaging plate reader 
FI 
Fluctuation index 
FSH 
Follicle-stimulating hormone 
GBM 
Glioblastoma multiforme 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte colony stimulating factor 
GCPR 
G-Coupled Protein Receptor 
GGT 
Gamma-glutamyl transpeptidase 
GLP 
Good Laboratory Practice 
GM-CSF 
Granulocyte macrophage colony stimulating factor 
hCXCR4 
Human chemokine (C-X-C Motif) receptor 4 
Hct 
Hematocrit 
hERG 
Human Ether-à-go-go-Related Gene 
Hgb 
Hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
HNSTD 
Highest non-severely toxic dose 
HRT 
Hormone replacement therapy 
IB 
Investigator’s Brochure 
IC50 
Concentration of an inhibitor which causes the response (or binding) to be 
reduced by half 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IDH1 
Isocitrate dehydrogenase 1 
 
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Abbreviation 
Definition 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug (application) 
INR 
International normalized ratio  
IP 
Investigational product 
IRB 
Institutional review board 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
IV 
Intravenous 
K-M 
Kaplan-Meier  
KPS 
Karnofsky Performance Status 
λz 
Terminal rate constant 
LC3 
Microtubule-associated protein 1A/1B-light chain 3 
LC-MS/MS 
Liquid chromatography – mass spectrometry/mass spectrometry 
LDH 
Lactate dehydrogenase  
M10 
Major metabolite of USL311 
mCRM 
Modified continual reassessment method 
MCH 
Mean corpuscular hemoglobin 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGMT 
O(6)-methylguanine-DNA methyltransferase 
MRI 
Magnetic resonance imaging  
MTD 
Maximum tolerated dose  
NCI 
National Cancer Institute  
Nestin 
A protein marker of neural stem cells 
NYHA 
New York Heart Association 
ORR% 
Objective response rate 
OS 
Overall survival 
pCXCR4 
Phosphorylated chemokine (C-X-C Motif) receptor 4 
PD 
Pharmacodynamic 
PET 
Positron emission tomography 
PFS 
Progression free survival 
PFS-6m 
6-month progression free survival 
PICC 
Peripherally inserted central catheter 
 
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Abbreviation 
Definition 
PK 
Pharmacokinetic  
PRN 
Pro re nata, as needed 
PT 
Prothrombin time  
PTT 
Partial thromboplastin time 
PV 
Pharmacovigilance 
QA 
Quality assurance 
QOL 
Quality of life 
QT 
The measure of time between the start of the Q wave and the end of a T 
wave in the heart’s electrical cycle 
QTc 
The corrected measure of time between the start of the Q wave and the 
end of a T wave in the heart’s electrical cycle 
QTcF 
Fridericia corrected QT interval 
RANO 
Response Assessment in Neuro-Oncology 
RBC 
Red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended phase 2 dose 
RT 
Radiotherapy 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SDF-1 
Stromal cell-derived factor 1, ligand for CXCR4 (also known as 
CXCL12) 
STD 10 
Severely toxic dose in 10% of animals 
t1/2 
Terminal plasma half-life 
tmax 
Time point of observed Cmax 
tmin 
Time of minimum observed plasma concentration 
tlast 
Time of last measurable plasma concentration 
TdP 
Torsade de Pointes 
TEAEs 
Treatment emergent adverse events 
TK 
Toxicokinetics 
TMZ 
Temozolomide 
US 
United States 
ULN 
Upper limit of normal  
USL311 
6-{4-[1-(propan-2-yl)piperidin-4-yl]-1,4-diazepan-1-yl}-N-(pyridin-4-
yl)pyridine-2-carboxamide 
 
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1. 
INTRODUCTION 
1.1. 
Background Information 
1.1.1. 
Disease Background 
Glioblastoma multiforme (GBM) is a primary brain neoplasm, consisting of a genetically and 
phenotypically heterogeneous group of tumors (1, 2). Worldwide, there are an estimated 
240,000 cases of brain and nervous system tumors per year and GBM has the worst prognosis 
(3). Moreover, approximately 10,000 – 14,000 patients are diagnosed with GBM each year in 
the United States (4). Despite aggressive treatment including surgical resection, chemotherapy 
and radiotherapy, median survival time for patients with GBM is reported to be only 15.7 
months (5). The tumor almost invariably leads to neurological compromise and death. Due to 
its high degree of invasiveness, radical resection of the primary tumor mass is rarely curative. 
Infiltrating tumor cells invariably remain within the surrounding brain, leading to disease 
progression or recurrence, either locally or distant from the primary tumor (6). Recurrent 
disease occurs in more than 90% of patients and less than 5% of the patients are alive at 5 years 
(7). 
The disease is thought to derive from a subpopulation of highly tumorigenic cells: glioblastoma 
stem cells which have a high propensity for recurrence (8). This hypothesis is supported by 
substantial experimental evidence (9-12). GBM stem cells, unlike the majority of the rapidly 
dividing tumor cells, are considered relatively quiescent. This renders them more resistant to 
conventional chemotherapy and radiotherapy (10). While most differentiated cancer cells die 
from chemotherapy and radiotherapy, cancer stem cells (CSCs) are believed to be triggered 
and repopulate to form recurrent tumors. CSCs are considered the primary source of invasion. 
Therefore, there is a clear need for novel treatment options which target the CSCs. 
Standard-of-care for patients with newly diagnosed GBM is a surgical resection, if feasible, 
followed by radiation and temozolomide (Temodar®; TMZ). Maximal surgical resection is 
desired but this needs to be consistent with preservation of neurologic function, and in some 
patients, such as those who have disease that is not amenable to surgery or who have poor 
overall clinical condition, the best that can be achieved is a biopsy. Adjuvant radiotherapy 
improves local control and survival (13, 14) and adjuvant chemotherapy with TMZ improves 
progression free and overall survival (15, 16), although the effect is somewhat modest. 
However, in almost every case the disease will relapse. 
Many of these patients with relapsed/recurrent GBM have significant tumor related symptoms 
and morbidity. Treatment is given with palliative intent and all treatments are associated with 
side effects. The mainstay of management of these patients with recurrent disease is systemic 
chemotherapy. Only 20 to 30% of patients may be eligible for a second resection (7) and 
survival ranges up to 36 weeks (17, 18). There is no evidence that patients treated with surgery 
have better outcomes that those given chemotherapy in this setting. The role of re-irradiation 
is also uncertain given that most patients will have already received maximal doses of 
conventional radiotherapy and prospective randomized trials are lacking. However, selected 
patients with good performance status may benefit from high precision radiation techniques 
such as stereotactic radiosurgery (19). Chemotherapy options for recurrent disease include 
bevacizumab and nitrosoureas. In Phase 3 t rials where lomustine (1-(2-chloroethyl)-3-
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cyclohexyl-1-nitrosourea; CCNU) was the comparator arm, progression free survival and 
overall survival were reported as 2.7 and 9.8 months respectively in one trial (20) and 1.6 and 
7.1 months respectively in another trial (21). The most important determinant of outcome in 
these patients is pre-treatment performance status. 
The failure of conventional treatments and consequent poor prognosis highlights the clear 
unmet medical need for novel treatment options for patients with recurrent GBM after first line 
therapy. Given the central role of CSCs in GBM recurrence, treatment modalities that target 
CSCs within the central nervous system (CNS) may prove beneficial in the setting of recurrent 
GBM. 
1.1.2. 
USL311 Background 
USL311 (6-{4-[1-(propan-2-yl) piperidin-4-yl]-1,4-diazepan-1-yl}-N-(pyridin-4-yl) pyridine-
2-carboxamide) is a selective antagonist of the chemokine receptor, C-X-C motif receptor 
4 (CXCR4). CXCR4 is a G-coupled protein receptor (GCPR) whose natural endogenous 
ligand is the cytokine stromal cell derived factor 1 (SDF-1) also known as C-X-C motif 
chemokine 12 ( CXCL12). CXCR4 manipulation, in combination with granulocyte colony 
stimulating factor (G-CSF), has proven to improve the outcome of hematopoietic (22) and 
endothelial progenitor (23) stem cell mobilization.  
Recently, several studies have demonstrated the existence of CSCs for a variety of different 
tumor types, which constitute a reservoir of self-sustaining tumor cells with the ability to 
maintain tumor growth. Many of these cells express CXCR4 and respond to SDF-1, suggesting 
that CSCs represent a subpopulation capable of initiating metastasis in response to CXCR4 
activation (24). There is also compelling evidence for a prominent role of CXCR4 in the 
establishment and protection of cancer stem-like niches in the bone marrow, which protect 
such cells from chemotherapy resulting in high relapse rates in some hematopoietic cancers 
(25). Additionally, SDF-1 is highly expressed in internal organs that represent the primary 
metastatic destinations of the corresponding cancer cells (26). Thus, CXCR4 overexpression 
by tumor cells makes them responsive to chemotactic gradients of SDF-1 and thereby promotes 
metastasis. 
CXCR4 is one of the most common chemokine receptors that is overexpressed in over 
23 different cancers (27). Published data on m alignancies with overexpression of CXCR4 
include, but are not limited to: gliomas, neuroblastomas, astrocytomas, cervical, colorectal, 
thyroid, oral, esophageal, breast, ovarian, melanoma, prostate, lung, liver, renal, soft-tissue 
sarcomas and pancreatic cancer (27, 28). Moreover, CXCR4 overexpression correlates with 
poor prognosis in many types of cancer including, but not limited to: GBM (29), renal cell 
carcinoma (30), hepatocellular carcinoma (31), colorectal cancer (32), non-small cell lung 
cancer (33, 34), breast cancer (35), esophageal cancer (36) and prostate cancer (37). Due to the 
correlation of CXCR4 overexpression with a poor prognosis and also the involvement of 
CXCR4 in metastasis, CXCR4 is hypothesized to be a potential therapeutic target for a wide 
variety of cancers. 
In GBM specifically, a strong correlation between CXCR4 expression and increasing 
histologic grade was observed in GBM tissue samples. In GBM patients, CXCR4 expression 
was associated with increased extent and intensity of T2-weighted perilesional magnetic 
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resonance imaging (MRI) signal abnormalities (38, 39). These findings suggest that increased 
CXCR4 expression correlates with increased tumor grade. Blockade of CXCR4 prevents both 
the vasculogenesis and recurrence of GBM tumors after radiation treatment in animal models 
(40). CXCR4 expression on CSCs is implicated in migration, self-renewal, as well as resistance 
to chemotherapy/radiotherapy and thus CXCR4 antagonism is expected to limit these 
processes and render CSCs more sensitive to concurrent therapies. In a human GBM cell line, 
administration of a CXCR4 antagonist (AMD3100, plerixafor) induced a significant increase 
in apoptosis (41). Similarly, in animal xenograft experiments, plerixafor significantly inhibited 
growth of the tumors by increasing apoptosis and decreasing proliferation of the tumor cells 
(42, 43). 
These data from the literature provide the rationale for investigating USL311 as a potential 
anticancer agent for the treatment of solid tumors, including GBM. 
1.2. 
Nonclinical Study Findings for USL311  
A brief summary of the nonclinical study findings are provided here; for more information, 
please refer to the Investigator’s Brochure (IB). 
1.2.1. 
Primary Pharmacology (Efficacy) 
The nonclinical pharmacology and efficacy of USL311 was characterized using studies of 
CXCR4 receptor activity in various cancer cell lines and in vitro assays, and in vivo using 
xenograft tumor models of GBM.  
1.2.1.1. 
In Vitro Studies 
USL311 is a potent antagonist of CXCR4 in mouse, rat, and human, with half maximal 
inhibitory concentrations [IC50] shown to be 5.4, 5.8, and 1.1 nM [2.3, 2.4 and 0.46 ng/mL], 
respectively, in several in vitro studies. In these studies, cellular (blockade of cyclic adenosine 
monophosphate [cAMP] and β-arrestin readouts using human and mouse receptors) and 
cell-mediated (inhibition of SDF-1-induced chemotaxis) responses were blocked by incubation 
with USL311 in a concentration-dependent manner. The antagonism was shown to be highly 
selective for CXCR4 when measured against 19 separate chemokine receptors, 71 ot her 
receptors and receptor classes, and 27 enzyme systems, with minimal to no activity at other 
receptors. 
1.2.1.2. 
In Vivo Studies 
Numerous experiments were designed to assess the effect of USL311 (50 mg/kg/day orally, 
5 days out of 7 c ontinuously) either alone or in combination with anti-angiogenic 
chemotherapy (bevacizumab and sunitinib) as well as cytotoxic chemotherapy (TMZ) and/or 
radiotherapy (RT) on the growth of subcutaneous xenograft tumors in nude mice. As compared 
to vehicle, single-agent USL311 significantly inhibited the growth of T98G-, U251-, and 
U87MG-derived tumors induced in nude mice (p <0.001). The delay in tumor growth with 
single-agent USL311 administration was similar to that observed with single-agent treatment 
with the comparators in these models (i.e., bevacizumab, sunitinib, RT, TMZ, and RT + TMZ). 
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In combination with the anti-angiogenic therapeutics, bevacizumab or sunitinib, USL311 
inhibited the regrowth of T98G-, U251-, and U87MG-derived tumors in nude mice. Both 
USL311 and bevacizumab (4 mg/kg IV every 4 days, 8 injections total) were found to delay 
tumor growth in all three GBM cell line-derived xenografts tested, and the combination 
delayed progression significantly more than either agent alone (p ≤ 0.0001). Similar results 
were observed when USL311 was combined with sunitinib (40 mg/kg orally daily x 3 weeks), 
where both USL311 and sunitinib delayed tumor growth in all three GBM cell line-derived 
xenografts tested and the combination of USL311 + sunitinib delayed progression significantly 
more than either agent alone for all three tumor types (p ≤ 0.0001). The greater effect of 
USL311 in combination with either bevacizumab or sunitinib suggests that USL311 may 
potentiate the efficacy with anti-angiogenic chemotherapy. 
Similarly, when combined with RT (2 Gy/every two days x 3 cycles), TMZ (16 mg/kg x 5 days 
orally) or RT + TMZ, USL311 significantly inhibited the regrowth of T98G-, U251-, and 
U87MG-derived tumors induced in nude mice. The delay in tumor regrowth was significantly 
greater for the combination of USL311 with RT, TMZ, and RT + TMZ as compared to 
treatment with RT, TMZ, or RT + TMZ without USL311, including in the T98G cell line which 
is resistant to TMZ (as it has an unmethylated O(6)-methylguanine-DNA methyltranferase 
[MGMT] promoter and therefore high MGMT expression). When administered with TMZ or 
RT plus TMZ, USL311 can inhibit tumor growth by 90%. The USL311-based combinations 
demonstrated an apparently synergistic effect (combination index = 0.39 – 0.75 with values <1 
indicating synergy), suggesting that USL311 may potentiate the efficacy of RT (i.e., serve as 
a radiosensitizer) and cytotoxic chemotherapy regimens. In the latter case, the effect may 
conceivably be enhanced through continued dosing of a cytotoxic with USL311 as 
administration of TMZ was limited to the first 5 days of the experiment.  
In summary, single-agent USL311 inhibited the growth of all GBM cell line-derived tumors 
as well as tumor regrowth when administered in combination bevacizumab, sunitinib, RT, 
TMZ, and RT + TMZ, with resultant increases in mouse survival.  
1.2.2. 
Secondary Pharmacology 
1.2.2.1. 
In vivo mobilization of hematopoietic progenitors and WBCs by USL311 
In addition to the proposed anti-cancer effects, a key PD effect of CXCR4 manipulation is the 
mobilization of hematopoietic stem cells and white blood cells (WBCs) from the bone marrow 
to the bloodstream. The CXCR4 targeting agent, plerixafor (AMD3100; Mozobil®), is used 
clinically in combination with granulocyte-colony stimulating factor (G-CSF) to mobilize 
hematopoietic stem cells to the peripheral blood for collection and subsequent autologous 
transplantation. The ability of single-dose USL311 (30 mg/kg subcutaneously) to induce in 
vivo mobilization of hematopoietic progenitors and WBCs from bone marrow in mice was 
investigated both alone and in combination with G-CSF (5 µg/day x 2 days). 
Compared to vehicle, statistically significant increases in WBC count (1.7- to 1.9-fold, 
p <0.05) were observed following dosing with USL311 as compared to vehicle, which was 
further increased in the presence of G-CSF (~3-fold). While both G-CSF and plerixafor 
(5 mg/kg subcutaneously) resulted in significant increases in hematopoietic progenitor cells in 
the blood compared to vehicle, no i ncrease was seen following single-agent USL311 
 
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administration. Both USL311 and plerixafor potentiated the effects of G-CSF on hematopoietic 
progenitor cell mobilization; however most of these findings were not statistically significant. 
The difference in response to USL311 and plerixafor is attributed to differences in mechanism 
of action, as USL311 is a strict CXCR4 antagonist whereas plerixafor has been demonstrated 
to be a partial CXCR4 agonist. These results suggest that while increases in WBC count may 
be observed following USL311 administration, hematopoietic progenitor cells are not expected 
to be increased in the blood and thus maintained within the protective environment of the bone 
marrow when patients are dosed with USL311. 
The ability of USL311 to increase the mobilization of WBCs and hematopoietic progenitor 
cells will be explored by measuring WBC count and CD34+ count (a marker of hematopoietic 
progenitor cells) at PK sampling matched time points. Additionally, SDF-1 levels may be 
measured at PK sampling matched time points, because increased SDF-1 levels are thought to 
be involved in the mobilization of hematopoietic progenitor cells (44) (see Section 8.7.3). 
1.2.2.2. 
Effects of USL311 on angiogenesis in wound healing 
Due to the involvement of the SDF-1/CXCR4 signaling pathway in angiogenesis, a study was 
conducted to assess the effect of USL311 on the progression of wound healing and specifically 
the process of wound angiogenesis. These effects were investigated in a study of wound 
healing in CD-1 mice using a model of standardized, full-thickness excisional wounds on the 
dorsal flanks of study animals. USL311 was administered orally at 10 or 50 m g/kg/day 
24 hours prior to wounding which was followed, in a subset of animals, with daily dosing for 
9 days post-wounding. 
As compared to control (dosing vehicle), USL311 had no significant impact on overall wound 
closure, wound contraction, or the wound closure process of epithelialization. No significant 
effects on wound healing were observed upon histological evaluation. With regard to 
angiogenesis, in animals that received only a pre-wounding dose of USL311, angiogenesis was 
significantly increased by Day 10 post-wounding. In contrast, in animals that received both 
pre- and post-wounding USL311, a minor impairment of angiogenesis was observed by Day 
10 post-wounding and did not increase with USL311 dose. 
In conclusion, while USL311 showed small effects on wound angiogenesis, these effects were 
not sufficient to affect wound healing in the mouse and thus, it is expected that USL311 will 
not delay healing in patients who have recently undergone surgery. 
1.2.3. 
USL311 Pharmacokinetics/Toxicokinetics 
The PK and toxicokinetics (TK) of USL311 were investigated in a series of nonclinical studies 
addressing the absorption, distribution, metabolism, and excretion (ADME) of USL311 in 
mouse, rat, dog, and cynomolgus monkey. The following is a brief summary, please refer to 
the Investigator’s Brochure for more information. 
Following intravenous (IV) administration in mouse, rat, dog, and cynomolgus monkey, 
plasma USL311 concentrations exhibited a very rapid fall followed by a long, low terminal 
phase with a t 1/2 on the order of several days. In rat and dog studies, plasma USL311 PK 
appeared generally linear and dose-proportional increases in USL311 exposure were observed 
in plasma, brain and cerebrospinal fluid (CSF) samples. Consistent with the low plasma 
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USL311 concentrations exhibited during the terminal phase, minimal accumulation of USL311 
was observed upon w eekly IV dosing. In contrast, tissue USL311 concentrations were 
significantly higher than those in the plasma, with tissue:plasma USL311 concentration ratios 
ranging from >100 (brain) to >10,000 (liver) with repeat IV or oral USL311 administration, 
consistent with the high volume of distribution across species. Following single-dose IV 
administration of radiolabeled USL311 to rats, significant uptake of radiolabeled drug was 
observed in most organs, including across the blood-brain barrier, as radioactivity was 
detectable in the brain up to 14 days post dose. This is consistent with estimated tissue USL311 
half-lives on the order of 4 – 8 days. However, despite its long terminal half-life USL311 
clearance is high, generally exceeding liver blood flow across species. 
Plasma protein binding of USL311 is low, with in vitro estimates of USL311 fraction unbound 
in the plasma of 0.6 for rats and dogs and 0.8 for humans. As USL311 concentrations are higher 
in the whole blood versus the plasma (1.6 to 2.8-fold for humans), blood samples will be 
collected for analysis of USL311 PK in both the blood and plasma (see Section 8.6.1). 
Metabolism of USL311 is attributed to both cytochrome P450 (CYP450) and 
CYP450-independent processes, specifically CYP3A4 and CYP2D6 and carboxylesterase 
activity (CES1 and CES2). In human hepatocyte experiments, the most abundant metabolites 
represented hydroxylation (M1) and dealkylation (M6 and M8) of USL311, as well as amide 
hydrolysis to carboxylic acid (M10) and 4-aminopyridine (4-AP, M26). The latter are the major 
metabolites observed following IV USL311 administration to rats, dogs and cynomolgus 
monkeys, with terminal half-lives similar to USL311. Plasma M10 exposures ranged from 2% 
(rat) to 120% (dog) of USL311 exposures and plasma 4-AP exposures were 3–20% of USL311 
exposures in both species. In vitro studies suggest that formation of both M10 and 4-AP is 
primarily a CYP450-independent process, which has been attributed in part to CES1 and CES2 
activity although CYP2D6 may also contribute. In contrast, CYP3A4 does not contribute to 
M10/4-AP formation but rather appears to be primarily responsible for the formation of a 
number of minor metabolites. 
In vitro CYP450-interaction studies indicate that USL311 is unlikely to inhibit CYP1A2, 2C8, 
2C9 or 2C19. USL311 displayed competitive inhibition of both CYP2D6 and CYP3A4 at high 
concentrations (IC50 > 10 μM [4.22 μg/mL]), although the latter appears to be sub-site specific 
as inhibition was only observed with midazolam as a substrate and not with testosterone. No 
time-dependent CYP450 inhibition was observed. In human hepatocytes, USL311 (up to 
60 μM [25.3 μg/mL]) did not increase CYP1A2 or 2B6 activity, although a decrease in 
CYP2B6 activity was noted suggesting possible inhibition. USL311 did increase CYP3A4 
activity by approximately 3-fold at 1 μM and 10 μM [0.42 and 4.22 μg/mL] concentration; 
however, this was not observed at the highest concentration (60 μM [25.3 μg/mL]) which is 
attributed to concomitant inhibition of CYP3A4 by USL311. 
Studies in rats and dogs indicated that USL311 is excreted primarily via the biliary excretion 
in the feces. Excretion via the urine accounts for less than 2% of the total dose. 
A summary of the mean plasma USL311 TK parameters from the pivotal rat and dog 
toxicology studies is shown in Table 13. 
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Table 13: 
Mean plasma USL311 TK parameters in rats and dogs (males and 
females combined) following weekly 2-hour IV infusions of USL311 
Species 
Study 
Day 
Dose 
(mg/kg/
week)a 
Cmax 
(ng/mL) 
AUC0-168 
(ng.hr/ 
mL) 
AUC0-∞ 
(ng hr/ 
mL) 
CL 
(L/hr/ 
kg) 
Vss 
(L/kg) 
Terminal  
t1/2 
(hr) 
Rat 
Day 1 
15 
258 
1240 
1260 
11.9 
269 
31.1 
100 
2510 
13100 
13800 
7.25 
248 
48.7 
300/250b 
11300 
50200 
55400 
5.42 
251 
95.3 
Day 29 
15 
493 
2350 
-- 
-- 
-- 
-- 
100 
2730 
19200 
-- 
-- 
-- 
-- 
300/250b 
4510 
57200 
-- 
-- 
-- 
-- 
Dog 
Day 1 
5 
65.7 
1040 
1260 
4.10 
375 
86.2 
40 
1420 
11600 
14100 
2.92 
261 
106 
80 
3460 
23500 
25900 
3.12 
242 
99.6 
Day 29 
5 
84.2 
1900 
-- 
-- 
-- 
-- 
40 
2140 
15300 
-- 
-- 
-- 
-- 
80 
2150 
25000 
-- 
-- 
-- 
-- 
a Administered as a 2-hour IV infusion 
b TK parameters for 300/250 mg/kg/dose group represent a 300 mg/kg dose on Day 1 and a 250 mg/kg dose on Day 29.  
Dose was decreased due to mortality in this treatment group. 
1.2.3.1. 
USL311 Lysosomal trapping 
The complex, multi-phasic PK profile and extensive tissue distribution exhibited by USL311 
is attributed to sequestration within lysosomes (i.e., “lysosomal trapping”), cellular organelles 
that play a key role in various metabolic processes. USL311 has been shown to be 
lysosomotropic in vitro, and other lysosomotropic drugs exhibit similar PK and toxicology 
profiles as USL311, including a long terminal phase secondary to slow redistribution of intact 
drug from the lysosomes and a propensity for both drug-induced phospholipidosis and QTc 
prolongation (see Section 1.2.4). Consequently, it is presumed that despite the extensive tissue 
uptake a majority of USL311 may be lysosomally-trapped, as indicated by CSF concentrations 
(often used as a surrogate of unbound concentrations in the CNS) which were more than 
100-fold lower than total brain tissue concentrations of USL311 in nonclinical studies. The 
unbound concentration of USL311 in the CNS will be assessed by collecting CSF in Phase 2 
(see Section 8.6.2), which will provide information about the availability of study drug able to 
interact with the CXCR4 receptor in the CNS. However, it should be noted that lysosomal 
trapping may contribute to USL311’s putative anti-cancer effect through inhibition of 
autophagy, a homeostatic cellular recycling process which is disrupted by other 
lysosomotropic drugs (e.g., chloroquine, hydroxychloroquine) leading to enhanced tumor cell 
death in vitro (45). The ability of USL311 to inhibit autophagy within tumor cells will be 
explored by measuring biomarkers of autophagy (e.g., LC3, Beclin-1) in resected tumor 
samples (see Section 8.7.2). 
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1.2.3.2. 
4-Aminopyridine Metabolite 
Based on in vitro and in vivo data, 4-AP is expected to be one of the primary metabolites of 
USL311 observed in humans. This metabolite is a broad-spectrum potassium channel blocker 
and is a US FDA-approved drug marketed under the name dalfampridine (Ampyra®) to 
improve walking in patients with multiple sclerosis. Of note, the prescribing information for 
dalfampridine carries a contraindication in patients with a history of seizures and a warning 
regarding an increased risk of seizures which may be increased in patients with moderate to 
severe renal impairment (creatinine clearance [CrCL] < 50 mL/min) (46). A plasma 4-AP 
concentration of 100 ng/mL is considered a likely threshold above which patients are at an 
increased risk of seizures in the absence of other risk factors (47). Relative to plasma USL311 
concentrations, exposure to 4-AP was low in nonclinical studies following USL311 
administration as a weekly 2-hour IV infusion, with mean plasma 4-AP concentrations 
< 35 ng/mL and < 75 ng/mL at the rat STD 10 (severely toxic dose in 10% of animals) and the 
dog HNSTD (highest non-severely toxic dose), respectively. As the starting USL311 dose of 
60 mg/m2 represents 1/10 of the rat STD 10, and subjects with renal insufficiency 
(CrCL < 60 mL/min) are excluded from participation, it is  anticipated that plasma 4-AP 
concentrations will be low and will not exceed the 100 ng/mL threshold for increased risk of 
seizure. 
Blood samples will be collected for evaluation of 4-AP PK and as data becomes available 
during study conduct, plasma 4-AP concentrations observed following USL311 administration 
will be considered for dose escalation decisions. 
For more information on 4-AP, please refer to the prescribing information for dalfampridine 
(Ampyra®). 
1.2.4. 
Toxicology and Safety Pharmacology 
To establish the safety of USL311 the nonclinical package was designed in accordance with 
International Conference on H armonization (ICH) S9 guidelines, and includes studies 
conducted via IV and oral administration. The nonclinical toxicology package includes: 
• 4-week Good Laboratory Practice (GLP) toxicology assessments in rats and dogs 
incorporating safety pharmacology endpoints, urinary phospholipidosis biomarker, 
and toxicokinetic endpoints 
• 7-day and 28-day exploratory repeated-dose studies in both rats and dogs 
• Single-dose exploratory toxicology study using a single cardiovascular-telemetry 
implanted dog to confirm tolerated dose in a drug-naïve dog 
• non-GLP Ames and mouse lymphoma screening assays 
• non-GLP hERG assays for Safety Pharmacology 
• GLP assessments of hemolysis and flocculation in vitro 
Lethal doses were defined in both rats and dogs following IV and oral administration. In rats, 
mortality was observed following weekly IV administration (2-hour infusion) at doses of 
300 mg/kg/dose and higher, and following oral daily dosing at 100 mg/kg/day and higher. In 
dogs, administration of USL311 was associated with mortality at 100 mg/kg and higher. 
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Minimal decreases in body weight (i.e., decreased weight gains) and food consumption have 
been observed at higher doses. Consistent across studies, administration of USL311 was 
associated with transient CNS-related clinical signs including, but not limited to, tremors, 
ataxia, unsteady gait, slow deliberate movement, lethargy, semi-closed eyes, salivation, 
vomiting, and diarrhea on the day of infusion. Functional observational battery assessments on 
Days 9 and 23 of the rat GLP toxicology study found no evidence of lasting neurotoxicity. 
Likewise, there was no evidence of neuropathology in the rat or dog toxicology studies.  
A possible interaction of USL311 with anesthesia administration was uncovered in the dog 
GLP toxicology study during the CSF collection on Day 15 that occurred within 1 hour after 
the end of the 2-hour USL311 infusion. Male and female dogs given the highest USL311 dose 
(80 mg/kg/dose) exhibited twitching and kicking following IV dexmedetomidine 
administration, with the effect being more severe in the female dogs. For the female dogs, 
additional IV dexmedetomidine was given to reduce movement and ensure full sedation for 
the CSF collection. This effect appears to be acute as it was only observed when the dogs were 
immediately anesthetized following USL311 infusion. When approximately 24 hou rs 
intervened between the final USL311 infusion and anesthesia, the effect was not observed. The 
proposed mechanism for the interaction is that greater concentrations of 4-AP were formed at 
the higher doses administered to the dogs demonstrating the possible interaction. 4-AP acts as 
a neuroexcitatory agent through blockade of potassium channels, as well as through multiple 
other mechanisms, while systemic anesthetics act as neuroinhibitory agents through a variety 
of different mechanisms, depending on the agent used. Thus, the interaction occurs due to 
opposing pharmacological mechanisms which only appear to occur at high doses of USL311 
resulting in high concentrations of 4-AP.  
In vitro hERG cardiac channel assays found a relatively low IC50 of 1.5–2.6 µM. ECG 
assessments in the dog toxicology studies (collected from 3 hours from the start of infusion) 
demonstrated QT prolongation with up to a 12% increase in Fridericia corrected QT interval 
(QTcF) relative to time-matched control following IV doses of USL311 of 40 m g/kg and 
higher. These effects (also seen in exploratory toxicology studies) were found to be correlated 
with plasma USL311 concentrations such that the QTcF interval decreased following the end 
of the 2-hour infusion and a return to near baseline was noted by approximately 12-20 hrs post 
dose. The prolongation in QTcF attenuated with repeated dosing, as the largest effect on QTcF 
interval was observed following the first dose of USL311. Increased heart rates were also noted 
at USL311 doses of 40 mg/kg and higher, but the primary effect on heart rate in the dog GLP 
toxicology study was lower heart rates following infusion with repeated dosing. The no-
observed effect level (NOEL) for QTcF prolongation and heart rate effects was 5 mg/kg in the 
pivotal dog IV toxicology study, corresponding to a human equivalent dose of 100 mg/m2 
which is higher than the 60 mg/m2 starting IV dose. 
For both species, clinical pathology changes including a 2-fold increase in AST have been 
observed. Increases in WBC counts have been observed and are expected pharmacology for 
USL311 (see Section 1.2.2.1). With the higher doses in the pivotal rat GLP toxicology study, 
some mild changes in RBC parameters (including decreased MCV and MCH and increased 
RBC count) were observed, increased inorganic phosphorus (males only), increased urine 
volume with decreased specific gravity (females only), and increased urine magnesium:urine 
creatinine ratio with no correlative changes in serum magnesium or calcium. In the pivotal dog 
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GLP toxicology, a shorter aPTT was observed with higher doses of USL311 in female dogs. 
Histologically, treatment with USL311 produced microscopic changes consistent with 
phospholipidosis in a number of tissues. Dose- and time-related vacuolar/foamy changes in 
phagocytic and epithelial cells were also consistent with intracellular accumulation of USL311, 
most likely within lysosomes (see Section 1.2.3.1), and with recruitment plus proliferation of 
phagocytic and inflammatory cells. With once weekly IV dosing in rats, minimal degeneration 
and necrosis of skeletal muscle have been observed with doses at or above the STD 10. 
Dose related increases in the urinary BMP phospholipidosis biomarker have been observed in 
the rat and dog toxicology studies to support the microscopic findings indicative of drug-
induced phospholipidosis.  
Acceptable local tolerance has been demonstrated in the GLP toxicology studies in the 
catheterized animals. In vitro hemolysis and flocculation assays indicate that USL311 will be 
compatible with blood when administered at physiologically relevant concentrations, and there 
was no evidence of hemolysis observed in any of the toxicology studies conducted in rats and 
dogs. Further, Ames and mouse lymphoma screening assays indicate that USL311 is not 
mutagenic. 
The nonclinical studies conducted to date support the use of USL311 in the clinic and based 
on both rat and dog findings, an adequate safety margin exists to initiate first in human dosing. 
Calculations based on the algorithm for first-in-human dose selection in the ICH S9 guidance 
demonstrate that the rat STD 10 provides the most conservative clinical starting dose (Table 
14) for the IV dose in Part 1a. 
Table 14: 
Clinical Starting Dose Estimated from GLP Toxicology Studies 
Based on Pivotal GLP  
Toxicology Studies 
Human Equivalent  
Dosea 
Clinical Start Dose per ICH S9 
Algorithms 
Rats 
STD 10 = 100 mg/kg/dose 
600 mg/m2 
1/10 STD 10 = 60 mg/m2 
Dogs 
HNSTD = 80 mg/kg/dose 
1600 mg/m2 
1/6 HNSTD = 267 mg/m2 
a Human Equivalent Dose calculations are based on body surface scaling per the U.S. FDA Guidance for Industry: 
Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers, 
CDER, July 2005 
Part 1b of  the study will resume under this amendment with dosing initiation of an oral 
formulation of USL311, at a starting dose of 40 mg once daily in 3-week (21-day) cycles. The 
selected 40 mg daily oral starting dose is comparable to the 30 mg daily starting dose based on 
1/6 HNSTD in dogs (5 mg/kg/day oral daily dose) and is lower than the ~60 mg daily dose 
calculated based on the maximum IV dose tested in humans (250 mg/m2 weekly, divided into 
daily doses). USL311 plasma pharmacokinetics are dose-proportional and minimal to no 
plasma accumulation is expected for USL311 and its main metabolites after daily oral dosing. 
In addition, a fixed-dosing approach is considered to be appropriate for future studies given 
that USL311 pharmacokinetics are not influenced by body size. Daily oral dosing is anticipated 
to further mitigate the concentration-related QT effect, compared to IV bolus weekly dosing. 
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1.3. 
Clinical Study Findings for USL311 
There are no completed clinical trials of USL311. This study represents the first-in-human 
study of USL311. 
As of the date of this amendment, data from 13 subjects participating in the Part 1a IV Dose 
Escalation portion of this study have been collected at USL311 doses of 60, 120, 180, and 250 
mg/m2 via 2- or 4-hour IV infusion. Interim data from the first 8 subjects suggested a potential 
USL311-related increase in the QT interval, which was transient, resolved post-end of infusion, 
and exhibited an apparent correlation with plasma USL311 concentrations (i.e., Cmax). Based 
on these observations, a longer duration of USL311 infusion (i.e., slower infusion rate) was 
expected to decrease the magnitude of QT-prolongation and, therefore; the infusion duration 
was increased from 120 minutes (2 hours) to 240 minutes (4 hours) in Amendment #3. Dosing 
with the 4-hour infusion was initiated at the highest safe dose of USL311 as determined from 
subjects who received USL311 via a 2-hour infusion (i.e., prior to Amendment #3). Subjects 
who were previously enrolled and were actively participating at the time Protocol Amendment 
#3 was activated would continue study participation according to Protocol Amendment #2. 
After 13 subjects were evaluable (i.e., had completed Cycle 1 dosing, at minimum) in Part 1a 
IV Dose Escalation, the Dose Escalation Committee halted dose escalation, although no DLTs 
had occurred, due to continuing dose-related increases in QTcF prolongation that was not 
ameliorated by increasing the infusion duration. Part 1b of the study will resume under this 
amendment with dosing initiation of an oral formulation of USL311, at a starting dose of 40 
mg once daily in 3-week (21-day) cycles. The selected 40 mg daily oral starting dose is 
comparable to the 30 mg daily starting dose based on 1/6 HNSTD in dogs (5 mg/kg/day oral 
daily dose) and is lower than the ~60 mg daily dose calculated based on the maximum IV dose 
tested in humans (250 mg/m2 weekly, divided into daily doses). USL311 plasma 
pharmacokinetics are dose-proportional and minimal to no plasma accumulation is expected 
for USL311 and its main metabolites after daily oral dosing. In addition, a fixed-dosing 
approach is considered to be appropriate for future studies given that USL311 
pharmacokinetics are not influenced by body size. Daily oral dosing is anticipated to further 
mitigate the concentration-related QT effect, compared to IV bolus weekly dosing. 
As of the date of this amendment there were no active subjects currently participating in Part 
1a IV Dose Escalation. All subsequent Part 1 participants will be enrolled in Part 1b, Oral Dose 
Escalation. 
 
 
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2. 
STUDY OBJECTIVES 
2.1. 
Phase 1: Parts 1 and 2 Dose-Escalation in Subjects with Advanced 
Solid Tumors 
2.1.1. 
Primary Objectives 
The primary objectives of the Phase 1 dose-escalation are to: 
• Determine the MTD and RP2D of USL311 as a single agent in subjects with 
advanced solid tumors for whom no standard-of-care treatment is recognized or who 
have failed or are intolerant to the standard-of-care treatment (Part 1) 
• Determine the MTD and RP2D of USL311 in combination with lomustine in 
subjects with advanced solid tumors for whom no standard-of-care treatment is 
recognized or who have failed or are intolerant to the standard-of-care treatment 
(Part 2) 
2.1.2. 
Secondary Objectives 
The secondary objectives of the Phase 1 dose-escalation are to: 
• Assess the safety and tolerability of USL311 as a single agent and in combination 
with lomustine  
• Determine preliminary efficacy parameters such as PFS-6m, ORR%, DCR, PFS and 
OS of USL311 as a single agent and in combination with lomustine 
• Determine the PK profile of USL311 in plasma and whole blood and of lomustine 
in plasma (prior to and with concomitant USL311 administration) 
• Evaluate the drug interaction potential between USL311 and lomustine 
2.1.3. 
Exploratory Objectives 
The exploratory objectives of the Phase 1 dose-escalation are to: 
• Determine effects of USL311 on systemic markers of CXCR4 inhibition, including 
measurement of CD34+ cells, and WBC count 
• Measure effects of USL311 on a urine biomarker of phospholipidosis, BMP 
• Investigate exposure-response relationships for USL311 as a single agent and in 
combination with lomustine 
2.2. 
Phase 2: Parts 3 and 4 Dose-Expansion in Subjects with 
Relapsed/Recurrent GBM 
2.2.1. 
Primary Objectives 
The primary objectives of the Phase 2 dose-expansion are to: 
 
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• Determine the percentage PFS-6m of USL311 as a single agent in subjects with 
relapsed/recurrent GBM who previously received standard-of-care treatment in the 
first-line setting and who are candidates for re-resection (Part 3). 
• Determine the percentage PFS-6m of USL311 in combination with lomustine in 
subjects with relapsed/recurrent GBM who previously received standard-of-care 
treatment in the first-line setting and who are candidates for re-resection (Part 4)  
2.2.2. 
Secondary Objectives 
The secondary objectives of the Phase 2 dose-expansion are to: 
• Assess the safety and tolerability of USL311 as single agent and in combination with 
lomustine in subjects with relapsed/recurrent GBM 
• Assess ORR%, PFS, DCR and OS of USL311 as single agent and in combination 
with lomustine in subjects with relapsed/recurrent GBM  
• Determine the PK profile of USL311 in plasma and whole blood and of lomustine 
in plasma 
2.2.3. 
Exploratory Objectives 
The exploratory objectives of the Phase 2 dose-expansion are to: 
• Assess PD markers of CXCR4 inhibition in tumor samples following pre-surgical 
administration of USL311 for comparison with subjects randomized to receive no 
pre-surgical USL311 treatment. These markers may include, but are not limited to, 
the following: 
− Tumor pCXCR4 profile 
− Tumor markers of autophagy (e.g., LC3, Beclin-1) 
− Tumor markers of vasculogenesis (e.g., CD11b) and cancer stem cell survival 
and proliferation (e.g., nestin, CD133) 
• Determine biodistribution of USL311 to the brain/CSF in resected tissue samples 
and CSF samples following pre-surgical administration of USL311 to investigate 
CNS penetration and for correlation with clinical response and/or PD data 
• Assess exposure-response relationships for USL311 as a single agent and in 
combination with lomustine 
• Assess 
health-related 
QOL 
and 
subject 
reported 
outcomes 
(EORTC 
QLQ-C30/BN20) 
 
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3.2.1. 
Part 1a – Dose-Escalation in Advanced Solid Tumors of Single Agent IV 
USL311 
Subjects in Part 1awill participate in the following visits: 
• Screening Visit (within 28 to 2 days of Cycle 1-Day 1) 
• Baseline Visit (within 1 day of Cycle 1-Day 1) 
• Treatment Phase Visits for Cycle 1 (Visits on Day 1, Day 2, Day 3, Day 5, Day 8, 
and Day 15) 
• Treatment Phase Visits for Cycle 2+ (Visits on Day 1, Day 8, and Day 15) 
• End of Treatment Visit (within 14 da ys of the decision to discontinue on-study 
treatment) 
• Follow-up Visit (within 28 days of last dose of USL311; may be same visit as End 
of Treatment Visit) 
• Long Term Follow-up Visits (quarterly visit or phone call until subject death or 
study termination) 
During the IV Treatment Phase, treatment will be administered once weekly in 3-week (21-
day) cycles. USL311 will initially be administered IV over 120 minutes (2 hours, Protocol 
Amendment #2) or 240 minutes (4 hours, Protocol Amendment #3) on Days 1, 8, and 15 of a 
21-day cycle. Subjects will be monitored by study staff for at least 8 hours after the start of the 
infusion for their first dose of USL311. 
Dosing with the 4 hou r infusion will be initiated at the highest safe dose of USL311 as 
determined from subjects who received USL311 via a 2 hour  infusion (viz., prior to 
Amendment #3). Subjects who were previously enrolled and are actively participating at the 
time Protocol Amendment #3 is activated will continue study participation according to 
Protocol Amendment #2. 
There re a total of 31 possible IV dose levels specified between 40 mg/m2 and 1660 mg/m2. 
Dose levels are defined to be in approximately 15% increments. Specifically, the dose levels 
in mg/m2, are shown in Table 15 below: 
Table 15: 
USL311 Available IV Doses for Dose Escalation 
Available Doses (mg/m2) 
40 
120 
320 
820 
50 
140 
360 
920 
60 
160 
400 
1040 
70 
180 
450 
1170 
80 
200 
510 
1310 
90 
220 
570 
1480 
100 
250 
650 
1660 
110 
280 
730 
 
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Dose escalation will begin with the single agent with enrollment of subjects to the 60 mg/m2 
dose. A rationale for the selection of the starting dose and administration duration is provided 
in Section 6.1.2.1. Three subjects will be treated at the initial dose of 60 mg/m2 and evaluated 
by the DEC, after all three subjects had completed Cycle 1, before the dose was escalated/de-
escalated. The 40 and 50 mg/m2 dose levels were de-escalation dose levels. Dose-escalation 
was to follow a modified continual reassessment method (mCRM) design. The dose escalation 
strategy is further described in Section 3.2.4. 
For each dose escalation, one (1) subject will be enrolled at the new dose level and will be 
treated and observed from Cycle 1-Day 1 through Cycle 1-Day 8 for tolerance to the dose 
before additional subjects may be treated at that dose level. Details are provided in the Dose 
Escalation Management Plan. 
At each dose-escalation point, the DEC (see Section 3.2.6) will review the safety data, any 
available PK/PD data, and all other relevant subject data in order to recommend the subsequent 
dose level and IV infusion duration. Clinical judgment will always supersede the model-
based recommendations for dose-escalation, meaning that clinical judgment can be applied to 
reduce the increment of dose escalation or elect not to dose escalate in favor of accruing more 
subjects at that dose level. 
Treatment cycles will be repeated every 21-days until disease progression, unacceptable 
toxicity, withdrawal of consent, Investigator decision to discontinue treatment, or Sponsor 
decision to terminate the study. 
3.2.2. 
Part 1b – Dose-Escalation in Advanced Solid Tumors of Single Agent Oral 
USL311 
Subjects in Part 1b will participate in the following visits: 
• Screening Visit (within 28 to 2 days of Cycle 1-Day 1) 
• Baseline Visit (within 1 day of Cycle 1-Day 1) 
• Treatment Phase Visits for Cycle 1 (Visits on Day 1, Day 2, Day 3, Day 5, Day 8, 
and Day 15) 
• Treatment Phase Visits for Cycle 2+ (Visits on Day 1, Day 8, and Day 15) 
• End of Treatment Visit (within 14 da ys of the decision to discontinue on-study 
treatment) 
• Follow-up Visit (within 28 days of last dose of USL311; may be same visit as End 
of Treatment Visit) 
• Long Term Follow-up Visits (quarterly visit or phone call until subject death or 
study termination) 
Treatment will be administered once daily in 3-week (21-day) cycles. USL311 will be 
administered as oral tablets once daily in the morning under fasted conditions for 2 hours 
before and 2 hours after the dose on Cycle 1-Days 1, 2, 8, and 15 and on Cycle 2-Day 1. For 
all other outpatient dosing days the subject should be instructed to make an effort to take the 
88 of 272


oral tablets at least 1 hour before or at least 1 hour after their meal, and they will be instructed 
to document in their diary the time of any food eaten prior to dosing and for 1 hour after dosing.  
It is recommended that subjects take their dose at the same time each day, except for visit days, 
when the dose will be held and taken during the clinic visit. If a dose is missed in the morning, 
and fewer than 12 hours have elapsed since the planned administration time, the subject should 
take the missed dose. If more than 12 hours have elapsed since the planned administration time, 
the missed dose should be skipped.  A diary will be provided to the subject to document the 
date and time of each daily dose and the time of any food eaten prior to dosing and for 1 hour 
after dosing. 
There is a total of 27 possible dose levels specified between 20 mg and 1440 mg. Dose levels 
are defined to be in approximately 15% increments, and rounded down to the nearest multiple 
of 20 in order to accommodate dosing with the available 20 mg and 100 mg strengths of the 
USL311 oral formulation. The dose levels in mg, are shown in Table 16, below: 
Table 16: 
USL311 Available Oral Doses for Dose-Escalation 
Available Doses (mg) 
20 
180 
400 
1100 
40 
200 
460 
1260 
60 
220 
520 
1440 
80 
240 
580 
 
100 
260 
660 
 
120 
280 
740 
 
140 
320 
840 
 
160 
360 
960 
 
Dose escalation will begin in the single agent oral formulation with enrollment of subjects to 
the 40 mg dose. A rationale for the selection of the starting dose and administration duration 
is provided in Section 6.1.2.1. The 20 mg dose level is a de-escalation dose level. Dose-
escalation will follow a modified continual reassessment method (mCRM) design. The dose 
escalation strategy is further described in Section 3.2.4. 
For each dose-escalation, one (1) subject will be enrolled at the new dose level and will be 
treated and observed from Cycle 1-Day 1 through Cycle 1-Day 8 for tolerance to the dose 
before additional subjects may be treated at that dose level. Details are provided in the Dose 
Escalation Management Plan. 
At each dose-escalation point, the DEC (see Section 3.2.6) will review the safety data, any 
available PK/PD data, and all other relevant subject data in order to recommend the subsequent 
dose level. Clinical judgment will always supersede the model-based recommendations for 
dose-escalation, meaning that clinical judgment can be applied to reduce the increment of dose 
escalation or elect not to dose escalate in favor of accruing more subjects at that dose level. 
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3.2.3. 
Part 2 – Dose Escalation in Solid Tumors of Combination USL311 plus 
Lomustine 
Once the MTD is determined for single agent USL311, dose-escalation of USL311 in 
combination with lomustine may begin. Subjects in Part 2 will participate in the following 
visits: 
• Screening Visit (within 28 days of Cycle 1-Day 1) 
• Treatment Phase Visits for Cycle 1 (Visits on Day 1, Day 8, Day 9, Day 15, Day 22, 
Day 29, Day 36, and Day 43) 
• Treatment Phase Visits for Cycle 2+ (Visits on Day 1, Day 2, Day 8, Day 15, Day 
22, Day 29, and Day 36) 
• End of Treatment Visit (within 14 d ays of decision to discontinue on-study 
treatment) 
• Follow-up Visit (within 28 days of last dose on USL311; may be same visit as End 
of Treatment Visit) 
• Long Term Follow-up Visits (quarterly visit or phone call until subject death or 
study termination) 
During the Treatment Phase, lomustine will be administered as a single oral dose every 7 weeks 
(during Cycle 1) and every 6 weeks for subsequent cycles (Cycle 2+) and USL311 will be 
administered as an oral tablet once daily  during Cycle 1 s tarting on Day 8 o r over the 
subsequent 6-week cycles (during Cycle 2+) starting on D ay 1. To evaluate drug-drug 
interaction potential between USL311 and lomustine, the first dose of lomustine in Cycle 1 
will be administered on Cycle 1-Day 1, one week prior to the first dose of USL311 (Day 8). 
All remaining doses of lomustine (Cycle 2+) will be administered on Day 2 of the cycle. 
USL311 will be administered daily, continuously as of Cycle 1-Day 8, with no break between 
cycles.  Subjects will be monitored by study staff for at least 4 hours after their first dose of 
USL311. 
This dose escalation for USL311 in combination with lomustine will also be conducted 
according to a mCRM model similar to that described for the single agent in Part 1. However, 
the dose range will be informed by results of USL311 as a single agent. The starting dose of 
USL311 when combined with lomustine will be at least two (2) evaluated dose levels below 
the MTD determined for USL311 as a single agent and the starting dose of lomustine will be 
90 mg/m2. A dose de-escalation for lomustine to 80 mg/m2 may occur depending on t he 
tolerability of the initial lomustine dose. If USL311 is escalated in combination with lomustine 
to the same dose level as the single agent MTD, no further escalation of USL311 will be 
allowed. However, subsequent subjects may be enrolled to evaluate dose escalation of 
lomustine up to a maximum of 130 mg/m2 in combination with USL311 (dosed at the MTD). 
The dose escalation strategy is further described in Section 3.2.4. 
For each dose-escalation, one (1) subject will be enrolled at the new dose level and will be 
treated and observed from Cycle 1-Day 1 t hrough Cycle 1-Day 15 f or tolerance to the 
combination dose before additional subjects may be treated at the dose level. Details are 
provided in the Dose Escalation Management Plan. 
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At each dose-escalation point, the DEC (see Section 3.2.6) will review the safety data, any 
available PK/PD data, and all other relevant subject data in order to recommend the subsequent 
dose level. Clinical judgment will always supersede the model-based recommendations for 
dose-escalation, meaning that clinical judgment can be applied to reduce the increment of dose 
escalation or elect not to dose escalate in favor of accruing more subjects at that dose level. 
Treatment cycles beyond Cycle 1 will be repeated every 6 weeks (42-days) until disease 
progression, unacceptable toxicity, withdrawal of consent, Investigator decision to discontinue 
treatment, or Sponsor decision to terminate the study. The MTD will be determined for 
USL311 in combination with lomustine, and all available safety, PK, and PD data will be 
reviewed by the DEC and Sponsor prior to determining the RP2D. The RP2D will be 
determined by the DEC and Sponsor after considering the safety, PK/PD, and preliminary 
efficacy outcomes and may be equal to or lower than the MTD. 
3.2.4. 
Dose-Escalation Strategy 
During Phase 1 dose escalation, subjects will receive study drug USL311 in Part 1 or USL311 
in combination with lomustine in Part 2 at increasing doses. Decisions on dose-escalation will 
be made according to the mCRM design and reviewed by the DEC as described in 
Section 3.2.6. Complete details of the mCRM model and its operating characteristics for Part 
1 are provided in Appendix 1a. An additional report containing the details of the mCRM model 
and its operating characteristics for Part 2 is described in Appendix 1b. The target dose-limiting 
toxicity (DLT) rate is 33%. The MTD will be defined as the highest safe dose, where safe is 
defined by having at least a 50% probability that the DLT rate is less than 33%. This definition 
for safety is consistent with the maximum likelihood estimate for the probability of DLT. If 
the DLT rate is estimated to be exactly 33%, the probability the DLT rate is less than 33% will 
be equal to 50%. Therefore, doses with a mean estimated DLT rate less than 33% will be 
considered safe by this definition and doses with a mean estimated DLT rate greater than 33% 
will be considered unsafe by this definition. Subjects may never be assigned to a dose that is 
considered unsafe according to this definition. 
A dose-toxicity model will be used to determine which doses are safe and to assign subjects to 
doses, i.e. to assign subjects to the highest expected safe dose. However, assignment of dose 
levels is also governed by rules concerning the speed of dose escalation and rules that 
determine whether an untried dose level may be skipped. When the dose is escalated, it may 
only escalate to the highest safe dose that is no more than a 100% increase over the current 
dose level. If the dose must be de-escalated, the dose will de-escalate to the highest safe dose 
regardless of how large a decrease in dose level. As long as no DLT has yet been observed, 
there must be complete DLT information through Cycle 1 on a t least 2 subjects in order to 
escalate. Once the first DLT is observed in the study (Part 1 and Part 2), there must be complete 
DLT information through Cycle 1 on at least 3 subjects in order to escalate. 
In the dose-toxicity model, non-DLT toxicity events (i.e. grade 2 toxicities) will inform the 
probability of DLT at each dose level. The DLT observation period, for the purpose of 
dose-escalation, is one (1) cycle. Once a subject has completed this first cycle, DLT 
observation period, the subject will be considered to have complete DLT information for the 
purposes of making dose escalation decisions for the next subject enrolling into the study (Part 
1 and Part 2). However, DLTs may also appear in later cycles. If a DLT appears at any time 
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through subsequent cycles of treatment, a subject’s DLT status and mCRM model will be 
updated to reflect the late cycle DLT. 
The first three subjects will be enrolled as a dosing cohort in Part 1 (and possibly for Part 2). 
There must be complete DLT information on these three subjects in order to enroll the 4th 
subject. Starting with the 4th subject enrolled, there will be open enrollment to the study 
meaning that subjects can be enrolled as they become available for the study, however, 
generally, there may be no more than 3 subjects enrolled in the study (Part 1 and Part 2) with 
unknown DLT information at any time. 
This study will be monitored for safety and for success in identifying the MTD. If no doses are 
safe, dose escalation will stop and no MTD will be declared. Alternatively, dose escalation 
may be stopped early when we are sufficiently confident the MTD has been identified. We 
characterize this by having either estimated the MTD with high probability, or by having a 
sufficient number of subjects with complete DLT information at and around the MTD. If the 
dose escalation is not stopped early for safety or for success in identifying the MTD it will 
continue to the maximum sample size of 40 subjects. Refer to Appendix 1b for more detailed 
information regarding the stopping rules and determination of the MTD for dose-escalation. 
No intra-subject dose-escalation will be allowed until the MTD is established, at which time 
subjects who have received at least 12 weeks of study drug(s) without evidence of progression 
may receive study drug up to the RP2D, at the discretion of the Investigator and with approval 
of the Sponsor. 
3.2.5. 
Dose-Limiting Toxicity  
A DLT will be defined as one or more of the following toxicities occurring during treatment 
during Phase 1 (Parts 1 and 2) dose-escalation. All toxicities are considered related to study 
drug (either USL311 and/or lomustine) unless the event is clearly and incontrovertibly due to 
another cause (e.g., a subject’s underlying disease). Toxicities will be graded according to the 
NCI CTCAE version 4.03.  
Hematologic Toxicity: 
• Grade 4 neutropenia lasting > 7 days in the absence of growth factor support 
• Grade 3 neutropenia of any duration associated with fever ≥ 38.5°C 
• Grade 3 thrombocytopenia with bleeding  
• Any other grade 4 hematologic toxicity 
Non-hematologic Toxicity: 
• Grade 3 nausea, vomiting, and/or diarrhea that lasts > 48 hours despite maximum 
medical support 
• Grade 3 electrolyte imbalance that does not correct within 48 hours to < grade 2 
despite maximal medical intervention 
• Grade 3 fatigue that does not improve to ≤ grade 2 within 5 days 
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• Grade 3 QTcF interval prolongation with a > 60 ms change from baseline 
− For DLT assessment based on safety ECGs, baseline is defined as the last 
ECG collected prior to the first dose of study drug.  For DLT assessment 
based on extracted ECGs, baseline is defined as the closest time-matched 
extracted ECG (triplicate average) from Cycle 1-Day -1 for Part 1 or the 
average of the Cycle 1-Day 1 ECG extractions for Part 2 
• Any other grade ≥ 3 adverse event (AE) considered possibly related to study drug(s), 
except: 
− Non-hematologic laboratory grade 3 AE that is asymptomatic and/or rapidly 
reversible (returned to baseline or to grade ≤ 1 within 7 days) unless identified 
as clinically relevant by the Investigator 
Other Toxicities: 
• Any IV dose(s) or 7 consecutive oral doses missed within Cycle 1 due to a possible 
study drug(s)-related toxicity 
• Inability to administer scheduled cycle of treatment within 21 days of the scheduled 
start of Cycle 2 due to a possible study drug(s)-related toxicity 
3.2.6. 
Dose Escalation Committee 
During dose-escalation for Phase 1 (Parts 1 and 2), the safety data, any available PK/PD data, 
and other relevant subject data will be reviewed by the DEC. The DEC will comprise, at a 
minimum, Sponsor Medical Monitor, Contract Research Organization (CRO) Medical 
Monitor and the study site Investigator(s) (or designee). Other representatives may be involved 
in data review and the dose-escalation decision, as appropriate. All dose-escalation steps and 
dose schedule and infusion duration, if applicable, recommendations will be agreed upon by 
the DEC before dosing at the next dose level or determining the MTD and RP2D. Detailed 
information is provided in the Dose Escalation Management Plan. 
3.3. 
Phase 2 – Dose-Expansion in Relapsed/Recurrent GBM 
Dose-expansion components will 1) assess safety, PK/PD and efficacy of USL311 as a single 
agent in subjects with relapsed/recurrent GBM eligible for re-resection (Part 3), and 2) assess 
safety, PK/PD and efficacy of the combination of USL311 with lomustine in subjects with 
relapsed/recurrent GBM eligible for re-resection (Part 4). 
The dose-expansion component will determine the PFS-6m of single-agent USL311 (Part 3) 
and of USL311 in combination with lomustine (Part 4). 
 
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3.3.1. 
Part 3 – Dose-Expansion in GBM of Single Agent USL311 
Once the RP2D of single agent USL311 has been determined by the DEC and Sponsor, Part 3 
will assess preliminary efficacy of single agent USL311. Subjects in Part 3 will participate in 
the following visits:  
• Screening Visit (within 28 days of Pre-surgical Dosing, Day 1 for those randomized 
to pre-surgical treatment and within 28 days of Surgery for those randomized to no 
pre-surgical treatment) 
• Pre-surgical Dosing Phase Visits (Visits on Day 1, Day 2, Day 3, Day 5, and Day 8+ 
only for those randomized to pre-surgical treatment)  
• Surgery (after one to three weeks of treatment during Pre-surgical Dosing for those 
randomized to pre-surgical treatment; following screening for those randomized to 
no pre-surgical treatment)  
• Post-surgical Treatment Phase Visits for Cycle 1 (Visits on Day 1, Day 2, Day 8, 
and Day 15)  
• Post-surgical Treatment Phase Visits for Cycle 2+ (Visits on Day 1, Day 8, and 
Day 15) 
• End of Treatment Visit (within 14 d ays of decision to discontinue on-study 
treatment) 
• Follow-up Visit (within 28 days of last dose on USL311; may be same visit as End 
of Treatment Visit)  
• Long Term Follow-up Visits (quarterly visit or phone call until subject death or 
study termination) 
Approximately 20 subjects with relapsed/recurrent GBM, who are candidates for re-resection, 
will be enrolled. Subjects will be randomized to receive either once daily oral pre-surgical 
treatment with USL311 or no USL311 treatment prior to surgery (see Section 6.2). Subjects 
randomized to receive pre-surgical treatment with USL311 are required to receive at least one 
week of treatment prior to surgery, and may receive up to a maximum of three weeks of 
treatement prior to surgery at the single agent USL311 RP2D defined in Part 1. The length of 
treatment will depend on the surgery date. Scheduling of the surgery, as part of standard-of-
care, should not be delayed due to the pre-surgical treatment. Following surgery, all subjects 
(including those randomized to no pre-surgical treatment) will initiate treatment with once 
daily, oral USL311 within 28 days post-surgery, although treatment delays may be considered 
based upon discussions between Sponsor or designee and Investigator. Subjects must have 
fully recovered from surgery, including surgical wound healing, prior to initiating therapy. 
USL311 will be administered once daily during every 3-week (21-day) Cycle with no breaks 
between cycles. Subjects will be monitored by study staff for at least 4 hours after 
administration of their first dose of USL311. Treatment Cycles will be repeated every 3 weeks 
(21 days) until disease progression, unacceptable toxicity, withdrawal of consent, Investigator 
decision to discontinue treatment, or Sponsor decision to terminate the study.  
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Exploratory (translational) studies will be performed on resected tissue following surgery to 
determine biodistribution of USL311 in the tumor and to assess PD markers (see 
Section 8.7.2). 
3.3.2. 
Part 4 – Dose Expansion in GBM of USL311 in Combination with Lomustine 
Once RP2D of USL311 in combination with lomustine has been determined by the DEC and 
Sponsor, Part 4 will assess preliminary efficacy of the combination. Subjects in Part 4 will 
participate in the following visits:  
• Screening Visit (within 28 days of Pre-surgical Treatment Dosing, Day 1 for those 
randomized to pre-surgical treatment and within 28 da ys of Surgery for those 
randomized to no pre-surgical treatment)  
• Pre-surgical Dosing Phase Visits (Visits on Day 1, Day 2, Day 3, Day 5, and Day 8+; 
only for those randomized to pre-surgical treatment) 
• Surgery (between ≥ 24 hours and < 8 days after the last dose administered during 
Pre-surgical Dosing for those randomized to pre-surgical treatment; following 
screening for those randomized to no pre-surgical treatment)  
• Post-surgical Treatment Phase Visits for Cycle 1 (Visits on Day 1, Day 2, Day 8, 
Day 15, Day 22, Day 29, and Day 36) 
• Post-surgical Treatment Phase Visits for Cycle 2+ (Visits on Day 1, Day 2, Day 8, 
Day 15, Day, 22, Day 29, and Day 36) 
• End of Treatment Visit (within 14 d ays of decision to discontinue on-study 
treatment) 
• Follow-up Visit (within 28 days of last dose on USL311; may be same visit as End 
of Treatment Visit)  
• Long Term Follow-up Visits (quarterly visit or phone call until subject death or 
study termination) 
Approximately 20 subjects with relapsed/recurrent GBM, and who are candidates for 
re-resection, will be enrolled. Subjects will be randomized to receive once daily oral pre-
surgical treatment with USL311 or no USL311 treatment prior to surgery (see Section 6.2). 
Subjects randomized to receive pre-surgical treatment are required to receive at least one week 
of treatment of USL311 (at the RP2D defined in Part 2) prior to surgery, and may receive up 
to a maximum of three weeks of treatment prior to surgery at the USL311 RP2D defined in 
Part 2. The length of treatment received will depend on the surgery date. Scheduling of the 
surgery, as part of standard-of-care, should not be delayed due to the pre-surgical treatment. 
Following surgery, all subjects (including those randomized to no pre-surgical treatment) will 
initiate treatment with once daily, oral USL311 in combination with lomustine within 28 days 
post-surgery, although treatment delays may be considered based upon discussions between 
Sponsor or designee and Investigator. Subjects must have fully recovered from surgery, 
including surgical wound healing, prior to initiating therapy. USL311 will be administered 
daily during  every 6-week (42-day) cycle, with no breaks between cycles. Lomustine will be 
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administered on Day 2 of every 6-week (42-day) cycle. Subjects will be monitored by study 
staff for at least 4 hours after administration of their first dose of USL311. Treatment cycles 
will be repeated every 42 days until disease progression, unacceptable toxicity, withdrawal of 
consent, Investigator decision to discontinue treatment, or Sponsor decision to terminate the 
study. 
Exploratory (translational) studies will be performed on resected tissue following surgery to 
determine biodistribution of USL311 in the tumor and to assess PD markers 
(see Section 8.7.2). 
3.3.3. 
Surgical Re-Resection 
During Part 3 and Part 4, s ubjects with relapsed/recurrent GBM will have a surgical 
re-resection of the tumor performed as part of their standard-of-care treatment per the 
Investigator’s discretion. Subjects will complete the surgery following the investigational 
site’s surgical procedures. During surgery, a CSF sample (see Section 8.6.2) and tumor tissue 
sample (see Section 8.7.2) will be collected and stored according to instructions in the lab 
manual. Participation in Part 3 and Part 4 will not influence the area of surgical re-resection or 
the amount of tumor resected, as these will be determined by the Investigator as a component 
of their standard-of-care treatment. 
The subject will be informed in the consent form about the reason for collecting samples and 
how the samples will be obtained and stored. Any data obtained from analysis of tumor tissue 
or CSF samples will be used for translational research, and subject confidentiality will be 
preserved internally and in any presentations or publications. 
A baseline response assessment using the RANO criteria will be performed ≤ 72 hours after 
surgery. If initiation of treatment following surgery is delayed for 3-4 weeks, a repeat baseline 
response assessment using the RANO criteria will be performed ≤ 7 days prior to study drug(s) 
dosing. Following surgery, all subjects will subsequently receive single agent USL311 (Part 
3) or USL311 in combination with lomustine (Part 4) within 28 days (4 weeks), although 
treatment delays may be considered based upon discussions between Sponsor or designee and 
Investigator. Subjects must have fully recovered from surgery, including surgical wound 
healing, prior to initiating therapy. 
3.4. 
End of Study 
The definition for the end of the study is the time of data cutoff for the final analysis or the 
time of last subject/last visit, whichever occurs later. The end of the study will be reached after 
all subjects have received 6 months of treatment or have discontinued.  
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4. 
RATIONALE 
4.1. 
Rationale for Study 
The improvement of treatment for relapsed/recurrent GBM remains a significant unmet 
medical need as there are currently limited options for patients with relapsed/recurrent GBM. 
One potential target for treatment of GBM, as well as other solid tumor types, is the chemokine 
receptor, CXCR4. CXCR4 is overexpressed in a wide range of solid tumors, including GBM, 
and overexpression appears to be a negative prognostic factor for overall survival (27, 28). 
Examples of these tumor types in which CXCR4 overexpression is correlated with a poor 
prognosis include, but are not limited to, GBM (29), renal cell carcinoma (30), hepatocellular 
carcinoma (31), colorectal cancer (32), non-small cell lung cancer (33, 34), breast cancer (35), 
esophageal cancer (36) and prostate cancer (37). 
Additionally, several studies have demonstrated the existence of CSCs for a variety of different 
tumor types which constitute a reservoir of self-sustaining tumor cells with the ability to 
maintain tumor growth. Many of these cells express CXCR4 and respond to SDF-1, suggesting 
that CSCs represent a subpopulation capable of initiating metastasis in response to CXCR4 
activation (24). As the CXCR4 receptor and its chemokine ligand SDF-1 have roles in tumor 
growth and metastasis, antagonism of the SDF-1/CXCR4 signaling pathway is expected to 
inhibit migration and self-renewal of CSCs while also rendering these cells more sensitive to 
concurrent therapies. 
These data from the literature provide the rationale for investigating USL311 as a potential 
anticancer agent for the treatment of solid tumors, including GBM. 
4.2. 
Rationale for Study Design 
Dose-escalation using a mCRM design in subjects with advanced solid tumors is a standard 
method in the early phase clinical development of novel anticancer treatment. Subjects with 
advanced solid tumors are those for which no standard-of-care treatment is recognized or who 
have failed or are intolerant to the standard-of-care treatment will participate in the dose 
escalation portion of the study. Dose escalation will allow for the identification of the MTD 
and RP2D of single agent USL311 (Part 1) and the identification of the MTD and RP2D of 
USL311 in combination with lomustine. 
Dose expansion will allow a more robust investigation of the preliminary efficacy as well as 
the safety, PK and PD of study drug USL311 alone, and in combination with lomustine, in the 
target population of relapsed/recurrent GBM. 
Surgical re-resection is performed as part of standard-of-care for select GBM patients. The 
pre-surgical study design was employed in a recent study in which patients with GBM 
requiring tumor re-resection for recurrent disease received preoperative lapatinib (48). 
Lapatinib concentrations and epidermal growth factor receptor (EGFR) phosphorylation were 
then assessed in surgical specimens. A similar study design was used to evaluate the efficacy, 
PK and PD of effects of cilengitide (49). In this study, subjects were initially randomized to 
cilengitide treatment or no treatment for the pre-surgical period of the study, and all subjects 
continued treatment post-surgery until progressive disease. The study design involving 
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surgical re-resection as part of the evaluation of USL311 allows for the evaluation of both PK 
and PD markers in the targeted brain tissue.  
Additionally, surgery at progression does not appear to be a prognostic marker for improved 
PFS-6m or OS for patients with relapsed/recurrent GBM (50); thus, PFS-6m results reported 
in this study would depend on effects from study drug(s) administration and not from the 
surgical procedure. Furthermore, USL311 does not affect wound healing in animal models; 
therefore, patients who have recently undergone surgery should not exhibit delayed healing. 
4.3. 
Rationale of Study Population 
Subjects with advanced solid tumors for which no standard-of-care treatment is recognized or 
who have failed or are intolerant to the standard-of-care treatment, will be selected to 
participate in the Phase 1 dose-escalation portion of this study. This population commonly 
participates in Phase 1 dose-escalation oncology studies to determine the RP2D. Subjects with 
advanced solid tumors commonly participate in studies with single agent  study drug and in 
studies with a combination of agents for both  study drug and currently approved agents. Due 
to the mechanism of action for USL311 it is possible many different types of solid tumors may 
experience therapeutic benefit from treatment. 
Adult subjects with relapsed/recurrent GBM eligible for re-resection will participate in the 
Phase 2 dose-expansion portion of this study. Relapsed/recurrent GBM subjects are the target 
population for single agent USL311 and USL311 in combination with lomustine. Due to the 
mechanism of action and CNS penetration of USL311, GBM patients are expected to 
experience therapeutic benefit as described in Section 4.4. 
4.4. 
Rationale for Study Treatment 
The study drug  is USL311, a CXCR4 antagonist under investigation for the treatment of 
relapsed/recurrent GBM. Evidence from the literature suggests possible efficacy of CXCR4 
antagonists for the treatment of GBM. Additionally, evidence from the non-clinical studies 
suggest possible efficacy of USL311 for the treatment of GBM. Rationale for the 
recommended starting dose and administration is provided in Section 6.1.2. USL311 is a 
CXCR4 antagonist that has demonstrated nonclinical efficacy in both in vitro and in vivo 
models when administered in combination with cytotoxics, anti-angiogenics and/or radiation. 
Specifically, in the murine models, single agent USL311 has demonstrated CXCR4 blockade 
which resulted in delayed progression of xenograft tumors derived from GBM-based cell lines, 
and has demonstrated the ability to delay tumor regrowth in combination with chemotherapy 
and radiotherapy. Notably, USL311 demonstrates extensive uptake in a range of tissues and 
crosses the blood-brain barrier, making it suitable for the treatment of CNS malignancies, 
including GBM. The extensive tissue uptake is attributed in part to “lysosomal trapping” of 
USL311, which may also contribute to USL311’s putative anti-cancer effect through inhibition 
of autophagy, a homeostatic cellular recycling process which is disrupted by other 
lysosomotropic drugs leading to enhanced tumor cell death (see Section 1.2.3.1). 
Lomustine is the selected combination agent for the clinical development of USL311. 
Lomustine, a cytotoxic drug, is a nitrosourea used in the treatment of certain oncologic 
conditions and functions as an alkylating agent. Although lomustine is primarily used in brain 
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tumors (both primary and metastatic) and Hodgkin’s disease, it has also been used or under 
investigation for use in the second or third line setting, in combination with other therapeutics, 
in a number of other cancers including; lung cancer, multiple melanoma, colorectal cancer, 
liver cancer and advanced breast cancer. Lomustine is commonly used in recurrent GBM and 
has also been used as the comparator in recent registration-directed trials in this setting. 
Lomustine is an acceptable choice of chemotherapy to combine with USL311 given that it has 
shown improved median and 6-month PFS as monotherapy for relapsed/recurrent GBM 
compared to historical controls and has been combined with other novel agents in 
relapsed/recurrent GBM (20, 21). 
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5. 
SUBJECT POPULATION 
During Phase 1 dose-escalation, the study population will be subjects with advanced solid 
tumors for which no s tandard-of-care treatment is recognized or who have failed or are 
intolerant to the standard-of-care treatment.  
During Phase 2 dose-expansion the study population will be subjects with relapsed/recurrent 
GBM whom are candidates for re-resection, having previously received definitive first line 
treatment. 
5.1. 
Number of Subjects 
The total number of subjects will depend on the number of dose levels assessed in Phase 1 
(Parts 1a/1b and 2). It is expected that approximately 6-40 subjects with advanced solid tumors 
be enrolled for Part 1b single agent USL311 dose-escalation and approximately an additional 
6-40 subjects with advanced solid tumors be enrolled for Part 2 USL311 in combination with 
lomustine dose-escalation. It is expected that approximately 20 subjects with 
relapsed/recurrent GBM will be enrolled for each Phase 2 (Parts 3 and 4) dose-expansion 
cohort, with a total of approximately 40 subjects. A total of 13 subjects were enrolled in Part 
1a with IV USL311. The total number of subjects for Phase 1 and 2 combined is expected to 
be approximately 65-133 subjects. 
5.2. 
Eligibility Criteria 
Questions about eligibility criteria should be addressed prior to enrollment. The eligibility 
criteria for this study have been carefully considered. Eligibility criteria are standards used to 
ensure that subjects who enter this study are medically appropriate candidates for this therapy. 
For the safety of the subjects, as well as to ensure that the results of this study can be useful 
for making treatment decisions regarding other patients with similar diseases, there will be no 
exceptions to eligibility requirements at screening. 
5.2.1. 
Inclusion Criteria 
Individuals eligible to participate in this study must meet all of the following criteria: 
Criteria for both Phase 1 dose-escalation and Phase 2 dose-expansion: 
1. Provide signed and dated informed consent prior to study-specific screening procedures  
2. ≥ 18 years old 
3. Karnofsky performance status (KPS) ≥ 70  
4. Must have adequate bone marrow and renal/hepatic function at the Screening Visit and 
at Baseline, defined as: 
a. ANC ≥ 1,500/mm3 without granulocyte colony-stimulating factor (G-CSF) support 
within 7 days preceding the lab assessment 
b. Platelet count ≥ 100,000/mm3, without transfusion within 7 days preceding the lab 
assessment 
c. Hgb ≥ 9 g/dL, without transfusion support within 7 da ys preceding the lab 
assessment 
 
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d. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 3 times 
upper limit of normal (ULN) 
e. Total serum bilirubin ≤ 1.5 times ULN, except in subjects with known Gilbert’s 
Syndrome ≤ 3 times ULN  
f. Serum creatinine ≤ 1.5 times ULN with an estimated creatinine clearance of 
≥ 60 mL/min (calculated by the Cockcroft-Gault equation), or creatinine clearance 
corrected for body surface area (BSA) ≥ 60 mL/min/1.73 m2 (determined from 24-
hour urine collection) per Investigator discretion 
g. Activated partial thromboplastin time/partial thromboplastin time (aPTT/PTT) and 
prothrombin time (PT) ≤ 1.5 ULN 
h. Baseline potassium, sodium, calcium (corrected for albumin) and magnesium 
levels within normal limits, or above the ULN if considered not clinically 
significant per the Investigator. Baseline potassium, sodium, calcium (corrected for 
albumin) and magnesium levels below lower limit of normal must be corrected to 
within the normal range, or above the ULN if considered not clinically significant 
per the Investigator, by supplementation prior to starting study drug(s). 
5. Disease-free period of > 2 years from any other previous malignancies, excluding 
curatively treated basal cell carcinoma, squamous cell carcinoma of the skin, or 
carcinoma in situ of the cervix. Subjects with prostate cancer Stage 1 that do not require 
treatment may also be included. 
6. Women of childbearing potential (WOCBP) must have two negative pregnancy tests, the 
first during Screening and the second within 24 hours prior to first administration of study 
drug(s) and must agree to use highly effective physician-approved contraception (see 
Appendix 2) from Screening to 90 days following the last study drug administration. 
Male subjects must be surgically sterile or must agree to use highly effective 
physician-approved contraception from Screening to 90 days following the last study 
drug administration (a barrier method of contraception must be employed by all subjects 
[male and female], when having sexual intercourse, regardless of other methods) 
a. Females are considered not of childbearing potential if they meet any of the 
following criteria: 
• Postmenopausal with > 1 year since last menses and: 
− If younger than 65 years old, with a FSH > 40 mIU/mL 
− If ≥ 65 years old and not on HRT, with a FSH > 30 mIU/mL 
− If ≥ 65 years old and on H RT, the FSH requirement in not applicable. 
Postmenopausal females on HRT will be allowed if the treatment is stable 
for at least 6 months prior to dosing of study drug(s) 
• Written medical documentation of being sterilized (e.g. hysterectomy, double 
oophorectomy, bilateral salpingectomy). Note: Tubal ligation is not considered 
a form of permanent sterilization. 
7. Must be able and willing to comply with the study visit schedule and study procedures 
8. Must be able to take oral medications 
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9. Must have available archived tumor tissue and be willing and able to provide consent for 
study access to such tissue 
10. For subjects with a history of seizures, must be adequately controlled on a stable regimen 
of anti-epileptic drugs 
Criteria for Phase 1 only, dose-escalation in advanced solid tumors: 
11. Histologically or cytologically documented diagnosis of solid tumor for which no 
standard therapy is recognized or have failed or intolerant to the standard-of-care 
treatment 
12. Inoperable metastatic or locally advanced, unresectable disease 
13. Subjects must have either evaluable or measurable disease 
14. Subjects with treated (surgically excised or irradiated) and stable brain metastases are 
eligible as long as the subject has adequately recovered from treatment and the treatment 
was ≥ 28 days prior to initiation of study drug(s) and baseline brain computed 
tomography (CT) with contrast or magnetic resonance imaging (MRI) ≤ 14 days of 
initiation of study drug is negative for new brain metastases.  
Criteria for Phase 2 only, dose-expansion in relapsed/recurrent GBM: 
15. Histologically confirmed diagnosis of GBM  
16. Subjects must have documented recurrence after first-line treatment  
17. Prior first-line treatment must have included radiation and temozolomide 
18. Subject is suitable for re-resection, per Investigator discretion, as a component of their 
clinical care 
19. No more than one prior resection (Note: biopsy does not count as prior resection) 
5.2.2. 
Exclusion Criteria 
Individuals who meet any of the following exclusion criteria will not be eligible to participate 
in the study: 
1. Subjects who have had recent systemic anticancer therapies, interventional device 
treatment and/or radiotherapy either within 14 days prior to first dose of study drug(s) or 
have not recovered (to grade ≤ 1) from all clinically significant toxicities related to prior 
therapies 
2. Subjects who have had any major surgery (not including re-resection surgery required in 
Phase 2) within 28 days prior to first dose of study drug(s), or minor surgery within 
14 days prior to first day of study drug(s)  
3. For 14 days prior to first day of study drug(s) treatment, administration of any strong 
cytochrome P450 3A4 (CYP3A4) inducers including, but not limited to, the following: 
carbamazepine, ethotoin, mephenytoin, phenobarbital, phenytoin, primidone, rifabutin, 
rifampin, and St. John’s Wort 
 
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4. For 14 days prior to the first day of study drug(s) treatment, administration of any strong 
cytochrome P450 3A4 (CYP3A4) inhibitors including, but not limited to, the following: 
amprenavir, ataznavir, boceprevir, clarithromycin, conivaptan, fosamprenavir, indinavir, 
itraconazole, ketoconazole, lopinavir, nefazodone, posaconazole, ritonavir, saquinavir, 
telaprevir, telithromycin, and voriconazole 
5. For 14 days prior to first dose of study drug(s) treatment, administration of any agent 
with moderate-to-high risk to prolong the QTc interval or to cause Torsades de Pointes 
(see Appendix 3) 
6. Subjects who have been treated with an investigational agent or investigational 
interventional device within 21 days prior to the first dose of study drug(s) 
7. Subject is growth factor dependent or transfusion dependent, or has received growth 
factor support or transfusion support within 14 days prior to the first dose of study drug(s) 
8. History of significant cardiac disease. Significant cardiac disease includes the following: 
a. Second/third degree heart block  
b. Significant ischemic heart (e.g. myocardial infarction, unstable angina, Grade 3 or 
4 [Canadian Cardiovascular Society] angina, hospitalization for ischemic heart 
disease) within 2 years of first dose of study drug(s) 
c. Family history of long QT syndrome; mean Fridericia corrected QT interval (QTcF) 
> 450 msec on at least two separate ECGs prior to study start 
d. Poorly controlled hypertension per Investigator opinion  
e. Congestive heart failure of NYHA Class II or worse (slight limitation of physical 
activity; comfortable at rest, but ordinary physical activity results in fatigue, 
palpitation, or dyspnea) 
9. Episode of status epilepticus within 1 year prior to the first dose of study drug(s) 
10. Pregnant or breastfeeding  
11. Any other significant co-morbid conditions that in the opinion of the Investigator would 
impair study participation or cooperation, including known or suspected history of 
significant allergic reaction or hypersensitivity to any components of the USL311 
formulation 
Criteria for Phase 1 only, dose-escalation in advanced solid tumors 
12. Subjects with lymphoma as primary cancer 
Criteria for Phase 2 only, dose expansion in relapsed/recurrent GBM: 
13. Subjects unable or unwilling to consent to the provision of resected tissue after surgery 
14. Prior treatment with plerixafor or another CXCR4 inhibitor 
15. Prior treatment with bevacizumab 
16. Prior treatment with lomustine and/or carmustine 
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5.3. 
Prior and Concomitant Medications 
All prescription and over-the-counter medications taken by a subject from 28 days prior to the 
first dose of study drug(s) until the Follow-up Visit will be recorded on the designated 
electronic case report form (eCRF). The Investigator may prescribe additional medications 
during the study, as long as the prescribed medication is not prohibited by the protocol. In the 
event of an emergency, any required medications may be prescribed without prior approval, 
but the Medical Monitor or designee must be notified of the use of any prohibited medications 
immediately thereafter. Any concomitant medications changed, added or discontinued during 
the study should be recorded on the eCRF, including the indication and the start and end dates 
of treatment, as applicable. 
5.3.1. 
Permitted Medications 
All supportive therapy for optimal medical care will be given during the study period at the 
discretion of the Investigator(s) within the parameters of the protocol and documented as 
concomitant medications on the designated eCRF. The following medications are permitted, 
per Investigator discretion, but may have limitations in place during the duration of the study. 
• Anticonvulsants: Anticonvulsants may be used as clinically indicated. Doses at 
study entry and at specific time points of the treatment must be recorded. Note: The 
use of enzyme inducing antiepileptic drugs (EIAEDs) are not permitted. 
• Antiemetics: Use of prophylactic oral antiemetics should be used consistent with 
ASCO guidelines (51) or other institutional practice guidelines. Use of antiemetics 
with known QTc prolongation potential are not permitted during the study. Only the 
antiemetic agents listed below are permitted: 
− Granisetron, palonosetron, aprepitant, fosaprepitant, dexamethasone, and 
lorazepam 
• Anticoagulants: Prophylactic therapy with aspirin, a low-molecular weight heparin, 
or a Factor Xa inhibitor is acceptable. Warfarin and dabigatran are not permitted. 
• Corticosteroids: Corticosteroids may be used as clinically indicated. Doses at study 
entry and at specific time points of the treatment must be recorded. 
Note: Documentation of corticosteroid use is important for evaluation of response 
using the RANO criteria (see Appendix 6). 
• Electrolyte Replacement Therapy: Electrolyte replacement administered should 
stabilize the subject within the normal range, or above the ULN if considered not 
clinically significant per the Investigator, prior to dosing of study drug(s).  
• Hematopoietic Growth Factors: Erythrocyte growth factors (e.g. erythropoietin) are 
not to be administered prophylactically but may be prescribed per institutional 
guidelines for anemia if this is deemed appropriate by the Investigator. Transfusions 
are also permitted. Granulocyte growth factors (e.g., G-CSF and GM-CSF) are not 
to be administered prophylactically but may be prescribed by the Investigator for 
severe neutropenia if this is deemed appropriate. However, study drug(s) should be 
held for at least 24 hours after the expected duration of activity for any granulocyte 
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growth factors. The administration of granulocyte growth factors should be 
consistent with ASCO guidelines (52). 
• Systemic Anesthetics: Systemic anesthetics are permitted but should not be given 
within 24 hours of USL311. USL311 may decrease the effectiveness (i.e., higher 
doses of the anesthetic may be required) of systemic anesthetics when used within 
24 hours of the infusion. The Medical Monitor should be informed if systemic 
anesthetics are to be administered outside of the surgical re-resection required for 
Phase 2. 
• Low Risk QTc Interval Prolonging Agents: Medications with low risk to prolong 
the QTc interval may be used at the discretion of the Investigator.  
5.3.2. 
Prohibited Medications 
The following medications are prohibited during the duration of the study: 
• Other Anticancer Agents: Subjects may not receive any other anticancer therapies 
while on s tudy prior to disease progression. This includes systemic anticancer 
(both cytotoxic and non-cytotoxic) therapies, interventional devices, and 
radiotherapy. 
• CYP3A4 Strong Inhibitors and Inducers: Subjects may not receive any substances 
which are known strong inducers or inhibitors of CYP3A4 (see Table 17), including 
drugs, herbs, and nutritional supplements, as they may alter the PK of USL311. If 
the subject is taking any of these restricted substances at the time of screening, the 
time between the last dose of that substance and study drug(s) administration must 
be at least 14 days. 
Table 17: 
Prohibited Cytochrome P450 Enzyme Interaction Medications 
Cytochrome P450 Enzyme 
Medication Name 
Strong CYP3A4 Inducers  
carbamazepine, ethotoin, mephenytoin, phenobarbital, phenytoin, 
primidone, rifabutin, rifampin, and St. John’s Wort 
Strong CYP3A4 Inhibitors 
amprenavir, ataznavir, boceprevir, clarithromycin, conivaptan, 
fosamprenavir, indinavir, itraconazole, ketoconazole, lopinavir, 
nefazodone, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, 
and voriconazole 
 
• Moderate-to-High Risk QTc Interval Prolonging Agents: Subjects may not receive 
any medication with a known moderate-to-high probability of prolonging the QTc 
interval or to cause Torsades de Pointes (see Appendix 3). If the subject is taking 
any of the restricted medications at the time of screening, the time between the last 
dose of the medication and study drug(s) administration must be at least 14 days. If 
one of these medications needs to be administered during the study (i.e., an antibiotic 
with moderate-to-high QTc interval prolongation risk), the Medical Monitor must 
be contacted before initiating treatment with the restricted medication and attempts 
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should be made to avoid administration within 24 hours after the administration of 
USL311.  
• Gastric acid lowering agents – For subjects receiving oral USL311 only: subjects 
should try to limit ta king antacids within 1 hour  prior to or after USL311 
administration. If a patient is taking a histamine type 2 antagonist or a proton pump 
inhibitor, it is preferable the subject take the medication at least 1 hour after USL311 
administration. 
• Other Investigational Agent: No other investigational agent (medication or device) 
may be used during the duration of the study. 
5.4. 
Dietary and Other Protocol Restrictions 
There are dietaryrestrictions during the course of this study. 
For subjects receiving oral USL311 only: 
In Parts 1b, 2, 3 and 4, USL311 will be administered as oral tablets once daily in the morning 
under fasted conditions for 2 hours before and 2 hours after the dose on PK sampling days.  
For all other outpatient dosing days the subject should be instructed to make an effort to take 
the oral tablets at least 1 hour before or at least 1 hour after their meal, and they will be 
instructed to document in their diary the time of any food eaten prior to dosing and for 1 hour 
after dosing. 
5.5. 
Subject Withdrawal or Discontinuation 
Subjects may withdraw their consent to participate in the study at any time without prejudice. 
The Investigator must withdraw any subject who requests to be withdrawn. A subject’s 
participation in the study may be discontinued at any time at the discretion of the Investigator 
and in accordance with his/her clinical judgment. 
The Sponsor must be notified of all subject withdrawals as soon as possible. The Sponsor also 
reserves the right to discontinue the study at any time for either clinical or administrative 
reasons and to discontinue participation by an individual Investigator or site for poor 
enrollment or noncompliance. 
Reasons for which the Investigator or Sponsor may withdraw administration of study drug 
include, but are not limited to, the following: 
• Subject experiences a serious or intolerable AE or clinically significant laboratory 
abnormality  
• Subject requires medication or medical procedure prohibited by the protocol  
• Subject does not adhere to study requirements specified in the protocol 
• Subject was erroneously admitted into the study or does not meet entry criteria 
• Subject is lost to follow-up 
• Subject enrolls in a different clinical study 
 
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• Subject becomes pregnant (see Section 9.3.3 for details on the reporting procedures 
to follow in the event of pregnancy) 
• Subjects may be removed from study if considered by the Investigator or Sponsor 
to be in the best interest of the subject  
For subjects who withdraw, procedures and assessments for the End of Treatment Visit 
(see Section 7.3) should be performed (unless the subject withdraws consent to do so). If the 
subject withdraws consent, this request must be documented in the study records, and signed 
by the Investigator. At this time, the subject will be asked if he/she agrees to be followed-up 
for collection of survival information. This agreement must be documented in the study records 
and signed by the Investigator. The study staff may also use a public information source (e.g., 
county records) to obtain information about survival status. 
If a subject fails to return for scheduled visits, a documented effort must be made to determine 
the reason. Additionally, a documented effort must be made to request for follow-up survival 
information. If the subject cannot be reached by telephone, a certified letter should be sent to 
the subject requesting contact with the Investigator. This information should be recorded in the 
study records.  
The Investigator or designee must explain to each subject, before enrollment into the study, 
that for the evaluation of study results, the subject’s protected health information obtained 
during the study may be shared with the study Sponsor, regulatory agencies, and IRB/IEC. It 
is the Investigator’s (or designee’s) responsibility to obtain written permission to use protected 
health information per country-specific regulations, such as the Health Insurance Portability 
and Accountability Act (HIPAA) in the US, from each subject. If permission to use protected 
health information is withdrawn, it is  the Investigator’s responsibility to obtain a written 
request, to ensure that no further data will be collected from the subject and the subject will be 
removed from the study. 
5.6. 
Subject Identification and Replacement of Subjects 
Subjects in Phase 1 (Parts 1 and 2 dose-escalation) who discontinue the study before they have 
completed the first cycle of treatment for reasons other than toxicity will be replaced. A subject 
must meet one of the following criteria to be evaluable for cohort DLT/MTD/dose-escalation 
decisions:  
• Received all 3 scheduled infusions or received ≥ 16 of 21 daily oral doses of single 
agent USL311 during Cycle 1, has completed Cycle 1-Day 21 and has not 
experienced a DLT (Part 1)  
• Received all of the 6 scheduled infusions or received ≥ 32 of 42 daily oral doses of 
USL311 as well as the Cycle 1 lomustine dose, has completed Cycle 1-Day 49 and 
has not experienced a DLT (Part 2) 
• Experienced a DLT 
• Withdrew from the study prior to completing Cycle 1 due to an AE considered by 
the investigator to be at least possibly related to study drug(s)  
 
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If a subject does not meet any of these criteria, the subject is not evaluable for dose-escalation 
decisions and will be replaced. 
In Phase 2, all subjects will be treated until progression or another withdrawal criterion is met 
(see Section 5.5). Subjects will be enrolled to have approximately 20 evaluable subjects in Part 
3 and 20 evaluable subjects in Part 4. 
5.7. 
Duration of Subject Participation 
The duration of each subject’s participation will be variable. Subjects who tolerate Cycle 1 
treatment and do not have progressive disease, treatment failure or relapse are eligible to 
continue to receive treatment until they experience unacceptable toxicity, disease progression, 
meet any of the withdrawal criteria, or the study is terminated by the Sponsor. Subjects 
removed from the study for unacceptable AEs will be followed until AE resolution (return to 
normal or baseline) or the subject’s condition has stabilized to the satisfaction of the 
Investigator. Additionally, subjects will be followed quarterly (every 3 months ± 1 week) 
according to the criteria defined in Section 7.4. 
5.8. 
Informed Consent 
Each prospective subject will provide written informed consent before any screening 
evaluations or other study procedures are performed. 
Informed consent will be given by means of a standard statement, written in non-technical 
language, which explains the nature of the study, its purpose, procedures, expected duration, 
alternative therapy available, the benefits and risks involved in study participation, and any 
discomfort study participation may entail. The Investigator or his/her designee must emphasize 
to the subject that study participation is entirely voluntary and that consent regarding study 
participation may be withdrawn at any time without penalty or loss of benefits to which the 
subject is otherwise entitled or affecting subsequent medical treatment or relationship with the 
treating physician. 
The subject will read and consider the statement and be allowed to ask any questions before 
signing and dating it, and he/she should be given a copy of the signed and dated document. 
The person conducting the informed consent discussions must personally date and sign the 
ICF. The Investigator will retain the original signed ICF. 
Some subjects will provide written consent in the form of an assent form before any screening 
evaluation or other study procedure is performed, if required by local law or IRB/IEC policy. 
The assent form will provide similar information as the informed consent form, and the same 
procedures will be followed as described above for the informed consent form. The assent form 
must be signed and dated by the subject and the qualified research professional obtaining the 
assent. 
No subject can enter the study and no s tudy-specific procedures can be performed before 
informed consent has been obtained. 
Prior to consenting subjects, the Investigator or designee must submit the informed consent 
form with the study protocol for IRB/IEC approval. All proposed informed consent forms must 
be reviewed and approved by the Sponsor or its designee before submission to the IRB/IEC. 
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All informed consent and assent forms will be reviewed by the IRB/IEC and approved (IRB) 
or a favorable opinion received (IEC) before use in this study. Informed consent will be 
obtained in a manner consistent with Good Clinical Practice (GCP)/International Conference 
on Harmonization (ICH). A copy of the approved version must be provided to the Sponsor or 
the study monitor after IRB approval/IEC favorable opinion. 
5.9. 
Authorization to Use and Disclose Medical Information 
Each subject will be identified by initials (3 letters) and a unique subject number. In countries 
where the subjects’ initials cannot be used by local regulations, study centers will use dummy 
initials. 
All countries must follow local law(s) for authorization to use and disclose medical 
information. 
Information obtained from standard-of-care procedures, including those performed prior to the 
subject signing the informed consent, that occur within the protocol-defined windows (e.g., 
Screening window) may be obtained and utilized when applicable. 
The remainder of this section only applies to study centers in the United States. 
Under US federal law, subject study records cannot be used or disclosed for research purposes 
unless an authorization to use and disclose medical information is signed by each subject prior 
to participation in the study. The Investigator or designated assistant will explain to each 
subject the purpose of the subject authorization and the disclosures agreed to by signing the 
authorization document. Subjects will be given an authorization document and will have the 
opportunity to ask questions. Subjects must also be informed of the following: 
• They may not participate in the study unless the authorization is signed; however, 
they have the right to revoke this authorization (in writing) at any time 
• If they discontinue from the study, they are not required to revoke the authorization 
to use and disclose their medical information 
• If they discontinue from the study and do decide to revoke their authorization to use 
and disclose their medical information, the information that has already been 
collected in their study records may be used and disclosed as necessary to protect 
the integrity of the research project 
After this explanation and before any study-specific procedures have been performed, the 
subject will voluntarily sign and date an authorization document. Prior to participation in the 
study, the subject will receive a copy of the signed and dated written authorization. 
Authorization to disclose Protected Health Information for research will be obtained in 
accordance with HIPPA regulations 45 CFR Parts 160 and 164. 
 
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6. 
STUDY TREATMENT INFORMATION 
6.1. 
Study Treatment Administration and Doses 
The study drug  used for the IV portion of Part 1 (Part 1a) is USL311 Injection Solution.  The 
study drug used for the oral portion of Part 1 (Part 1b) as well as for Parts 2-4, is USL311 20 
mg or 100 mg tablets. 
The combination agent used in this study is lomustine (CCNU). 
6.1.1. 
Directions for Administration 
During Part 1 and Part 3, USL311 will be administered as single agent and during Part 2 and 
Part 4, USL311 will be administered in combination with lomustine. 
6.1.1.1. 
USL311 IV Preparation 
USL311 Injection Solution requires dilution with a 250 mL infusion bag of 0.9% Sodium 
Chloride Injection, USP prior to administration to produce a final concentration of the intended 
dose. 
USL311 IV is dosed based on the subject's BSA calculated using the DuBois and DuBois 
equation. 
First, aseptically withdraw the same volume required for the dose of USL311 Injection 
Solution from the 250 mL infusion bag of 0.9% Sodium Chloride and dispose of the waste. 
The removal of this volume will ensure the final volume of the admixture will be 250 mL. 
Next, aseptically withdraw the volume of USL311 from the product vial needed for the 
required dose of USL311 and immediately transfer to the 250 mL infusion bag of 0.9% Sodium 
Chloride. After transferring, thoroughly mix the contents of the infusion bag. The admixture 
should be a clear and colorless to slightly yellow solution.  
Use only 0.9% Sodium Chloride Injection, USP, for dilution, as outlined above. No other 
diluents have been assessed for compatibility. 
Parenteral drug products should be inspected visually for particulate matter and discoloration 
prior to administration whenever solution and container permit. Vials of USL311 Injection 
Solution are for single use only. Any unused solution should be discarded according to 
institutional procedures. 
6.1.1.2. 
USL311 Admixture Stability 
USL311 Injection Solution contains no antimicrobial preservative. The admixture should be 
prepared as close as possible to the time of subject administration. Once diluted, the final 
admixed product may be stored for no more than 6 hours at room temperature (15-30°C or 59-
86°F) or no more than 24 hours under refrigeration (2-8°C or 36-46°F). Administration of the 
admixed product must be complete within 24 hours. 
6.1.1.3. 
USL311 IV Administration 
USL311 will be administered through a peripheral IV line over a nominal duration of 120 
minutes (2 hours, Protocol Amendment #2) or 240 minutes (4 hours, Protocol Amendment #3) 
 
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once weekly, although longer infusion durations may be considered as warranted based on 
clinical observations during the study.  
If the subject has other forms of venous access (peripherally inserted central catheter line 
[PICC line] or central line), these may be used instead of a peripheral IV line, per Investigator 
discretion. USL311 start and stop times of the infusion will be documented, and the stop time 
should be within +/- 10 minutes of the nominal time relative to the start of infusion (i.e., start 
time plus 240 minutes). Any unplanned interruption in USL311 infusion needs to be 
documented along with the corresponding start and stop times of the infusion. USL311 will be 
administered on Days 1, 8, and 15 of a 21-day (3 week) cycle in Part 1a. 
6.1.1.4. 
USL311 Oral Administration 
In Parts 1b, 2, 3 and 4, USL311 will be administered as oral tablets once daily in the morning 
under fasted conditions for 2 hours before and 2 hours after the dose on PK sampling days.  
For all other outpatient dosing days, the subject should be instructed to make an effort to take 
the oral tablets at least 1 hour before or at least 1 hour after their meal, and they will be 
instructed to document in their diary the time of any food eaten prior to dosing and for 1 hour 
after dosing. 
If a dose is missed in the morning, and fewer than 12 hours have elapsed since the planned 
administration time, the subject should take the missed dose.  If more than 12 hours have 
elapsed since the planned administration time, the missed dose should be skipped. The time 
and date of daily administration of USL311 will be documented in a diary provided to the 
subject, see Section 6.6.1. 
6.1.1.5. 
Lomustine Administration 
Lomustine will not be administered in Part 1 and Part 3 or during the pre-surgical treatment 
period of Part 4. 
Lomustine should be administered per the instructions found in the package insert (see 
Appendix 4). It is recommended to administer lomustine on an empty stomach to help prevent 
lomustine induced nausea and vomiting. Lomustine is dosed based on the subject’s BSA, 
calculated using the DuBois and DuBois equation. All doses of lomustine should be rounded 
to the nearest 10 mg by the Investigator. 
In Part 2, Cycle 1 only, a single oral dose of lomustine will be administered on Day 1 as part 
of a 49-day (7-week) cycle and will be administered in the clinic. For all subsequent cycles in 
Part 2 (Cycle 2+), a single oral dose of lomustine will be administered on Day 2 as part of a 
42-day (6-week) cycle and will be administered in the clinic during Cycle 2 but  for all 
subsequent cycles, lomustine may be dispensed for outpatient administration as allowed per 
site standard of practice. If outpatient dosing of lomustine is not allowed per site standard of 
practice, lomustine will be administered in the clinic. 
In Part 4, dosing with lomustine will initiate following surgical re-resection and will be 
administered as a single oral dose on Day 2 as part of a 42-day (6-week) cycle. The first dose 
of lomustine (Cycle 1) will be administered in the clinic, whereas for all subsequent cycles 
(Cycle 2+), lomustine may be dispensed for outpatient administration. If outpatient dosing of 
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lomustine is not allowed per site standard of practice, lomustine will be administered in the 
clinic. 
For all outpatient doses (if applicable) in Parts 2 and 4, the subject will be instructed to take 
lomustine as a single dose on Cycle Day 2. If lomustine is administered as an outpatient dose, 
clinic staff will follow-up by phone with the subject within 48 hours after Day 2 to collect the 
following: time and date of lomustine administration, concomitant medications, and AEs. 
Note: In the case of emesis after dosing with lomustine and the expulsion of the capsule, 
lomustine will not be re-dosed. 
6.1.2. 
Selection of Treatment and Doses 
6.1.2.1. 
Phase 1 
Part 1a – Single Agent IV USL311 Dose Escalation: 
The first-in-human starting dose of USL311 will be 60 mg/m2 administered as a 2-hour IV 
infusion. The Severely Toxic Dose in 10% of animals (STD 10) was determined as 100 mg/kg 
USL311 administered as a weekly 2-hour IV infusion in the rat. Based on scaling by BSA, the 
human equivalent dose to the STD 10 is 600 mg/m2 and thus the starting dose is equivalent to 
1/10th of the rat STD 10. This dose is lower than the projected first-in-human starting dose of 
267 mg/m2 calculated as 1/6 of the Highest Non-Severely Toxic Dose (HNSTD) in dogs (80 
mg/kg as a weekly 2-hr infusion). 
A weekly dosing schedule was selected as USL311 exhibits a prolonged terminal half-life 
following IV administration in nonclinical species. This is attributed to the extensive tissue 
uptake and slow elimination from the tissues including the brain. The predicted terminal half-
life in humans is estimated on t he order of days to weeks and thus target USL311 
concentrations may be achieved and maintained with a weekly IV dosing schedule. 
As of November 17, 2016, data from 8 subjects participating in Part 1 of this study (as defined 
prior to Protocol Amendment #3) has been collected at USL311 doses of 60, 120 a nd 180 
mg/m2 via 2 hr IV infusion. Interim data from these subjects suggested a potential USL311-
related increase in the the QT interval, with an apparent correlation with plasma and blood 
USL311 concentrations concentration-dependent manner. Based on t hese observations, a 
longer duration of USL311 infusion (i.e., slower infusion rate) was expected to decrease the 
magnitude of QT-prolongation and therefore as of Amendment #3 the the infusion duration 
was increased from 120 minutes (2 hours) to 240 minutes (4 hours). 
Dosing with the 4 hour infusion was initiated at the highest safe dose of USL311 as determined 
from subjects who received USL311 via a 2 ho ur infusion (viz., prior to Amendment #3 
Subjects who were previously enrolled and are actively participating at the time Protocol 
Amendment #3 was activated continued study participation according to Protocol Amendment 
#2. 
Dose-escalation was to occur as described in criteria outlined in Section 3.2.1 and Section 
3.2.3. All dose-escalation decisions will be determined by the DEC (see Section 3.2.5). 
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Part 1b – Single Agent Oral USL311 Dose Escalation: 
After 13 subjects were evaluable (i.e., had completed Cycle 1 dosing, at minimum) in Part 1a 
IV Dose Escalation, the DEC halted dose escalation, although no DLTs had occurred, due to 
continuing dose-related increases in QTcF prolongation that was not ameliorated by increasing 
the infusion duration. Part 1b of the study will resume under this amendment with dosing 
initiation of an oral formulation of USL311, at a starting dose of 40 mg once daily in 3-week 
(21-day) cycles. 
Dose escalation will begin in the single agent oral formulation with enrollment of subjects to 
the 40 mg dose. Treatment will be administered once daily in 3-week (21-day) cycles. USL311 
will be administered as oral tablets once daily in the morning under fasted conditions for 2 
hours before and 2 hours after the dose on Cycle 1-Days 1, 2, 8, and 15 and on Cycle 2-Day 1.  
For all other outpatient dosing days, the subject should be instructed to make an effort to take 
the oral tablets at least 1 hour before or at least 1 hour after their meal, and they will be 
instructed to document in their diary the time of any food eaten prior to dosing and for 1 hour 
after dosing.  It is recommended that subjects take their dose at the same time each day, except 
for visit days, when the dose will be held and taken during the clinic visit. 
The selected 40 mg daily oral starting dose is comparable to the 30 mg daily starting dose 
based on 1/6 HNSTD in dogs (5 mg/kg/day oral daily dose) and is lower than the ~60 mg daily 
dose calculated based on the maximum IV dose tested in humans (250 mg/m2 weekly, divided 
into daily doses). USL311 plasma pharmacokinetics are dose-proportional and minimal to no 
plasma accumulation is expected for USL311 and its main metabolites after daily oral dosing. 
In addition, a fixed-dosing approach is considered to be appropriate for future studies given 
that USL311 pharmacokinetics are not influenced by body size. Daily oral dosing is anticipated 
to further mitigate the concentration-related QT effect, compared to IV bolus weekly dosing. 
Part 2 – USL311 in Combination with Lomustine Dose Escalation: 
The starting dose of lomustine will be 90 mg/m2. The starting dose for lomustine was selected 
based on t he anticipated tolerability of the dose based on doses typically used in clinical 
practice. The maximum lomustine dose allowed during dose escalation is 130 mg/m2 which is 
the maximum dose allowed per the package insert (see Appendix 4). The starting dose of oral 
USL311 used in combination with lomustine in Part 2 w ill be established following 
determination of the MTD of USL311 in Part 1b. The starting dose will be no higher than 2 
evaluated dose levels below the MTD determined in Part 1. The dose levels will be determined by 
those doses of USL311 evaluated in Part 1b. 
Dose-escalation will occur as described in criteria outlined in Section 3.2.2 and Section 3.2.3. 
All dose-escalation decisions will be determined by the DEC (see Section 3.2.4).  
6.1.2.2. 
Phase 2 
Part 3 – Single Agent USL311 Dose Expansion in Relapsed/Recurrent GBM: 
The RP2D for single-agent USL311 that will be evaluated in Part 3 will be equal to, or lower 
than, the MTD determined in Study Part 1b. 
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Part 4 – USL311 in Combination with Lomustine Dose Expansion in Relapsed/Recurrent 
GBM: 
The RP2D regimen for USL311 in combination with lomustine that will be evaluated in Part 
4 will be equal to, or lower than, the MTD for the combination determined in Study Part 2. 
6.1.3. 
Risks and Toxicities 
6.1.3.1. 
USL311 
As this study will be the first-in-human use of USL311, predictions of potential clinical 
toxicities are based on the animal toxicology studies. Potential toxicities identified from the 
animal toxicology studies, using much higher doses than the planned doses to be studied in the 
clinical human studies, include drug-induced phospholipidosis (DIPL), QTc interval 
prolongation, and tremors. Details from the animal toxicology studies are describe in Section 
1.2.4 and IB. 
DIPL is the excessive accumulation of phosopholipids and drug in lysosomes. It is unclear of 
the significance of toxicity associated with DIPL, and it is observed in multiple marketed 
agents (53). DIPL will be measured through an exploratory biomarker di-docosahexaenoyl 
(22:6)-bis(monoacylglycerol) phosphate (BMP) described in Section 8.7.3. 
DIPL is often associated with QTc prolongation (54) as was observed in the canine nonclinical 
toxicology studies. QTc prolongation may increase the risk of arrhythmias, most significantly 
Torsades de Pointes (TdP); however, no a rrhythmias were observed in the nonclinical 
toxicology studies. QTc prolongation has been observed in Part 1a of the clinical study. 
Cardiac monitoring will be used during the dosing of study drug(s) as described in Section 
8.4.7. 
In the nonclinical studies, 4-AP was identified as a metabolite of USL311 (see Section 1.2.3.2). 
4-AP (46) is a marketed drug approved as a treatment in Multiple Sclerosis. 4-AP is associated 
with increased risk of seizure activity above a likely threshold plasma concentration of about 
100 ng/ml (47). It is not expected that the plasma concentrations of 4-AP will approach the 
threshold concentration at the starting dose of USL311 and subsequent doses during dose 
escalation and the RP2D. The 4-AP plasma concentration will be measured as part of the PK 
assessment (see Section 8.6.1). 
Similar in class agents include plerixafor (55) which is a CXCR4 partial agonist. Common 
toxicities occurring ≥ 10% of patients include diarrhea, nausea, fatigue, injections site 
reactions, headache, arthralgia, dizziness, and vomiting. 
It is not known whether USL311 causes phototoxicity. However, subjects receiving USL311 
should be cautioned to avoid unprotected sun exposure. 
6.1.3.2. 
Lomustine 
Bone marrow suppression, notably thrombocytopenia and leukopenia, is the most common and 
severe of the toxic effects of lomustine. Blood counts will be monitored at each treatment visit 
to monitor for bone marrow suppression. At the recommended dosage, courses of lomustine 
should not be given more frequently than every 6 weeks. The bone marrow toxicity of 
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lomustine is cumulative and therefore dosage adjustment must be considered on the basis of 
nadir blood counts from prior dose. Dose modifications will occur due to toxicity as described 
in Section 6.1.5.2. 
Lomustine is listed a moderate-to-high emetogenic drug, thus nausea and vomiting may occur 
with lomustine administration. Subjects will be able to take prophylactic antiemetic agents, per 
ASCO guidelines (51) and the discretion of the Investigator. For a list of permitted antiemetics 
see Section 5.3.1. 
For more information about toxicities see Appendix 4 for the lomustine (Gleostine®) package 
insert. 
6.1.4. 
Monitoring and Toxicity Management 
Each subject receiving USL311 alone, or in combination with lomustine, will be evaluable for 
safety at each study visit. Toxicity will be assessed according to the NCI CTCAE version 4.03. 
Dose adjustments will be made according to the system showing the greatest degree of toxicity 
or the toxicity of greatest concern.  
6.1.5. 
Dose Modifications 
6.1.5.1. 
USL311 Dose Modifications 
Dosing of USL311 may be interrupted to allow for recovery from toxicity, with IV doses 
delayed for up to 14 days beyond the scheduled dosing day or daily dosing held for up to 14 
days. Thereafter, treatment at the same or a reduced USL311 dose can be considered, based 
upon discussions between Sponsor or designee and Investigator, if the subject has not 
developed progressive disease. Subjects with toxicities that require interruptions of greater 
than 14 days should be discontinued from the study.  During Part 2 and Part 4, the combination 
of USL311 and lomustine will be considered, and the most likely agent(s) responsible for the 
observed toxicity will be modified. Dose modifications should be made based on observed 
toxicity as follows:  
• Grade 1 or 2 toxicity: No requirement for dose interruption or dose reduction. If the 
toxicity persists at grade 2, a dose reduction to the next lower dose level may be 
implemented at the discretion of the Investigator. 
• Grade 3 toxicity: Dosing should be stopped. USL311 dosing may resume at the next 
lower dose level when toxicity resolves to grade 1 or returns to baseline. 
• Grade 4 toxicity: Dosing should be stopped. USL311 may resume at a lower dose 
level (1-2 dose level decrease) with the approval of the medical monitor when 
toxicity resolves to grade 1 or returns to baseline. 
USL311 will be permanently discontinued for individual subjects as a result of any unresolved 
Grade 3 or Grade 4 toxicity or based on a decision by the subject or Investigator that continued 
USL311 treatment is not in the subject’s best interest. 
USL311 dose modification criteria based on ECG assessments: 
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• To determine eligibility to initiate treatment, the last safety ECG performed prior to the 
first administration of study drug(s) will be used as baseline. The baseline QTcF 
interval must be ≤ 450 msec before the first dose of study drug(s).  If the baseline QTcF 
interval is > 450 msec, the subject will not be eligible for the study.  
• On subsequent doses, the predose safety ECG on the day of dosing will be used to 
determine eligibility for dosing.  Subjects will be eligible to receive the dose of USL311 
if the predose QTcF interval is < 501 msec, per Investigator discretion.  
• If any post-dose QTcF interval is ≥ 501 msec, repeat ECG assessments will occur at 
least every 30 minutes until the QTcF interval is < 501 msec.  
• USL311 dosing may be interrupted, per Investigator discretion, based on findings from 
real-time bedside ECG or scheduled and unscheduled ECG assessments. 
6.1.5.2. 
Lomustine Dose Modifications 
Lomustine dose modifications will be based on lomustine prescribing information (see 
Appendix 4). Doses subsequent to the initial dose should be adjusted according to the 
hematologic response of the subject to the preceding dose. The following schedule (Table 18) 
is suggested as a guide to dosage adjustments: 
Table 18: 
Lomustine Dosage Adjustment Guide 
Nadir After Prior Dose 
Percentage of  
Prior Dose to be Given 
Leukocytes (/mm3) 
Platelets (/mm3) 
≥4000 
≥100,000 
100% 
3000 – 3999 
75,000 – 99,999 
100% 
2000 – 2999 
25,000 – 74,999 
70% 
<2000 
<25,000 
50% 
A repeat course of lomustine should not be given until circulating blood elements have returned 
to acceptable levels (platelets above 100,000/mm3; leukocytes above 4000/mm3), and this is 
usually in 6 weeks. Blood counts should be monitored weekly and repeat courses should not 
be given before 6 weeks because the hematologic toxicity is delayed and cumulative. 
The use of granulocyte growth factor support will be consistent with the ASCO guidelines 
(52). 
Lomustine will be permanently discontinued for individual subjects as a result of any 
unresolved Grade 3 or Grade 4 toxicity or based on a decision by the subject or Investigator 
that continued lomustine treatment is not in the subject’s best interest. 
6.1.6. 
Duration of Treatment 
Subjects who tolerate Cycle 1 treatment and do not have progressive disease, treatment failure 
or relapse are eligible to continue to receive treatment until they experience unacceptable 
toxicity, disease progression, meet any of the withdrawal criteria, or the study is terminated by 
the Sponsor. 
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6.1.7. 
Treatment Compliance 
During study visits for all parts of the study, f USL311 (IV or oral) will be administered under 
the supervision of qualified study center personnel. As IV study drug is administered by 
qualified study center personnel in Part 1a, treatment compliance is expected to be 100%. 
For Parts 1b, 2, 3 and 4, at each weekly visit (i.e., Day 1, Day 8, Day 15, etc.), USL311 tablets 
will be dispensed from a bulk supply, returned drug will be counted and compliance calculated. 
USL311 will be administered in the clinic on each visit day; on all other days it will be self-
administered as an outpatient by the subject and documented in a patient diary. The diary will 
be brought to each weekly visit for review and reconciliation against the pill counts to confirm 
that the diary is being completed accurately.  If compliance drops below 70%, patients will be 
re-educated on t he need for remaining compliant with daily dosing. Intentional non-
compliance could be cause for discontinuation from the study. 
Lomustine will be administered in the clinic for Part 2 on Cycle 1-Day 1 and Cycle 2-Day 2 
and for Part 4 on Cycle 1-Day 2. Lomustine will be administered under the supervision of 
qualified study center personnel and treatment compliance is expected to be 100% for these 
doses. For all other cycles, lomustine will be administered on Day 2 of the cycle which may 
occur on an outpatient basis if allowed per site standard of practice. If lomustine is administered 
as an outpatient dose, clinic staff will follow-up by phone with the subject within 48 hours 
after Day 2 to collect the following: time and date of lomustine administration, concomitant 
medications, and AEs. If lomustine is administered as an outpatient dose, compliance will be 
captured through these follow-up phone calls. 
The allowable dosing windows are defined in the footnotes of Table  1 – Table  7. Dosing 
outside of the windows requires approval based upon discussion between Sponsor or designee 
and Investigator. 
6.2. 
Treatment Randomization 
Randomization will not occur in the Phase 1 dose-escalation portion (Parts 1 and 2). Subjects 
in the Phase 2 dose-expansion (Parts 3 and 4) in relapsed/recurrent GBM will be randomized 
after the Screening visit to one of the four possible treatments shown in Figure 3. 
Subjects may begin enrolling into Part 3 (N = 20) after the completion of enrollment in Part 1 
and determination of the RP2D for single agent USL311 and subjects may begin enrolling into 
Part 4 (N = 20) after the completion of enrollment in Part 2 and the determination of the RP2D 
for USL311 in combination with lomustine. In Parts 3 and 4, 18 subjects in each part will be 
randomized to receive pre-surgical USL311 treatment and 2 subjects in each part to receive no 
pre-surgical USL311 treatment. All subjects in Part 3 will receive post-surgical USL311 
treatment, whereas all subjects in Part 4 will receive post-surgery USL311 treatment in 
combination with lomustine. 
Due to the potentially staggered start of Parts 3 a nd 4, a minimization randomization 
mechanism will be used to assign subjects to Phase 2 treatment in order to obtain a target of 
approximately 40 response-evaluable subjects at the end of the study. Minimization is 
considered to be an appropriate randomization method for this type of scenario to ensure 
well-balanced randomization between treatments. 
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The study drug supplies will be labeled appropriate to their use. USL311 and lomustine will 
be identified as unblinded treatments. The USL311 label will contain at a minimum the 
following information: 
• Legal requirements as specified by country-specific regulations 
• Protocol number 
• Instructions for use (if required) 
• Name and address of sponsor 
• Quantity/contents 
• Batch/Lot number 
• Storage conditions 
• Expiration date, as applicable 
• “Caution: New Drug – Limited by Federal law to investigational use” will also 
appear on t he immediate package of vial used during the study as required by 
21 CFR §312.6, as applicable 
• Each container of study drug will be clearly labeled with study-specific information 
meeting all the applicable regulatory requirements. 
Clinical study drug supplies will be labeled in the official language of the country of the study 
site, if applicable. 
6.6. 
Handling, Storage and Accountability 
USL311 Injection Solution is stable for the lot life indicated on the package labeling when 
stored refrigerated at 2-8°C (36-46°F). After admixing, the admixed product may be stored for 
no more than 6 hours at room temperature (15-30°C or 59-86°F) or no more than 24 hours 
under refrigeration (2-8°C or 36-46°F). Administration of the admixed product must be 
complete within 24 hours. 
USL311 tablets will be stored between 20-25°C. Documentation of shipment inventory 
including expiration date will be provided to each site on the shipping inventory form. Tablets 
will be dispensed in a child resistant container and will include dosing instructions. Lomustine 
capsules are stable for the lot life indicated on package labeling when stored in well-closed 
containers at room temperature (25°C [77°F]); excursions permitted to 15–30°C (59–86°F). 
Avoid excessive heat (over 40°C, 104°F). Caution should be exercised when handling 
lomustine capsules. It is recommended that individuals handling lomustine wear gloves for 
protection. Refer to Appendix 4 for the lomustine package insert and special handling 
procedures.  
The Sponsor requires Investigators or designee to maintain adequate drug inventory and 
security at all times. Upon receipt of the study drug, the Investigator (or his/her designee) will 
perform an inventory of the shipment, comparing the shipment inventory to actual study drug 
received, and complete and sign an inventory log. The Investigator (or his/her designee) must 
count and verify that the shipment contains all the items that appear on the shipment inventory. 
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The Investigator must immediately notify the Sponsor (or its designee) or the drug-distribution 
contractor of any damaged or unusable study drug that the study center receives and document 
any damaged or unusable study drug in the inventory log. 
Only after receipt of all required documentation from a study center will the Sponsor (or its 
designee) notify the drug distribution contractor to distribute the initial study drug to that study 
center. Additional study drug will be shipped as needed to the study center. The Investigator 
(or his/her designee) will retain in the study file a copy of the shipment inventory received with 
the study drug supply. Each time study drug is dispensed to a subject, the Investigator (or 
his/her designee) will record the quantity and a description (e.g., subject number) on the drug 
accountability log. The Investigator (or his/her designee) will also document any subsequent 
returns or losses of study drug on the drug accountability log. 
Drug-accountability records will be available to the study monitor for review at each study-
center visit. The study monitor will inspect drug supplies and accountability records throughout 
conduct of the study at the study center to confirm inventory control and proper study drug 
storage. The study monitor will record any discrepancies and/or deficiencies and report them 
to the Investigator and to the Sponsor (or its designee) and will document the Investigator’s 
plan for resolution of any drug inventory or storage issues. 
6.6.1. 
Dispensing of Study Drug 
All study drugs will be dispensed by qualified study-center personnel and will be documented 
in the drug accountability log.  
USL311 20 m g and 100 mg tablets will be dispensed in adequate quantities based on the 
subject’s assigned daily dose. Separate child-resistant containers should be used for 20 mg 
tablets and 100 mg tablets.  
At Cycle 1-Day 1, a 10-day supply of USL311 tablets (to cover the potential visit window +3 
days) will be dispensed to the subject, along with a patient diary, which will be maintained by 
each subject to track their administration of study drug; the patient will be trained on the proper 
use of the diary and will be instructed to make an entry each day after taking their dose of 
USL311.  Subjects will also be instructed to bring their remaining medication and their diaries 
to each study visit, and to refrain from taking their USL311 dose on the days of clinic visits, 
in particular for return visits on Days 2, 3 and 5 of Cycle 1.  Subjects will be dosed during 
clinic visits from their own supply of USL311.  After reviewing the diary for accountability, a 
new supply of study drug should be dispensed to replace administered drug such that the 
subject again has a 10-day supply of USL311 tablets.  In the event that the subject fails to bring 
their medication with them to the clinic, a 10-day supply should be dispensed from the 
pharmacy, and the subject’s in-clinic dose should be administered from this supply. 
For lomustine specifically, doses will be administered in the clinic for Part 2 on Cycle 1-Day 
1 and Cycle 2-Day 2 and for Part 4 on Cycle 1-Day 2. For all other cycles, lomustine will be 
administered on Day 2 of the cycle which may occur on an outpatient basis if allowed per site 
standard of practice. The outpatient doses will be dispensed during the Day 1 Visit of the cycle. 
If lomustine will be administered in the clinic, the dose will be dispensed on the dosing day. 
 
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6.6.2. 
Return and Disposition of Clinical Supplies 
At the conclusion of the study, a final inventory of study drug shipped to, dispensed by, and 
remaining at the study center will be performed by the clinical research associate (CRA). This 
reconciliation will be logged on the drug accountability form, and the form will be signed and 
dated. If any supplies are missing, this discrepancy must be indicated on t he drug 
accountability/ return forms along with an explanation of the discrepancy. Any discrepancies 
noted will be investigated, resolved, and documented before return or destruction of unopened 
study drug. The Investigator (or his/her designee) must return all unopened study drug to the 
Sponsor (or its designee) unless alternative arrangements for drug disposal are authorized by 
the Sponsor. A copy of the drug-accountability records should be sent to the Sponsor (or its 
designee), and the Investigator (or his/her designee) must retain the originals of these drug-
accountability records for his/her files in accordance with 21 CFR § 312.59. 
No study drug will be retained at any study center after the study is completed; all study drugs 
will be returned to the Sponsor (or its designee) for destruction or destroyed on site according 
to regulations, as applicable. 
 
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7. 
STUDY VISIT SCHEDULE AND ASSESSMENTS 
Tables for the schedule of visits and timing of assessments are detailed in Study Schedule of 
Visits and Assessments, Table 1 – Table 7. Only assessments required for the study are listed 
in the tables, any additional assessments or repeat assessments should be performed as 
indicated and according to clinical practice. 
All study assessments should be performed at the visits and nominal time points outlined in 
the tables found in the Study Schedule of Visits and Assessments, Table 1 – Table 7. Actual 
completion date and times will be recorded in the source document and eCRF. Other logistical 
considerations (e.g., order of events and assessment windows) will be outlined in 
study-specific procedures found in the footnotes of the Study Schedules of Visits and 
Assessments.  
7.1. 
Screening Phase 
All subjects will provide written informed consent before any study-specific procedure is 
performed. 
During screening, subjects will undergo assessments to determine if they are eligible to 
participate in the study according to the inclusion/exclusion criteria. In Parts 1 and 2, Screening 
Visit assessments must be performed within 28 days of Cycle 1-Day 1, and in Parts 3 and 4, 
within 28 days of Pre-surgical Dosing, Day 1 for those randomized to pre-surgical USL311 
treatment and within 28 days of Surgery for those randomized to no pre-surgical treatment. If 
the Screening Visit falls outside of the 28-day window prior to the first Treatment Phase day, 
the subject will be allowed to complete the Screening Visit assessments again. The repeated 
Screening Visit will be used to determine eligibility. 
All Screening Visit assessments must be performed, and subjects must meet eligibility 
requirements prior to the subject entering the Treatment Phase. Any screening results falling 
outside of the reference ranges may be repeated at the discretion of the Investigator. 
The screening assessments will be performed in each study part unless specified below.  
Screening Visit: 
The following assessments will be performed during the Screening Visit: 
• Obtain informed consent of subject or assent of subject, if applicable (see Section 
5.8) 
• Assessment of inclusion/exclusion criteria (see Section 5.2) 
• Collect medical history (see Section 8.4.2) 
• Collect oncologic history (see Section 8.4.3) 
• Physical examination (see Section 8.4.5.1) 
• Neurological examination (see Section 8.4.5.2) 
• Vital signs (see Section 8.4.6) 
• Collect KPS (see Section 8.4.1) 
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• Safety ECG (Parts 1 a nd 2 onl y) or Extracted ECG (Part 3 a nd 4 o nly) (see 
Section 8.4.7)  
• Blood sample collection for serum pregnancy test for all females of child bearing 
potential (see Section 8.4.9)  
• Blood sample collection for clinical laboratory tests (see Section 8.4.8) 
• Urine sample collection for UA (see Section 8.4.8) 
• Tumor assessment by RECIST v.1.1 criteria (Parts 1 and 2 only; see Section 8.2.2) 
or by RANO criteria (see Section 8.2.3) as appropriate 
• Collect adverse events occurring after written informed consent is obtained (see 
Section 9.1.1) 
• Collect prior and concomitant medication information (see Section 8.4.4) 
• Confirm availability of archival tumor tissue (see Section 8.4.10) 
• Perform EORTC QLQ-C30/BN20 (Parts 3 and 4 only; see Section 8.7.1) 
Baseline Visit (Day -1, Part 1 Only): 
The following assessments will be performed during the Baseline Visit (Day -1) in Part 1 only: 
• Assessment of inclusion/exclusion criteria (see Section 5.2) 
• Physical examination (see Section 8.4.5.1) 
• Vital signs (see Section 8.4.6) 
• Collect KPS (see Section 8.4.1) 
• Holter-extracted ECG (see Section 8.4.7) 
• Blood or urine sample collection for serum or urine pregnancy test, respectively, for 
all females of child bearing potential (see Section 8.4.9) 
• Blood for clinical laboratory tests (see Section 8.4.8) 
• Blood sample for cytochrome P450 genotyping (see Section 8.4.8.2) 
• Blood sample for optional pharmacogenomics analyses (see Section 8.4.8.3)  
− Note: May be collected at a later visit if determined appropriate per the 
clinical site 
• Urine sample collection for UA (see Section 8.4.8) 
• Adverse event monitoring (see Section 9.1.1) 
• Concomitant medication monitoring (see Section 8.4.4) 
• Urine sample collection for BMP analysis (see Section 8.7.3) 
The following screening safety assessments are required to be repeated at Baseline (Day -1) 
only for subjects for whom screening assessments were performed > 3 da ys before 
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Cycle 1-Day 1 (1st dose of USL311): inclusion/exclusion criteria, physical examinations, UA, 
and clinical laboratory tests. If collected ≤ 3 days prior to Cycle 1-Day 1, these assessments do 
not need to be repeated. 
7.2. 
Treatment Phase 
Following the completion of the Screening Phase, subject will be eligible to enter into the 
Treatment Phase of the study. 
7.2.1. 
Part 1a Treatment 
Subjects enter the Treatment Phase in Part 1 on Cycle 1-Day 1. Treatment with single agent 
USL311 will be administered in 21-day cycles. 
Cycle 1 Visits: 
The following assessments will be performed during Cycle 1: 
• USL311 IV administration in the clinic (see Section 6.1.1.3) 
− Day 1, Day 8, and Day 15 
• Physical examination (see Section 8.4.5.1) 
− Day 8 and Day 15 
• Neurological examination (see Section 8.4.5.2)  
− Day 1, Day 8, and Day 15 
• Vital signs (see Section 8.4.6) 
− Day 1, Day 8, and Day 15  
• Holter-extracted ECG (see Section 8.4.7) 
− Day 1, Day 2, Day 8, and Day 15 
• Safety ECG (see Section 8.4.7) 
− Day 1, Day 8 and Day 15 
• Real-time bedside ECG (see Section 8.4.7)  
− Day 1, Day 8, and Day 15 
• Blood sample collection for clinical laboratory tests (see Section 8.4.8) 
− Day 8 and Day 15 
• Adverse events monitoring (see Section 9.1.1) 
− Continuous through Cycle 1 
• Concomitant medication monitoring (see Section 8.4.4) 
− Continuous through Cycle 1 
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• Blood sample collection for USL311 PK (see Section 8.6.1; Table 8) 
− Day 1, Day 2, Day 3, Day 5, Day 8, and Day 15  
• Blood sample collection for CD34+ cell count (see Section 8.7.3; Table 8) 
− Day 1 and Day 2  
• Blood sample collection for WBC count (see Section 8.7.3; Table  8) 
− Day 1, Day 2, Day 3, Day 5, Day 8, and Day 15  
• Blood samples for SDF-1 analysis (see Section 8.7.3; Table  8) 
Day 1 and Day 2Visits for Part 1a, Cycle 1 are on Day 1, Day 2, Day 3, Day 5, Day 8 and Day 
15. See Table  1 for the schedule of events on each day of the cycle and timing of assessments. 
During Cycle 1, the Baseline (Day -1), Day 1 and Day 2 visits will occur on consecutive days, 
whereas Day 3 and Day 5 assessments (PK and PD samples) will be collected according to the 
acceptable time windows specified in Table  8. All remaining Cycle 1 visits will occur on the 
scheduled study day or ≤ 3 days post the scheduled study day. 
Cycle 2+ Visits: 
The following assessments will be performed during Cycle 2 and all subsequent cycles: 
• USL311 IV administration (see Section 6.1.1.3) 
− Day 1, Day 8, and Day 15 
• Physical examination (see Section 8.4.5.1)  
− Day 1, Day 8, and Day 15 
• Neurological examination (see Section 8.4.5.2) 
− Day 1, Day 8, and Day 15 
• Vital signs (see Section 8.4.6) 
− Day 1, Day 8, and Day 15 
• Collect KPS (see Section 8.4.1)  
− Day 1 of even numbered cycles only 
• Holter-extracted ECG (see Section 8.4.7) 
− If clinically indicated from experience in Cycle 1 
• Safety ECG (see Section 8.4.7) 
− If clinically indicated from experience in Cycle 1 
• Real-time bedside ECG (see Section 8.4.7) 
− If clinically indicated from experience in Cycle 1 
• Blood or urine sample collection for serum or urine pregnancy test, respectively, for 
all females of child bearing potential (see Section 8.4.9)  
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− Day 1 of even numbered cycles only 
• Blood sample collection for clinical laboratory tests (see Section 8.4.8) 
− Day 1, Day 8, and Day 15 
• Urine sample collection for UA (see Section 8.4.8) 
− Day 1 only 
• Tumor assessment by RECIST v.1.1 criteria (see Section 8.2.2) or by RANO criteria 
(see Section 8.2.3) as appropriate  
− Cycle 3-Day 1 then every 6 weeks (± 7 days) thereafter 
• Adverse event monitoring (see Section 9.1.1) 
− Continuous through Cycle 2+ 
• Concomitant medication monitoring (see Section 8.4.4) 
− Continuous through Cycle 2+ 
• Blood sample collection for USL311 PK (see Section 8.6.1; Table  8) 
− Day 1, Cycle 2 only 
• Blood sample collection for WBC count (see Section 8.7.3; Table  8) 
− Day 1, Cycle 2 only 
• Urine sample collection for BMP analysis (see Section 8.7.3) 
− Day 1 of even-numbered cycles only 
The study visits for Part 1a, Cycle 2+ are on Day 1, Day 8 and Day 15. See Table  1 for the 
schedule of events on each day of the cycle and timing of assessments. For all visits in Cycle 
2+ (up to but not including the End of Treatment Visit), visits will occur a minimum of 7 days 
and a maximum of 14 days (unless treatment is on hold for safety reasons) from the previous 
dose of USL311. 
7.2.2. 
Part 1b Treatment 
Subjects enter the Treatment Phase in Part 1b on Cycle 1-Day 1. Treatment with single agent 
USL311 will be administered in 21-day cycles.  
Cycle 1 Visits: 
The following assessments will be performed during Cycle 1: 
• USL311 dispensing (see Section 6.6.1) 
− Day 1, Day 8, and Day 15 
• USL311 administration in the clinic (see Section 6.1.1.4) 
− Day 1, Day 2, Day 8, and Day 15 
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• Physical examination (see Section 8.4.5.1) 
− Day 8 and Day 15 
• Neurological examination (see Section 8.4.5.2)  
− Day 1, Day 8, and Day 15 
• Vital signs (see Section 8.4.6) 
− Day 1, Day 8, and Day 15  
• Holter-extracted ECG (see Section 8.4.7) 
− Day 1, Day 2, Day 8, and Day 15 
• Safety ECG (see Section 8.4.7) 
− Day 1, Day 2, Day 8 and Day 15 
• Real-time bedside ECG (see Section 8.4.7)  
− Day 1, Day 8, and Day 15 
• Blood sample collection for clinical laboratory tests (see Section 8.4.8) 
− Day 8 and Day 15 
• Adverse events monitoring (see Section 9.1.1) 
− Continuous through Cycle 1 
• Concomitant medication monitoring (see Section 8.4.4) 
− Continuous through Cycle 1 
• Blood sample collection for USL311 PK (see Section 8.6.1; Table  9) 
− Day 1, Day 2, Day 8, and Day 15  
• Blood sample collection for CD34+ cell count (see Section 8.7.3; Table  9) 
− Day 1 and Day 2  
• Blood sample collection for WBC count (see Section 8.7.3; Table  9) 
− Day 1, Day 2, Day 8, and Day 15  
Visits for Part 1b, Cycle 1 are on Day 1, Day 2, Day 8 and Day 15. See Table  2 for the schedule 
of events on each day of the cycle and timing of assessments. During Cycle 1, the Baseline 
(Day -1), Day 1 and Day 2 visits will occur on consecutive days. All remaining Cycle 1 visits 
will occur on the scheduled study day or ≤ 3 days post the scheduled study day. 
Cycle 2+ Visits: 
The following assessments will be performed during Cycle 2 and all subsequent cycles: 
• USL311 dispensing (see Section 6.6.1) 
− Day 1, Day 8, and Day 15 
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• USL311 administration in the clinic (see Section 6.1.1.4) 
− Day 1, Day 8 and Day 15 
• Physical examination (see Section 8.4.5.1)  
− Day 1, Day 8, and Day 15 
• Neurological examination (see Section 8.4.5.2) 
− Day 1, Day 8, and Day 15 
• Vital signs (see Section 8.4.6) 
− Day 1, Day 8, and Day 15 
• Collect KPS (see Section 8.4.1)  
− Day 1 of even numbered cycles only 
• Holter-extracted ECG (see Section 8.4.7) 
− Day 1, then only if clinically indicated  
• Safety ECG (see Section 8.4.7) 
− Day 1, then only if clinically indicated  
• Real-time bedside ECG (see Section 8.4.7) 
− If clinically indicated from experience in Cycle 1 
• Blood or urine sample collection for serum or urine pregnancy test, respectively, for 
all females of child bearing potential (see Section 8.4.9)  
− Day 1 of even numbered cycles only 
• Blood sample collection for clinical laboratory tests (see Section 8.4.8) 
− Day 1, Day 8, and Day 15 
• Urine sample collection for UA (see Section 8.4.8) 
− Day 1 only 
• Tumor assessment by RECIST v.1.1 criteria (see Section 8.2.2) or by RANO criteria 
(see Section 8.2.3) as appropriate  
− Cycle 3-Day 1 then every 6 weeks (± 7 days) thereafter 
• Adverse event monitoring (see Section 9.1.1) 
− Continuous through Cycle 2+ 
• Concomitant medication monitoring (see Section 8.4.4) 
− Continuous through Cycle 2+ 
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• Blood sample collection for USL311 PK (see Section 8.6.1; Table  9) 
− Day 1, Cycle 2 only 
• Blood sample collection for WBC count (see Section 8.7.3; Table  9) 
− Day 1, Cycle 2 only 
• Urine sample collection for BMP analysis (see Section 8.7.3) 
− Day 1 of even numbered cycles only 
The study visits for Part 1b, Cycle 2+ are on Day 1, Day 8 and Day 15. See Table  2 for the 
schedule of events on each day of the cycle and timing of assessments. For all visits in Cycle 
2+ (up to but not including the End of Treatment visit), visits will occur within ±3 days of the 
scheduled visit. 
7.2.3. 
Part 2 Treatment 
Subjects enter the Treatment Phase in Part 2 on the first day of study drug(s) administration. 
Treatment with USL311 in combination with lomustine will be administered in 42-day cycles, 
except in Cycle 1 which will be a 49-day cycle. Screening safety assessments are only required 
to be repeated at Cycle 1-Day 1 (baseline) for subjects for whom screening assessments were 
performed > 3 days before Cycle 1-Day 1 (1st dose of lomustine): inclusion/exclusion criteria, 
physical examinations, UA, and clinical laboratory tests. If collected ≤ 3 days prior to Cycle 1-
Day 1, t hese assessments do not  need to be repeated and the screening results will be 
considered baseline. 
Cycle 1 Visits: 
The following assessments will be performed during Cycle 1: 
• Assessment of inclusion/exclusion criteria (see Section 5.2) 
− Day 1 only 
• Lomustine administration (see Section 6.1.1.5) 
− Day 1 only 
• USL311 dispensing (see Section 6.6.1) 
− Day 8, Day 15, Day 22, Day 29, Day 36, and Day 43 
• USL311 administration in-clinic (see Section 6.1.1.4) 
− Day 8, Day 9, Day 15, Day 22, Day 29, Day 36, and Day 43 
• Physical examination (see Section 8.4.5.1)  
− Day 1, Day 8, Day 15, Day 22, Day 29, Day 36, and Day 43 
• Neurological examination (see Section 8.4.5.2) 
− Day 8, Day 15, Day 22, Day 29, Day 36, and Day 43 
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• Vital signs (see Section 8.4.6) 
− Day 1, Day 8, Day 15, Day 22, Day 29, Day 36, and Day 43 
• Collect KPS (see Section 8.4.1) 
− Day 1 only 
• Holter-extracted ECG (see Section 8.4.7) 
− Day 1, Day 8, Day 9, Day 15, Day 22, Day 29, Day 36, and Day 43 
• Safety ECG (see Section 8.4.7) 
− Day 1, Day 8, Day 9, Day 15, Day 22, Day 29, Day 36, and Day 43 
• Real-time bedside ECG (see Section 8.4.7)  
− Day 8, Day 15, Day 22, Day 29, Day 36, and Day 43 
• Blood or urine sample collection for serum or urine pregnancy test, respectively, 
for all females of child bearing potential (see Section 8.4.9) 
− Day 1 only 
• Blood sample collection for clinical laboratory tests (see Section 8.4.8) 
− Day 1, Day 8, Day 15, Day 22, Day 29, Day 36, and Day 43 
• Urine sample collection for UA (see Section 8.4.8) 
− Day 1 only 
• Blood sample for cytochrome P450 genotyping (see Section 8.4.8.2) 
− Day 1 only 
• Blood sample for optional pharmacogenomics analyses (see Section 8.4.8.3)  
− Day 1 or may be collected at a later visit if determined appropriate per the 
clinical site 
• Adverse event monitoring (see Section 9.1.1) 
− Continuous through Cycle 1 
• Concomitant medication monitoring (see Section 8.4.4) 
− Continuous through Cycle 1 
• Blood sample collection for USL311 PK analysis (see Section 8.6.1; Table  10) 
− Day 8, Day 9, Day 15 and Day 22 
• Blood sample collection for lomustine PK analysis (see Section 8.6.1; Table  10) 
− Day 1 only 
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• Blood sample collection for CD34+ cell count (see Section 8.7.3; Table  10) 
− Day 8, Day 9, Day 15 and Day 22 
• Blood sample collection for WBC count (see Section 8.7.3; Table  10) 
− Day 8, Day 9, Day 15 and Day 22 
• Urine sample collection for BMP analysis (see Section 8.7.3) 
− Day 1 only 
The study visits for Part 2 Cycle 1 are on Day 1, Day 8, Day 9, Day 15, Day 22, Day 29, Day 
36, and Day 43. See Table  3 for the schedule of events on each day of the cycle and timing of 
assessments. During Cycle 1-Day 8 a nd Day 9 visits will occur on c onsecutive days. All 
remaining Cycle 1 visits will occur on the scheduled study day or ≤ 3 days post the scheduled 
study day. 
Cycle 2+ Visits: 
The following assessments will be performed during Cycle 2 and all subsequent cycles: 
• USL311 dispensing (see Section 6.6.1) 
− Day 1, Day 8, Day 15, Day 22, Day 29, and Day 36 
• USL311 administration in the clinic (see Section 6.1.1.4) 
− Day 1, Day 2, Day 8, Day 15, Day 22, Day 29, and Day 36 
• Lomustine administration (see Section 6.1.1.5) 
− Day 2 only 
• Physical examination (see Section 8.4.5.1) 
− Day 1, Day 8, Day 15, Day 22, Day 29, and Day 36 
• Neurological examination (see Section 8.4.5.2) 
− Day 1, Day 8, Day 15, Day 22, Day 29, and Day 36 
• Vital signs (see Section 8.4.6) 
− Day 1, Day 8, Day 15, Day 22, Day 29, and Day 36 
• Collect KPS (see Section 8.4.1) 
− Day 1 only 
• Holter-extracted ECG (see Section 8.4.7) 
− Day 1, then if clinically indicated 
• Safety ECG (see Section 8.4.7) 
− Day 1, then if clinically indicated  
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• Real-time bedside (see Section 8.4.7) 
− If clinically indicated from experience in Cycle 1 
• Blood or urine sample collection for serum or urine pregnancy test, respectively, for 
all females of child bearing potential (see Section 8.4.9) 
− Day 1 only 
• Blood sample collection for clinical laboratory tests (see Section 8.4.8) 
− Day 1, Day 8, Day 15, Day 22, Day 29, and Day 36 
• Urine sample collection for UA (see Section 8.4.8) 
− Day 1 only 
• Tumor assessment by RECIST v.1.1 criteria (see Section 8.2.2) or by RANO criteria 
as appropriate (see Section 8.2.3) 
− Cycle 2-Day 1 then every 6 weeks (± 7 days) thereafter 
• Adverse event monitoring (see Section 9.1.1) 
− Continuous through Cycle 2+ 
• Concomitant medication monitoring (see Section 8.4.4) 
− Continuous through Cycle 2+ 
• Blood sample collection for USL311 PK analysis (see Section 8.6.1; Table  10) 
− Day 1 and Day 2, Cycle 2 only 
• Blood sample collection for lomustine PK analysis (see Section 8.6.1; Table  10) 
− Day 2, Cycle 2 only 
• Blood sample collection for WBC count (see Section 8.7.3; Table  10) 
− Day 1, Cycle 2 only 
• Urine sample collection for BMP analysis (see Section 8.7.3) 
− Day 1 only 
The study visits for Part 2 Cycle 2+ are on D ay 1, Day 2 (Cycle 2 on ly, if lomustine is 
administered as an outpatient dose for future cycles), Day 8, Day 15, Day 22, Day 29, and 
Day 36. See Table  3 for the schedule of events on e ach day of the cycle and timing of 
assessments. For all visits in Cycle 2+ (up to but not including the End of Treatment Visit), 
visits will occur within ± 3 days of the scheduled visit. 
7.2.4. 
Part 3 Treatment 
Subjects enter the Treatment Phase in Part 3 on t he first day of pre-surgical USL311 
administration for those randomized to pre-surgical treatment or on the day of surgery for those 
randomized to no pr e-surgical treatment. Post-surgical treatment with USL311 will be 
administered in 21-day cycles.  
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Screening safety assessments are required to be repeated at Pre-surgical Dosing, Day 1 (for 
those randomized to pre-surgical treatment) or Surgery (for those randomized to no 
pre-surgical treatment) only for subjects for whom screening assessments were performed 
> 3 days before Pre-surgical Dosing, Day 1 (for those randomized to pre-surgical treatment) 
or Surgery (for those randomized to no pre-surgical treatment): inclusion/exclusion criteria, 
physical examination, neurological examination, UA, and clinical laboratory tests. For those 
randomized to no pre-surgical treatment, ECG and vital signs will also be repeated. If collected 
≤ 3 days prior to Pre-surgical Dosing, Day 1 (for those randomized to pre-surgical treatment) 
or Surgery (for those randomized to no pre-surgical treatment), these assessments do not need 
to be collected and screening results will be considered baseline 
For those randomized to no pr e-surgical treatment, if the safety assessments need to be 
repeated, the pre-surgical physical examination and neurological examination performed as 
part of standard-of-care and performed closest to the day of surgery may be used as baseline 
only if it is not feasible to perform the physical and neurological examinations on the day of 
surgery. 
Pre-surgical Dosing Visits: 
The assessments within the Pre-surgical Dosing Visits only apply to subjects randomized to 
receive pre-surgical treatment with USL311. Subjects randomized to receive no U SL311 
treatment prior to surgery will not participate in any of the assessments within the Pre-surgical 
Dosing period. 
The following assessments will be performed during the Pre-surgical Dosing Visits: 
• Assessment of inclusions/exclusion criteria (see Section 5.2) 
− Day 1 only 
• USL311 dispensing (see Section 6.6.1) 
− Day 1, Day 8+ 
• USL311 administration in-clinic (see Section 6.1.1.3) 
− Day 1, Day 2, Day 3, Day 5 and Day 8+ 
• Physical examination (see Section 8.4.5.1) 
− Day 1 and Day 8+ 
• Neurological examination (see Section 8.4.5.2) 
− Day 1 and Day 8+ 
• Vital signs (see Section 8.4.6) 
− Day 1 and Day 8+ 
• Collect KPS (see Section 8.4.1) 
− Day 1 only 
• Holter-extracted ECG (see Section 8.4.7)  
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− Day 1, Day 2, Day 3, Day 5 and Day 8+ 
• Real-time beside ECG (see Section 8.4.7) 
− Day 1, Day 2, Day 3, Day 5 and Day 8+ 
• Blood or urine sample collection for serum or urine pregnancy test, respectively, 
for all females of child bearing potential (see Section 8.4.9) 
− Day 1 only 
• Blood sample collection for clinical laboratory tests (see Section 8.4.8) 
− Day 1 and Day 8+ 
• Urine sample collection for UA (see Section 8.4.8) 
− Day 1 only 
• Adverse event monitoring (see Section 9.1.1) 
− Continuous through Pre-surgical Dosing 
• Concomitant medication monitoring (see Section 8.4.4) 
− Continuous through Pre-surgical Dosing 
• Blood sample collection for USL311 PK analysis (see Section 8.6.1; Table  11) 
−  Day 1, Day 2, Day 3, Day 5, and Day 8 
Subjects randomized to receive pre-surgical treatment with USL311 are required to receive at 
least one week of treatment prior to surgery, and may receive up to a maximum of three weeks 
of treatment with USL311 (at the single agent RP2D defined in Part 1) prior to surgery. The 
length of treatment received will depend on the surgery date. Scheduling of the surgery, as part 
of standard-of-care, should not be delayed due to the pre-surgical treatment. Surgical 
re-resection may occur at any time from Day 2 onwards. USL311 will be administered on a 
daily schedule until Surgery. Assessments within the Pre-surgical Dosing Visits that are 
pending at the time of surgery will no longer be required and will not be performed post-
surgery. 
The study visits for Pre-surgical Dosing for Part 3 are on Day 1, Day 2, Day 3, Day 5, and 
Day 8+. See Table  4 for the schedule of events on each day of the cycle and timing of 
assessments. During the Pre-surgical Dosing, Day 1 and Day 2 visits will occur on consecutive 
days, whereas Day 3, Day 5, and Day 8 assessments (PK samples; dosing on Day 8 if possible) 
will be collected according to the acceptable time windows specified in Table  11. All 
remaining Pre-Surgical Dosing Visits are dependent on the length of pre-surgical USL311 
treatment received and will occur within ± 3 days of scheduled visit. 
Surgery (Re-resection) Visit: 
For subjects randomized to pre-surgical treatment with USL311, Surgery (re-resection) may 
occur at any time from Day 2 onwards. For subjects randomized to receive no U SL311 
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treatment prior to surgery, Surgery (re-resection) will occur following the Screening Visit with 
the Screening Day -28 to Day -1 window calculated relative to day of surgery.  
The following assessments or procedures will be performed during the day of Surgery 
(re resection) for only those subjects randomized to no pre-surgical treatment: 
• Assessment of inclusions/exclusion criteria (see Section 5.2) 
• Physical examination (see Section 8.4.5.1) 
• Neurological examination (see Section 8.4.5.2) 
• Vital signs (see Section 8.4.6) 
• Collect KPS (see Section 8.4.1) 
• Holter-extracted ECG (see Section 8.4.7) 
• Blood or urine sample collection for serum or urine pregnancy test, respectively, for 
all females of child bearing potential (see Section 8.4.9) 
• Blood sample collection for clinical laboratory tests (see Section 8.4.8) 
• Urine sample collection for UA (see Section 8.4.8) 
The following assessments or procedures will be performed during the day of Surgery 
(re-resection) for all subjects in Part 3: 
• Perform re-resection surgery (see Section 3.3.3) 
• Collect any adverse events (see Section 9.1.1) 
• Collect concomitant medication information (see Section 8.4.4) 
• Blood sample collection for USL311 PK analysis (see Section 8.6.1; Table  11) 
• CSF sample collection (see Section 8.6.2) 
• Resected brain tissue sample collection (see Section 8.7.2) 
• Tumor assessment by RANO criteria (see Section 8.2.3)  
− Performed ≤ 72 hours after surgery with EORTC QLQ-C30/BN20. If initiation 
of treatment following surgery is delayed for 3-4 weeks, a r epeat baseline 
response assessment using the RANO criteria along with EORTC 
QLQ-C30/BN20 will be performed ≤ 7 days of study drug dosing. 
• Perform EORTC QLQ-C30/BN20 (see Section 8.7.1) 
− Performed ≤ 72 hours after surgery with response assessment using RANO 
criteria. If initiation of treatment following surgery is delayed for 3-4 weeks, a 
repeat baseline EORTC QLQ-C30/BN20 along with response assessment using 
RANO criteria will be performed ≤ 7 days of study drug dosing. 
See Table  5 (for those randomized to no pre-surgical treatment) for the schedule of events on 
the day of the surgery and timing of assessments for Part 3. 
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Cycle 1 Visits: 
Following surgery, all subjects (including those randomized to no pre-surgical treatment) will 
initiate treatment of USL311. Cycle 1-Day 1 (post-surgery) will be initiated ≤ 28 days of 
Surgery, although treatment delays may be considered based upon di scussions between 
Sponsor or designee and Investigator. Subjects must have fully recovered from surgery, 
including surgical wound healing, prior to initiating therapy. Post-surgical treatment with 
single agent USL311 will be administered in 21-day cycles.  
The following assessments will be performed during Cycle 1: 
• Assessment of inclusions/exclusion criteria (see Section 5.2) 
− Day 1 only 
• USL311 dispensing (see Section 6.6.1) 
− Day 1, Day 8 and Day 15 
• USL311 administration in-clinic (see Section 6.1.1.3) 
−  Day 1, Day 2, Day 8, and Day 15 
• Physical examination (see Section 8.4.5.1) 
− Day 1, Day 8, and Day 15 
• Neurological examination (see Section  8.4.5.2)  
− Day 1, Day 8, and Day 15 
• Vital signs (see Section 8.4.6) 
− Day 1, Day 8, and Day 15 
• Collect KPS (see Section 8.4.1) 
− Day 1 only 
• Holter-extracted ECG (see Section 8.4.7) 
− Day 1, Day 2, Day 8 and Day 15 
• Real-time bedside ECG (see Section 8.4.7) 
− Day 1 only 
• Blood or urine sample collection for serum or urine pregnancy test, respectively, for 
all females of child bearing potential (see Section 8.4.9) 
− Day 1 only 
• Blood sample collection for clinical laboratory tests (see Section 8.4.8) 
− Day 1, Day 8, and Day 15 
• Urine sample collection for UA (see Section 8.4.8) 
− Day 1 only 
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• Blood sample for cytochrome P450 genotyping (see Section 8.4.8.2) 
− Day 1 only 
• Blood sample for optional pharmacogenomics analyses (see Section 8.4.8.3)  
− Day 1 or may be collected at a later visit if determined appropriate per the 
clinical site 
• Adverse event monitoring (see Section 9.1.1) 
− Continuous through Cycle 1 
• Concomitant medication monitoring (see Section 8.4.4) 
− Continuous through Cycle 1 
• Blood sample collection for USL311 PK analysis (see Section 8.6.1; Table  12) 
− Day 1, Day 2, Day 8, and Day 15 
The study visits for Part 3 Cycle 1 are on Day 1, Day 2, Day 8 and Day 15. See Table  4 (for 
those randomized to pre-surgical treatment) and Table  5 (for those randomized to no 
pre-surgical treatment) for the schedule of events on each day of the cycle and timing of 
assessments. For Cycle 1-Day 1 and Day 2 visits will occur on consecutive days, whereas all 
remaining Cycle 1 visits should occur on the scheduled study day or ≤ 3 days post the 
scheduled study day.  
Cycle 2+ Visits: 
The following assessments will be performed during Cycle 2 and all subsequent cycles: 
• USL311 dispensing (see Section 6.6.1) 
o Day 1, Day 8 and Day 15 
• USL311 administration in-clinic (see Section 6.1.1.3) 
− Day 1, Day 8, Day 15 
• Physical examination (see Section 8.4.5.1)  
− Day 1, Day 8, Day 15 
• Neurological examination (see Section 8.4.5.2)  
− Day 1, Day 8, Day 15 
• Vital signs (see Section 8.4.6) 
− Day 1, Day 8, Day 15 
• Collect KPS (see Section 8.4.1) 
− Day 1 of even numbered cycles only 
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• Holter-extracted ECG (see Section 8.4.7) 
− Cycle 2-Day 1 then if clinically indicated 
• Real-time bedside ECG (see Section 8.4.7) 
− If clinically indicated 
• Blood or urine sample collection for serum or urine pregnancy test, respectively, for 
all females of child bearing potential (see Section 8.4.9) 
− Day 1 of even numbered cycles only 
• Blood sample collection for clinical laboratory tests (see Section 8.4.8) 
− Day 1, Day 8, Day 15 
• Urine sample collection for UA (see Section 8.4.8) 
− Day 1 only 
• Tumor assessment by RANO criteria (see Section 8.2.3) 
− Cycle 3-Day 1 then every 6 weeks (± 7 days) thereafter and at 6 months (± 7 
days) 
• Adverse event monitoring (see Section 9.1.1) 
− Continuous through Cycle 2+ 
• Concomitant medication monitoring (see Section 8.4.4) 
− Continuous through Cycle 2+ 
• Perform EORTC QLQ-C30/BN20 (see Section 8.7.1) 
− Every 6 weeks (± 7 days) and at 6 months (± 7 days) 
The study visits for Part 3 Cycle 2+ are on Day 1, Day 8 and Day 15. See Table  4 (for those 
randomized to pre-surgical treatment) and Table  5 (for those randomized to no pre-surgical 
treatment) for the schedule of events on each day of the cycle and timing of assessments. For 
all visits in Cycle 2+ (up to but not including the End of Treatment Visit), visits will occur 
within ± 3 days of scheduled visit. 
7.2.5. 
Part 4 Treatment 
Subjects enter the Treatment Phase in Part 4 on t he first day of pre-surgical USL311 
administration for those randomized to pre-surgical treatment or on the day of surgery for those 
randomized to no treatment. Post-surgical treatment with USL311 in combination with 
lomustine will be administered in 42-day cycles. 
Screening safety assessments are required to be repeated at Pre-surgical Dosing, Day 1 (for 
those randomized to pre-surgical treatment) or Surgery (for those randomized to no 
pre-surgical treatment) only for subjects for whom screening assessments were performed 
> 3 days before Pre-surgical Dosing, Day 1 (for those randomized to pre-surgical treatment) 
or Surgery (for those randomized to no pre-surgical treatment): inclusion/exclusion criteria, 
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physical examination, neurological examination, UA, and clinical laboratory tests. For those 
randomized to no pre-surgical treatment, ECG and vital signs will also be repeated. If collected 
≤ 3 days prior to Pre-surgical Dosing, Day 1 (for those randomized to pre-surgical treatment) 
or Surgery (for those randomized to no pre-surgical treatment), these assessments do not need 
to be collected and screening results will be considered baseline. 
For those randomized to no pr e-surgical treatment, if the safety assessments need to be 
repeated, the pre-surgical physical examination and neurological examination performed as 
part of standard-of-care and performed closest to the day of surgery may be used as baseline 
only if it is not feasible to perform the physical and neurological examinations on the day of 
surgery. 
Pre-surgical Dosing Visits: 
The assessments within the Pre-surgical Dosing only apply to subjects randomized to receive 
pre-surgical treatment with USL311. Subjects randomized to receive no USL311 treatment 
prior to surgery will not participate in any of the assessments within the Pre-surgical Dosing 
period. 
The following assessments will be performed during the Pre-surgical Dosing Visits: 
• Assessment of inclusions/exclusion criteria (see Section 5.2) 
− Day 1 only 
• USL311 dispensing (see Section 6.6.1) 
− Day 1, Day 8, then weekly thereafter 
• USL311 administration in-clinic (see Section 6.1.1.3) 
− Day 1, Day 2, Day 3, Day 5 and Day 8, then weekly thereafter 
• Physical examination (see Section 8.4.5.1) 
− Day 1 and Day 8, then weekly thereafter  
• Neurological examination (see Section 8.4.5.2) 
− Day 1 and Day 8, then weekly thereafter  
• Vital signs (see Section 8.4.6) 
− Day 1 and Day 8, then weekly thereafter  
• Collect KPS (see Section 8.4.1) 
− Day 1 only 
• Holter-extracted ECG (see Section 8.4.7) 
− Day 1, Day 2, Day 3, Day 5 and Day 8, then weekly thereafter  
• Real-time bedside ECG (see Section 8.4.7) 
− Day 1 and Day 8, then weekly thereafter  
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• Blood or urine sample collection for serum or urine pregnancy test, respectively, for 
all females of child bearing potential (see Section 8.4.9) 
− Day 1 only 
• Blood sample collection for clinical laboratory tests (see Section 8.4.8) 
− Day 1 and Day 8, then weekly thereafter  
• Urine sample collection for UA (see Section 8.4.8) 
− Day 1 only 
• Adverse event monitoring (see Section 9.1.1) 
− Continuous through Pre-surgical Dosing 
• Concomitant medication monitoring (see Section 8.4.4) 
− Continuous through Pre-surgical Dosing 
• Blood sample collection for USL311 PK analysis (see Section 8.6.1; Table  11) 
− Day 1, Day 2, Day 3, Day 5, and Day 8 
Subjects randomized to receive pre-surgical treatment with USL311 are required to receive at 
least one week of treatment prior to surgery, and may receive up to a maximum of three weeks 
of treatment of USL311 (at the RP2D defined in Part 2) prior to surgery. The length of 
treatment received will depend on t he surgery date. Scheduling of the surgery, as part of 
standard-of-care, should not be delayed due to the pre-surgical treatment. Surgical re-resection 
may occur at any time from Day 2 onwards. USL311 will be administered on a daily schedule 
until Surgery. Assessments within the Pre-surgical Dosing period that are pending at the time 
of surgery will no longer be required and will not be performed post-surgery. 
The study visits for Pre-surgical Dosing for Part 4 are on Day 1, Day 2, Day 3, Day 5, and 
Day 8, then weekly thereafter. See Table  6 for the schedule of events on each day of the cycle 
and timing of assessments. During the Pre-surgical Dosing, Day 1 and Day 2 visits will occur 
on consecutive days, whereas Day 3, Day 5, and Day 8 assessments (PK samples) will be 
collected according to the acceptable time windows specified in Table  11. All remaining Pre-
Surgical Dosing visits are dependent on the number of pre-surgical USL311 doses received 
and will occur within ± 3 days of scheduled visit.Surgery (re-resection) Visit: 
For subjects randomized to pre-surgical treatment with USL311, Surgery (re-resection) may 
occur at any time from Day 2 onwards; USL311 will be administered daily until surgery.  For 
subjects randomized to receive no USL311 treatment prior to surgery, Surgery (re-resection) 
will occur following Screening with the Screening Day -28 to Day -1 window calculated 
relative to day of surgery.  
The following assessments or procedures will be performed during the day of Surgery 
(re-resection) for only those subjects randomized to no pre-surgical treatment: 
• Assessment of inclusions/exclusion criteria (see Section 5.2) 
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• Physical examination (see Section 8.4.5.1) 
• Neurological examination (see Section 8.4.5.2) 
• Vital signs (see Section 8.4.6) 
• Collect KPS (see Section 8.4.1) 
• Holter-extracted ECG (see Section 8.4.7) 
• Blood or urine sample collection for serum or urine pregnancy test, respectively, for 
all females of child bearing potential (see Section 8.4.9) 
• Blood sample collection for clinical laboratory tests (see Section 8.4.8) 
• Urine sample collection for UA (see Section 8.4.8) 
The following assessments or procedures will be performed during the day of Surgery 
(re-resection) for all subjects in Part 4: 
• Perform re-resection surgery (see Section 3.3.3) 
• Collect any adverse events (see Section 9.1.1) 
• Collect concomitant medication information (see Section 8.4.4) 
• Blood sample collection for USL311 PK analysis (see Section 8.6.1; Table  11) 
• CSF sample collection (see Section 8.6.2) 
• Resected brain tissue sample collection (see Section 8.7.2) 
• Tumor assessment by RANO criteria (see Section 8.2.3) 
− Performed ≤ 72 hours after surgery with EORTC QLQ-C30/BN20. If initiation 
of treatment following surgery is delayed for 3-4 weeks, a r epeat baseline 
response assessment using the RANO criteria along with EORTC 
QLQ-C30/BN20 will be performed ≤ 7 days of study drug dosing. 
• Perform EORTC QLQ-C30/BN20 (see Section 8.7.1)  
− Performed ≤ 72 hours after surgery with response assessment using RANO 
criteria. If initiation of treatment following surgery is delayed for 3-4 weeks, a 
repeat baseline EORTC QLQ-C30/BN20 along with response assessment using 
RANO criteria will be performed ≤ 7 days of study drug dosing. 
See Table  6 for those randomized to pre-surgical treatment) and Table  7 (for those 
randomized to no pre-surgical treatment) for the schedule of events on the day of the surgery 
and timing of assessments for Part 4. 
Cycle 1 visits: 
Following surgery, all subjects (including those randomized to no pre-surgical treatment) will 
initiate treatment of USL311 in combination with lomustine. Cycle 1-Day 1 (post-surgery) will 
be initiated ≤ 28 days of Surgery, although treatment delays may be considered based upon 
discussions between Sponsor or designee and Investigator. Subjects must have fully recovered 
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from surgery, including surgical wound healing, prior to initiating therapy. Post-surgical 
Treatment with single agent USL311 in combination with lomustine will be administered in 
42-day cycles. 
The following assessments will be performed during Cycle 1: 
• Assessment of inclusions/exclusion criteria (see Section 5.2) 
− Day 1 only 
• USL311 dispensing (see Section 6.6.1) 
− Day 1, Day 8, Day 15, Day 22, Day 29, and Day 36 
• USL311 administration in clinic (see Section 6.1.1.3) 
− Day 1, Day 2, Day 8, Day 15, Day 22, Day 29, and Day 36 
• Lomustine administration (see Section 6.1.1.4) 
− Day 2 only 
• Physical examination (see Section 8.4.5.1)  
− Day 1, Day 8, Day 15, Day 22, Day 29, and Day 36 
• Neurological examination (see Section 8.4.5.2)  
− Day 1, Day 8, Day 15, Day 22, Day 29, and Day 36 
• Vital signs (see Section 8.4.6) 
− Day 1, Day 8, Day 15, Day 22, Day 29, and Day 36 
• Collect KPS (see Section 8.4.1) 
− Day 1 only 
• Holter-extracted ECG (see Section 8.4.7) 
− Day 1, Day 2, Day 8, Day 15 
• Real-time bedside ECG (see Section 8.4.7) 
− Day 1 only 
• Blood or urine sample collection for serum or urine pregnancy test, respectively, for 
all females of child bearing potential (see Section 8.4.9) 
− Day 1 only 
• Blood sample collection for clinical laboratory tests (see Section 8.4.8) 
− Day 1, Day 8, Day 15, Day 22, Day 29, and Day 36 
• Urine sample collection for UA (see Section 8.4.8) 
− Day 1 only 
• Blood sample for cytochrome P450 genotyping (see Section 8.4.8.2) 
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− Day 1 only 
• Blood sample for optional pharmacogenomics analyses (see Section 8.4.8.3)  
− Day 1 or may be collected at a later visit if determined appropriate per the 
clinical site 
• Adverse event monitoring (see Section 9.1.1) 
− Continuous through Cycle 1 
• Concomitant medication monitoring (see Section 8.4.4) 
− Continuous through Cycle 1 
• Blood sample collection for USL311 PK analysis (see Section 8.6.1; Table  12) 
− Day 1, Day 2, Day 8, and Day 15 
• Blood sample collection for lomustine PK analysis (see Section 8.6.1; Table  12) 
− Day 2 only 
The study visits for Part 4 Cycle 1 are on Day 1, Day 2, Day 8, Day 15, Day 22, Day 29, and 
Day 36. See Table  6 (for those randomized to pre-surgical treatment) and Table  7 (for those 
randomized to no pre-surgical treatment) for the schedule of events on each day of the cycle 
and timing of assessments. For Cycle 1-Day 1 and Day 2 visits will occur on consecutive days, 
whereas all remaining Cycle 1 visits will occur on the scheduled study day or within 3 days 
post the scheduled study day. 
Cycle 2+ Visits: 
The following assessments will be performed during Cycle 2 and all subsequent cycles: 
• USL311 dispensing (see Section 6.6.1) 
− Day 1, Day 8, Day 15, Day 22, Day 29, and Day 36 
• USL311 administration (see Section 6.1.1.3) 
− Day 1, Day 2, Day 8, Day 15, Day 22, Day 29, and Day 36 
• Lomustine administration (see Section 6.1.1.4) 
− Day 2 only 
• Physical examination (see Section 8.4.5.1) 
− Day 1, Day 8, Day 15, Day 22, Day 29, and Day 36 
• Neurological examination (see Section 8.4.5.2) 
− Day 1, Day 8, Day 15, Day 22, Day 29, and Day 36 
• Vital signs (see Section 8.4.6) 
− Day 1, Day 8, Day 15, Day 22, Day 29, and Day 36 
• Collect KPS (see Section 8.4.1) 
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− Day 1 only 
• Holter-extracted ECG (see Section 8.4.7) 
− Day 1 then if clinically indicated 
• Real-time bedside ECG (see Section 8.4.7) 
− If clinically indicated 
• Blood or urine sample collection for serum or urine pregnancy test, respectively, for 
all females of child bearing potential (see Section 8.4.9) 
− Day 1 only 
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• Blood sample collection for clinical laboratory tests (see Section 8.4.8) 
− Day 1, Day 8, Day 15, Day 22, Day 29, and Day 36 
• Urine sample collection for UA (see Section 8.4.8) 
− Day 1 only 
• Tumor assessment by RANO criteria (see Section 8.2.3) 
− Cycle 2-Day 1, then every 6 weeks (± 7 days) thereafter and at 6 months (± 7 
days) 
• Adverse event monitoring (see Section 9.1.1) 
− Continuous through Cycle 2+ 
• Concomitant medication monitoring (see Section 8.4.4) 
− Continuous through Cycle 2+ 
• Perform EORTC QLQ-C30/BN20 (see Section 8.7.1) 
− Every 6 weeks (± 7 days) and at 6 months (± 7 days) 
The study visits for Part 4 Cycle 2+ are on Day 1, Day 2 (only if lomustine is administered in 
the clinic), Day 8, Day 15, Day 22, Day 29, and Day 36. See Table  6 (for those randomized 
to pre-surgical treatment) and Table  7 (for those randomized to no pre-surgical treatment) for 
the schedule of events on each day of the cycle and timing of assessments. For all visits in 
Cycle 2+ (up to but not including the End of Treatment Visit), visits will occur within ± 3 days 
of scheduled visit. 
7.3. 
End of Treatment/Follow-up Visit 
The Treatment Phase will end and subjects will discontinue treatment if any of the following 
occurs: 
• Subject experiences progressive disease, treatment failure or relapse  
• Subject experiences unacceptable toxicity (see Section 6.1.4) 
• Subject meets any of the withdrawal criteria (see Section 5.5) 
• The study is terminated by the Sponsor 
The End of Treatment Visit will occur ≤ 14 days of the decision to discontinue on-study 
treatment, whereas the Follow-up Visit will occur ≤ 28 days of the last dose of USL311. The 
End of Treatment visit may be the same as the Follow-up Visit; however, the Follow-up Visit 
should occur as close to 28 da ys after the last dose USL311 treatment as possible, per 
Investigator discretion. Treatment related AEs ongoing at End of Treatment Visit should be 
followed to resolution or until the Investigator considers them chronic or stable. The Follow-up 
Visit, or the End of Treatment Visit, as applicable, will be considered the last Treatment Phase 
visit. 
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The following assessments will be performed during the End of Treatment and Follow-up 
Phase: 
End of Treatment Visit: 
• Physical examination (see Section 8.4.5.1) 
• Neurological examination (see Section 8.4.5.2) 
• Vital signs (see Section 8.4.6) 
• Collect KPS (see Section 8.4.1) 
• Holter-extracted ECG (Parts 3 and 4 only; see Section 8.4.7) 
• Safety ECG (Parts 1 and 2 only; see Section 8.4.7) 
• Blood or urine sample collection for serum or urine pregnancy test, respectively, for 
all females of child bearing potential (see Section 8.4.9) 
• Blood sample collection for clinical laboratory tests (see Section 8.4.8) 
• Urine sample collection for UA (see Section 8.4.8) 
• Tumor assessment by RECIST v.1.1 criteria (Parts 1 and 2 only; see Section 8.2.2) 
or RANO criteria (see Section 8.2.3) 
• Collect any adverse events (see Section 9.1.1) 
• Collect concomitant medication information (see Section 8.4.4) 
• Perform EORTC QLQ-C30/BN20 (Parts 3 and 4 only; see Section 8.7.1) 
Follow-up Visit: 
• Physical examination (see Section 8.4.5.1) 
• Neurological examination (see Section 8.4.5.2)  
• Vital signs (see Section 8.4.6) 
• Collect KPS (see Section 8.4.1) 
• Blood sample collection for clinical laboratory tests (see Section 8.4.8) 
• Collect any adverse events (see Section 9.1.1) 
• Collect concomitant medication information (see Section 8.4.4) 
See Table  1 – Table  7, for the schedule of events and timing of assessments for Parts 1a, 1b, 
2, 3 (pre-surgical treatment), 3 (no pre-surgical treatment), 4 (pre-surgical treatment) and 4 (no 
pre-surgical treatment).  
7.4. 
Long-term Follow-up Phase 
All subjects who discontinue from study treatment, and are willing to be contacted, will be 
followed for survival information. The Long-term Follow-up Phase will begin after the Follow-
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up Visit, or the End of Treatment Visit, as applicable. If a subject is unable to attend the End 
of Treatment Visit, the Long-term Follow-up Phase will begin upon investigator determination 
that the subject has ended the Treatment Phase. Survival follow-up information will be 
collected via telephone calls and/or clinic visits quarterly (every 3 months ± 1 week) until 
death, loss to follow-up, End of Study (refer to Section 3.4), withdrawal of consent, initiation 
of subsequent treatment for the target tumor, administrative reasons, or study termination by 
the Sponsor. 
In Part 3 and Part 4, if a subject discontinues treatment for non-progression reasons and has 
not initiated any new oncology treatment, a 6 month visit for response assessment using RANO 
criteria and for collecting the EORTC QLQ-C30/BN20 health-related QOL questionnaire will 
occur. 
7.5. 
Unscheduled Visits 
As appropriate, assessments at any Unscheduled Visit should follow the assessment schedule 
at the closest weekly visit. 
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8. 
EFFICACY AND SAFETY ENDPOINTS AND ASSESSMENTS 
The Study Schedules of Visits and Assessments in Table  1 – Table  7 describe the specific 
timing of required assessments and procedures for each part of the study. Refer to the specific 
table for each study part for this information. 
8.1. 
Efficacy Endpoints 
The efficacy endpoint of PFS-6m (secondary endpoint for Parts 1 and 2 and primary endpoint 
for Parts 3 and 4) will be determined in all subjects with solid tumors utilizing RECIST v.1.1 
criteria and in subjects with primary brain tumors (e.g., GBM) utilizing RANO criteria. During 
Parts 1 and 2, in subjects with advanced solid tumors, tumor progression/response will be 
determined by local site reads and evaluations will be performed by qualified readers who have 
been trained in the applicable criteria. RECIST v.1.1 or RANO criteria will be used as 
applicable. In Parts 3 and 4, i n subjects with relapsed/recurrent GBM, tumor 
progression/response will be based on blinded independent central review (BICR). RANO 
criteria will be used for all subjects. In Parts 3 and 4, site reads will be performed using RANO 
criteria by qualified readers who have been trained in the applicable criteria and the site reads 
will be performed primarily for subject management. 
Secondary efficacy outcomes will also include ORR, DCR, PFS, and OS for all 4 study parts. 
8.2. 
Efficacy Assessments 
A secondary objective of Parts 1 and 2 of the study and primary objective of Parts 3 and 4 of 
the study is to make a preliminary assessment of the efficacy of USL311 in subjects with 
advanced solid tumors (Parts 1 and 2) or subjects with relapsed/recurrent GBM (Parts 3 and 
4). Tumors will be assessed radiographically and response to treatment will be determined by 
RECIST v.1.1 or  RANO criteria. RECIST v.1.1 criteria, will be utilized by trained and 
qualified site radiologist(s) in evaluating advanced solid tumor subjects in Parts 1 and 2. RANO 
criteria will be utilized by trained and qualified radiologist(s) in evaluating primary brain tumor 
subjects and GBM subjects in all 4 study parts. 
Allowable imaging modalities for tumor measurements in Parts 1 and 2 include 
contrast-enhanced CT and contrast-enhanced MRI; contrast-enhanced computed tomography 
(CT)/positron emission tomography (PET) will only be accepted if the CT portion of the scan 
is performed with IV contrast enhancement and of diagnostic quality. Ultrasound, radiographs, 
or other imaging modalities may be utilized for standard-of-care management but cannot be 
used to select target or nontarget lesions at baseline or for tumor response evaluation. For the 
RANO criteria, contrast enhanced MRI is preferred. CT is an option ONLY for subjects unable 
to undergo MR imaging due to safety concerns. To ensure comparability, the baseline 
radiographs/scans and subsequent radiographs/scans to assess response should be performed 
using identical techniques, unless otherwise clinically required. 
References for the RECIST v.1.1 criteria are included in Appendix 5 and for the RANO criteria 
in Appendix 6. 
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8.2.1. 
Evaluation of Response and Progression 
Tumor response and progression can frequently be difficult to measure directly. Serial 
physical/neurological exams and CT/MRI scans may provide a guide to the actual course.  
Detailed information about the evaluation of response and progression will be included in the 
Imaging Site Procedural Manual and Imaging Core Lab Manual. 
8.2.2. 
Response Evaluation Criteria in Solid Tumors (RECIST) 
The assessment of tumor response via RECIST v.1.1 criteria (56, 57) will be used for subjects 
with advanced solid tumors in Phase 1 (Parts 1 and 2). The article describing RECIST v.1.1 
criteria is included in Appendix 5. 
8.2.3. 
Response Assessment in Neuro-Oncology Criteria (RANO) 
The assessment of tumor response via RANO criteria (58) will be used for subjects with 
primary brain tumors in Phase 1 (Parts 1 and 2) and subjects with GBM in Phase 2 (Parts 3 and 
4). The article describing RANO criteria is included in Appendix 6, Safety Endpoints. 
8.3. 
Safety Endpoints 
The safety endpoints of interest are incidence of treatment emergent adverse events (TEAEs), 
including DLTs and SAEs; change in clinical laboratory tests (serum chemistry, hematology, 
coagulation assessments, UA); change in vital signs; change in ECGs (including real-time 
bedside ECG); change in physical examination; change in neurological examination; change 
in concomitant medication use; and change in BMP levels (Parts 1 and 2). 
8.4. 
Safety and Screening Assessments 
Safety in this study will be determined from evaluation of DLTs, (S)AEs, clinical laboratory 
assessments, ECGs, vital signs assessments, physical examinations, neurological 
examinations, concomitant medications and BMP levels (Parts 1 and 2). All subjects will be 
evaluable for safety.  
SAEs will be recorded beginning at the time of signing of the ICF until the Follow-up Visit. If 
an SAE is received after the Follow-up Visit and is assessed by the Investigator as being at 
least possibly related to study drug(s), it will be reported to the Sponsor. All AEs ongoing at 
the End of Treatment Visit will be followed until resolution or until the condition is considered 
chronic/stable by the Investigator or the initiation of new anticancer therapy. The 
determination, evaluation, and reporting of AEs will be performed as outlined in Section 9. 
The NCI CTCAE version 4.03 will be used to grade the severity of AEs in this study. Subjects 
will be assessed for AEs at each clinical visit and as necessary throughout the study. 
8.4.1. 
Karnofsky Performance Status (KPS) Scale Criteria 
Performance status will be measured using the KPS Scale (see Appendix 7). 
The KPS Scale index allows subjects to be classified as to their functional impairment. This 
can be used to compare effectiveness of different therapies and to assess the prognosis in 
individual subjects. The lower the KPS score, the worse the survival for most serious illnesses 
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(59). It is recommended, where possible, that a subject’s performance status is assessed by the 
same individual throughout the study. 
8.4.2. 
Medical History 
Medical histories will be obtained according to the site’s standard operating procedures, if 
applicable, or as determined by the Investigator or standard of practice. Medical histories will 
include demographic data (date of birth, sex, race, and ethnicity); histories of acute, chronic, 
or infectious disease; surgical histories; and any reported conditions affecting major body 
systems. All findings on medical history will be evaluated by the Investigator for clinical 
significance. Any new or clinically significant changes in the subject’s medical history 
between signing of the IRB/IEC-approved ICF and the first dose of study drug(s) will be 
recorded on the AE eCRF page. 
8.4.3. 
Oncologic History 
Oncologic histories will be obtained according to the site’s standard operating procedures, if 
applicable, or as determined by the Investigator or standard of practice. Oncology history will 
include disease course and prior cancer treatments including radiotherapy, surgery and 
systemic therapies. For systemic therapies only, the date of last therapy and best response to 
therapy should be documented for each therapy, if possible. Any residual toxicity related to 
prior treatments should be documented in the eCRF. All findings on oncologic history will be 
evaluated by the Investigator for clinical significance. Any new or clinically significant 
changes in the subject’s oncologic history between signing of the IRB/IEC-approved ICF and 
the first dose of study drug(s) will be recorded on the AE eCRF page. 
In Parts 3 a nd 4, t he prognostic markers O6-methyl-guanyl-methyl-transferase (MGMT) 
promoter methylation status and isocitrate dehydrogenase 1 (IDH-1) mutational status should 
be documented in the eCRF if the status has already been determined as part of their clinical 
care. 
8.4.4. 
Concomitant Medications 
All concomitant medications (including over-the-counter and herbal treatments) will be 
recorded from 28 days before the first dose of study drug(s) until the Follow-up Visit. For 
primary brain tumor and GBM subjects, corticosteroid use including any changes in dose 
and/or frequency will be documented for RANO criteria assessment.  
For the first dose of USL311 for each subject during Part 1 and Part 2, administration 
information for as needed (PRN) medications will be collected from 24 hours prior to USL311 
administration through clinic discharge. The information collected will include the name of the 
medication, dose administered, and administration date and time and will be documented in 
the designated eCRF.  
Any medication administered prior to the Follow-up Visit and with a stop date on or after the 
first dose of study drug(s) (or indicated as continuing) will be documented as concomitant 
medications. The reported medications will be reviewed and evaluated by the Investigator to 
determine if they affect a subject’s eligibility or continued participation in the study. 
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8.4.5. 
Clinical Examinations 
Any clinically significant abnormality identified during the physical or neurological 
examinations at Screening will be recorded in the subject’s medical history. Any new clinically 
significant findings/abnormalities or worsening of Screening findings that meet the definition 
of an AE must be recorded as both an examination finding and as an AE. 
8.4.5.1. 
Physical Examination 
Physical examinations at Screening, Baseline (for Part 1 only) and Day 1 of Cycle 2+, and at 
the Follow-up visit will be complete assessments in Parts 1 and 2. Physical examinations at 
Screening, Day 1 of each cycle post-surgery, and at the Follow-up visit should be complete 
assessments in Parts 3 and 4. Other scheduled physical examinations for all study parts may 
be abbreviated, at the discretion of the Investigator, to identify changes from baseline or 
evaluate changes based on the subject’s clinical symptoms. The complete physical examination 
will include assessments of the skin, head, eyes, ears, nose, throat, neck, thyroid, lungs, heart, 
abdomen, lymph nodes, and extremities. Height, weight, body mass index (BMI), and BSA 
(calculated using DuBois and DuBois equation) will be recorded. Weight, BMI, and BSA to 
be reported at each visit with a scheduled physical examination, height at Screening Visit only. 
8.4.5.2. 
Neurological Examination 
Neurological examinations will be performed during all study parts. Neurological 
examinations will be performed according to the schedules shown in Table 1 – Table 7 in the 
Schedule of Visits and Assessments. 
Neurological examinations at Screening and at Follow-up will be complete assessments. 
During the first day of USL311 dosing a complete neurological examination will be performed 
prior to dosing and more than 4 hours after oral dosing, prior to clinic discharge (for Part 1a, 
the complete neurological exam was to be performed anytime between the 5 hr nominal PK 
time point up to clinic discharge). During other USL311 dosing days for Cycle 1, neurological 
examinations will be performed prior to in-clinic dosing and may be abbreviated examinations. 
Other scheduled neurological examinations will be performed prior to dosing only, as 
applicable, and may be abbreviated examinations, at the discretion of the Investigator, to 
identify changes from baseline or evaluate changes based on the subject’s clinical symptoms. 
In Part 1a, neurological examinations will be performed ≤ 0.5 hr (mid-infusion) and ≤ 1 hr (end 
of infusion) after the nominal time point unless otherwise stated.The complete neurological 
exam will consist of evaluations of the following: Mental status (including orientation, memory 
and quality/fluency of speech), cranial nerves II-XII, motor strength of the upper and lower 
limbs, deep tendon reflexes, sensory exam, station and gait, Romberg test, coordination, 
nystagmus, and abnormal movements.  
The abbreviated neurological examination will consist of the following: Mental status 
(including orientation, memory and quality/fluency of speech), finger-to-nose test, heel-to-shin 
test, rapid alternating movements, nystagmus, and tremor or other abnormal movements. In 
Part 1a, during the infusion of USL311, the abbreviated neurological exam may be performed 
in a manner to allow for minimal disruptions in dosing. 
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8.4.6. 
Vital Signs 
Vital signs will be measured and managed according to the site’s standard operating 
procedures, if applicable, or as determined by the Investigator or standard of practice. Vital 
signs will consist of blood pressure (systolic and diastolic blood pressure, mmHg), pulse rate 
(bpm), respiratory rate (breaths/min), and temperature (°C or °F). Subjects should be in a semi-
recumbent position for at least 5 mins prior to the collection of vital signs. Vital signs at each 
nominal time point will be collected ± 10 mins relative to the nominal time point. When 
multiple assessments are scheduled at the same nominal time point ECG assessment (including 
semi-recument positioning, which is to begin at least 20 minutes prior to the nominal time 
point, will be completed first, and remaining assessments will be collected after the ECGs, 
with the PK sample being collected at the nominal time point.    
Vital signs will be collected prior to in-clinic USL311 dosing and prior to clinic discharge.  
Additional vital signs assessments should be performed if clinically indicated.   
Any clinically significant change in vital signs will be recorded as an AE. Clinically significant 
changes in vital signs should be confirmed by a repeat measurement (within 5 minutes of the 
original measurement) before recording as an AE.  
8.4.7. 
Electrocardiogram Monitoring 
Cardiovascular assessments will be completed with the use of Holter monitors provided by a 
central reader, utilizing three different approaches to collect and monitor cardiovascular safety:  
Holter-extracted ECGs, Safety 12-lead ECGs and real-time bedside ECG and heart rate 
monitoring.  
The ECG variables will include, but are not limited to, ventricular heart rate/RR interval and 
the PR, QRS, QT, and QTc (QTcB and QTcF) intervals. The Investigator will review the ECG 
report and indicate the clinical significance of all abnormal findings, and then sign and store 
the ECG report in the subject’s study file. Any clinically significant change in the ECG per the 
CTCAE criteria will be recorded as an AE.  
For grading of QT prolongation according to CTCAE criteria, the Fridericia-corrected QT 
interval, QTcF, will be utilized. 
To determine eligibility for initiating treatment, the last safety ECG performed prior to the first 
administration of study drug(s) will be used as baseline. The baseline QTcF interval must be 
≤ 450 msec before the first dose of study drug(s). If the baseline QTcF interval is > 450 msec, 
the subject will not be eligible for the study. Prior to subsequent in-clinic dosing, subjects will 
be eligible to receive the dose of USL311 if the predose QTcF interval is < 501 msec, per 
Investigator discretion. If any post-infusion or post-dose QTcF interval is ≥ 501 msec, repeat 
ECG assessments will occur at least every 30 minutes until the QTcF interval is < 501 msec. 
USL311 dosing may be interrupted, per Investigator discretion, based on findings from real-
time bedside ECG or scheduled and unscheduled ECG assessments. 
Frequency of ECGs should be increased if/when clinically indicated and may be included at 
subsequent cycles if clinically indicated. 
 
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Holter-Extracted Electrocardiograms 
12-Lead ECGs will be extracted from the Holter monitor by the ECG central reader and 
interpreted according to their standard operating procedures.  The central reader will extract 
ECGs in triplicate with replicates at least 2 minutes apart. To facilitate the 12-lead ECG 
extractions, subjects will be required to rest with the Holter monitor in place in a semi-
recumbent position during the length of the ECG collection period and for at least 5 minutes 
prior to the ECG collection period. Each ECG collection period spans from -15 minutes to -5 
minutes prior to the nominal time point. Therefore, subjects should begin to rest in the 
semi-recumbent position at least 20 minutes prior to the ECG extraction nominal timepoint  
(e.g., if the nominal timepoint corresponds to 10:00 am, the subject should begin to rest in a 
semi-recumbent position no later than 9:40 am, so that ECG collection can take place between 
9:45 and 9:55 am). Once available, the ECG reports for the extractions will be provided to the 
site by the central reader for assessment of clinical significance and AE reporting, as 
appropriate, but will not be available for real-time safety assessment. Instead, the scheduled 
safety ECGs are to be printed and used for real-time safety assessment. 
Additionally, in Part 2, for the baseline ECG extractions on Cycle 1-Day 1, subjects should 
rest in the semi-recumbent position from -80 min (i.e., 20 minutes prior to the -60 minute 
nominal time point) through -20 min prior to lomustine administration. 
During Part 1, time-matched ECGs will be used on Day -1 and Day 1 of Cycle 1. During 
Day -1, collection will occur for approximately 8.5 hours occurring at the equivalent time 
points (± 30 mins) as those planned on Day 1. The approximate clock times at which the ECG 
collections are planned to occur on Day 1 should be utilized for the corresponding time points 
on Day -1 for ECG collections. Timepoints for the ECG extractions for all study Parts are 
described in Table  1 – Table  4. 
For DLT assessment based on extracted ECGs baseline is defined as the closest time-matched 
extracted ECG (triplicate average) from Cycle 1-Day -1 for Part 1 or the average of the pre-
dose Cycle 1-Day 1 ECG extractions for Part 2. 
Safety Electrocardiogram 
During Part 1 and Part 2, safety ECGs will be generated as PDFs or printouts of ECGs from 
the provided laptop by clinic staff at scheduled timepoints during the visits, for the purpose of 
monitoring subject safety and treatment decisions by the Investigator.  Safety ECGs at the 
Screening and End of Treatment visits will be recorded in triplicate with replicates at least 2 
minutes apart. Single (i.e., non-triplicate) safety ECGs will also be collected at the timepoints 
described in Table  1 – Table  3. 
Prior to performing safety ECGs, subjects will rest in the semi-recumbent position for at least 
5 minutes and remain in this position throughout the ECG collection period.  When safety 
ECGs are to be collected at the same nominal time as an ECG extraction, the safety ECGs 
should be collected during the ECG extraction period which spans from -15 minutes to -5 
minutes prior to the nominal time point. Additional safety ECGs may be collected per 
Investigator discretion and should be collected for clinically significant changes from baseline.  
Frequency of safety ECGs should be increased if/when clinically indicated and may be 
included at subsequent cycles if clinically indicated.  Safety ECG printouts from the equipment 
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may be collected per Investigator discretion and should be collected for clinically significant 
changes from baseline. 
For DLT assessment based on safety ECGs, baseline is defined as the last ECG collected prior 
to the first dose of study drug. 
Real-Time Bedside ECG and Heartrate Monitoring 
Real-time bedside ECGs and heart rates will be monitored by clinic staff from prior to in-clinic 
dosing, or start of infusion with USL311 through clinic discharge (up to approximately 6 hours 
post  or dosing) on days where real-time monitoring is required. Real-time monitoring of ECG 
and heart rate will be accomplished through the use of Holter monitors with real-time ECG 
waveform displays on a bedside laptop. Holter monitors will also be equipped with alerts for 
heart rates above a set threshold. Real-time monitoring will be performed at subsequent cycles 
as clinically indicated. 
8.4.8. 
Clinical Laboratory Assessments 
All routine clinical laboratory assessment will be performed by the study center’s local 
laboratory facilities. Sampling for serum chemistry, hematology, UA and coagulation 
assessments can be drawn within 24 hour s prior to study drug administration. Laboratory 
assessments scheduled for the day of study drug dosing must be available and assessed for 
toxicity before dosing. All clinical laboratory results must be available and reviewed by the 
Investigator or sub-Investigator prior to start of subsequent treatment cycles of study drug(s).  
The total volume of blood loss for clinical safety laboratory assessments will be approximately 
20 mL per clinic visit. Subject fasting is not required before collection of clinical laboratory 
blood or urine samples. All subjects will have the clinical laboratory tests performed as listed 
in Table 19. The last assessment collected prior to the Cycle 1-Day 1 dose will be considered 
the baseline. 
Table 19: 
Clinical Laboratory Tests 
Serum Chemistrya 
Albumin 
Alkaline Phosphate (ALP) 
Alanine Aminotransferase (ALT) 
Aspartate Aminotransferase (AST) 
Bicarbonate (CO2) 
Blood Urea Nitrogen (BUN) (or urea 
as applicable) 
Calcium 
Chloride 
Creatinine 
Creatine Phosphokinase (CPK) 
Gamma-glutamyltransferase (GGT) 
Glucose  
Lactate Dehydrogenase (LDH) 
Magnesium 
Phosphorus or Phosphate 
Potassium 
Sodium 
Total Bilirubin 
Total Protein 
Uric Acid 
Hematology 
Absolute Neutrophil Count (ANC) 
Absolute Lymphocyte Count (ALC) 
Hematocrit (Hct) 
Hemoglobin (Hgb) 
Mean Corpuscular Volume (MCV) 
Platelet Count 
Red Blood Cell (RBC) Count 
White Blood Cell (WBC) 
Count with Differential 
Urinalysisb 
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Blood 
Bilirubin 
Glucose 
Ketones 
Leucocyte esterase 
Nitrite 
pH 
Protein 
Specific gravity 
Coagulation Assessments 
Activated Partial Thromboplastin 
Time (aPTT) / Partial Thromboplastin 
Time (PTT) 
International Normalized Ratio (INR) 
Prothrombin Time (PT) 
a Baseline potassium, sodium, calcium (corrected for albumin) and magnesium levels below lower limit of normal must be 
corrected to within the normal range, or above the ULN if considered not clinically significant per the Investigator, prior 
to starting study drug. 
b Dipstick UA; microscopy if clinically indicated. Potentially clinically significant findings include a positive test for 
protein (does not include trace findings), blood, nitrite and/or leukocyte esterase. 
Blood and urine samples will be collected by qualified study center personnel and those 
samples to be used for clinical laboratory assessment will be sent to be analyzed by the local 
laboratory for the serum chemistry, hematology, UA, and coagulation assessments.  
Note: A single urine sample may be collected and split for BMP biomarker, urine dipstick 
analysis, and/or urine pregnancy testing. 
8.4.8.1. 
Abnormal Clinical Laboratory Findings 
The Investigator will exercise medical judgment in deciding whether abnormal laboratory 
values are clinically significant. In some cases, significant changes within the range of normal 
will require similar judgment by the Investigator. In general, an abnormal laboratory value 
should be considered clinically significant if it results in treatment or prompts more intensive 
diagnostic evaluation. Repeating a laboratory test is not, in itself, a criterion for considering a 
result as clinically significant. 
Any abnormal test results determined to be clinically significant by the Investigator should be 
repeated (at the Investigator’s discretion) until the cause of the abnormality is determined, the 
value returns to baseline or to within normal limits, or the Investigator determines that the 
abnormal value is no longer clinically significant. 
All abnormal clinical laboratory result pages should be initialed and dated by an Investigator, 
along with a comment regarding whether or not the result is clinically significant. Clinical 
laboratory results should be compared to baseline values and only those values that have 
clinical sequelae will be considered clinically significant. Each clinically significant laboratory 
result should be recorded as an AE (see Section 9.1.3). The diagnosis, if known, associated 
with abnormalities in clinical laboratory tests that are considered clinically significant by the 
Investigator will be recorded on the AE eCRF page. 
8.4.8.2. 
Cytochrome P450 Genotyping 
Blood samples for genotyping of CYP2D6 and CYP3A will be collected during all 4 study 
parts according to the site’s standard procedures, if applicable, or as determined by the 
Investigator or standard of practice. The date and time of each collection should be recorded 
on the appropriate eCRF page. Further information for the handling, collection, storage, and 
shipping of genotyping samples will be provided in a separate laboratory sample handling 
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manual. Samples will be stored at a long-term storage facility under contract by the Sponsor 
and analyzed up to a maximum of 5 years after study completion, after which time the samples 
will be destroyed by incineration. Subjects have the right to refuse and to have their samples 
destroyed at any time. At the conclusion of the study, samples will be de-identified and handled 
in accordance with FDA guidance or other country specific guidances, as applicable. 
8.4.8.3. 
Pharmacogenomics 
In addition to the sample collected for cytochrome P450 genotyping, a sample may be collected 
during all study parts from subjects who have consented to participate in the 
pharmacogenomics component of the study. Participation is optional and a separate IRB/IEC 
approved informed consent form must be obtained for participation. Subjects who do not wish 
to participate in the pharmacogenomics research may still participate in the study. For those 
subjects that consent to participate in the pharmacogenomics component, an 8 mL blood 
sample will be collected for DNA isolation and pharmacogenomics analysis. In the event of 
DNA extraction failure, a replacement blood sample may be requested from the subject.  
Data will be analysed in the context of this study but may also be explored in aggregate with 
data from other studies. Pharmacogenomics research may consist of analysis of one or more 
candidate genes or the analysis of genetic markers throughout the genome or analysis of the 
entire genome in relation to USL311. The pharmacogenomic samples will only be used for 
investigations related to the disease and the study treatment in the context of this clinical 
program. They will not be used for broad exploratory analyses for unspecified disease or 
population genetics. DNA samples may be analysed for genetic factors contributing to the 
subject’s response to USL311 or other study treatment, in terms of PK, efficacy, tolerability, 
and safety. Such genetic factors may include genes for drug metabolizing enzymes, drug 
transport proteins, genes within the target pathway, or other genes believed to be related to 
study treatment response. Some genes currently insufficiently characterised or unknown may 
be understood to be important at the time of analysis. The samples may also be used for the 
development of diagnostic tests related to USL311 (or study treatments of this class). The 
results of pharmacogenomic analyses may be reported in a separate study summary. 
Data arising from all biosamples will be subject to the country-specific confidentiality 
standards. Further information for the handling, collection, storage, and shipping of genotyping 
samples will be provided in a separate laboratory sample handling manual. Samples will be 
stored at a l ong-term storage facility under contract by the Sponsor and analyzed up t o a 
maximum of 5 years after study completion, after which time the samples will be destroyed by 
incineration. Subjects have the right to refuse and to have their samples destroyed at any time. 
At the conclusion of the study, samples will be de-identified and handled in accordance with 
FDA guidance or other country specific guidance’s, as applicable. 
8.4.9. 
Pregnancy Testing 
Female subjects of childbearing potential are required to have a s erum pregnancy test for 
beta-human chorionic gonadotropin (β-hCG) at Screening. If positive, a confirmatory serum 
(required) pregnancy test will be performed. Female subjects with a positive pregnancy test 
and subsequent confirmation at Screening do not meet eligibility criteria for enrollment. If 
 
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treatment with study drug is stopped for ≥ 14 days, subject should have a negative pregnancy 
test prior to restarting study drug(s).  
Females are considered not of childbearing potential if they meet any of the following criteria: 
• Postmenopausal with > 1 year since last menses and:  
− If younger than 65 years old, with a follicle-stimulating hormone (FSH) > 40 
mIU/mL 
− If ≥ 65 years old and not on hormone replacement therapy (HRT), with a 
FSH > 30 mIU/mL 
− If ≥ 65 years old and on HRT, the FSH requirement is not applicable. 
Postmenopausal females on HRT will be allowed if the treatment is stable for 
at least 6 months prior to dosing of study drug(s) 
• Written medical documentation of being sterilized (e.g. hysterectomy, double 
oophorectomy, bilateral salpingectomy). Note: Tubal ligation is not considered a 
form of permanent sterilization. 
Additional pregnancy testing (serum or urine) will occur at regular intervals during each study 
part.  
Blood and urine samples will be collected by qualified study center personnel and those 
samples to be used for clinical laboratory assessment will be sent to be analyzed by the local 
laboratory for the pregnancy screens. Refer to Section 9.3.3 for details on t he reporting 
procedures to follow in the event of pregnancy. 
Note: A single urine sample may be collected and split for BMP biomarker, urine dipstick 
analysis, and/or urine pregnancy testing. 
8.4.10. 
Archived Tumor Histology 
During the Screening eligibility assessment for all 4 study parts, the availability of tumor block 
and/or slides (stained and/or unstained) used for diagnosis of the solid tumor (Parts 1 and 2) or 
GBM (Parts 3 and 4) must be confirmed for each subject. As soon as possible following the 
administration of the first dose of study drug(s), the tumor slides should be sent to the identified 
specialty lab. 
8.5. 
Pharmacokinetic Endpoints 
Blood samples will be collected for analysis of whole blood concentrations and plasma 
concentrations of USL311 and its metabolites as well as plasma concentrations of lomustine. 
Blood and plasma PK parameters will be calculated for USL311 and its metabolites, and 
plasma PK parameters will be calculated for lomustine and/or its metabolites. 
Non-compartmental and/or compartmental-based PK methods will be utilized and will include 
the following PK parameters as supported by the available data: 
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Table 20: 
Pharmacokinetic Parameters 
Dose Number 
Pharmacokinetic Parameters 
First Dose 
Cmax, tmax, tlast, AUC0-t,  AUC0-tau, AUC0-∞,  AUC % Extrapolated, *CL/F, λz, Terminal t1/2 
Subsequent 
Doses 
Cmax, tmax, Cmin, tmin, Cavg, Fluctuation Index (FI), AUC0-tau, *CLss/F, λz, Terminal t1/2, 
*VZ/F; Accumulation Ratio and AUC Ratio  
* Calculated for USL311 and lomustine (parent drug) only 
Additional PK parameters (e.g., area under the moment curve [AUMC], Mean Residence 
Time, metabolite:parent ratios, blood:plasma ratios) may be calculated as warranted.  
CSF collection (see Section 8.6.2) is not required in Parts 1 and 2 but may occur as part of a 
Phase 1 sub-study at select sites and in a subset of subjects. In Parts 3 and 4, CSF collection 
will occur in all subjects during the surgical resection procedure. CSF samples will be used to 
evaluate the biodistribution of USL311 and its metabolites to the CNS and for PK/PD 
correlations.  
8.6. 
Pharmacokinetic Assessments 
8.6.1. 
Whole Blood and Plasma Sample Collection 
Blood samples will be collected for the determination of whole blood and plasma 
concentrations and PK. Samples will be collected according to the schedule in Table  8 for Part 
1a, Table  9 for Part 1b, Table  10 for Part 2, and Table  11 and Table  12 for Parts 3 and 4. 
Additionally, at the occurrence of an SAE or DLT, unscheduled blood samples for USL311 
and lomustine (Parts 2 and 4 only) should be collected as soon as possible relative to the event. 
Blood samples will be collected in the arm contralateral to that containing the IV catheter for 
USL311 infusion via a saline flush catheter or by direct venipuncture. Samples will not be 
collected from the site of study drug infusion. Approximately 4 ml of blood will be collected 
at each time point for the analysis of whole blood (2 mL) and plasma (2 mL) USL311, M10 
and 4-AP concentrations. Approximately 4 mL of blood will be collected at each time point 
for the analysis of plasma lomustine and/or its metabolites concentrations (Parts 2 and 4 only). 
Samples will be collected in blood collection tubes containing EDTA K2 anticoagulant, 
inverted several times, and immediately be placed in an ice bath. The clock times of all blood 
draws will be recorded and reported for each subject. All tubes will be labeled with the subject 
identification number, protocol, and planned blood draw time point. 
The total volume of blood collected for USL311 PK analysis is approximately 88 mL for Part 
1a, approximately 76 mL for part 1b, approximately 108 mL for Part 2, and approximately 112 
mL for Parts 3 and 4 (including Pre-surgical USL311 dosing). The total volume of blood 
collected for lomustine PK analysis is approximately 64 mL in Part 2 and approximately 32 
mL in Part 4. 
Blood samples for determination of the whole blood and/or plasma concentrations of study 
drug/metabolites will be analyzed at contract laboratories designated by the Sponsor. Samples 
will be analyzed using a validated bioanalytical method. Additional exploratory PK analyses 
such as metabolite profiling and analysis of USL311 concentrations in blood fractions (e.g., 
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WBCs, erythrocytes) may be conducted using the backup samples. If conducted, this analysis 
will be performed independent of the clinical study and described in a separate analysis report. 
As PK data become available, some samples may become optional, if warranted based on 
ongoing PK data analysis during the study conduct. Specific samples and the rationale for 
making them optional will be documented. 
Detailed instructions for PK sample collection, processing, storage, and shipping will be 
provided by the analytical laboratory. 
8.6.2. 
Cerebrospinal Fluid Sample Collection 
Collection of CSF will be used to evaluate the biodistribution of USL311 to the CNS and 
PK/PD correlations. 
In Parts 1 and 2, CSF sample collection is not required.  However, if determined to be feasible 
and appropriate, CSF may be collected as part of a sub-study at select sites and in a subset of 
subjects. In the sub-study, CSF samples would be collected by lumbar puncture according to 
each site’s institutional procedures to obtain approximately 1 mL of CSF from each subject. 
Subjects with lumbar puncture contraindications, as determined by the Investigator, would not 
be eligible for the potential collection of CSF during Parts 1 and 2. 
In Parts 3 and 4, all subjects will have a CSF sample collected during the re-resection surgical 
procedure. The CSF sample will be collected from the operative field at the time of resection. 
Approximately 1 mL of CSF will be collected from each subject.  
Detailed instructions for CSF sample collection, processing, storage, and shipping will be 
provided by the analytical laboratory. 
8.7. 
Exploratory Assessments 
The goal of exploratory, biomarker, PD analyses will be to potentially correlate measurable 
markers with prognosis, clinical results and/or safety observations and inform future 
development of USL311. Additionally, quality of life (QOL) assessments will allow for subject 
reported improvements. 
Biomarkers not currently listed in the protocol, and relevant to the drug activity, might be 
added to the list of biomarkers to be assessed if they are determined as relevant based on 
publication of research made available during the time this study is ongoing. If possible, 
archiving of biomarker samples (including tumor tissue samples) is recommended to facilitate 
future biomarker testing. For those subjects who consent, some samples may be stored for 
future research. Samples will be stored for a maximum of 15 years at a long-term storage 
facility under contract by the Sponsor. At a maximum, the samples will be destroyed after 15 
years by incineration. Subjects have the right to refuse and to have their samples destroyed at 
any time. At the conclusion of the study, samples will be de-identified and handled in 
accordance with FDA guidance or other country specific guidance’s, as applicable. 
8.7.1. 
Quality of Life Assessment 
In Phase 2, Q OL and subject reported outcomes will be assessed using the European 
Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire, 
 
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supplemented with a brain-cancer module (EORTC QLQ-C30/BN20). The assessment of 
quality of life via EORTC QLQ-C30/BN20 is described in Appendix 8. 
The QLQ-C30 is a 30-item self-report questionnaire that has patients rate the items on a 4-point 
scale, with 1 ― “not at all” to 4 ― “very much.” The questionnaire measures several domains, 
including physical functioning, role functioning, emotional functioning, cognitive functioning, 
social functioning, fatigue, pain, nausea and vomiting, and several single items (dyspnea, 
insomnia, anorexia, constipation, diarrhea, and financial impact). The BN20 consists of 
4 scales comprising multiple items (future uncertainty, visual disorder, motor dysfunction, 
communication deficit) and 7 single items (headache, seizures, drowsiness, hair loss, itching, 
difficulty with bladder control, and weakness of both legs) and is intended to be completed by 
patients with primary brain tumors. The combined instrument takes an average of 8 minutes to 
complete. 
8.7.2. 
Resected Tissue Collection 
During Parts 3 and 4, tissue will be collected during the re-resection surgery (see Section 3.3.3) 
from each consenting subject. Since the identification of biomarkers that correlate with disease 
activity and the efficacy or safety of treatment is rapidly evolving, some analyses might be 
determined after or instead of the below mentioned analyses. 
Tumor samples will be used to measure biomarkers or changes in biomarkers related to the 
CXCR4 pathway, and/or study drug effects when possible. Exploratory (translational) studies 
on resected tissue may be performed to determine biodistribution of USL311 in the tumor and 
assess pharmacodynamic markers (pCXCR4 profile, autophagy markers [e.g., LC3, Beclin-1], 
markers of vasculogenesis [e.g., CD11b] and cancer stem cell survival and proliferation [e.g., 
nestin, CD133]). Genetic testing for the prognostic markers MGMT promoter methylation 
status and IDH-1 mutational status may also be performed. 
Samples will be analyzed at a laboratory designated by the Sponsor. Tissue samples collected 
for assessment of the exploratory objectives will be analysed using appropriately qualified 
and/or validated assay methods. Detailed instructions for tissue sample collection, processing, 
storage, and shipping will be provided by the specialty laboratory. 
8.7.3. 
Collection of Other Biomarkers 
Other biomarkers will be collected during the study; these include but are not limited to the 
following for analysis of target engagement and DIPL. 
Target Engagement Biomarkers: 
All blood samples for target engagement biomarkers will be collected through a saline flush 
catheter or by direct venipuncture in the limb contralateral to that containing the IV catheter 
for drug infusion, if applicable. Samples will not be collected from the site of study drug 
infusion. The clock times of all blood draws will be recorded and reported for each subject. 
All tubes will be labeled with the subject identification number, protocol, and planned blood 
draw time point. 
The following biomarkers will be monitored in Parts 1 and 2 as markers of CXCR4 target 
engagement: 
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• Hematopoietic CD34+ cell count: Approximately 6 mL of blood will be collected 
at each nominal time point to measure whole blood CD34+ count. Samples will be 
collected in blood collection tubes containing EDTA K2 anticoagulant. Samples 
will be collected at the nominal time points described in Table  8, Table  9 and 
Table  10. The total volume of blood collected for CD34+ count in Part 1a is 
approximately 36 mL, in Part 1b approximately 30 mL, and in Part 2 is 
approximately 36 mL. 
• SDF-1: For Part 1a only, approximately 2 mL of blood samples will be collected at 
each time point to measure plasma SDF-1. Samples will be collected in blood 
collection tubes containing EDTA K2 anticoagulant. Samples will be collected at the 
time points described in Table  8. The total volume of blood collected for SDF-1 
samples in Part 1a is approximately 12 mL. 
• WBC Count and Differential: Approximately 2 mL of blood will be collected at 
each nominal time point to measure whole blood WBC count and differential. 
Samples will be collected in blood collection tubes containing EDTA K2 
anticoagulant. Samples will be collected at the nominal time points described in 
Table 8, Table 9 and Table 10. The total volume of blood collected for WBC count 
in Part 1a is approximately 40 mL, in Part 1b is approximately 102 mL and in Part 
2 is approximately 132 mL. 
Blood samples for determination of the target engagement biomarkers will be analyzed at 
specialty laboratories designated by the Sponsor. Detailed instructions for biomarker sample 
collection, storage, and shipping will be provided by the laboratory. 
DIPL Biomarker: 
The following biomarker will be monitored in Parts 1 and 2 as a marker of DIPL: 
• di-docosahexaenoyl (22:6)-bis(monoacylglycerol) phosphate (BMP): Urine samples 
will be collected to measure BMP as urine is the most sensitive matrix for USL311-
induced BMP changes in the animal studies. Samples will be collected according to 
Table  1 – Table  3. 
Urine samples for determination of BMP will be analyzed at a specialty laboratory designated 
by the Sponsor. Detailed instructions for biomarker sample collection, storage, and shipping 
will be provided by the specialty laboratory. 
Note: A single urine sample may be collected and split for BMP biomarker, urine dipstick 
analysis, and/or urine pregnancy testing. 
8.8. 
Appropriateness of Measures 
Tumor response, based on radiological measurement and RECIST v.1.1 criteria (56, 57), is a 
standard and well-accepted efficacy endpoint in clinical oncology for solid tumors. 
Additionally, tumor response, based on radiological measurement and RANO criteria (58), is 
standard and well-accepted efficacy endpoint in clinical neuro-oncology. 
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The safety and PK endpoints in this study are standard and well-understood endpoints in 
clinical oncology.  
For drugs targeting GBM, blood brain barrier penetration is critical and blood and plasma 
concentrations may not reflect concentrations within the CNS. CSF samples provide a direct 
and accessible measure of blood brain barrier penetration and CNS exposure. Moreover, 
nonclinical data indicates that CSF concentrations provide a reasonable surrogate of unbound 
drug concentrations in the CNS. 
The assessment of QOL via EORTC QLQ-C30/BN20 is a well-accepted tool for the 
assessment of QOL. Health-related QOL, symptom burden, and neurocognitive measures have 
been validated in the brain tumor population as additional indicators of treatment benefit (60). 
The PD assessments in blood samples (CD34+ cell count, WBC count and differential) were 
selected as systemic biomarkers of CXCR4 pathway modulation. CD34 is an antigen found on 
hematopoietic stem cells. Other agents that target the CXCR4 pathway (i.e, plerixafor) have 
been shown to mobilize CD34+ stem cells. USL311 has been demonstrated to mobilize WBCs 
in nonclinical studies (see Section 1.2.2.1) and clinical trials have demonstrated that other 
CXCR4 pathway modulators increase WBC count (61, 62). 
Tissue sample biomarkers were selected for the following reasons and these include; target 
activity (pCXCR4 profile), autophagy markers (e.g., LC3, Beclin-1), markers of 
vasculogenesis (e.g., CD11b) and cancer stem cell survival and proliferation (e.g., nestin, 
CD133). 
Nonclinical toxicology testing demonstrated that USL311 has the potential to cause DIPL. The 
BMP biomarker is a s ensitive and specific measure of DIPL (63). BMP is a lysosomal 
phospholipid that is increased in the tissues and biological matrices (urine, plasma, serum) of 
humans with DIPL. BMP that has been cleared or released by the kidney itself can be detected 
in the urine and urine sediment (64). The total volume of blood collected for study assessments 
will vary with each subject throughout the study and will depend on the duration of 
participation in the study. The total volume of blood collected during the study for any one 
subject is not expected to cause any harm. 
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9. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
The Investigator or designee and research site staff are responsible for the detection, 
documentation, classification, reporting, and follow-up of events meeting the definition of 
anAE or SAE. 
Spontaneously reported or observed AEs will be recorded throughout the study from the time 
of signing the ICF until the Follow-up Visit. AEs will be elicited using a non-leading question. 
Regardless of seriousness, intensity, or presumed relationship to study drug, all AEs will be 
recorded in the source documentation and entered on the appropriate eCRF from the time the 
subject signs the informed consent until the end of the Follow-up Visit (≤ 28 days after the last 
dose of study drug). After this time period, the only SAEs that need to be collected and reported 
to the Sponsor are those that are felt by the Investigator to be at least possibly related to study 
drug. All measures required for management of AEs will be recorded in the source 
documentation. 
This study will utilize the NCI CTCAE version 4.03 for AE reporting. 
9.1. 
Definitions 
9.1.1. 
Adverse Events 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product 
and may not necessarily have a causal relationship with the administered treatment. An AE can 
therefore be any unfavorable and unintended sign (including a clinically significant laboratory 
abnormality, for example), symptom, or disease temporally associated with the use of a study 
drug, whether or not related to the study drug. During the study, an AE can also occur outside 
the time that the study drug(s) was given (e.g., during a washout period). 
Examples of AEs include the following: 
• A symptom or disease not previously observed in the subject that emerges during 
the course of the study 
• Exacerbation of a pre-existing illness following the start of the study 
• Increase in frequency, or intensity of a pre-existing episodic event or condition 
• Condition that leads to a medical or surgical procedure (e.g., surgery, endoscopy, 
tooth extraction, transfusion) may be an AE, but the procedure itself is not an AE 
• Complications that occur as a result of non-drug protocol-imposed interventions 
(e.g., AEs related to Screening procedures, medication washout, or no treatment 
run-in) 
An AE does not include: 
• Relapse or progression of the underlying malignant disease; however, the associated 
signs, symptoms, or diagnosis should be recorded as AEs (e.g., “jaundice” due to 
new of increasing liver metastases, or “tumor pain” or “bone pain” due to 
progressive disease) 
 
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• Death due to the underlying malignant disease 
• Day to day fluctuations of pre-existing disease or conditions present or detected at 
the start of the study that do not represent a worsening of the disease or condition 
• Situations 
where 
an 
untoward 
medical 
occurrence 
has 
not 
occurred 
(e.g., hospitalizations for cosmetic elective surgery; medical or surgical procedures 
such as endoscopy, or transfusion; social and/or convenience admissions) 
• Overdose of either study drug or concurrent medication without any signs or 
symptoms 
The Investigator will evaluate AEs using the following guidelines: 
• Description of Event (if the event consists of a cluster of signs and symptoms, a 
diagnosis should be recorded [e.g., flu syndrome] rather than each sign and 
symptom) 
• Onset Date 
• Stop Date 
• Intensity 
• Seriousness 
• Relationship to study drug 
• Frequency 
• Outcome 
• Action taken (with regard to study drug): no change, permanent discontinuation, 
temporarily stopped) 
9.1.2. 
Serious Adverse Events and Serious Unexpected Adverse Events 
It is important to distinguish between SAEs and severe AEs. Severity is a measure of intensity, 
whereas seriousness is defined by the criteria provided below. An AE of severe intensity need 
not necessarily be considered serious. For example, a migraine headache that incapacitates a 
subject for many hours may be considered to be a severe AE, but it is not an SAE. 
Seriousness, as provided in FDA Title 21, CFR Part 312 and the guidelines of the ICH GCP 
(CPMP/ICH/135/95), define an SAE as any untoward medical occurrence that occurs at any 
dose of study drug(s): 
• Results in death, 
• Is life-threatening (immediate risk of death at the time of the event), 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
• Results in persistent or significant disability/incapacity, or 
• Is a congenital anomaly/birth defect. 
 
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• 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 subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
A serious and unexpected AE is an SAE that is not identified in nature, intensity, or frequency 
in the risk information set out in the Investigator’s Brochure and/or on the label of the drug. 
The Investigator must record whether or not the AE meets the definition of serious. If the event 
is serious, the investigator must complete an electronic SAE Report Form. 
9.1.3. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
Abnormal laboratory findings (e.g., from clinical chemistry, hematology, or UA) or other 
abnormal assessments (e.g., from vital signs or ECG) should not be listed on the AE eCRF 
page unless signs or symptoms are present or the laboratory finding or assessment is deemed 
clinically significant by the Investigator or designee (confirmed by repeat laboratory testing). 
If a laboratory value or assessment is related to a medically defined new or worsening of a 
preexisting diagnosis or syndrome, the diagnosis or syndrome, not the individual laboratory 
values, will be recorded on the AE eCRF page. If a medically defined diagnosis or syndrome 
cannot be made and the subject is asymptomatic, a clinically significant laboratory or 
assessment value will be recorded as an AE. 
All clinically significant abnormal laboratory results or assessments will be followed until they 
resolve (return to normal or baseline values) or stabilize, or until they are judged by the 
Investigator to be no longer clinically significant. 
9.2. 
Evaluation of Adverse Events and Serious Adverse Events 
The Investigator or designee is responsible for making an assessment as to the seriousness, 
intensity, causality, and outcome of an AE. 
9.2.1. 
Classification of Adverse Event Intensity 
The Investigator will determine the severity of each event by using NCI CTCAE v.4.03 grading 
criteria. Adverse events that do not have a corresponding NCI CTCAE term will be assessed 
according to the general guidelines for grading used in the NCI CTCAE as stated in Table 21 
below. 
If there is insufficient information to determine intensity, the AE must still be reported; the 
intensity/grading can be added after additional information is received. Classification for 
asymptomatic abnormalities will be according to the Investigator or designee’s discretion and 
any applicable site standard operating procedures. 
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Table 21: 
Classifications for Adverse Event Intensity/Grading 
Description 
Grade 
Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
1 
Moderate: minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL)a 
2 
Severe or medically significant but not immediately life-threatening: hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADLb 
3 
Life threatening or debilitating: consequences; urgent intervention indicated 
4 
Death related to AE 
5 
a Instrumental ADL refer to the following examples: preparing meals, shopping for groceries or clothes, using the 
telephone, managing money. 
b Self-care ADL refer to the following examples: bathing, dressing and undressing, feeding oneself, using the toilet, taking 
medications, not bedridden. 
9.2.2. 
Classification of Adverse Event Causality 
For each recorded AE or SAE, the Investigator or designee must make an assessment of 
causality for USL311 (and for lomustine when applicable) based on the following criteria to 
determine the relationship between the AE or SAE and study drug(s). The Investigator must 
make a causality assessment (relationship to study drug[s]) based on the following 5 causality 
terms in Table 22. 
Table 22: 
Relationship to Study Drug 
Relationship 
Attribution 
Description 
Unrelated to study 
drug 
Not related 
The AE is not temporally correlated with study drug(s) 
administration; the AE is clearly explained by another mechanism. 
Probably not 
related 
The AE is not reasonably, temporally correlated with study 
drug(s) administration; is more likely explained by another 
mechanism. 
Related to study 
drug 
Possibly related 
The AE is temporally correlated with study drug(s) 
administration; can be explained equally well by study drug(s) 
exposure or another mechanism. 
Probably related 
The AE is temporally correlated with study drug(s) administration 
and is more likely explained by study drug(s) exposure than by 
another mechanism. 
Related 
The AE is temporally correlated with study drug(s) 
administration; the AE is more clearly explained by study drug(s) 
exposure than by another mechanism. 
 
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9.2.3. 
Classification of Adverse Event Outcome 
For each recorded AE or SAE, the Investigator or designee must make an assessment of 
outcome at the time of last observation. The outcome of AEs or SAEs will be documented as 
follows: 
Table 23: 
Classifications for Adverse Event Outcomes 
Classification 
Definition 
Fatal 
The AE results in death. 
Resolved 
The AE or SAE has ended. 
Improved 
The AE or SAE is not yet resolved, but improving. 
Resolved with 
Sequelae 
The AE or SAE has ended but changes are noted from baseline that are stable or 
chronic. 
Unresolved 
The AE has not ended. 
An AE outcome can only be categorized as unresolved, if the AE is: 
ongoing at the end of the reporting period (i.e., after the Follow-up Visit) and the 
Investigator deems that further follow-up is not medically required; 
lost to follow-up after repeated unsuccessful attempts to contact the subject; 
ongoing and referred to the subject’s physician or a specialist. 
The Investigator’s assessment of causality for individual AE reports is part of the study 
documentation process. Regardless of the causality assessment for individual AE/SAE reports, 
the Sponsor will promptly evaluate all reported safety information against cumulative product 
experience to identify and expeditiously communicate possible new safety findings to 
Investigators and applicable regulatory authorities. 
9.3. 
Reporting Procedures 
The reporting period for both AEs and SAEs is the period from the time signing the ICF 
through the Follow-up Visit (≤ 28 days after the last dose of study drug[s]). If an AE or SAE 
remains unresolved at the conclusion of the study, the Investigator will assess whether 
continued follow-up of the AE or SAE is warranted, and the results of this assessment must be 
documented. Resolution is defined as the return to baseline status or stabilization of the 
condition with the expectation that it will remain chronic. The Investigator should follow all 
unresolved AEs and SAEs until the events are resolved or stabilized, or the subject is lost to 
follow-up. Outcome of AEs (with dates) should be documented on t he appropriate eCRF 
page(s) and in the subject’s medical record.  
9.3.1. 
Serious Adverse Events and Serious Unexpected Adverse Events 
Any SAE, whether expected or unexpected, irrespective of relationship to study treatments, 
experienced by a study subject, will be reported to the Sponsor by the Investigator or designee, 
on an electronic SAE Report Form within 24 hours but no later than one business day of 
learning of the event. Information regarding the SAE will be transmitted to Chiltern 
International pharmacovigilance (PV); contact information and timelines are listed below in 
Table 24. 
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Table 24: 
SAE Reporting Information 
Type of 
SAE 
Reporting 
Timeframe 
Primary 
Reporting Method 
Primary Contact 
Secondary Contact 
Fatal or  
Life-
threatening 
SAEs 
Immediately 
from 
becoming 
aware of the 
SAE 
Phone call to 
Proximagen and/or 
Chiltern Medical 
Monitors 
Chiltern International PV 
Medical Monitor Phone:  
423-990-0289 
Email:  
global.SAEinbox@chilter
n.com   
Tze-Chiang Meng, MD 
Office: 952-658-7440 
Mobile: 952-818-5850 
Email: 
TCMeng@proximagen.co
m 
Immediately 
but no later 
than 24 hours 
from 
becoming 
aware of the 
SAE 
Electronic SAE 
report form in EDC 
Merge 
Email 
Chiltern International PV 
Email: 
global.SAEinbox@chilter
n.com 
Email:  
drugsafetyUSL311@prox
imagen.com 
 
Non-Fatal 
or Life-
threatening 
SAEs 
Immediately 
but no later 
than 24 hours 
from 
becoming 
aware of the 
SAE. 
Electronic SAE 
report form in EDC 
Merge 
Email 
Chiltern International PV 
Email: 
global.SAEinbox@chilter
n.com 
Email:  
drugsafetyUSL311@prox
imagen.com 
The Sponsor assumes responsibility for appropriate reporting of SAEs to the regulatory 
authorities. Reporting of SAEs to the appropriate regulatory authorities will be completed by 
the Sponsor or its representatives. The Sponsor, or its representatives, will also report to the 
Investigator, all SAEs (including those from other USL311 studies), that are unlisted and 
associated with the use of the study drug(s). The Investigator (or the Sponsor, where required) 
must report these events to the appropriate IRB)/IEC that approved the protocol (unless 
otherwise required and documented by the IRB/IEC). 
All additional follow-up evaluations for SAEs will be reported to the Sponsor in the same 
timeframes as listed above. All SAEs must be followed until they are resolved (return to normal 
or baseline) or the subject’s condition has stabilized, or until they are judged by the Investigator 
to be no longer clinically significant. If a subject dies, a death certificate and any available post 
mortem findings (including histopathology) must be provided to the Sponsor (or its designee). 
9.3.2. 
Any Adverse Event 
Regardless of seriousness, intensity, or presumed relationship to study drug(s), all AEs will be 
recorded in the source documentation and on the AE eCRF page. SAEs also require completion 
of the electronic Serious Adverse Event Form. If necessary, paper forms will be used as back 
up. Whenever possible, diagnoses will be recorded when signs and symptoms are due to a 
common etiology. In addition, the Investigator must record his or her opinion as to the intensity 
of the AE and whether the AE is related to study drug. All measures required for management 
of the AE will be recorded in the source documentation. 
 
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9.3.3. 
Pregnancy 
Any subject who becomes pregnant during the study will be immediately withdrawn and will 
be scheduled for the End of Treatment and Follow-up Visits. Research site staff will report the 
pregnancy to Chiltern within 24 hours of learning of the pregnancy. The Investigator must 
complete the Pregnancy Notification Form provided by the Sponsor. The Investigator 
willperiodically follow up with the subject until delivery or termination of the pregnancy, 
providing necessary updated information to Chiltern using the Pregnancy Outcome Form. 
Information on the status of the mother and the child will be forwarded to Chiltern using the 
Pregnancy Notification Follow-up Form. Generally, follow-up will occur within 6−8 weeks 
following the expected delivery date. Any premature termination of the pregnancy will also be 
reported on this form. 
Although pregnancy occurring in a clinical study is not considered to be an AE or SAE, any 
pregnancy complication or elective termination of a pregnancy for medical reasons, will be 
recorded as an AE or SAE and will be followed as such. A spontaneous abortion is always 
considered to an SAE and requires completion of an SAE Form.  
9.4. 
Follow-up of Adverse Events and Serious Adverse Events 
All AEs and SAEs must be followed until they are resolved (return to normal or baseline), the 
subject’s condition has stabilized, or until they are judged by the Investigator to be no longer 
clinically significant. Supplemental measurements and/or evaluations may be necessary to 
fully investigate the nature and/or causality of an AE or SAE. This may include additional 
laboratory tests, diagnostic procedures, or consultation with other healthcare professionals. If 
the subject dies, a death certificate and any available postmortem findings (including 
histopathology) must be provided to the Sponsor. 
If it becomes unlikely that any additional information can be obtained (e.g., subject or health 
care practitioner refuses to provide additional information, the subject is lost to follow-up), the 
Investigator or designee will ensure that the follow-up includes any pertinent supplemental 
investigations (e.g., laboratory tests or investigations, histopathological examinations or 
consultation with other health care professionals) to elucidate the nature and/or causality of the 
AE or SAE. 
SAEs that occur after the Follow-up Visit will be collected only if the events are considered 
by the Investigator to be at least possibly related to study drug. 
9.5. 
Urgent Safety Measures 
The regulations governing clinical trials state that the Sponsor and Investigator are required to 
take appropriate urgent safety measures to protect subjects against any immediate hazards that 
may affect the safety of subjects, and that the appropriate regulatory bodies should be notified 
according to their respective regulations. According to the European Union (EU) Clinical Trial 
Directive 2001/20/EC, “…in the light of the circumstances, notably the occurrence of any new 
event relating to the conduct of the trial or the development of the investigational medicinal 
product where that new event is likely to affect the safety of the subjects, the Sponsor and the 
Investigator shall take appropriate urgent safety measures to protect the subjects against any 
immediate hazard. The Sponsor shall forthwith inform the competent authorities of those new 
 
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events and the measures taken and shall ensure that the IRB/IEC is notified at the same time.” 
The reporting period for these events which may require the implementation of urgent safety 
measures is the period from the time of signing of the ICF through the completion of the 
Follow-up Visit. Investigators are required to report any events that may require the 
implementation of urgent safety measures to Sponsor within 24 hours. 
Examples of situations that may require urgent safety measures include discovery of the 
following: 
• An immediate need to revise the study drug administration (i.e., modified dose 
amount or frequency not defined in protocol) 
• Detrimental study conduct or management 
• Discovery that the quality or safety of the study drug does not meet established 
safety requirements 
 
 
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10. 
DATA ANALYSIS AND STATISTICAL PROCEDURES 
10.1. 
General Statistical Considerations 
Complete details of the statistical analyses to be performed will be documented in statistical 
analysis plan(s), which will be completed prior to locking the database. This document will 
include more detail of analysis populations, summary strategies, and any amendments to the 
proposed analyses listed here, if necessary. Any deviations to the procedures outlined in the 
statistical analysis plan(s) will be outlined in the final study report. Additional statistical 
analyses other than those described in this section may be performed if deemed appropriate 
and will be described in the statistical analysis plan(s) (SAP). 
Efficacy, safety, PK, PD and QOL assessments will be summarized separately for Phase 1 
(Parts 1 and 2, the “dose-escalation cohorts”) and Phase 2 (Parts 3 and 4, the “dose-expansion 
cohorts”) of the study. Additional summaries and analyses of pooled Phase 1 and 2 data may 
also be generated. Part 1a (USL311 IV administration) may be analyzed separately; 
furthermore, subjects administered 2-hour and 4-hour infusions may be displayed separately.  
Details of the handling of Part 1a will be described in the SAP. Descriptive and summary 
statistics will be presented by dose group and overall, as appropriate. Statistics will include 
number of observations, mean, standard deviation, median, range, and inter-quartile range for 
continuous variables, and the number and percent for categorical variables; 95% or 90% 
confidence intervals will be presented where appropriate. Additional statistics such as 
geometric mean and coefficient of variation (CV%) may be calculated as warranted. 
10.2. 
Interim Analysis 
No formal interim analysis will be performed in this study. After each part in Phase 1, the MTD 
for single agent USL311 (Part 1) and USL311 in combination with lomustine (Part 2) will be 
determined by the DEC. The DEC will determine the RP2D which will be used for Phase 2 
dosing for single agent USL311 (Part 3) and USL311 in combination with lomustine (Part 4). 
10.3. 
Missing Data 
Handling of missing data, drop-outs, outliers and censoring rules will be described in the 
SAP(s). 
10.4. 
Analysis Data Sets 
The following data sets will be defined for data analysis: 
• Full Analysis Data Sets will include all subjects who receive at least one dose of 
USL311 or lomustine.  This will be the analysis set for all efficacy analyses. 
• Safety Analysis Data Sets will include all subjects who received at least one dose 
USL311 or lomustine and have at least one post-baseline safety evaluation. This will 
be the analysis set for all Safety analyses. 
• MTD-Evaluable Data Sets will include all subjects in Phase 1 (dose-escalation) 
who complete one cycle of treatment and assessment or who discontinue before 
 
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completing the first cycle because of toxicity. This will be the analysis set for MTD 
determination in the Phase 1. 
• Pharmacokinetic (PK) Analysis Data Sets will include all subjects who have 
received at least one dose of USL311 or lomustine and have at least one quantifiable 
post-dose blood or plasma concentration of either drug. 
• Pharmacodynamic (PD) Analysis Data Sets will include all subjects who have 
received at least one dose of USL311 or lomustine and have at least one evaluable 
post treatment assessment for the given PD measure. 
• Response-Evaluable Analysis Data Sets will consist of those subjects who have 
received at least one dose of USL311 or lomustine and have evaluable disease at 
baseline. 
− In Parts 3 and 4, subjects must have received at least one dose of USL311 or 
lomustine post-surgery and have at least one non-missing efficacy assessment 
(i.e., imaging or survival assessment) 
• Exposure-Response Analysis Data Sets will be constructed for each PD or 
response endpoint to be evaluated for correlation with PK data. The exposure-
response analysis sets will consist of all subjects in the PK Analysis Set that also 
have an evaluable PD/response pretreatment assessment and at least one post 
treatment PD/response assessment. 
10.5. 
Dispositions, Demographics, and Other Baseline Characteristics 
Demographics and baseline characteristics (e.g., age, sex, race, ethnicity, body weight) will be 
summarized using descriptive statistics for the Safety Population.  
The number of subjects in each of the treatment groups will be presented, in addition to the 
number of subjects who complete each visit. The reasons for all post-randomization 
discontinuations will be tabulated and grouped by treatment and major reason. All deviations 
related to study inclusion or exclusion criteria, conduct of the trial, subject management, or 
subject assessment will be described. 
10.6. 
Medical and Surgical History 
Medical and surgical history will be coded according to the Medical Dictionary for Regulatory 
Activities (MedDRA®) and the incidences will be tabulated for the Safety Population. 
10.7. 
Efficacy Endpoints Analysis 
Efficacy will be evaluated in both Phase 1 and Phase 2 components. In Phase 1, preliminary 
efficacy parameters such as PFS-6m, ORR%, DCR and OS will be determined using RECIST 
v.1.1 or RANO criteria as appropriate. The Phase 2 analyses will characterize efficacy in 
subjects in the dose expansion cohorts treated at the RP2D for USL311 as a single agent and 
in combination with lomustine as determined by % PFS-6m, PFS, OS, ORR%, DCR, and as 
defined by RANO criteria. 
 
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There is no formal hypothesis testing in this trial for efficacy endpoints. Approximately 
20 evaluable subjects will be studied in each of the two Phase 2 dose-expansion groups to 
provide a preliminary estimate of efficacy in relapsed/recurrent GBM. The primary objective, 
PFS-6m, will be calculated with two-sided 90% confidence interval (CI) using K-M 
product-limit estimate of PFS. This will be performed based on both the full analysis set and 
response-evaluable set. Median PFS will be calculated using K-M product-limit estimates and 
presented with two-sided 90% CIs. 
Every effort will be made to ensure complete, accurate and timely data collection, and to avoid 
missing data. 
10.8. 
Safety Endpoints Analysis 
Adverse event (AE) data will be descriptively evaluated. Descriptive statistics (e.g., number of 
observations, means, standard deviations, medians, maximum and minimum values) will be 
used to summarize continuous variables. Frequencies, proportions, and the exact 95% 
confidence intervals (CI), when appropriate, will be used to summarize categorical variables. 
Subject listings will also be provided.  
In both Phase 1 and Phase 2, the incidence and duration of toxicities will be tabulated according 
to the NCI-CTCAE version 4.03. All laboratory results and vital sign measurements will be 
summarized using appropriate descriptive statistics.  T he schedule of assessments tables 
describes the timing of required evaluations.  
Safety and tolerability will be evaluated in both Phase 1 and Phase 2 components. The Phase 
1 primary analyses will include determination of the MTD and RP2D for USL311 as a single 
agent and in combination with lomustine. All available safety, tolerability, PK and PD data 
will be considered by Sponsor in dose escalation decisions.  
Additional safety analyses other than those described in this section may be performed if 
deemed appropriate and will be described in detail in a separate analysis plan. 
10.9. 
Pharmacokinetic Endpoints Analyses 
Blood (as appropriate) and plasma concentrations of each analyte (USL311, M10, 4-AP, as 
well as lomustine and/or its metabolites) will be listed for each individual subject and 
descriptive statistics will presented for each time point by dose and treatment.  As warranted, 
PK data will be presented in tables and graphical displays with time “0” assigned to the dosing 
time of each treatment. 
Blood and plasma PK parameters for each analyte will be calculated using non-compartmental 
and/or compartmental methods (such as population PK analysis) as appropriate using actual 
sample collection times post-dose. Individual subject PK parameters will be listed and 
descriptive statistics will be calculated by dose and treatment. Mean and individual subject 
blood (USL311, M10 and 4-AP only) and plasma concentration-time profiles will be presented 
on rectilinear and semi-logarithmic scales stratified by dose and treatment. 
Concentrations of USL311 and its metabolites in CSF and tumor samples will be listed for 
each individual subject and descriptive statistics will be calculated by dose and treatment. 
 
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Assessments of USL311 dose proportionality will be performed using standard methods (i.e., 
power model approach) and will be supported by graphical analysis. 
Assessment of a PK drug-drug interaction between USL311 and lomustine will be via 
comparison of USL311 and lomustine PK parameters (AUC, Cmax) when administered in 
combination to the PK parameters of each agent when administered alone. Statistical analysis 
will be performed using standard methods (i.e., analysis of variance [ANOVA], non-linear 
mixed effect modeling) and will be supported by graphical analysis. 
Correlations between PK parameters and safety, efficacy and/or PD metrics may be explored 
graphically and if relationships are observed, exploratory analyses may be performed. 
Additional exploratory analyses may be conducted and will be described in detail in a separate 
analysis plan. 
10.10. 
Pharmacodynamic Endpoints Analyses 
PD data obtained from the exploratory/translational analyses will be summarized using 
descriptive statistics as appropriate. Correlations between PD measures and safety and/or 
efficacy metrics may be explored graphically and if relationships are observed, exploratory 
analyses may be performed. PD parameters (i.e., peak concentrations, area under the curve) 
may be calculated and additional exploratory analyses may be conducted and will be described 
in detail in a separate analysis plan. 
10.11. 
Quality of Life/ Patient Reported Outcome Measures 
In Phase 2, changes in health-related QOL and patient reported outcome measures will be 
assessed based on the EORTC QLQ-C30/BN20. The QLQ-C30 is a 30-item self-report 
questionnaire that measures several domains, including physical functioning, role functioning, 
emotional functioning, cognitive functioning, social functioning, fatigue, pain, nausea and 
vomiting, and several single items. The BN20 consists of 4 scales comprising multiple items 
(future uncertainty, visual disorder, motor dysfunction, communication deficit) and 7 single 
items (headache, seizures, drowsiness, hair loss, itching, difficulty with bladder control, and 
weakness of both legs). 
10.12. 
Sample Size Calculation 
There is no formal hypothesis testing in this trial, thus no calculation of sample size was 
calculated. See Section 5.1 for an approximation of the number of subjects to be enrolled in 
the study. 
10.13. 
Data Collection and Electronic Data Capture 
The study site will use a validated electronic data capture (EDC) system to enter subject data 
onto eCRFs. Data will be collected using the EDC system and entered into a quality controlled 
clinical database. Prior to the commencement of the study, items to be included in the clinical 
database will be determined and suitable paper source documents will be created to ensure the 
appropriate collection of all required data. Clinical staff conducting the study will record the 
required data onto source documents and will enter the appropriate data from source documents 
into the clinical database. All entries, corrections, and alterations will be made by the 
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11. 
ADMINISTRATIVE PROCEDURES 
11.1. 
Regulatory Approval 
This study requires application to the appropriate regulatory body in the countries concerned. 
The study will only be undertaken following receipt of written approval or acknowledgement 
of receipt (depending on local regulation) from the regulatory bodies by the Sponsor, or 
following submission to appropriate authorities, whichever is required by the respective 
countries. 
This study requires authorization by any member state Regulatory Authority where the clinical 
study will be conducted in accordance with National law requirements. The study will only be 
undertaken by the Sponsor following receipt of written approval from the Regulatory 
Authority. 
11.2. 
Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) Approval 
The Sponsor or its designee must receive signed and dated written confirmation that the study 
protocol and ICF and assent forms have been approved or favorably reviewed by the IRB/IEC 
before the study center will be initiated. The IRB/IEC Membership Roster (or assurance 
number, if applicable) must also be supplied to the Sponsor or its designee before center 
initiation. 
The Investigator will provide the IRB/IEC with all appropriate material, including the protocol, 
Investigator’s Brochure (IB), the ICF including compensation procedures, and any other 
written information provided to the subjects, including all ICFs translated to a language other 
than the native language of the clinical site. The study will not be initiated and study drug 
supplies will not be shipped to the site until appropriate documents from the IRB/IEC 
confirming unconditional approval of the protocol, the ICF and all subject recruitment 
materials are obtained in writing by the Investigator and copies are received at Sponsor or its 
designee. The approval document should refer to the study by protocol title and Sponsor 
protocol number (if possible), identify the documents reviewed, and include the date of the 
review and approval. Sponsor will ensure that the appropriate reports on the progress of the 
study are made to the IRB/IEC and Sponsor by the Investigator in accordance with applicable 
guidance documents and governmental regulations. 
Any amendment(s) to the study protocol that affect the study design, study procedures, or risk 
to study subjects, and any corresponding change to the informed consent or assent forms, must 
be approved by the IRB/IEC before the change is implemented, in conformance with GCP. If 
any such changes are made to the informed consent or assent forms, subjects that are still active 
in the study will be re-consented using the new form(s). 
 
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11.3. 
Ethical Conduct of Study 
This study will be conducted in accordance with the following: 
• United States (US) Code of Federal Regulations (CFR) sections that address clinical 
research studies, and/or other national and local regulations, as applicable 
Specifically, this study is based on adequately performed laboratory and animal 
experimentation. The study will be conducted under a protocol reviewed and approved by an 
IRB and will be conducted by scientifically and medically qualified persons. The benefits of 
the study are in proportion to the risks. The rights and welfare of the subjects will be respected 
and subject participation continued as long as the Investigators conducting the study do not 
find the hazards to outweigh the potential benefits. 
Each subject will provide written, informed consent before any study-specific tests or 
evaluations are performed. 
11.4. 
Study Personnel 
The Investigator should maintain a list of appropriately qualified persons who are delegated to 
perform significant study-related duties. In addition, the Investigator should maintain a 
signature sheet to document signatures, initials, and study responsibilities of all persons 
authorized to make entries and/or corrections to the eCRF. 
Prior to beginning the study, the Investigator at each site must provide to Sponsor or designee, 
a fully executed and signed US Food and Drug Administration (FDA) Form FDA 1572 and a 
Financial Disclosure Form. All sub-Investigators and research coordinators with significant 
study-related duties must be listed on Form FDA 1572. Financial Disclosure Forms must also 
be completed for all sub-Investigators listed on the Form FDA 1572 who will be directly 
involved in the treatment or evaluation of subjects in this study. 
The study will be administered and monitored by employees or representatives of the Sponsor. 
Clinical Research Associates (CRAs) or trained designees will monitor each site on a periodic 
basis and perform verification of source documentation for each subject as well as other 
required review processes. Sponsor’s Regulatory Affairs Department, in conjunction with 
Sponsor Pharmacovigilance (or designee) will be responsible for the timely reporting of SAEs 
to appropriate regulatory authorities as required. 
Clinical laboratory evaluations will be performed at the local laboratories associated with the 
study sites. The specific laboratories and instructions for sample collection, processing and 
shipment is provided in the laboratory manual. Special laboratory assessments (including, but 
not limited to, tumor tissue sample, WBC, CD34+ and BMP) will be performed at contract 
laboratories designated by the Sponsor. 
 
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11.5. 
Ongoing Information for Institutional Review Board 
Unless otherwise instructed by the IRB/IEC, the Investigator (or his/her designee) must submit 
to the IRB/IEC at a minimum: 
• Information on SAEs from the Investigator’s study center, as soon as possible  
• Expedited safety reports from the Sponsor or its representatives, as soon as possible  
• Periodic or annual reports on the progress of the study 
11.6. 
Data Handling and Record Keeping 
11.6.1. 
Case Report Forms 
The Investigator is responsible for the quality of the data recorded for this study. These 
recorded data should be a complete and accurate account of each subject’s record collected 
during the study. Subject data that are collected may be substantiated by 2 types of source 
documents at the study center, paper and electronic (electronic source data is defined as 
electronic information not directly entered into the EDC system). Source data collected 
electronically or via paper will be entered onto the eCRFs in the EDC system. The eCRFs will 
be completed according to guidelines provided by the Sponsor or its designee. 
Access to the EDC system will be granted to trained and authorized study personnel only, and 
user IDs and passwords must not be shared with other individuals. Only staff designated by 
the principal Investigator on the Delegation of Authority form will be eligible to enter or make 
edits to the data. Qualified research personnel will accurately enter data from clinic source 
documents into the eCRFs provided for this study. Data will be entered into the eCRF shortly 
after each subject’s visit. Study center personnel will exercise due diligence to ensure that 
study data are entered accurately and in their entirety from the study center’s source documents 
into the appropriate data fields. 
The Investigator must review all data entries on a regular basis for completeness and accuracy. 
When changes or corrections are made to existing entries in the EDC system, the reason for 
the change must be clearly delineated. The Investigator agrees to transfer study data into the 
EDC system in a timely fashion and to make the records available to the study monitor for full 
inspection. In addition, data queries should be answered promptly. 
Although the study eCRF is the primary database for the study, all data entered into the eCRF 
must be recorded in the source documents, and any missing data must be explained. Source 
data will be retained by the study center as described in Section 10.13. 
At the end of the study, by electronically signing the eCRFs the Investigator is attesting to 
his/her responsibility for the quality of all data recorded, as well as attesting that the data 
represents a complete and accurate record of each subject’s participation in the study. 
11.6.2. 
Source Documentation 
Source documents are considered to be all information in original records and certified copies 
of original records of clinical findings, observations, data or other activities in a clinical study 
necessary for the reconstruction and evaluation of the study. 
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The Investigator agrees to allow inspections of the study site and any source documentation, 
by clinical research and audit personnel from the Sponsor or designee, external auditors or 
representatives of regulatory authorities. Direct access to the subject’s medical/clinical records 
is necessary to verify and corroborate the data recorded on the eCRFs. 
11.7. 
Study Monitoring 
The Sponsor is responsible to regulatory authorities for ensuring the proper conduct of the 
study regarding protocol adherence and validity of the data recorded on the eCRFs. The 
Sponsor (or its designee) has therefore assigned study monitors and Medical Monitors to this 
study. The duties of these monitors are to aid the Investigator and the Sponsor in the 
maintenance of complete, legible, well-organized, and easily retrievable data. In addition, a 
monitor will explain and ensure the Investigator’s understanding of all applicable regulations 
concerning the clinical evaluation of a pharmaceutical product (whether licensed or 
unlicensed) and ensure an understanding of the protocol, reporting responsibilities, and the 
validity of the data. 
In order to perform their role well, the monitors must be given direct access to primary subject 
data that support data on the eCRFs for the study (e.g., hospital and general practice charts, 
appointment books, original laboratory records). The Investigator must exercise judgment 
regarding information in a subject’s chart that is not relevant to the performance, observations, 
or conduct of this study. The Investigator must make available such records to the Sponsor, 
designated contract research organization (CRO), quality assurance (QA), IRB/IEC, and 
regulatory personnel for inspection and copying. Because this enters into the realm of subject 
confidentiality, this fact must be included in the information signed by the subject. 
The Investigator should agree, as a minimum requirement, to record the following information 
in the subject notes:  
• Subject identification number  
• Protocol identification number  
• Date that the subject gave written informed consent  
• All visit dates  
• All AEs  
• All concomitant medications 
Entries in the subject notes must contain the signature or initials of the person making the 
entries, and the date that the entry was made. 
The study monitor will perform source-data verification at each monitoring visit. 
 
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11.8. 
Quality Assurance and Auditing Procedures 
To ensure compliance with GCP and applicable regulations, the Sponsor may conduct a QA 
audit of the study center, including inspection of study-center processes and study-related 
documents. 
The Investigator will permit the Sponsor representatives and regulatory authorities to conduct 
inspections before, during, or after completion of the study. If a regulatory authority requests 
an inspection, the Investigator must immediately inform the Sponsor of the request. 
As appropriate, the Sponsor Clinical QA may be involved in ensuring protocol compliance 
through auditing activities as well as tracking resolution of any Corrective and Preventive 
Actions (CAPA) that may be required. 
11.8.1. 
Access to Source Documentation 
Source data are all original records of clinical findings, observations, or other activities in a 
clinical study, which are necessary to achieve study objectives and protect subject safety. 
Source data are contained in source documents. Examples of these original documents and data 
records include:  
• Hospital records 
• Clinical and office charts 
• Laboratory notes 
• Memoranda 
• Pharmacy dispensing records 
• Recorded data from automated instruments 
• Copies or transcriptions certified after verification as being accurate and complete 
• X-rays, microfiches, photographic negatives, microfilm, or magnetic media 
• Subject files, including records kept at the pharmacy, laboratories, and at medico-
technical departments involved in the clinical study 
Source documents are the original documents used by the Investigator or hospital/institution 
that allows verification of the existence of the subject and substantiates the integrity of data 
collected during the study. Source documents will be available to support all data recorded in 
the eCRF, unless otherwise specified in the eCRF. The Investigator must allow designated 
representatives of the Sponsor and regulatory inspectors to have direct access to the source 
documents to verify the data reported in the eCRFs. 
The Investigator must maintain source documents for each subject in the study, including 
source documents that are generated by the subject. All information in the eCRFs must be 
traceable to these source documents, which are generally maintained in the subject’s file. The 
source documents should contain all demographic and medical information as well as a copy 
of the signed ICFs provided by the subject. 
 
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11.9. 
Policy on Research Misconduct in Clinical Research 
In accordance with GCP, it is the Sponsor’s policy always to investigate suspected cases of 
research misconduct. 
11.10. 
Use of Information and Publication Policy 
All information regarding the study drug supplied by the sponsor to the investigator is 
privileged and confidential information. The investigator agrees to use this information to 
accomplish the study and will not use it for other purposes without consent from the sponsor. 
It is understood that there is an obligation to provide the sponsor with complete data obtained 
during the study. The information obtained from the clinical study will be used towards the 
development of the study drug and may be disclosed to regulatory authorities, other 
investigators, corporate partners, or consultants as required. A description of this clinical trial 
will be available on http://www.ClinicalTrials.gov, as required by U.S. Law, 
www.ClinicalTrialsregister.eu, and http://reec.aemps.es. This Web sites will not include 
information that can identify patients, but may include a summary of the results. 
All information concerning the study drug is considered confidential and shall remain the sole 
property of the sponsor. The investigator(s) agree to use this information only in conducting 
the study and shall not use it for any other purposes without the sponsor’s written approval. 
The investigator(s) agree not to disclose the sponsor’s confidential information to anyone 
except to persons involved in the study that need such information to assist in conducting the 
study, and then only on like terms of confidentiality and non-use. 
It is understood by the investigator(s) that the information developed from this clinical study 
will be used by the sponsor in connection with the development of the study drug, and therefore 
may be disclosed as required to competent authorities. To allow for the use of the information 
derived from clinical studies, it is understood that there is an obligation to provide the sponsor 
with complete test results and all data developed in the study. No publication or disclosure of 
study results will be permitted except as specified in a separate, written, agreement between 
the sponsor and the investigator(s). 
11.11. 
Amendment to Protocol 
Approval of a protocol amendment by the Investigator’s IRB/IEC must be obtained before 
implementation of the protocol amendment, with the following exceptions: 
• When necessary to eliminate apparent immediate hazard to the subject 
• When the change involves logistical or administrative aspects of the study 
The protocol amendment must be signed and dated by both the Sponsor and the Investigator. 
The Sponsor will submit protocol amendments to the appropriate regulatory authorities (if 
required)/Ethics Committee (if required) and notify other Investigators using this protocol. 
11.12. 
Deviations from Protocol 
Departures from a written protocol for individual subjects are inherent to clinical research and 
are categorized by the Sponsor as deviations from protocol. A major deviation is a departure 
 
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from the protocol which may have impact on the safety or protection of the subject(s), or on 
the overall quality of the data, and is of sufficient significance to warrant Corrective Action 
and Preventive Action (CAPA). Minor deviations may appear to be of little or no consequence, 
but nonetheless they should be reported so that they can be assessed for their effect on the 
analysis. Examples of deviations include the following: 
• Failure to obtain informed consent 
• Violation of inclusion/exclusion criteria  
• Failure to report SAEs 
• Drug dispensing/dosing errors 
• Administration of an excluded concomitant medication during the course of the 
study 
• PK-blood sampling time deviations 
• PD-blood sampling time deviations 
The IRB/IEC will be informed of protocol deviations in a timely manner that is consistent with 
the IRB’s requirements. 
The same protocol deviation that occurs for multiple subjects must be recorded separately for 
each subject. 
The Investigator should contact the Sponsor if continuing the subjects in the study is called 
into question due to a protocol deviation. 
11.13. 
Records of Study 
The Investigator will retain essential study documents for at least 2 years after the last approval 
of a marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region, or for at least 2 years after the formal discontinuation 
of clinical development of the study drug, USL311. Examples of essential documents include 
the following: 
• IRB/IEC correspondence indicating approval/favorable opinion of the study 
protocol, ICFs, and all amendments to either of these documents 
• All source documents and laboratory records  
• ICFs signed by the subject 
• Subject assent forms, when applicable  
• Completed Form FDA 1572 
• Statement of Investigator 
If required by the applicable regulatory authorities or by an agreement with the Sponsor, these 
documents should be retained for a longer period (approximately 15 years). The Investigator 
must notify the Sponsor if he/she changes his/her study-center address or plans to transfer these 
documents to another Investigator. 
 
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11.14. 
Completion of Study 
It is agreed that the Sponsor may terminate this study before the expiration of the agreed upon 
time period, provided a written notice is submitted at a reasonable time in advance of intended 
termination. 
11.15. 
Study Funding 
The costs necessary to perform the study will be agreed with the Investigator and/or the 
management of the study facility, and will be documented in a separate financial agreement 
that will be signed by the Investigator and the Sponsor. 
11.16. 
Financial Disclosure 
Clinical Investigators are required to provide financial disclosure information to allow the 
Sponsor to submit the complete and accurate certification or disclosure statements required 
under 21 CFR § 54. As defined in 21 CFR § 54.2, a Clinical Investigator is a listed or identified 
Investigator or sub-Investigator who is directly involved in the treatment or evaluation of 
research subjects. The term also includes the spouse and each dependent child of the 
Investigator. In addition, Investigators must promptly update financial disclosure information 
if any relevant changes occur during the course of the investigation and for 1 year following 
completion of the study. 
 
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APPENDICES 
APPENDIX 1A. ADAPTIVE DESIGN REPORT FOR THE PART 1 
DOSE-ESCALATION OF IV USL311 IN SUBJECTS WITH 
ADVANCED SOLID TUMORS ............................................... 192 
APPENDIX 1B. ADAPTIVE DESIGN REPORT FOR THE PART 1B 
DOSE-ESCALATION OF ORAL USL311 IN SUBJECTS WITH 
ADVANCED SOLID TUMORS ............................................... 204 
APPENDIX 2. 
HIGHLY EFFECTIVE CONTRACEPTIVE METHODS ........ 217 
APPENDIX 3. 
MEDICATIONS WITH QTC PROLONGATION RISK ......... 218 
APPENDIX 4. 
LOMUSTINE (GLEOSTINE®) PACKAGE INSERT .............. 221 
APPENDIX 5. 
RESPONSE ASSESSMENT USING RECIST V.1.1 CRITERIA
.................................................................................................... 232 
APPENDIX 6. 
RESPONSE ASSESSMENT USING RANO CRITERIA ........ 253 
APPENDIX 7. 
KARNOFSKY PERFORMANCE STATUS SCALE ............... 264 
APPENDIX 8. 
EUROPEAN ORGANIZATION FOR RESEARCH AND 
TREATMENT OF CANCER QUALITY-OF-LIFE 
QUESTIONNAIRE, WITH A BRAIN-CANCER MODULE 
(EORTC QLQ-C30/BN20) ........................................................ 265 
APPENDIX 9. 
PROTOCOL AMENDMENT CHANGES................................ 268
 
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Adaptive Design Report for the Phase I Dose Escalation Study of USL311 in 
Patients with Advanced Solid Tumors Across Two Infusion Times 
Submitted to Upsher-Smith 
December 22, 2016 
 
 
 
1.0 Introduction 
 
This is a Phase I dose-escalation study of USL311 in patients with advanced solid 
tumors. The primary objective of this trial is to characterize the dose-toxicity 
relationship and to estimate the maximum tolerated dose (MTD).  Dose escalation to 
determine the MTD will be conducted according to a modified continual 
reassessment method (mCRM).  This design report serves as an update to the initial 
report to now accommodate two different infusion times.  In particular, an additive 
parameter is added to the dose-toxicity model to estimate the difference in the 
probability of a grade 2 toxicity or higher as well as the probability of a DLT 
resulting between the two infusion schedules.  A one-time change in the infusion 
schedule will occur at the sponsor’s discretion and all future subjects will be 
enrolled under the new infusion schedule. 
 
 
2.0 Single Agent and Combination 
 
USL311 will first be considered as a single agent.  This report focuses on the mCRM 
for dose escalation of USL311 as a single agent.  This portion of the trial will enroll a 
maximum of 40 patients.  When dose escalation of USL311 as a single agent is 
complete, dose escalation for USL311 in combination will be initiated.  In 
combination, only the dose of USL311 will be escalated.  This dose escalation will 
also be conducted according to an mCRM similar to that described here.  However, 
the dose range for the combination will be informed by results of USL311 as a single 
agent.   
 
3.0 Dose Escalation 
 
3.1 Overview 
 
The primary objective of the dose escalation portion of the study is to estimate an 
MTD.  The MTD will be the highest dose that has a dose-limiting toxicity (DLT) rate 
less than 33%.   
 
 
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There are a total of 31 possible dose levels between 40 mg/m2 and 1660 mg/m2.  
Dose levels are defined to be in approximately 15% increments.  Specifically, for 
each dose d = 1,….,31 the dose levels (vd), in mg/m2, are:  
 
40 
120 
320 
820 
50 
140 
360 
920 
60 
160 
400 
1040 
70 
180 
450 
1170 
80 
200 
510 
1310 
90 
220 
570 
1480 
100 
250 
650 
1660 
110 
280 
730 
 
 
 
Dose escalation will be conducted according to a mCRM. Non-DLT toxicity events 
(i.e. grade 2 toxicities) will inform the probability of DLT at each dose level. Dose 
escalation is also conducted according to a set of rules that govern entry into the 
study and assignment of dose level. These rules allow skipping untried dose levels 
provided they are estimated to be safe.  The trial is continuously monitored for 
safety and for early stopping for successfully identifying the MTD. 
 
3.2 DLT Observation Period 
 
The DLT observation period, for the purpose of dose-escalation, is one cycle.  One 
cycle is 3 weeks in length.  Once a patient has completed this first cycle DLT 
observation period, the patient will be considered to have complete DLT 
information for the purposes of making dose escalation decisions for the next 
patient enrolling into the trial.  However, DLTs may also appear due to cumulative 
toxicity, in later cycles.  If a DLT appears at any time through the first three cycles of 
treatment, a patient’s DLT status will be updated to reflect the late cycle DLT.   
 
For example, a patient may experience no DLT events in their first cycle.  This 
patient would be recorded as having completed the DLT observation period with no 
DLT.  The next patient enrolled would be assigned a dose level based on that current 
data.  If the patient then experiences a DLT in the second cycle, their DLT status 
would be updated to reflect the DLT.  All future patients enrolled would be assigned 
a dose level based on data inclusive of that DLT that occurred in the patient’s second 
cycle.  In this manner, late cycle DLT information will be taken into account in the 
dose-toxicity model with the same weight as a first cycle DLT and will inform dose 
level assignments for the next patients enrolling into the trial.   
 
 
 
 
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3.3 Dose-Toxicity Model 
 
For each dose d = 1,….,31, we model the ordinal outcome of no toxicity event, non-
DLT (i.e. grade 2) toxicity event, or a DLT. We model the log odds of a grade 2 
toxicity or higher for dose d and infusion schedule I (I=0 for initial infusion schedule 
and 1 for longer infusion schedule), 
 
log
π ≥grade2
1−π ≥grade2
⎛
⎝
⎜
⎞
⎠
⎟= ρd ,I  
 
with a three-parameter model  
 
 ρd ,I =α + β(vd −60)+θI . 
 
Here, we assume that the 60mg/m2 dose is the referent dose and as such α refers to 
the log-odds of a grade 2 toxicity or higher under this dose level.  The second 
parameter, β, refers to the log-odds increase in the probability of a grade 2 toxicity 
or higher per one unit increase/decrease in mg/m2.  The final parameter, θ, refers to 
the log-odds increase or decrease in the probability of a grade 2 toxicity or higher 
under the longer infusion schedule.   
 
We model the log odd-odds of a DLT toxicity  
 
 
log
π DLT
1−π DLT
⎛
⎝⎜
⎞
⎠⎟= µd ,I   
 
 
as related to non-DLTs by including an additive term, γ, which must be less than 0,  
 
 
µd ,I =(α +γ )+β(vd −60)+θI.   
 
This parameterization assumes that grade 2 toxicities or higher will occur more 
frequently than the subset of DLT toxicities only and γ defines how much of the total 
probability of a grade 2 toxicity or higher will be assigned to this subset.   We also 
assume that the additive increase or decrease in the curves attributed to the change 
in infusion schedule is the same for DLTs and grade 2 toxicities or higher.    
 
We place the following independent prior distributions on the parameters.   
 
α ~ N(–0.5, 3); 
β ~ N+(0.004, 0.008);  
γ ~ N-(0, 2); 
 
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θ ~ N(0, 1). 
 
 
The model will be updated as frequently as necessary.  In particular, the model may 
be updated as each patient is enrolled into the trial, and/or after each patient is 
treated and assessed for DLT.  When the model is updated, the distributions of all 
parameters are updated and the MTD per infusion schedule is estimated based on 
the posterior probability of DLT at each dose.   
 
Additionally, we define a dose as safe if there is at least a 50% probability that the 
DLT rate is less than 33%,  
Pr(πd,I < 33%) > 50%. 
 
This definition for safety is consistent with the maximum likelihood estimate for the 
probability of DLT.  If the DLT rate is estimated to be exactly 33%, the Pr(πd,I < 33%) 
will be equal to 50%.  Therefore, doses with a mean estimated DLT rate less than 
33% will be considered safe by this definition and doses with a mean estimated DLT 
rate greater than 33% will be considered unsafe by this definition.  The upper 
bound of 33% is justified by the fact that GBM is a highly lethal cancer (has 95% 
mortality over 5 years) and by the fact that late DLTs will also be counted toward 
the MTD calculation. 
 
3.4 Dose Escalation Rules 
 
3.4.1 Entry into the Study 
 
Dose escalation begins with enrollment of patients to the 60 mg/m2 dose.  The 40 
and 50 mg/m2 dose levels are de-escalation dose levels.  The first three patients will 
be enrolled as a dosing cohort to the 60 mg/m2 dose.  There must be complete DLT 
information on these three patients in order to enroll the 4th patient.  Starting with 
the 4th patient, there is open enrollment to the study meaning that patients can be 
enrolled as they become available for the study. The “queue” refers to the number of 
patients that have been allocated to doses, but have not yet completed the 
observation period (one cycle for dose escalation). For safety purposes we want to 
keep the queue size moderate to prevent large numbers of patients being enrolled at 
any one time.  There may no more than 3 patients enrolled in the trial across the 
two infusion schedules with uknown DLT information at any time. Patients cannot 
be enrolled for dose escalation if the queue maximum has been reached. 
 
3.4.2 Assignment of Dose Levels 
 
The dose-toxicity model under the currently enrolling infusion schedule will be used 
to determine which doses are safe and to assign patients to doses, i.e. to assign 
patients to the highest safe dose.  However, assignment of dose levels is also 
governed by rules concerning the speed of dose escalation and rules that determine 
what untried dose levels may be skipped.   
 
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When the dose is escalated, it may only escalate to the highest safe dose that is no 
more than a 100% increase over the current dose level. If the dose must be de-
escalated, the dose will de-escalate to the highest safe dose regardless of how large a 
decrease in dose level.  Within an infusion schedule, as long as no DLT has yet been 
observed there must be complete DLT information on at least 2 patients in order to 
escalate.  Once the first DLT is observed within an infusion schedule, there must be 
complete DLT information on at least 3 patients within in order to escalate.  These 
rules are applied to each infusion schedule separately.  Therefore, if a DLT is 
observed and then the longer infusion schedule is implemented, the trial may 
escalate within the longer schedule with 2 patients with complete information per 
dose level. Once a DLT is observed under the longer schedule, 3 patients complete at 
each dose level will be required.  
 
3.5 Interim Monitoring 
 
Dose escalation will be continuously monitored for safety and for success in 
identifying the MTD. In this section, we describe the pre-specified rules to stop the 
dose-escalation early.  If the dose-escalation is not stopped early, dose escalation 
will stop when the maximum of 40 patients has been enrolled.  At that time, the 
MTD will be the high safe dose as estimated by the dose toxicity model.   
 
3.5.1 Safety Monitoring 
 
If no doses are safe under the current infusion schedule, dose escalation will stop 
and no MTD will be declared. Formally, if the dose de-escalates to the 40 mg/m2 
dose level, and we have observed at least one patient with complete DLT 
information at that dose level, and  
 
Pr(πd,I < 33%) < 25% for all d = 1,…31 
 
then the trial will stop early for safety. 
 
3.5.2 Success in Identifying the MTD 
 
Dose escalation may be stopped early when we are sufficiently confident the MTD 
has been identified within the currently enrolling infusion schedule.  We 
characterize this by having either estimated the MTD with high probability, or by 
having a sufficient number of patients with complete DLT information at and around 
the MTD.  The trial may stop early for success in identifying the MTD if any one of 
the following three conditions are satisfied  
 
1. At least 10 patients across infusion schedules on the estimated MTD within 
the current infusion schedule have complete DLT information 
 
 
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2. At least 15 patients across infusion schedules on the estimated MTD within 
the current infusion schedule +/- one dose level have complete DLT 
information 
 
3. There is at least an 80% probability that the current highest safe dose level 
+/- one dose level is the MTD within the current infusion schedule 
 
 
4.0 Operating Characteristics 
 
For the purpose of simulation assume the following observed current trial data 
under the shorter infusion schedule:  
 
• Dose 60: 3 subjects complete with 0 DLTs and 0 grade 2 toxicities 
• Dose 120: 4 subjects complete with 0 DLTs and 4 grade 2 toxicities 
• Dose 180: 1 subject complete without a DLT and with a grade 2 toxicity 
 
We also assume that a one-time change in the infusion schedule will occur when a 
DLT is observed and that and all future patients enrolled will be treated at a longer 
infusion schedule. Once the change occurs, all dose-escalation decisions will be 
conducted using the dose-toxicity model estimates under the longer infusion 
schedule.     
 
To evaluate how the dose escalation design performs under the change in infusion 
schedule, we simulated the study considering different dose-toxicity scenarios 
under the longer infusion schedule (Figure 4.1).  The MTD for the shorter infusion 
schedule is assumed to be 280 for each scenario since under the currently observed 
data the MTD is estimated to be 280. For each scenario, we show the operating 
characteristics of the trial based on 1,000 simulations per scenario.  Plots show the 
sample size distribution and the cumulative probability of MTD across the 31 dose 
levels.  The true DLT scenario is shown for reference along with a line indicating a 
33% DLT rate.  
 
We summarize the performance of the dose escalation design by showing the mean 
sample size, the mean number of DLTs, the mean number of patient treated within 
one dose level of the MTD, and the probability of selecting a dose within one dose 
level of the true MTD as the MTD.    
 
Table 4.1 provides the following operating characteristics: 
• Mean number of total patients enrolled 
• Mean number of observed DLTs 
• Mean number of patients enrolled to the true MTD +/- 1 dose level 
• Probability the true MTD +/- 1 dose level is selected as the most likely MTD 
or for Scenario 4 where all doses are considered unsafe this is the probability 
that no MTD is selected.   
 
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Table 4.1: Summary Operating Characteristics 
Scenario  
(MTD Shorter / 
Longer) 
Mean Patients 
Mean 
Number of 
DLTs 
Mean Number of 
Patients at MTD 
+/- 1 Dose Level 
Probability 
Selecting true 
MTD +/- 1 Dose 
Level 
Total 
Longer 
Infusion 
Schedule 
1 (280/280) 
32 
20 
8  
11 
0.60 
2 (280 / 400) 
34 
21 
7  
11 
0.75 
3 (280 / 510) 
35 
22 
7  
12 
0.88 
4 (280 / 650) 
35 
23 
7  
12 
0.88 
 
 
In Scenario 1 the MTD under both the shorter and longer infusion schedules is 
280mg/m2.  On average the trial enrolls 32 total patients (20 under the longer 
infusion schedule) with an average of 8 DLTs observed among these patients.  A 
mean of 11 patients are enrolled to 280 mg/m2 +/- one dose level and the likelihood 
that we choose a dose within this window as the MTD at the end of the trial is 0.60.  
The probability that we select an unsafe dose above this window as the MTD is 0.10 
and the probability that we select a non-optimal dose that is below this window is 
0.30.   
 
In Scenario 2-4  the MTD under the longer infusion schedule is 400-650 mg/m2.  On 
average the trials enroll approximately 34-35 patients (21-23 are under the longer 
infusion schedule).  A mean of 11-12 patients are enrolled at the MTD +/- one dose 
level and the likelihood that we choose a dose within this window as the MTD at the 
end of the trial is 0.75-0.88.  The probability that we select an unsafe dose above this 
window as the MTD is less than 5% and the probability that we select a non-optimal 
dose that is below this window is 10-20%.  Finally, the probability that the trial 
stops for futility and no dose is considered safe is less than 0.02.   
 
Figures 4.2-4.5 show more detailed operating characteristics for each scenario.  
The left panel of each plot below the red curve shows the true probability of DLT.  
The horizontal dashed line is at 33% for reference.  The black curve shows the 
cumulative probability of DLT.  The blue vertical lines show the mean number of 
patients enrolled at each dose and the blue rectangle shows the mean number of 
patients treated at the true MTD +/- one dose level.  The right panel shows the 
distribution of the total sample size across the 1000 simulated trials.  Dashed 
vertical line shows the mean total sample size. 
Conclusions 
 
This CRM design incorporates the ability to change the infusion schedule to a longer 
duration and appropriately model the shift in the dose-toxicity relationship that 
occurs.  This is a revision to the dose-toxicity modeling only, and does not impact 
the conduct of the trial for the patients who have already been enrolled or change 
the dose levels they would have been assigned to, nor does it impact the conduct of 
the trial for any future patients to be enrolled under the first, shorter, infusion 
schedule.   
 
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Figure 4.1: Dose toxicity scenarios.  Red lines correspond to the probability of a DLT, orange lines 
correspond to the probability of a grade 2 toxicity or higher.  Solid lines represent dose-toxicity curves 
under the longer infusion schedule and dotted lines under the short infusion schedule.   
 
 
0.0
0.2
0.4
0.6
0.8
1.0
Scenario 1
Dose
Probability
280
280
Pr(DLT)
Pr(Tox)
Short Infus on
Longer Infusion
0
400
800
1200
1600
0.0
0.2
0.4
0.6
0.8
1.0
Scenario 2
Dose
Probability
280
400
0
400
800
1200
1600
0.0
0.2
0.4
0.6
0.8
1.0
Scenario 3
Dose
Probability
280
510
0
400
800
1200
1600
0.0
0.2
0.4
0.6
0.8
1.0
Scenario 4
Dose
Probability
280
650
0
400
800
1200
1600
 
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Adaptive Design Report for the Phase I Dose Escalation Study of Oral Dosing of 
USL311 in Patients with Advanced Solid Tumors  
Submitted to Upsher-Smith 
January 5, 2018 
 
 
 
1.0 Introduction 
 
This is a Phase I dose-escalation study of oral dosing of USL311 in patients with 
advanced solid tumors. The primary objective of this trial is to characterize the 
dose-toxicity relationship and to estimate the maximum tolerated dose (MTD).  
Dose escalation to determine the MTD will be conducted according to a modified 
continual reassessment method (mCRM).  This study will enroll a maximum of 40 
patients.  
 
 
2.0 Dose Escalation 
 
2.1 Overview 
 
The primary objective of the dose escalation portion of the study is to estimate an 
MTD.  The MTD will be the highest dose that has a dose-limiting toxicity (DLT) rate 
less than 33%.   
 
There are a total of 27 possible dose levels between 20 mg and 1440 mg.  Dose 
levels are defined to be at least 15% apart rounded to the nearest 20 mg.  
Specifically, for each dose d = 1,….,27 the dose levels (vd), in mg, are:  
 
20 
180 
400 
1100 
40 
200 
460 
1260 
60 
220 
520 
1440 
80 
240 
580 
 
100 
260 
660 
 
120 
280 
740 
 
140 
320 
840 
 
160 
360 
960 
 
 
 
Dose escalation will be conducted according to a mCRM. Non-DLT toxicity events 
(i.e. grade 2 toxicities) will inform the probability of DLT at each dose level. Dose 
escalation is also conducted according to a set of rules that govern entry into the 
 
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study and assignment of dose level. These rules allow skipping untried dose levels 
provided they are estimated to be safe.  The trial is continuously monitored for 
safety and for early stopping for successfully identifying the MTD. 
 
2.2 DLT Observation Period 
 
The DLT observation period, for the purpose of dose-escalation, is one cycle.  One 
cycle is 3 weeks in length.  Once a patient has completed this first cycle DLT 
observation period, the patient will be considered to have complete DLT 
information for the purposes of making dose escalation decisions for the next 
patient enrolling into the trial.  However, DLTs may also appear due to cumulative 
toxicity, in later cycles.  If a DLT appears at any time through the first three cycles of 
treatment, a patients DLT status will be updated to reflect the late cycle DLT.   
 
For example, a patient may experience no DLT events in their first cycle.  This 
patient would be recorded as having completed the DLT observation period with no 
DLT.  The next patient enrolled would be assigned a dose level based on that current 
data.  If the patient then experiences a DLT in the second cycle, their DLT status 
would be updated to reflect the DLT.  All future patients enrolled would be assigned 
a dose level based on data inclusive of that DLT that occurred in the patient’s second 
cycle.  In this manner, late cycle DLT information will be taken into account in the 
dose-toxicity model with the same weight as a first cycle DLT and will inform dose 
level assignments for the next patients enrolling into the trial.   
 
2.3 Dose-Toxicity Model 
 
For each dose d = 1,….,27, we model the ordinal outcome of no toxicity event, non-
DLT (i.e. grade 2) toxicity event, or a DLT. We model the log odds of a grade 2 
toxicity or higher with a two-parameter model, 
𝑙𝑜𝑔
𝜋%&'()*+,)
1 −𝜋%&'()*+,)
= 𝛼+ 𝛽𝑣) −40 . 
 
Here, we assume that the 40mg dose is the referent dose and as such α refers to the 
log-odds of a grade 2 toxicity or higher under this dose level.  The second parameter, 
β, refers to the log-odds increase in the probability of a grade 2 toxicity or higher per 
one unit increase/decrease in mg. 
 
We model the log odd-odds of a DLT toxicity as related to non-DLTs by including an 
additive term, g, which must be less than 0,  
 
𝑙𝑜𝑔
𝜋789,)
1 −𝜋789,)
= 𝛼+ 𝛾+ 𝛽𝑣) −40 . 
 
 
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This parameterization assumes that grade 2 toxicities or higher will occur more 
frequently than the subset of DLT toxicities only and γ defines how much of the total 
probability of a grade 2 toxicity or higher will be assigned to this subset.    
 
We place the following independent prior distributions on the parameters.   
 
a ~ N( 2, 1); 
b ~ N+(0.004, 0.008);  
γ ~ N (0, 1). 
 
 
Figure 2.1 shows the prior dose-toxicity curve. The solid red line corresponds to the 
mean probability of a DLT toxicity at each dose.  The dotted orange line corresponds 
to the mean probability of a Grade 2 toxicity event or higher at each dose for each 
disease cohort.  The light shaded red region corresponds to 95% CI for the 
probability of a DLT toxicity at each dose. The MTD based on the prior distribution 
is 280 mg.   
 
 
 
Figure 2.1: Prior dose-toxicity curve. Solid red line represents the mean probability of a DLT at each dose.  The light 
shaded region is the corresponding 95% CI.  Dotted orange line represents the mean probability of a Grade 2 
toxicity or higher at each dose.  The horizontal red dotted line is at a 33% DLT rate for reference. 
 
0.0
0.2
0.4
0.6
0.8
1.0
Prior
Dose
Probability
0
200
400
600
800
1000
1200
1400
DLT
Grade2
280
 
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The model will be updated as frequently as necessary.  In particular, the model may 
be updated as each patient is enrolled into the trial, and/or after each patient is 
treated and assessed for DLT.  When the model is updated, the distributions of all 
parameters are updated and the MTD is estimated based on the posterior 
probability of DLT at each dose.   
 
Additionally, we define a dose as safe if there is at least a 50% probability that the 
DLT rate is less than 33%,  
Pr(πd < 33%) > 50%. 
 
This definition for safety is consistent with the maximum likelihood estimate for the 
probability of DLT.  If the DLT rate is estimated to be exactly 33%, the Pr(πd < 33%) 
will be equal to 50%.  Therefore, doses with a mean estimated DLT rate less than 
33% will be considered safe by this definition and doses with a mean estimated DLT 
rate greater than 33% will be considered unsafe by this definition.  The upper 
bound of 33% is justified by the fact that GBM is a highly lethal cancer (has 95% 
mortality over 5 years) and by the fact that late cycle DLTs will also be counted 
toward the MTD calculation. 
 
2.4 Dose Escalation Rules 
 
2.4.1 Entry into the Study 
 
Dose escalation begins with enrollment of patients to the 40mg dose.  The 20mg 
dose level is a de-escalation dose level.  The first patient will be enrolled to the 40mg 
dose.  Beginning with this first patient enrolled there is open enrollment to the 
study meaning that patients can be enrolled as they become available for the study. 
The “queue” refers to the number of patients that have been allocated to doses, but 
have not yet completed the observation period (one cycle for dose escalation). For 
safety purposes we want to keep the queue size moderate to prevent large numbers 
of patients being enrolled at any one time.  There may no more than 3 patients 
enrolled in the trial with unknown DLT information at any time. Patients cannot be 
enrolled for dose escalation if the queue maximum has been reached. 
 
2.4.2 Assignment of Dose Levels 
 
The dose-toxicity model will be used to determine which doses are safe and to 
assign patients to doses, i.e. to assign patients to the highest safe dose.  However, 
assignment of dose levels is also governed by rules concerning the speed of dose 
escalation and rules that determine what untried dose levels may be skipped.   
 
When the dose is escalated, it may only escalate to the highest safe dose that is no 
more than a 100% increase over the current dose level. If the dose must be de-
escalated, the dose will de-escalate to the highest safe dose regardless of how large a 
decrease in dose level. As long as no DLT has yet been observed, there must be 
complete DLT information on at least 2 patients at the current dose level in order to 
 
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escalate.  Once the first DLT is observed in the trial, there must be complete DLT 
information on at least 3 patients at the current dose level in order to escalate.  
 
2.5 Interim Monitoring 
 
Dose escalation will be continuously monitored for safety and for success in 
identifying the MTD. In this section, we describe the pre-specified rules to stop the 
dose-escalation early.  If the dose-escalation is not stopped early, dose escalation 
will stop when the maximum of 40 patients has been enrolled.  At that time, the 
MTD will be the high safe dose as estimated by the dose toxicity model.   
 
2.5.1 Safety Monitoring 
 
If no doses are safe, dose escalation will stop and no MTD will be declared. Formally, 
if the dose de-escalates to the 20mg dose level, and we have observed at least one 
patient with complete DLT information at that dose level, and  
 
Pr(pd < 33%) < 25% for all d = 1,…31 
 
then the trial will stop early for safety. 
 
2.5.2 Success in Identifying the MTD 
 
Dose escalation may be stopped early when we are sufficiently confident the MTD 
has been identified.  We characterize this by having either estimated the MTD with 
high probability, or by having a sufficient number of patients with complete DLT 
information at and around the MTD.  The trial may stop early for success in 
identifying the MTD if any one of the following three conditions is satisfied  
 
1. At least 10 patients on the estimated MTD have complete DLT information 
 
2. At least 15 patients on the estimated MTD +/- one dose level have complete 
DLT information 
 
3. There is at least an 80% probability that the current highest safe dose level 
+/- one dose level is the MTD and there are at least 3 patients on the 
estimated MTD with complete DLT information 
 
3.0 Example Trials 
 
In this section we present selected snapshots from single simulated trials to 
illustrate the dose escalation.  Tables show the observed data, including the total 
number of patients enrolled at each dose level, the number with complete DLT 
information, the number of grade 2 toxicity events, and the number of DLT events 
observed.  We also show quantities from the dose-toxicity model for each dose level 
including the probability of DLT, the probability the dose is safe, and the probability 
 
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the dose is the MTD.  The upper part of each table presents information for each 
dose level where patients have been enrolled. The lower part of each table 
highlights the current MTD +/- 1 dose level.  
 
4.1 Example Trial 1 
 
The first four patients are enrolled to 40 mg.  At least 2 patients must complete the 
DLT observation period before the trial can escalate. The fifth and sixth patients are 
available to be enrolled when all four of the patients enrolled to 40 mg are complete 
and there are no observed DLTs or Grade 2 toxicities.  The dose is escalated 100% to 
80 mg and the fifth and sixth patients are enrolled to this dose.  The current MTD is 
estimated to be 360 with a mean DLT rate of 0.31 (95% CI (0.51, 0.56)).  (Table 
4.1.1).  
 
Table 4.1.1:  5 Patients Enrolled and 4 with Complete DLT Information 
 
 
Observed Data 
Dose-Toxicity Model 
Quantities 
 
Dose 
Level 
(mg)  
N 
Enrolled 
N 
Complete 
N 
DLT 
N 
Grade 
2  
Pr 
DLT 
Pr 
Safe 
Pr 
 MTD 
Current and Last  
Dose Levels 
40 
4 
4 
0 
0 
0.03 
1.00 
0.00 
80 
2 
0 
0 
0 
0.04 
1.00 
0.01 
Highlight on 
Current MTD 
+/- 1 Dose Level 
320 
0 
0 
0 
0 
0.24 
0.62 
0.06 
360 
0 
0 
0 
0 
0.31 
0.56 
0.05 
400 
0 
0 
0 
0 
0.38 
0.49 
0.07 
Total 
For MTD 
Window 
0 
0 
0 
0 
 
 
0.18 
 
The next three patients are enrolled to the 160 mg dose after the two patients 
complete on 80 mg without any DLTs or Grade 2 toxicities. The estimated MTD 
increases to 400 mg. 
 
All three patients on the 160 mg dose level do not observe a DLT or Grade 2 toxicity, 
the estimated MTD increase to 520 mg and patients 10-13 are enrolled to dose level 
320.    
 
When all four of the patients at the 320 mg dose complete the DLT observation 
period, one has experienced a grade 2 toxicity and another one has experienced a 
DLT. The estimated MTD decreases from 520 mg to 360 mg.  With a DLT observed, 
now three patients complete through the DLT observation period are required for 
dose escalation.  There are 4 patients complete at the current dose level and the 
dose may increase, but no more than 100% or to the highest safe dose. The dose is 
escalated to the 360 mg dose level and patients 14-16 are enrolled to dose level 360 
(Table 4.1.2).   
 
 
 
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Table 4.1.2: 16 Patients Enrolled and 13 with Complete DLT Information 
 
 
Observed Data 
Dose-Toxicity Model 
Quantities 
 
Dose 
Level 
(mg)  
N 
Enrolled 
N 
Complete 
N 
DLT 
N 
Grade 
2  
Pr 
DLT 
Pr 
Safe 
Pr 
 MTD 
Current and Last  
Dose Levels 
320 
4 
4 
1 
1 
0.20 
0.79 
0.16 
360 
3 
0 
0 
0 
0.26 
0.63 
0.14 
Highlight on 
Current MTD 
+/- 1 Dose Level 
320 
4 
4 
1 
1 
0.20 
0.79 
0.16 
360 
3 
0 
0 
0 
0.26 
0.63 
0.14 
400 
0 
0 
0 
0 
0.33 
0.49 
0.16 
Total for 
MTD 
Window 
7 
4 
1 
1 
-- 
-- 
0.45 
 
The first patient on dose level 360 experiences a DLT and the trial de-escalates to 
dose level 320.  Patient 17 is enrolled to 320 mg.  The next patient on dose level 360 
also observes a DLT and the trial further de-escalates to dose level 280.  Patient 18-
20 are all enrolled to 280 mg.   
 
The trial continues enroll patients 21-27 to dose levels 280-320mg.  At this point in 
the trial the MTD is estimated to be 320 mg (DLT rate 0.30) and there are greater 
than 15 subjects (a total of 18) complete in the MTD window so the trial stops for 
successfully identifying the MTD.  In the MTD window 5/18 subjects experience a 
DLT and 6/18 experience a Grade 2 toxicity or higher. (Table 4.1.3).  
 
Table 4.1.3: Trial Stops enrollment for success in identifying the MTD 
 
 
Observed Data 
Dose-Toxicity Model 
Quantities 
 
Dose 
Level 
(mg)  
N 
Enrolled 
N 
Complete 
N 
DLT 
N 
Grade 
2  
Pr 
DLT 
Pr 
Safe 
Pr 
 MTD 
Current and Last  
Dose Levels 
280 
4 
4 
1 
1 
0.22 
0.91 
0.29 
320 
11 
11 
2 
5 
0.30 
0.62 
0.35 
Highlight on 
Current MTD 
+/- 1 Dose Level 
280 
4 
4 
1 
1 
0.22 
0.91 
0.29 
320 
11 
11 
2 
5 
0.30 
0.62 
0.35 
360 
3 
3 
2 
0 
0.40 
0.27 
0.17 
Total for 
MTD 
Window 
18 
18 
5 
6 
-- 
-- 
0.81 
 
 
 
 
 
 
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4.2 Example Trial 2 
 
The first three patients are enrolled to 40 mg by the time the first patient observes a 
DLT.  With one patient complete and one DLT on the 40 mg dose the current 
estimated DLT rate at 40 mg is 0.23 and this dose is still considered safe.  Patient 4 
is then enrolled to the 40 mg dose. (Table 4.2.1) 
 
Table 4.2.1: 4 Patients Enrolled; 1 Complete on 40 mg 
 
 
Observed Data 
Dose-Toxicity 
Model Quantities 
 
Dose 
Level 
(mg)  
N 
Enrolled 
N 
Complete 
N 
DLT 
N 
Grade 
2  
Pr 
DLT 
Pr 
Safe 
Pr 
 MTD 
Enrolled  
Dose Levels 
40 
4 
1 
1 
0 
0.23 
0.70 
0.07 
 
When the second patient enrolled to the 40 mg dose also observes a DLT the trial 
de-escalates to the 20 mg dose and Patient 5 is enrolled to this dose.  The probability 
that the 20 mg dose is safe is 0.41.  If this probability is less than 0.25 we will stop 
the trial early for futility. (Table 4.2.2) 
 
 
Table 4.2.2: 4 Patients Enrolled; 2 Complete on 40 mg 
 
 
Observed Data 
Dose-Toxicity 
Model Quantities 
 
Dose 
Level 
(mg)  
N 
Enrolled 
N 
Complete 
N 
DLT 
N 
Grade 
2  
Pr 
DLT 
Pr 
Safe 
Pr 
 MTD 
Enrolled  
Dose Levels 
20 
1 
0 
0 
0 
0.37 
0.41 
0.08 
40 
4 
2 
2 
0 
0.41 
0.33 
0.07 
 
 
When the patient enrolled to the 20 mg dose also observes a DLT the probability 
that this dose is safe drops to 0.08 and the trial stops early for futility.  The final 
analysis is shown in Table 4.2.3.  All 4 patients on dose level 40 experienced a DLT 
and the one patient on the 20mg dose experienced a grade 2 toxicity. No dose levels 
are considered safe.   
 
 
Table 4.2.3: Final Analysis; 5 Patients Complete on 20 and 40 mg 
 
 
Observed Data 
Dose-Toxicity 
Model Quantities 
 
Dose 
Level 
N 
Enrolled 
N 
Complete 
N 
DLT 
N 
Grade 
Pr 
DLT 
Pr 
Safe 
Pr 
 MTD 
 
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(mg)  
2  
Enrolled  
Dose Levels 
20 
1 
1 
0 
1 
0.54 
0.08 
0.03 
40 
4 
4 
4 
0 
0.58 
0.04 
0.02 
 
 
 
 
 
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4.0 Operating Characteristics 
 
To evaluate how the dose escalation design performs, we simulated the study 
considering different dose-toxicity scenarios (Figure 4.1).  
 
Figure 4.1: Dose toxicity scenarios 
For each scenario, we show the operating characteristics of the trial based on 1,000 
simulations per scenario.  Plots show the sample size distribution and the 
cumulative probability of MTD across the 27 dose levels.  The true DLT scenario is 
shown for reference along with a line indicating a 33% DLT rate.  We further 
summarize the performance of the dose escalation design by showing the mean 
sample size, the mean number of DLTs, the mean number of patient treated within 
one dose level of the MTD, and the probability of selecting a dose within one dose 
level of the true MTD as the MTD in Table 4.1.  Figure 4.2 shows the cumulative 
probability of selecting each dose on each scenario as well as the distribution of 
simulated trial sizes. 
 
In Scenario 1 all doses are unsafe. On average the trial enrolls approximately 13 
patients with an average of 6 DLTs observed among these patients. The likelihood 
that we claim that all doses are unsafe is 86% with the remaining 14% of trials 
choosing dose level 20 or 40mg. 
 
When the MTD is in the middle of the dosing grid (Scenarios 2 and 3 with MTDs of 
280 and 400) the trial enrolls on average 33 patients with 7-8 of them experiencing 
DLTs.  The mean number of patients on the true MTD +/- one dose level is 9-10 and 
the probability of selecting the true MTD +/- one dose level is 0.54  0.57.  In both 
scenarios, there is a 40% chance that we select an MTD less than one dose level 
below the true MTD and an 3-6% chance of selecting an MTD greater than one dose 
level above the true MTD. 
0.0
0.2
0.4
0.6
0.8
1.0
Scenario 1
Dose
Probability
0
200
400
600
800
1000
1400
0
Pr(DLT)
Pr(Tox)
0.0
0.2
0.4
0.6
0.8
1.0
Scenario 2
Dose
Probability
0
200
400
600
800
1000
1400
280
Pr(DLT)
Pr(Tox)
0.0
0.2
0.4
0.6
0.8
1.0
Scenario 3
Dose
Probability
0
200
400
600
800
1000
1400
400
Pr(DLT)
Pr(Tox)
0.0
0.2
0.4
0.6
0.8
1.0
Scenario 4
Dose
Probability
0
200
400
600
800
1000
1400
580
Pr(DLT)
Pr(Tox)
0.0
0.2
0.4
0.6
0.8
1.0
Scenario 5
Dose
Probability
0
200
400
600
800
1000
1400
740
Pr(DLT)
Pr(Tox)
0.0
0.2
0.4
0.6
0.8
1.0
Scenario 6
Dose
Probability
0
200
400
600
800
1000
1400
1440
Pr(DLT)
Pr(Tox)
 
214 of 272


 
 
11 / 13 
When the MTD is in the upper end of the dosing grid (Scenarios 3 and 4 with MTDs 
of 580 and 740) the trial enrolls on average 32 patients with 6 of them experiencing 
a DLT.  The mean number of patients on the true MTD +/- one dose level is 11-12 
and the probability of selecting the true MTD +/- one dose level is 0.79-0.85.  In 
Scenarios 4 and 5, the likelihood of selecting an MTD less than one dose level below 
the true MTD is 18% and 12% respectively and the likelihood of selecting an MTD 
greater than one dose level above the true MTD 3%.   
 
Finally, when the MTD is the maximum dose (1440 mg) the trial enrolls on average 
28 patients with approximately 3 of them experiencing a DLT.  The mean number of 
patients on the true MTD or one dose level below (1260) is 6 and the probability of 
selecting either 1440 or 1260 is 0.87.   
 
 
 
Table 4.1: Summary Operating Characteristics 
Scenario 
True MTD 
Mean 
Total 
Patients 
Mean 
Number of 
DLTs 
Mean Number of 
Patients at MTD 
+/- 1 Dose Level 
Probability 
Selecting true 
MTD +/- 1 Dose 
Level 
1 
0 
13 
6 
- 
0.86 
2 
280 
33 
8 
10 
0.54 
3 
400 
33 
7 
9 
0.57 
4 
580 
32 
6 
12 
0.79 
5 
740 
32 
6 
11 
0.85 
6 
1440 
28 
3 
6 
0.87 
 
 
 
 
 
215 of 272






Appendix 2. 
Highly Effective Contraceptive Methods 
Contraception methods that can achieve a failure rate of < 1% per year when used consistently 
are considered to be highly effective. Such methods include the following: 
• Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation. Note: Hormonal contraception may be susceptible to interaction 
with the study drug, which may reduce the efficacy of the contraception method. 
− Oral 
− Intravaginal 
− Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation. Note: 
Hormonal contraception may be susceptible to interaction with the study drug, which may 
reduce the efficacy of the contraception method. 
− Oral 
− Injectable 
− Implantable 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Vasectomized partner 
− Note: Vasectomised partner is a highly effective birth control method provided that 
partner is the sole sexual partner of the WOCBP trial participant and that the 
vasectomised partner has received medical assessment of the surgical success. 
• Sexual Abstinence 
− Note: Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with 
the study treatments. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the clinical trial and the preferred and usual lifestyle of the 
subject. 
 
 
218 of 272


Appendix 3. 
Medications with QTc Prolongation Risk 
High risk QTc prolongation medications are those that demonstrate a prolonged QTc interval 
after administration and are clearly associated with Torsade de Pointes (TdP), even when used 
as directed. Moderate risk QTc prolongation medications are those that have substantial 
evidence of causing QTc prolongation but do not have enough evidence of causing TdP when 
used as directed. The following table lists the medications with high and moderate QTc 
prolongation risk: 
This list may not be all-inclusive; direct any questions to the Medical Monitor. Additionally, 
please visit crediblemeds.org for more information. 
Appendix 3 – Table 1: 
Medications with QTc Prolongation Risk 
Medication Class 
High Risk Medications 
Moderate Risk Medications 
Antibiotics/ 
Antifungals 
Azithromycin  
Ciprofloxacin 
Clarithromycin 
Erythromycin 
Fluconazole 
Gatifloxacina 
Levofloxacin  
Moxifloxacin 
Pentamidine  
Sparfloxacina 
Bedaquiline 
Delamanida 
Gemifloxacin 
Norfloxacin 
Ofloxacin 
Roxithromycina 
Telavancin 
Telithromycin 
 
Antidepressants 
Citalopram 
Escitalopram 
Clomipramine 
Desipramine 
Imipramine 
Mirtazapine 
Nortriptyline 
Trimipramine 
Venlafaxine 
Antiemetics/ 
Antinausea 
Domperidonea 
Ondansetron 
Dolasetron 
Granisetronb 
Tropisetrona 
Antihistamines 
Astemizolea 
Terfenadinea 
 
Antimalarials/ 
Antivirals 
Chloroquine 
Halofantrine 
Atazanavir 
Foscarnet 
Rilpivirine 
Saquinavir 
 
219 of 272


Appendix 3 – Table 1: Medications with QTc Prolongation Risk (Continued) 
Medication Class 
High Risk Medications 
Moderate Risk Medications 
Antipsychotics 
Chlorpromazine  
Droperidol   
Haloperidol  
Levomepromazinea 
Mesoridazinea 
Pimozide  
Sulpiridea  
Thioridazine 
 
Aripiprazole 
Asenapine 
Clozapine 
Iloperidone 
Olanzapine 
Paliperidone 
Pipamperonea 
Promethazine 
Risperidone 
Sertindolea 
Anesthetics 
Cocaine (local anesthetic) 
Propofol  
Sevoflurane  
Dexmedetomidine 
Cardiovascular 
Amiodarone 
Bepridila 
Disopyramide 
Dofetilide 
Dronedarone 
Flecainide 
Ibutilide 
Procainamide (oral)a 
Quinidine 
Sotalol 
Israpidine 
Moexipril/hydrochlorothiazide 
Nicardipine 
Ranolazine 
 
Phosphodiesterase 3 
Inhibitors 
Anagrelide 
Cilostazol 
 
Opioids 
Levomethadyla 
Methadone 
Hydrocodone ERc 
Oncologic 
Arsenic trioxide  
Oxaliplatin 
Vandetanib  
Bortezomib 
Bosutinib 
Ceritinib 
Crizotinib 
Dabrafenib 
Dasatinib 
Degarelix 
Eribulin mesylate 
Lapatinib 
Leuprolide 
Nilotinib 
Panobinostat 
Pazopanib 
Sorafenib 
Sunitinib 
Tamoxifen 
Toremifene 
Vemurafenib 
Vorinostat 
 
220 of 272


Appendix 3 – Table 1: Medications with QTc Prolongation Risk (Continued) 
Medication Class 
High Risk Medications 
Moderate Risk Medications 
Other drugs 
Cisapridea 
Donepezil 
Probucola 
Papaverine HCL 
Alfuzosin 
Apomorphine 
Artenimol + piperaquine 
Atomoxetine 
Famotidine 
Felbamate 
Fingolimod 
Lithium 
Mifepristone 
Mirebegron 
Oxytocin 
Pasireotide 
Perflutren lipid 
microspheres 
Tacrolimus 
Tetrabenazine  
Tizanidine 
Tolterodine 
Vardenafil 
a Medication not available in the US 
b Published literature report minimal or no change to QTc interval with the administration of granisetron (65, 66). 
c Observed with extended release only 
 
221 of 272




 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
GleostineTM 
(lomustine) Capsules 
WARNINGS 
Gleostine (lomustine) should be administered under the supervision of a qualified physician 
experienced in the use of cancer chemotherapeutic agents. 
Bone marrow suppression, notably thrombocytopenia and leukopenia, which may contribute to 
bleeding and overwhelming infections in an already compromised patient, is the most common 
and severe of the toxic effects of Gleostine (see WARNINGS and ADVERSE REACTIONS). 
Since the major toxicity is delayed bone marrow suppression, blood counts should be monitored 
weekly for at least 6 weeks after a dose (see ADVERSE REACTIONS). At the recommended 
dosage, courses of Gleostine should not be given more frequently than every 6 weeks. 
The bone marrow toxicity of Gleostine is cumulative and therefore dosage adjustment must be 
considered on the basis of nadir blood counts from prior dose (see dosage adjustment table under 
DOSAGE AND ADMINISTRATION). 
DESCRIPTION 
GleostineTM (lomustine) (CCNU) is one of the nitrosoureas used in the treatment of certain 
neoplastic diseases. It is 1-(2-chloro-ethyl)-3-cyclohexyl-1-nitrosourea. It is a yellow powder 
with the empirical formula of C9H16ClN3O2 and a molecular weight of 233.71. Gleostine is 
soluble in 10% ethanol (0.05 mg per mL) and in absolute alcohol (70 mg per mL). Gleostine is 
relatively insoluble in water (<0.05 mg per mL). 
It is relatively un-ionized at a physiological pH. 
Inactive ingredients in Gleostine Capsules are magnesium stearate and mannitol. 
Reference ID: 3509888 
 
223 of 272


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
The structural formula is: 
Gleostine is available in 10 mg, 40 mg, and 100 mg capsules for oral administration. 
CLINICAL PHARMACOLOGY 
Although it is generally agreed that lomustine alkylates DNA and RNA, it is not cross resistant 
with other alkylators. As with other nitrosoureas, it may also inhibit several key enzymatic 
processes by carbamoylation of amino acids in proteins. 
Lomustine may be given orally. Following oral administration of radioactive lomustine at doses 
ranging from 30 mg/m2 to 100 mg/m2, about half of the radioactivity given was excreted in the 
urine in the form of degradation products within 24 hours. 
The serum half-life of the metabolites ranges from 16 hours to 2 days. Tissue levels are 
comparable to plasma levels at 15 minutes after intravenous administration. 
Because of the high lipid solubility and the relative lack of ionization at physiological pH, 
lomustine crosses the blood-brain barrier quite effectively. Levels of radioactivity in the CSF 
are 50% or greater than those measured concurrently in plasma. 
INDICATIONS AND USAGE 
Gleostine has been shown to be useful as a single agent in addition to other treatment 
modalities, or in established combination therapy with other approved chemotherapeutic agents 
in the following: 
Brain tumors—both primary and metastatic, in patients who have already received appropriate 
surgical and/or radiotherapeutic procedures. 
Reference ID: 3509888 
 
224 of 272


 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hodgkin’s disease—secondary therapy in combination with other approved drugs in patients 
who relapse while being treated with primary therapy, or who fail to respond to primary 
therapy. 
CONTRAINDICATIONS 
Gleostine should not be given to individuals who have demonstrated a previous 
hypersensitivity to it. 
WARNINGS 
Since the major toxicity is delayed bone marrow suppression, blood counts should be 
monitored weekly for at least 6 weeks after a dose (see ADVERSE REACTIONS). At the 
recommended dosage, courses of Gleostine should not be given more frequently than every 6 
weeks. 
The bone marrow toxicity of Gleostine is cumulative and therefore dosage adjustment must be 
considered on the basis of nadir blood counts from prior dose (see dosage adjustment table 
under DOSAGE AND ADMINISTRATION). 
Pulmonary toxicity from Gleostine appears to be dose related (see ADVERSE REACTIONS). 
Long-term use of nitrosoureas has been reported to be possibly associated with the 
development of secondary malignancies. 
Liver and renal function tests should be monitored periodically (see ADVERSE 
REACTIONS). 
Pregnancy Category D 
Gleostine can cause fetal harm when administered to a pregnant woman. Lomustine is 
embryotoxic and teratogenic in rats and embryotoxic in rabbits at dose levels equivalent to the 
human dose. There are no adequate and well controlled studies in pregnant women. If this drug 
is used during pregnancy, or if the patient becomes pregnant while taking (receiving) this drug, 
the patient should be apprised of the potential hazard to the fetus. Women of childbearing 
potential should be advised to avoid becoming pregnant. 
Reference ID: 3509888 
 
225 of 272


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226 of 272


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline pulmonary function studies should be conducted along with frequent pulmonary 
function tests during treatment. Patients with a baseline below 70% of the predicted Forced 
Vital Capacity (FVC) or Carbon Monoxide Diffusing Capacity (DLCO) are particularly at risk. 
Since Gleostine may cause liver dysfunction, it is recommended that liver function tests be 
monitored periodically. 
Renal function tests should also be monitored periodically. 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
Lomustine is carcinogenic in rats and mice, producing a marked increase in tumor incidence in 
doses approximating those employed clinically. Nitrosourea therapy does have carcinogenic 
potential in humans (see ADVERSE REACTIONS). Lomustine also affects fertility in male 
rats at doses somewhat higher than the human dose. 
Pregnancy 
Pregnancy Category D 
See WARNINGS. 
Nursing Mothers 
It is not known whether this drug is excreted in human milk. Because many drugs are excreted 
in human milk and because of the potential for serious adverse reactions in nursing infants from 
Gleostine, a decision should be made whether to discontinue nursing or to discontinue the drug, 
taking into account the importance of the drug to the mother. 
Pediatric Use 
See 
ADVERSE 
REACTIONS: 
Pulmonary 
Toxicity 
and 
DOSAGE 
AND 
ADMINISTRATION. 
Geriatric Use 
No data from clinical studies of Gleostine are available for patients 65 years of age and over to 
determine whether they respond differently than younger patients. Other reported clinical 
experience has not identified differences in responses between elderly and younger patients. In 
general, dose selection for an elderly patient should be cautious, reflecting the greater 
frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other 
drug therapy. 
Reference ID: 3509888 
 
227 of 272


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lomustine and its metabolites are known to be substantially excreted by the kidney, and the 
risk of toxic reactions to this drug may be greater in patients with impaired renal function. 
Because elderly patients are more likely to have decreased renal function, care should be taken 
in dose selection, and renal function should be monitored. 
ADVERSE REACTIONS 
Hematologic Toxicity 
The most frequent and most serious toxicity of Gleostine is delayed myelosuppression. It 
usually occurs 4 to 6 weeks after drug administration and is dose related. Thrombocytopenia 
occurs at about 4 weeks postadministration and persists for 1 to 2 weeks. Leukopenia occurs at 
5 to 6 weeks after a dose of Gleostine and persists for 1 to 2 weeks. Approximately 65% of 
patients receiving 130 mg/m2 develop white blood counts below 5000 wbc/mm3. Thirty-six 
percent developed white blood counts below 3000 wbc/mm3. Thrombocytopenia is generally 
more severe than leukopenia. However, both may be dose-limiting toxicities. 
Gleostine may produce cumulative myelosuppression, manifested by more depressed 
indices or longer duration of suppression after repeated doses. 
The occurrence of acute leukemia and bone marrow dysplasias have been reported in 
patients following long-term nitrosourea therapy. 
Anemia also occurs, but is less frequent and less severe than thrombocytopenia or 
leukopenia. 
Pulmonary Toxicity 
Pulmonary toxicity characterized by pulmonary infiltrates and/or fibrosis has been reported 
rarely with Gleostine. Onset of toxicity has occurred after an interval of 6 months or longer 
from the start of therapy with cumulative doses of Gleostine usually greater than 1100 mg/m2 . 
There is 1 report of pulmonary toxicity at a cumulative dose of only 600 mg. 
Delayed onset pulmonary fibrosis occurring up to 17 years after treatment has been reported in 
patients who received related nitrosoureas in childhood and early adolescence (1–16 years) 
combined with cranial radiotherapy for intracranial tumors. There appeared to be some late 
reduction of pulmonary function of all long-term survivors. This form of lung fibrosis may be 
slowly progressive and has resulted in death in some cases. In this long-term study of 
carmustine, all those initially treated at less than 5 years of age died of delayed pulmonary 
fibrosis. 
Reference ID: 3509888 
 
228 of 272


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
Gastrointestinal Toxicity 
Nausea and vomiting may occur 3 to 6 hours after an oral dose and usually last less than 
24 hours. Prior administration of antiemetics is effective in diminishing and sometimes 
preventing this side effect. Nausea and vomiting can also be reduced if Gleostine is 
administered to fasting patients. 
Hepatotoxicity 
A reversible type of hepatic toxicity, manifested by increased transaminase, alkaline 
phosphatase, and bilirubin levels, has been reported in a small percentage of patients receiving 
Gleostine. 
Nephrotoxicity 
Renal abnormalities consisting of progressive azotemia, decrease in kidney size, and renal 
failure have been reported in patients who received large cumulative doses after prolonged 
therapy with Gleostine. Kidney damage has also been reported occasionally in patients 
receiving lower total doses. 
Other Toxicities 
Stomatitis, alopecia, optic atrophy, and visual disturbances, such as blindness, have been 
reported infrequently. 
Neurological reactions, such as disorientation, lethargy, ataxia, and dysarthria have been noted 
in some patients receiving Gleostine. However, the relationship to medication in these patients 
is unclear. 
OVERDOSAGE 
Accidental overdose with lomustine has been reported, including fatal cases. Accidental 
overdose has been associated with bone marrow suppression, abdominal pain, diarrhea, 
vomiting, anorexia, lethargy, dizziness, abnormal hepatic function, cough, and shortness of 
breath. 
No proven antidotes have been established for Gleostine overdosage. In case of overdose, 
appropriate supportive measures should be taken. 
Reference ID: 3509888 
 
229 of 272


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
DOSAGE AND ADMINISTRATION 
The recommended dose of Gleostine in adult and pediatric patients as a single agent in 
previously untreated patients is 130 mg/m2 as a single oral dose every 6 weeks (see 
PRECAUTIONS: Information for Patients and HOW SUPPLIED: Directions to the 
Pharmacist). In individuals with compromised bone marrow function, the dose should be 
reduced to 100 mg/m2 every 6 weeks. When Gleostine is used in combination with other 
myelosuppressive drugs, the doses should be adjusted accordingly. All doses of Gleostine must 
be rounded to the nearest 10 mg by the prescriber (see HOW SUPPLIED). 
Doses subsequent to the initial dose should be adjusted according to the hematologic response 
of the patient to the preceding dose. The following schedule is suggested as a guide to dosage 
adjustment: 
Nadir After Prior Dose 
Percentage of Prior Dose 
to be Given 
Leukocytes (/mm3) 
Platelets (/mm3) 
≥4000 
3000–3999 
2000–2999 
<2000 
≥100,000 
75,000–99,999 
25,000–74,999 
<25,000 
100% 
100% 
70% 
50% 
A repeat course of Gleostine should not be given until circulating blood elements have 
returned to acceptable levels (platelets above 100,000/mm3; leukocytes above 4000/mm3), 
and this is usually in 6 weeks. Adequate number of neutrophils should be present on a 
peripheral blood smear. Blood counts should be monitored weekly and repeat courses 
should not be given before 6 weeks because the hematologic toxicity is delayed and 
cumulative. 
HOW SUPPLIED 
GleostineTM Capsules are available in individual bottles of 5 capsules each. 
NDC 58181-3032-5 
100 mg capsules (Green/Green) 
NDC 58181-3031-5 
40 mg capsules (White/Green) 
NDC 58181-3030-5 
10 mg capsules (White/White) 
Reference ID: 3509888 
 
230 of 272


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232 of 272














































Updated Response Assessment Criteria for High-Grade
Gliomas: Response Assessment in Neuro-Oncology
Working Group
Patrick Y. Wen, David R. Macdonald, David A. Reardon, Timothy F. Cloughesy, A. Gregory Sorensen,
Evanthia Galanis, John DeGroot, Wolfgang Wick, Mark R. Gilbert, Andrew B. Lassman, Christina Tsien,
Tom Mikkelsen, Eric T. Wong, Marc C. Chamberlain, Roger Stupp, Kathleen R. Lamborn,
Michael A. Vogelbaum, Martin J. van den Bent, and Susan M. Chang
From the Center for Neuro-Oncology,
Dana-Farber/Brigham and Women’s
Cancer Center; Division of Neurology,
Brigham and Women’s Hospital; Depart-
ment of Radiology, Massachusetts
General Hospital; Brain Tumor Center,
Department of Neurology, Beth Israel
Deaconess Medical Center, Boston, MA;
Preston Robert Tisch Brain Tumor
Center, Duke University Medical Center,
Durham, NC; Neuro-Oncology Program,
David Geffen School of Medicine at
University of California, Los Angeles, Los
Angeles; Division of Neuro-Oncology,
Department of Neurological Surgery,
University of California, San Francisco,
San Francisco, CA; Department of Medi-
cal Oncology, Mayo Clinic, Rochester,
MN; Department of Neuro-Oncology, The
University of Texas M.D. Anderson
Cancer Center, Houston, TX; Department
of Neurology and Brain Tumor Center,
Memorial Sloan-Kettering Cancer Center,
New York, NY; Department of Radiation
Oncology, University of Michigan Medical
Center, Ann Arbor; Department of Neuro-
Oncology, Henry Ford Hospital, Detroit,
MI; Fred Hutchinson Cancer Center,
Seattle, WA; Brain Tumor and Neuro-
Oncology Center, Department of Neuro-
surgery, Cleveland Clinic, Cleveland OH;
Department of Medical Oncology,
London Regional Cancer Program,
University of Western Ontario, London,
Ontario, Canada; Department of Neuro-
Oncology, University of Heidelberg,
Heidelberg, Germany; Centre Hospitalier
Universitaire Vaudois; University of
Lausanne, Lausanne, Switzerland; and
Neuro-Oncology Unit, Daniel den Hoed
Cancer Center/Erasmus University Hospi-
tal, Rotterdam, the Netherlands.
Submitted September 26, 2009;
accepted December 14, 2009;
published online ahead of print at
www.jco.org on March 15, 2010.
P.Y.W., D.R.M., M.A.V., M.J.v.d.B. and
S.M.C. contributed equally to this work.
Authors’ disclosures of potential con-
ﬂicts of interest and author contribu-
tions are found at the end of this
article.
Corresponding author: Patrick Y. Wen,
MD, Center for Neuro-Oncology, Dana
Farber/Brigham and Women’s Cancer
Center, SW430D, 44 Binney St,
Boston, MA 02115; e-mail: pwen@
partners.org.
© 2010 by American Society of Clinical
Oncology
0732-183X/10/2811-1963/$20.00
DOI: 10.1200/JCO.2009.26.3541
A
B
S
T
R
A
C
T
Currently, the most widely used criteria for assessing response to therapy in high-grade gliomas
are based on two-dimensional tumor measurements on computed tomography (CT) or magnetic
resonance imaging (MRI), in conjunction with clinical assessment and corticosteroid dose (the
Macdonald Criteria). It is increasingly apparent that there are signiﬁcant limitations to these criteria,
which only address the contrast-enhancing component of the tumor. For example, chemoradio-
therapy for newly diagnosed glioblastomas results in transient increase in tumor enhancement
(pseudoprogression) in 20% to 30% of patients, which is difﬁcult to differentiate from true tumor
progression. Antiangiogenic agents produce high radiographic response rates, as deﬁned by a
rapid decrease in contrast enhancement on CT/MRI that occurs within days of initiation of
treatment and that is partly a result of reduced vascular permeability to contrast agents rather than
a true antitumor effect. In addition, a subset of patients treated with antiangiogenic agents develop
tumor recurrence characterized by an increase in the nonenhancing component depicted on
T2-weighted/ﬂuid-attenuated inversion recovery sequences. The recognition that contrast en-
hancement is nonspeciﬁc and may not always be a true surrogate of tumor response and the need
to account for the nonenhancing component of the tumor mandate that new criteria be developed
and validated to permit accurate assessment of the efﬁcacy of novel therapies. The Response
Assessment in Neuro-Oncology Working Group is an international effort to develop new
standardized response criteria for clinical trials in brain tumors. In this proposal, we present the
recommendations for updated response criteria for high-grade gliomas.
J Clin Oncol 28:1963-1972. © 2010 by American Society of Clinical Oncology
INTRODUCTION
Gliomas are the most common form of malignant
primary brain tumors in adults, with an annual in-
cidence of approximately four to ﬁve per 100,000
people.1,2 Theevaluationoftreatmentinhigh-grade
gliomas currently relies either on the duration of
patientsurvivalor,morecommonlyinpatientswith
recurrent disease, the radiographic response rate or
progression-free survival (PFS).3,4 In 1990, Mac-
donald et al5 published criteria for response assess-
ment in high-grade gliomas (Table 1). These criteria
provided an objective radiologic assessment of
tumor response and were based primarily on
contrast-enhanced computed tomography (CT)
and the two-dimensional WHO oncology response
criteria using enhancing tumor area (the product of
the maximal cross-sectional enhancing diameters)
as the primary tumor measure.6,7 These criteria also
considered the use of corticosteroids and changes in
the neurologic status of the patient. The Macdonald
Criteria enabled response rates to be compared be-
tween clinical trials and have been widely used in
high-grade glioma studies since their introduction.
Although the Macdonald Criteria were devel-
oped primarily for CT scans, they have been extrap-
olatedtomagneticresonanceimaging(MRI),which
is now the standard neuroimaging modality used to
assess treatment response in high-grade gliomas.
Like CT scans, areas of the tumor with abnormal
vascular architecture and disrupted integrity of the
blood-brain barrier are depicted as the contrast-
enhancing component on MRI.8
In systemic cancers, one-dimensional tumor
measurements have become the standard criteria to
determine response. The Response Evaluation Cri-
teria in Solid Tumors (RECIST) ﬁrst introduced the
use of one-dimensional measurements in 20009 and
were recently revised (RECIST version 1.1).10 Sev-
eralstudieshavecomparedtheRECISTcriteriawith
JOURNAL OF CLINICAL ONCOLOGY
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© 2010 by American Society of Clinical Oncology
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255 of 272
















ROLE OF VOLUMETRIC AND ADVANCED MRI ASSESSMENT
Given the limitations of two-dimensional tumor measurements,
there is signiﬁcant interest in volumetric anatomic assessment. The
use of volumetric assessment would allow more accurate determina-
tion of the contrast-enhancing and nonenhancing volumes and over-
come the limitations of two-dimensional measurements of lesions
surrounding a surgical cavity.14-16 However, the RANO Working
Group and colleagues in neuroradiology do not believe that there is
sufﬁcient standardization and availability to recommend adoption of
volumetric assessment of tumor volume at present. Nonetheless, this
is an important area of research. Eventually, as volumetric imaging
becomes more standardized and widely available and as data validat-
ingthisapproachemerge,itmaybepossibletoincorporatevolumetric
measurements in the response assessment of high-grade gliomas.
Emerging data also suggest that advanced MRI techniques such
as perfusion imaging (dynamic susceptibility MRI), permeability im-
aging (dynamic contrast-enhanced MRI), diffusion imaging, mag-
netic resonance spectroscopy, and [18F]-ﬂuorothymidine and amino
acid positron emission tomography may predict tumor response or
allow the differentiation of nonenhancing tumor from other causes of
increasedFLAIRsignal.Thesetechniqueswillrequirerigorousclinical
validation studies before they can be incorporated into response crite-
ria used in clinical trials in high-grade gliomas.
OTHER METHODS OF DETERMINING EFFICACY
Growing data suggest that other end points such as neurocognitive
function,qualityoflife,andcorticosteroidusemaybeusedtomeasure
clinical beneﬁt. At present, these end points are not sufﬁciently vali-
dated to be incorporated into the current response criteria but could
be added in the future as further data emerge.
CONCLUSION
We propose updated response assessments for the evaluation of
therapies in high-grade gliomas incorporating MRI characteristics
to address the recognized and accepted limitations of the current
Macdonald Criteria. These recommendations were generated as part
of an international neuro-oncology effort with consensus building
and are an attempt to develop standardized assessment criteria. Im-
plementation into future clinical trials will be critical so we can
validate the criteria as a surrogate to end points such as survival
and, ultimately, improve the accuracy and efﬁciency of the early
evaluation of novel therapies.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
Although all authors completed the disclosure declaration, the following
author(s) indicated a ﬁnancial or other interest that is relevant to the subject
matter under consideration in this article. Certain relationships marked
with a “U” are those for which no compensation was received; those
relationships marked with a “C” were compensated. For a detailed
description of the disclosure categories, or for more information about
ASCO’s conﬂict of interest policy, please refer to the Author Disclosure
Declaration and the Disclosures of Potential Conﬂicts of Interest section in
Information for Contributors.
Employment or Leadership Position: None Consultant or Advisory
Role: Michael A. Vogelbaum, AstraZeneca (C), Schering-Plough (C)
Stock Ownership: None Honoraria: Michael A. Vogelbaum, BrainLAB,
BrainLAB, Genentech, Eisai Research Funding: None Expert
Testimony: None Other Remuneration: None
AUTHOR CONTRIBUTIONS
Conception and design: Patrick Y. Wen, David R. Macdonald, David A.
Reardon, Timothy F. Cloughesy, A. Gregory Sorensen, Evanthia Galanis,
John DeGroot, Wolfgang Wick, Mark R. Gilbert, Andrew B. Lassman,
Christina Tsien, Tom Mikkelsen, Eric T. Wong, Marc C. Chamberlain,
Roger Stupp, Kathleen R. Lamborn, Michael A. Vogelbaum, Martin J.
van den Bent, Susan M. Chang
Administrative support: Patrick Y. Wen
Provision of study materials or patients: Patrick Y. Wen, Susan M.
Chang, A. Gregory Sorensen
Collection and assembly of data: Patrick Y. Wen, David R.
Macdonald, David A. Reardon, Timothy F. Cloughesy, A. Gregory
Sorensen, Evanthia Galanis, John DeGroot, Wolfgang Wick,
Mark R. Gilbert, Andrew B. Lassman, Christina Tsien, Tom
Mikkelsen, Eric T. Wong, Marc C. Chamberlain, Roger Stupp,
Kathleen R. Lamborn, Michael A. Vogelbaum, Martin J. van den
Bent, Susan M. Chang
Data analysis and interpretation: Patrick Y. Wen, David R. Macdonald,
David A. Reardon, Timothy F. Cloughesy, A. Gregory Sorensen,
Evanthia Galanis, John DeGroot, Wolfgang Wick, Mark R. Gilbert,
Andrew B. Lassman, Christina Tsien, Tom Mikkelsen, Eric T. Wong,
Marc C. Chamberlain, Roger Stupp, Kathleen R. Lamborn, Michael A.
Vogelbaum, Martin J. van den Bent, Susan M. Chang
Manuscript writing: Patrick Y. Wen, David R. Macdonald, David A.
Reardon, Timothy F. Cloughesy, A. Gregory Sorensen, Evanthia Galanis,
John DeGroot, Wolfgang Wick, Mark R. Gilbert, Andrew B. Lassman,
Christina Tsien, Tom Mikkelsen, Eric T. Wong, Roger Stupp, Kathleen
R. Lamborn, Michael A. Vogelbaum, Martin J. van den Bent,
Susan M. Chang
Final approval of manuscript: Patrick Y. Wen, David R. Macdonald,
David A. Reardon, Timothy F. Cloughesy, A. Gregory Sorensen,
Evanthia Galanis, John DeGroot, Wolfgang Wick, Mark R. Gilbert,
Andrew B. Lassman, Christina Tsien, Tom Mikkelsen, Eric T. Wong,
Marc C. Chamberlain, Roger Stupp, Kathleen R. Lamborn, Michael A.
Vogelbaum, Martin J. van den Bent, Susan M. Chang
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1972
© 2010 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
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Appendix 7. 
Karnofsky Performance Status Scale 
 
Karnofsky Performance Status Scale 
Percent 
Description 
100 
Normal, no complaints, no evidence of disease 
90 
Able to carry on normal activity; minor signs or symptoms of disease 
80 
Normal activity with effort; some signs or symptoms of disease 
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 
50 
Requires considerable assistance and frequent medical care 
40 
Disabled, requires special care and assistance 
30 
Severely disabled, hospitalization indicated 
Death not imminent 
20 
Very sick, hospitalization indicated 
Death not imminent 
10 
Moribund, fatal processes progressing rapidly 
0 
Dead 
 
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Confidential 
Protocol P311-201 
 
Approved Protocol Version: Amendment 4 
Date: 02 Aug 2018 
Proximagen, LLC 
 
 
 
 
Proximagen, LLC 
505 Waterford Park 
Hwy 169 N, Suite 850 
Plymouth, MN 55441 
CLINICAL STUDY PROTOCOL 
Protocol Title: 
A Phase 1/2 Dose-escalation of USL311 as Single 
Agent and in Combination with Lomustine (CCNU) in 
Subjects with Advanced Solid Tumors, with 
Subsequent Single Agent and Combination Phase 2 
Cohorts for Subjects with Relapsed/Recurrent 
Glioblastoma Multiforme (GBM) 
Protocol Number: 
P311-201 
Protocol Version: 
Amendment 4 
Issue Date: 
02 Aug 2018 
 
Rationale for Amendment: 
In Protocol Amendment #3, in order to manage a potential USL311-related increase in the QT 
interval, which was transient, resolved post-end of infusion, and exhibited an apparent 
correlation with plasma USL311 concentrations (i.e., Cmax), the duration of intravenous (IV) 
infusion was increased from 120 minutes (2 hours) to 240 minutes (4 hours). Dosing with the 4-
hour infusion began at 180 mg/m2 and progressed to 250 mg/m2. After a total 13 subjects, 
including the original 8 subjects that prompted Amendment #3, were evaluable (i.e., had 
completed Cycle 1 dosing, at minimum), the Dose Escalation Committee halted dose escalation, 
although no DLTs had occurred, due to continuing dose-related increases in QTcF prolongation 
that was not ameliorated by increasing the infusion duration. 
The protocol is being amended to change to an oral formulation of USL311. Daily oral dosing is 
anticipated to mitigate the concentration-related QT effect, compared to IV bolus weekly dosing. 
The selected 40 mg daily oral starting dose is comparable to the 30 mg daily starting dose based 
on 1/6 HNSTD in dogs (5 mg/kg/day oral daily dose) and is lower than the ~60 mg daily dose 
calculated based on the maximum IV dose tested in humans (250 mg/m2 weekly, divided into 
daily doses). USL311 plasma pharmacokinetics are dose-proportional and minimal to no plasma 
accumulation is expected for USL311 and its main metabolites after daily oral dosing. A fixed-
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Confidential 
Protocol P311-201 
 
Approved Protocol Version: Amendment 4 
Date: 02 Aug 2018 
Proximagen, LLC 
 
 
dosing approach is considered to be appropriate for future studies given that USL311 
pharmacokinetics are not influenced by body size. 
An additional Phase 1 dose-escalation cohort of subjects with advanced solid tumors has been 
added (designated Part 1b) to determine the oral USL311 maximum tolerated dose (MTD), the 
recommended Phase 2 dose (RP2D), and starting dose for Phase 1 combination with oral 
lomustine. 
Summary of key changes 
Change 
Rationale 
Key sections affected 
Sponsor information changed to 
Proximagen LLC 
Divestiture of Proximagen 
subsidiary from Upsher-Smith 
Laboratories, LLC 
Title page; SAE reporting 
information contact information 
Rationale for oral starting dose 
Toxicology study in dogs with oral 
formulation 
1.2.4 Toxicology and Safety 
Pharmacology; 6.1.2.1 Phase 1 
Updated clinical study findings 
Experience available on 13 subjects 
1.3 Clinical Study Findings for 
USL311;  
Addition of Part 1b (oral) cohort 
Change to oral dose form for Part 
1b and all subsequent cohorts, with 
accompanying changes in schedule 
of assessments, including PK and 
PD 
Schedule of Visits and Assessments 
Table 2 and 9; 3.2.2 Part 1b -Dose-
escalation in Advanced Solid 
Tumors of Single Agent Oral 
USL311; 3.2.4 Dose-escalation 
Strategy; 3.2.5 Dose Limiting 
Toxicities; 7.2.2 Part 1b Treatment; 
8.6.1 Whole Blood and Plasma 
Sample Collection; 8.7.3 Collection 
of Other Biomarkers; Appendix 1b 
Adaptive Design Rpeort for the Part 
1b Dose-Escalation of Oral 
USL311 in Subjects with Advanced 
Solid Tumors 
Increase in subject number 
Addition of Phase 1 Part 1b oral 
dose cohort 
5.1 Number of subjects 
Addition of allergy/hypersensitivity 
to components of USL311 
formulation to Exclusion 11 and 
addition of Exclusion 17 regarding 
conditions that may have a 
significant effect on USL311 
absorption 
To cover oral formulation 
excipients and oral dosing 
5.2.2 Exclusion Criteria; 
Addition of concomitant 
medication and dietary restrictions 
To cover oral dosing 
5.3.2 Prohibited Medications; 5.4 
Dietary and Other Protocol 
Restrictions;  
Addition of oral dose and dosing 
information 
To cover oral dosing 
6.1 Study Treatment Administration 
and Doses; 6.1.1.4 USL311 Oral 
Administration; 6.1.5.1 USL311 
Dose Modification; 6.1.7 Treatment 
Compliance; 6.4 Study Drug 
Identification and Supply; 6.6 
Handling, Storage and 
Accountability; 6.6.1 Dispensing of 
Study Drug 
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Protocol P311-201 
 
Approved Protocol Version: Amendment 4 
Date: 02 Aug 2018 
Proximagen, LLC 
 
 
Removal of SDF-1 from Part 1b 
and beyond 
Validated assay not available 
8.7.3 Collection of Other 
Biomarkers 
Changes in assessments throughout 
To cover oral dosing 
Multiple 
Clarifications and typographical 
corrections 
Clarify prior text, make text 
consistent, and correct errors in 
prior protocol. Format and minor 
changes are not tracked. 
Multiple 
 
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SAP_001.pdf: 
  
 
 
 
 
 
                                 
Confidential 
 
 
 
 
Proximagen, LLC 
 
 
STATISTICAL ANALYSIS PLAN 
Protocol Number P311-201 
 
US IND # 127616 
EudraCT # 2015-004214-14 
 
A Phase 1/2 Dose-escalation of USL311 as Single Agent and in Combination with 
Lomustine (CCNU) in Subjects with Advanced Solid Tumors, with Subsequent Single 
Agent and Combination Phase 2 Cohorts for Subjects with Relapsed/Recurrent 
Glioblastoma Multiforme (GBM) 
 
SPONSOR 
 
Proximagen, LLC 
505 Waterford Park 
Hwy 169 N, Suite 850 
Plymouth, MN 55441 
 
 
Final 2.0 
15-JUL-2020


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Statistical Analysis Plan for P311-201 
15-JUL-2020 
 
 
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Page 2 of 27 
 
Table of Contents 
1 
List of Abbreviations and Definition of Terms.................................................... 4 
2 
Introduction .......................................................................................................... 6 
3 
Overall Study Design and Objectives .................................................................. 6 
3.1 
Study Objectives for Phase 1 ............................................................................... 6 
3.1.1 
Primary Objectives ............................................................................................... 6 
3.1.2 
Secondary Objectives ........................................................................................... 6 
3.1.3 
Exploratory Objectives ........................................................................................ 7 
3.2 
Trial Design and Study Procedures ...................................................................... 7 
3.3 
Treatments and Assignment to Treatments .......................................................... 8 
3.3.1 
Part 1a – Dose-Escalation in Advanced Solid Tumors of Single Agent IV 
USL311 …………………………………………………………………………………...8 
3.3.2 
Part 1b – Dose-Escalation in Advanced Solid Tumors of Single Agent oral 
USL311 …………………………………………………………………………………...9 
3.3.3 
Dose-Escalation Strategy ................................................................................... 10 
3.3.4 
Dose Escalation Committee (DEC) ................................................................... 11 
3.4 
Number of Subjects Planned .............................................................................. 11 
4 
General Analysis Conventions ........................................................................... 11 
4.1 
Partial Date Imputation ...................................................................................... 12 
4.2 
Study Periods ..................................................................................................... 13 
4.3 
Visit Windows ................................................................................................... 13 
5 
Analysis Populations .......................................................................................... 13 
5.1 
Full Analysis Data Set (FAS) ............................................................................ 13 
5.2 
Safety Analysis Data Set .................................................................................... 14 
5.3 
MTD-Evaluable Data Set ................................................................................... 14 
5.4 
Pharmacokinetic (PK) Analysis Data Set .......................................................... 14 
5.5 
Pharmacodynamic (PD) Analysis Data Set ....................................................... 14 
5.6 
Response-Evaluable Analysis Data Set (RES) .................................................. 14 
5.7 
Exposure-Response Analysis Data Set (RAS) ................................................... 14 
6 
Subject Disposition ............................................................................................ 14 
7 
Protocol Deviations ............................................................................................ 15 
8 
Demographic and Baseline Characteristics ....................................................... 15 
8.1 
Demographic Characteristics ............................................................................. 15 
8.2 
Medical History ................................................................................................. 16 
8.3 
Prior Cancer Treatment ...................................................................................... 16 
8.4 
Prior and Concomitant Medications .................................................................. 17 
9 
Efficacy Variables and Analysis ........................................................................ 17 
10 
Statistical/Analytical Issues ............................................................................... 19 
10.1 
Handling of Dropouts or Missing Data .............................................................. 19 
10.2 
Pooling of Centers in Multi-Center Studies ....................................................... 19 
10.3 
Multiple Comparisons/Multiplicity ................................................................... 20 
10.4 
Examination of Subgroups ................................................................................. 20 
10.5 
Interim Analysis and Data Monitoring .............................................................. 20 
11 
Pharmacokinetics/Pharmacodynamics ............................................................... 20 
11.1 
Pharmacokinetic analyses .................................................................................. 20 


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11.2 
Biomarker Samples (Pharmacodynamic Analyses) ........................................... 20 
11.3 
Exposure-Response Analyses ............................................................................ 20 
12 
Safety Analysis .................................................................................................. 21 
12.1 
Study Drug Exposure ......................................................................................... 21 
12.2 
Adverse Events .................................................................................................. 21 
12.2.1 
Overview of Treatment-Emergent Adverse Events ........................................... 22 
12.2.2 
Treatment-Emergent Adverse Events ................................................................ 22 
12.3 
Clinical Laboratory Data .................................................................................... 23 
12.4 
Physical and Neurological Examination ............................................................ 24 
12.5 
Vital Signs .......................................................................................................... 24 
12.6 
Electrocardiogram .............................................................................................. 24 
12.6.1 
Safety Electrocardiograms ................................................................................. 24 
12.6.2 
Extracted Electrocardiograms ............................................................................ 25 
12.6.3 
Real-Time Bedside ECG and Heartrate Monitoring .......................................... 25 
12.7 
Karnofsky Performance Status (KPS) Scale ...................................................... 25 
12.8 
Other Safety and Pharmacodynamic Assessments ............................................ 26 
13 
Quality Control .................................................................................................. 26 
 
 
 


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1 List of Abbreviations and Definition of Terms  
Abbreviation 
Description 
AE 
Adverse Event 
ATC-2 
Anatomical Therapeutic Chemical 2nd level 
ATC-3 
Anatomical Therapeutic Chemical 3rd level 
BMI 
Body Mass Index 
BSA 
Body Surface Area 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
CR 
Complete Response 
CRO 
Contract Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of Variation 
DCR 
Disease Control Rate 
DLT 
Dose-Limiting Toxicity 
DEC 
Dose Escalation Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eCTD 
Electronic Common Technical Document 
FAS 
Full Analysis Set  
ICH 
International Conference on Harmonisation 
IV 
Intravenous 
KM 
Kaplan-Meier 
KPS 
Karnofsky Performance Status 
mCRM 
Modified Continual Reassessment Method 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Pharmacodynamics 
PFS 
Progression Free Survival 
PFS-6m 
6-month Progression Free Survival 
PK 
Pharmacokinetics 
PR 
Partial Response 
PT 
Preferred Term 
RAS 
Exposure-Response Analysis Set 
RES 
Response-Evaluable Analysis Data Set 
RP2D 
Recommended Phase 2 Dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SOC 
System Organ Class 


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Abbreviation 
Description 
TEAE 
Treatment-Emergent Adverse Event 
WHO 
World Health Organization 
 


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2 Introduction  
This statistical analysis plan (SAP) describes the analysis method for Study P311-201 
protocol Amendment 4, dated 02-Aug-2018 with title “A Phase 1/2 Dose-escalation of 
USL311 as Single Agent and in Combination with Lomustine (CCNU) in Subjects with 
Advanced Solid Tumors, with Subsequent Single Agent and Combination Phase 2 
Cohorts for Subjects with Relapsed/Recurrent Glioblastoma Multiforme (GBM)”. This 
SAP will be finalized and approved prior to clinical database lock for Part 1 of the study. 
This SAP is for Part 1, Phase 1 monotherapy dose-escalation, of this study. The SAP for 
other parts of this study (Part 2, Phase 1 combination; Part 3, Phase 2 monotherapy, and 
Part 4, Phase 2 combination) will be described in separate SAPs, as applicable. 
Pharmacokinetics (PK) and Pharmacodynamics (PD) analyses will also be described in a 
separate SAP. 
This SAP supersedes the statistics considerations in the study protocol, and any 
substantial differences between protocol and SAP are identified. Any deviations to the 
analysis outlined in this SAP will be outlined in the final study report. 
3 Overall Study Design and Objectives 
3.1 Study Objectives for Phase 1 
3.1.1 Primary Objectives 
The primary objective of the Phase 1 dose-escalation is to: 
 Determine the maximum tolerated dose (MTD) and recommended Phase 2 dose 
(RP2D) of USL311 as a single agent in subjects with advanced solid tumors for 
which no standard-of-care treatment is recognized or who have failed or are 
intolerant to the standard-of-care treatment (Part 1) 
 Determine the MTD and RP2D of USL311 in combination with lomustine in 
subjects with advanced solid tumors for which no standard-of-care treatment is 
recognized or who have failed or are intolerant to the standard-of-care treatment 
(Part 2) 
The combination with lomustine objectives are outside the scope of this SAP. 
3.1.2 Secondary Objectives 
The secondary objectives of the Phase 1 dose-escalation are to: 
 Assess the safety and tolerability of USL311 as a single agent and in combination 
with lomustine 
 Determine preliminary efficacy parameters such as 6-month progression-free 
survival rate (PFS-6m), objective response rate (ORR%), disease control rate 


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(DCR), progression free survival (PFS) and overall survival (OS) of USL311 as a 
single agent and in combination with lomustine 
 Determine the pharmacokinetic (PK) profile of USL311 in plasma and whole 
blood, and of lomustine in plasma (prior to and with concomitant USL311 
administration) 
 Evaluate the drug interaction potential between USL311 and lomustine 
The combination with lomustine objectives are outside the scope of this SAP. The PK 
objectives are outside the scope of this SAP. 
3.1.3 Exploratory Objectives 
The exploratory objectives of the Phase 1 dose-escalation are to: 
 
 Determine effects of USL311 on systemic markers of CXCR4 inhibition, 
including measurement of CD34+ cells, and white blood cell count 
 Measure effects of USL311 on a urine biomarker of phospholipidosis, di-
docosahexaenoyl (22:6)-bis(monoacylglycerol) phosphate (BMP) 
 Investigate exposure-response relationships for USL311 as a single agent and in 
combination with lomustine 
 
The exposure-response relationship objective is outside the scope of this SAP. 
 
Note: Phase 2 objectives are described in detail in the protocol. 
3.2 Trial Design and Study Procedures 
This is a Phase 1/2 first-in-human, open-label, multicenter study. Phase 1 of the study is 
described below. The Phase 1 portion of the study consists of two parts, Part 1 and Part 2. 
Part 1 study the dose escalation of single-agent USL311 (IV for Part 1a or oral for Part 
1b) in subjects with advanced solid tumors. As of the date of protocol amendment 4, a 
total of 13 subjects were enrolled in Part 1a and treated with IV USL311 at doses of 60, 
120, 180, and 250 mg/m2. Even though no DLT was observed, the Dose Escalation 
Committee halted Part 1a dose escalation due to dose-related increase in QTcF 
prolongation that was not ameliorated by increasing infusion time. Part 1b studies dose 
escalation of oral USL311 in subjects with advanced solid tumors. Part 2 studies dose 
escalation of oral USL311 in combination with lomustine in subjects with advanced solid 
tumors. Subjects will only participate in one part of the study. Phase 1 (Parts 1 and 2) will 
be conducted at approximately 4 study sites. Additional sites may be added depending on 
study recruitment. 
 


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Figure 1. Phase 1 Study Components Flow Diagram 
 
Dose-escalation components will 1) assess safety, PK/PD and preliminary efficacy of 
USL311 as a single agent in subjects with advanced solid tumors for which no standard-
of-care treatment is recognized or who have failed or are intolerant to the standard-of-
care treatment, and 2) assess safety, PK/PD and preliminary efficacy of USL311 in 
combination with lomustine in subjects with advanced solid tumors for which no 
standard-of-care treatment is recognized or who have failed or are intolerant to the 
standard-of-care treatment. 
The dose-escalation component of Part 1 will determine the MTD and RP2D of single 
agent USL311.  
Study assessments of Part 1 of the study will be performed at the visits outlined in the 
Schedule of Visits and Assessments in Tables 1 (for Part 1a) and Table 2 (for Part 1b) of 
the protocol. 
3.3 
 Treatments and Assignment to Treatments 
3.3.1 Part 1a – Dose-Escalation in Advanced Solid Tumors of Single Agent 
IV USL311 
Subjects in Part 1a (IV USL311) were treated with weekly single agent US311 by IV 
infusion and participated in the following visits:  
 Screening Visit (within 28 to 2 days of Cycle 1, Day 1)  
 Baseline Visit (Day -1)  
 Treatment Phase Visits for Cycle 1 (Visits on Day 1, Day 2, Day 3, Day 5, Day 8, 
and Day 15)  
 Treatment Phase Visits for Cycle 2+ (Visits on Day 1, Day 8, and Day 15)  
 End of Treatment Visit (within 14 days of decision to discontinue on-study 
treatment)  
 Follow-up Visit (within 28 days of last dose on USL311; may be same visit as 
End of Treatment Visit)  
 Long Term Follow-up Visits (quarterly visit or phone call until subject death or 
study termination)  
Phase 1 (Part 1): 
USL311 Single Agent 
Dose-Escalation 
in Solid Tumors 
Phase 1 (Part 2): 
USL311 + Lomustine 
Dose-Escalation 
in Solid Tumors 
Single Agent MTD and 
RP2D Determined 
USL311 + Lomustine 
MTD and RP2D Determined 


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During the Treatment Phase, treatment was administered once every week in 3-week (21-
day) cycles. In Protocol Amendment 3, the duration of infusion for USL311 was 
increased from 120 minutes (2 hours) to 240 minutes (4 hours). As of Amendment 3, 
USL311 was administered as an intravenous (IV) infusion over 240 minutes (4 hours) on 
Days 1, 8, and 15 of a 21-day cycle. Subjects were monitored by study staff for at least 8 
hours after the start of the infusion for their first dose of USL311. 
Dosing with the 4 hour infusion was initiated at the highest safe dose of USL311 as 
determined from subjects who received USL311 via a 2 hour infusion (viz., prior to 
Amendment #3). Subjects who were previously enrolled and were actively participating 
at the time Protocol Amendment #3 was activated will continue study participation 
according to Protocol Amendment #2. 
As of the date of protocol amendment 4, a total of 13 subjects were enrolled in Part 1a 
and treated with IV USL311 at doses of 60, 120, 180, and 250 mg/m2. Even though no 
DLT was observed, the Dose Escalation Committee halted dose escalation of IV USL311 
due to dose-related increase in QTcF prolongation that was not ameliorated by increasing 
infusion time. 
Tumor assessments are carried out at Cycle 3 Day 1 and every 6 weeks (±7) thereafter. 
3.3.2 Part 1b – Dose-Escalation in Advanced Solid Tumors of Single Agent 
oral USL311 
Subjects in Part 1b (oral USL311) are treated with oral daily single agent US311 and are 
participated in the following visits: 
 Screening Visit (within 28 to 2 days of Cycle 1, Day 1) 
 Baseline Visit (Day -1) 
 Treatment Phase Visits for Cycle 1 (Visits on Day 1, Day 2, Day 8, and Day 15) 
 Treatment Phase Visits for Cycle 2+ (Visits on Day 1, Day 8, and Day 15) 
 End of Treatment Visit (within 14 days of decision to discontinue on-study 
treatment) 
 Follow-up Visit (within 28 days of last dose on USL311; may be same visit as 
End of Treatment Visit) 
 Long Term Follow-up Visits (quarterly visit or phone call until subject death, lost 
to follow-up or study termination) 
During the Treatment Phase, treatment will be administered in 3-week (21-day) cycles at 
a starting dose of 40 mg once daily. Treatment cycles will be repeated every 21 days until 
disease progression, unacceptable toxicity, withdrawal of consent, Investigator decision 
to discontinue treatment, or Sponsor decision to terminate the study. The MTD will be 
determined for single agent USL311, and all available safety, PK, and PD data will be 
reviewed by the DEC and Sponsor prior to confirming the optimal starting dosage for 
Part 2 (USL311 administration in combination with lomustine) and prior to determining 
the RP2D. The RP2D of single agent USL311 will be determined by the DEC and 


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Sponsor after considering the safety, PK/PD, and preliminary efficacy outcomes and may 
be equal to or lower than the MTD. 
3.3.3 Dose-Escalation Strategy 
During Phase 1 dose-escalation, subjects will receive study drug USL311 in Part 1a and 
1b at increasing doses. Decisions on dose-escalation will be made according to the 
mCRM design and reviewed by a dose escalation committee (DEC). Complete details of 
the mCRM model and its operating characteristics are provided in the Appendix 1 of the 
protocol. The target dose-limiting toxicity (DLT) rate is 33%. The MTD will be defined 
as the highest safe dose, where safe is defined by having at least a 50% probability that 
the DLT rate is less than 33%. This definition for safety is consistent with the maximum 
likelihood estimate for the probability of DLT. If the DLT rate is estimated to be exactly 
33%, the probability the DLT rate is less than 33% will be equal to 50%. Therefore, doses 
with a mean estimated DLT rate less than 33% will be considered safe by this definition 
and doses with a mean estimated DLT rate greater than 33% will be considered unsafe by 
this definition. Subjects may never be assigned to a dose that is considered unsafe 
according to this definition.  
A dose-toxicity model will be used to determine which doses are safe and to assign 
subjects to doses, i.e. to assign subjects to the highest safe dose. However, assignment of 
dose levels is also governed by rules concerning the speed of dose escalation and rules 
that determine whether an untried dose level may be skipped. When the dose is escalated, 
it may only escalate to the highest safe dose that is no more than a 100% increase over 
the current dose level. If the dose must be de-escalated, the dose will de-escalate to the 
highest safe dose regardless of how large a decrease in dose level. As long as no DLT has 
yet been observed, there must be complete DLT information through Cycle 1 on at least 2 
subjects in order to escalate. Once the first DLT is observed in the study, there must be 
complete DLT information through Cycle 1 on at least 3 subjects in order to escalate. A 
DLT is defined in Section 3.2.5 of the protocol. 
In the dose-toxicity model, non-DLT toxicity events (i.e. grade 2 toxicities) will inform 
the probalility of DLT at each dose level. The DLT observation period, for the purpose of 
dose-escalation, is one (1) cycle. Once a subject has completed this first cycle DLT 
observation period, the subject will be considered to have complete DLT information for 
the purposes of making dose escalation decisions for the next subject enrolling into the 
study (Part 1a and Part 1b). However, DLTs may also appear in later cycles. If a DLT 
appears at any time through subsequent cycles of treatment, a subjects DLT status and 
mCRM model will be updated to reflect the late cycle DLT. 
The first three subjects will be enrolled as a dosing cohort in Part 1. There must be 
complete DLT information on these three subjects in order to enroll the 4th subject. 
Starting with the 4th subject enrolled, there will be open enrollment to the study meaning 
that subjects can be enrolled as they become available for the study, however, there may 
be no more than 3 subjects enrolled in the study (Part 1a and Part 1b) with unknown DLT 
information at any time. 


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This study will be monitored for safety and for success in identifying the MTD. If no 
doses are safe, dose escalation will stop and no MTD will be declared. Alternatively, 
dose escalation may be stopped early when there are sufficient confidence the MTD has 
been identified. This is characterized by having either estimated the MTD with high 
probability, or by having a sufficient number of subjects with complete DLT information 
at and around the MTD. If the dose escalation is not stopped early for safety or for 
success in identifying the MTD it will continue to the maximum sample size of 40 
subjects for Part 1b. More detailed information regarding the stopping rules and 
determination of the MTD for dose-escalation is provided in Appendix 1 of the protocol. 
No intra-subject dose-escalation will be allowed until the MTD is established, at which 
time subjects who have received at least 12 weeks of study drug(s) without evidence of 
progression may receive study drug up to RP2D, at the discretion of the Investigator and 
with approval of the Sponsor. 
3.3.4 Dose Escalation Committee (DEC) 
During dose-escalation for Phase 1 (Parts 1 and 2), the safety data, any available PK/PD 
data, and other relevant subject data will be reviewed by the DEC. The DEC will 
comprise, at a minimum, Sponsor Chief Safety Officer (or designee), Contract Research 
Organization (CRO) Medical Monitor and the study site Investigator(s) (or designee). 
Other representatives may be involved in data review and the dose-escalation decision, as 
appropriate. All dose modification steps and dose schedule and infusion duration 
recommendations will be agreed upon by the DEC before dosing at the next dose level or 
determining the MTD and RP2D. Detailed information is provided in the Dose Escalation 
Management Plan. 
3.4 Number of Subjects Planned  
The total number of subjects in Part 1 will depend on the number of dose levels assessed 
in Phase 1 (Parts 1a and 1b). A total of 13 subjects were enrolled in Part 1a. It is expected 
that approximately 6-40 subjects with advanced solid tumors be enrolled for Part 1b 
single agent dose-escalation. There is no formal hypothesis testing in this trial, thus no 
sample size calculations were performed. 
4 General Analysis Conventions 
Data collected for the Phase I (Part 1a, Part 1b and Part 2) portion of this study will be 
documented using summary tables and subject data listings. Continuous variables will be 
summarized using descriptive statistics (number of subjects, mean, median, standard 
deviation, minimum, maximum, and inter-quartile range). Additional statistics such as 
geometric mean and coefficient of variation (CV%) may be calculated as warranted. 
Categorical variables will be summarized using counts and percentages or proportions. 
Confidence intervals (CIs) will be presented where appropriate. The Clopper-pearson 
exact method will be used to calculated CI. No formal statistical tests will be performed 
in this Phase 1 dose escalation study. Time to event variables will be summarized using 


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Kaplan-Meier estimates and CIs for the 25th, 50th, and 75th percentiles with the standard 
errors estimated by the Greenwood formula. 
Assessments will be displayed separately for Part 1a and Part 1b. Within each part of the 
study, data will be summarized by dose group and overall. 
Study days will be calculated relative to the first dose of USL311 . Day 1 will be the first 
day of study drug administration in the study, and the day prior to the first dose of study 
drug administration will be Day -1. There will be no Day 0. Time relative to dose for 
such endpoints as PK samples, vital signs, and electrocardiograms (ECGs) will be based 
on the start time of the infusion. 
Baseline will be the last assessment prior to the first dose of study drug unless otherwise 
indicated. 
Adverse events, medical history, and surgical history will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA), Version 19.0. Adverse event intensity 
will be graded according to the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) v 4.03. Concomitant medications will be coded 
using the World Health Organization (WHO) Drug Dictionary (March 2016). 
4.1 Partial Date Imputation 
Partial start dates and end dates for adverse events will be imputed as follows: 
 
Variable 
Missing Day 
Missing Day, 
Month 
Missing Day, 
Month, Year 
Adverse Event Start 
Date 
Assign first day of 
month unless it is 
the month of first 
dose of study drug. 
Otherwise, assign 
date of first dose of 
study drug. 
If imputed start date 
is after end date, 
assign start date = 
end date.  
Assign January 1 
unless the year is 
year of first dose of 
study drug. 
Otherwise, assign 
date of first dose of 
study drug. 
If imputed start date 
is after end date, 
assign start date = 
end date. 
Assign date of first 
dose of study drug. 
If imputed start date 
is after end date, 
assign start date = 
end date. 
Concomitant 
Medication Start 
date  
Assign first day of 
month  
 
Assign January 1 
No imputation 
Concomitant 
Medication End 
Assign last day of 
Assign December 
No imputation 


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date 
the month 
31 
Data for all subjects in the clinical database will be included in the data listings. 
Calculated (derived) variables will be listed as appropriate. All tables, listings, and 
figures will be programmed using SAS Version 9.3 or higher. 
4.2 Study Periods 
The following four study periods are planned for Part 1. 
- 
Screening phase – Screening Visit assessments must be performed within 28 days 
of Day 1. For part 1a and part 1b, subjects will also have Baseline visit at Day -1. 
- 
Treatment Phase - Treatment phase start at Day 1. Treatment with single agent 
USL311 will be administered in 21-day cycles.  
- 
The End of Treatment/Follow-up Visit – The End of Treatment Visit will occur ≤ 
14 days of the decision to discontinue on-study treatment whereas the Follow-up 
Visit will occur ≤ 28 days of the last dose of USL311. The End of Treatment visit 
may be the same as the Follow-up Visit; however, the Follow-up Visit should 
occur as close to 28 days after the last dose USL311 treatment as possible, per 
Investigator discretion. 
- 
Long-term Follow-up Phase - All subjects who discontinue from study treatment, 
and are willing to be contacted, will be followed for survival information (Long-
term Follow-up). The Long-term Follow-up Phase will begin after the Follow-up 
Visit or the End of Treatment Visit, as applicable. If a subject is unable to attend 
the End of Treatment Visit, the Long-term Follow-up Phase will begin upon 
investigator determination that the subject has ended the Treatment Phase. 
Survival follow-up information will be collected via telephone calls and/or clinic 
visits quarterly (every 3 months ± 1 week) until death, loss to follow-up, End of 
Study, withdrawal of consent, initiation of subsequent treatment for the target 
tumor, administrative reasons, or study termination by the Sponsor. 
4.3 Visit Windows 
Study visits are expected to occur according to the protocol schedule. All data will be 
tabulated per the evaluation visit as recorded on the electronic case report form (eCRF) 
even if the assessment is outside of the visit window. Data from unscheduled visits will 
not be included in summary tables and will only be displayed in listings. No imputation 
of data will be performed for missed assessments. For time-to-event analyses, evaluations 
will be based on the actual date of the event rather than on the visit of the event. 
5 Analysis Populations 
5.1 Full Analysis Data Set (FAS) 
The Full Analysis Data Set for Part 1 will include all subjects who receive at least one 
dose of USL311. This will be the analysis set for efficacy analyses. 


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5.2 Safety Analysis Data Set 
The Safety Analysis Data Set for Part 1 will include all subjects who receive at least one 
dose USL311 and have at least one post-baseline safety evaluation including adverse 
event, clinical laboratory data, physical and neurological examination, vital sign, 
electrocardiogram, Karnofsky performance score. This will be the analysis set for all 
safety analysis. 
5.3 MTD-Evaluable Data Set 
The MTD-Evaluable Data Set will include all subjects in Part 1 monotherapy dose-
escalation who complete one cycle of treatment and assessment or who discontinue 
before completing the first cycle because of dose limiting toxicity. This will be the 
analysis set for MTD determination for Phase I. 
5.4 Pharmacokinetic (PK) Analysis Data Set 
The PK Analysis Data Set will include all subjects who receive at least one dose of 
USL311 and have at least one quantifiable post-dose blood or plasma concentration of 
the drug. Summaries for the PK analysis data set are not described in this SAP. 
5.5 Pharmacodynamic (PD) Analysis Data Set 
The PD Analysis Data Set will include all subjects who receive at least one dose of 
USL311 and have at least one evaluable post-treatment assessment for the given PD 
measure. Summaries for the PD analysis data set are not described in this SAP. 
5.6 Response-Evaluable Analysis Data Set (RES) 
The Response-Evaluable Analysis Data Set will consist of those subjects who receive at 
least one dose of USL311 and have evaluable disease at baseline. 
5.7 Exposure-Response Analysis Data Set (RAS) 
An Exposure-Response Analysis Data Set may be constructed for each PD or response 
endpoint to be evaluated for correlation with PK data. If performed, the exposure-
response analysis set will consist of all subjects in the PK Analysis Set that also have an 
evaluable PD/response pretreatment assessment and at least one post-treatment 
PD/response assessment. The analyses for Exposure-Response Analyses are not 
described in this SAP. 
6 Subject Disposition 
Subject disposition will be summarized by dose group and overall for each part (1a or 1b) 
of the study as well as for overall Part 1. The number of subjects in each population and 
the number of subjects who complete study will be summarized by dose group and 
overall for Part 1a, Part 1b and Part 1. The reasons for discontinuing treatment and for 
discontinuing study will be summarized for the FAS population. 


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Subjects who are excluded from each population will be presented in a data listing, along 
with reasons for exclusion. 
Inclusion/exclusion data will be presented by subject in a data listing. 
7 Protocol Deviations 
Protocol deviations categorized as important will be summarized by dose group and 
overall of Part 1a or Part 1b, respectively and will be presented by subject in a data 
listing.  
8 Demographic and Baseline Characteristics 
8.1 Demographic Characteristics 
Demographic and baseline characteristics at study entry will be summarized by dose 
group and overall for Part 1a, Part 1b and Part 1 of the study for the FAS population. 
Demographic and baseline characteristics to be summarized are: 
 Continuous variables: 
o Age (years) 
o Weight (kg) 
o Height (cm) 
o Body mass index (BMI) (kg/m2) 
o Body surface area (BSA) (m2) 
o Time since initial diagnosis (years) 
Time since initial diagnosis is calculated as the date the informed consent was signed 
minus the date of initial diagnosis expressed in years. If the day of initial diagnosis is 
missing, 15 will be imputed for calculations. If only the year of initial diagnosis is 
present, time since initial diagnosis is calculated as the year the informed consent was 
signed minus the year of initial diagnosis. 
 Categorical variables: 
o Sex 
o Race 
o Ethnicity 
o Genotype (CYP2D6 and CYP3A), if available 
o Age category (<65, ≥65 years) 
o Karnofsky Performance Status (KPS) Scale (0, 10, 20, 30, …, 100) 
o Stage of disease at diagnosis (as listed on eCRF) 
o Stage of disease at study entry (as listed on eCRF) 
o Type of Cancer (as listed on eCRF) 


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8.2 
Medical History 
The number and percentage of subjects with each medical history condition collected on 
the eCRF will be summarized by MedDRA system organ class (SOC) and preferred term 
(PT) for the FAS population by dose group and overall for each part of the study. 
Medical and surgical history information will be reported by subject in a data listing. 
8.3 
Prior Cancer Treatment 
Prior radiotherapy, surgery, and systemic therapies will be summarized for the FAS 
population by dose group and overall for each part of the study. 
The following variables will be summarized: 
 Prior systemic therapy (yes/no) 
 Setting of systemic therapy (neo-adjuvant, adjuvant, radio-sensitising, locally 
advanced, metastatic) 
 Number of prior systemic therapy regimens 
 Time since last systemic therapy (days) 
 Best response to systemic therapy for last systemic therapy 
 Prior radiotherapy (yes/no) 
 Anatomical site of radiotherapy 
 Prior surgery for target tumor (yes/no) 
Time since last systemic therapy is calculated as the date the informed consent was 
signed minus the latest therapy end date expressed in days. If the day of therapy end date 
is missing, 15 will be imputed for calculations. If only the year is present, time since last 
systemic therapy will not be calculated. 
Results will be summarized by dose group and overall for each part of the study. 
Continuous variables will be summarized with descriptive statistics (number of subjects, 
mean, standard deviation, median, range, and inter-quartile range). Number of prior 
systemic therapy regimens will be summarized using descriptive statistics and will also 
be categorized and summarized using counts and percentages. All other variables listed 
above will be summarized using counts and percentages. 
Medications reported as prior systemic therapies will be summarized by the WHO Drug 
Dictionary Anatomical Therapeutic Chemical 3rd level (ATC-3) and preferred name for 
the full analysis set by dose group and overall for each part of the study. If the 3rd level 
term is not available, the next available level (e.g., ATC-2) will be used. A subject will 
only be counted once within each ATC-3 code and within each preferred name. 
Prior radiotherapy, surgery, and systemic therapies will be listed by subject in a data 
listing.  


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8.4 Prior and Concomitant Medications  
Concomitant medication are medications that were taken between the first and last day of 
study drug administration (i.e., start date < last dose date and end date > first dose date or 
ongoing). Prior medications are medications with a end date on or before the first day of 
study drug. 
Concomitant or prior medications will be summarized separately by the WHO Drug 
Dictionary Anatomical Therapeutic Chemical 3rd level (ATC-3) and preferred name for 
the safety population by dose group and overall for each part of the study. If the 3rd level 
term is not available, the next available level (e.g., ATC-2) will be used. A subject will 
only be counted once within each ATC-3 code and within each preferred name. 
All prior and concomitant medication data will be listed by subject. 
9 Efficacy Variables and Analysis 
Efficacy parameters will be determined using RECIST v1.1 or RANO criteria as 
appropriate. Efficacy variables include the following: 
 
6-month progression-free survival rate (PFS-6m)  
 Progression-free survival (PFS) 
 Objective response rate (ORR)  
 Disease control rate (DCR)  
 Overall survival (OS) 
Efficacy analyses will be summarized with summary statistics for the FAS and RES 
populations. Results will be summarized by dose group and overall for each part of the 
study. There is no formal hypothesis testing in this trial for efficacy endpoints. 
Six – month PFS rate will be calculated with two-sided 90% confidence interval (CI) 
using the Kaplan-Meier (KM) product-limit estimate of PFS. Number and percent of 
patients progressed at 6 months and number of patients censored at 6 months will be 
summarized descriptively. The analysis will be performed based on both the full analysis 
set and response-evaluable set. PFS is defined as the interval between the start of USL311 
and the earliest documented evidence of disease progression or death due to any cause. 
Subjects who do not have a documented date of progression or death will be censored at 
the date of the last adequate assessment. For patient not progressed at six-month, they 
will be censored at month 6 for PFS-6m analysis. For patients without post baseline 
tumor assessment and alive at the end of study will be censored at day 1. 
PFS will be summarized using KM methodology using 25th, 50th (median), and 75th 
percentiles with associated 2-sided 90% CIs as well as the number and proportion of 
censored observations. A KM plot may be provided. 
Best overall tumor response will be determined based on all overall tumor responses are 
collected following the hierarchical order of CR, PR, SD, PD, NE. A confirmed objective 


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response is defined as a response that persists on repeat imaging for two assessments with 
a time period of at least 4 weeks between the two assessments (Table 1). 
 
 


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Table 1. 
                 Overall response                     
Overall response      Subsequent  
 First time point       time point   BEST overall response 
CR  
 
 
CR 
CR 
CR  
 
 
PR 
SD, PD or PRa 
CR  
 
 
SD  
SD provided minimum criteria for SD duration met, otherwise, PD 
CR  
 
 
PD  
SD provided minimum criteria for SD duration met, otherwise, PD 
CR  
 
 
NE  
SD provided minimum criteria for SD duration met, otherwise NE 
PR  
 
 
CR  
PR 
PR 
 
 
PR  
PR 
PR 
 
 
SD  
SD 
PR 
 
 
PD 
SD provided minimum criteria for SD duration met, otherwise, PD 
PR  
 
 
NE 
SD provided minimum criteria for SD duration met, otherwise NE 
NE  
 
 
NE  
NE 
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the first 
time point. Under these circumstances, the original CR should be changed to PR and the best response is PR.  
 
ORR is defined as the proportion of subjects with a confirmed complete response (CR) or 
confirmed partial response (PR) relative to the total number of subjects in the 
corresponding analysis population. The ORR and 90% CI will be summarized. 
DCR is defined as the proportion of subjects who have a confirmed complete response 
(CR), confirmed partial response (PR), or stable disease (SD). The DCR and 90% CI will 
be summarized. 
Overall survival is defined as the interval between the start of USL311 and date of death 
due to any cause. Subjects who are still alive or who are lost to follow-up will be 
censored at the date of last contact. Overall survival will be summarized using KM 
methodology using 25th, 50th (median), and 75th percentiles with associated 2-sided 
90% CIs , as well as the number and proportion of censored observations. A KM plot 
may be provided.  
If central reader imaging analyses are performed, the maximal change of the sum of 
longest diameters for all target lesions from baseline may be shown in a waterfall plot. 
10 Statistical/Analytical Issues 
10.1 Handling of Dropouts or Missing Data 
No imputation of data will be performed for missed assessments. Imputation rules for 
missing AE start and end dates are described in Section 3.1. 
10.2 Pooling of Centers in Multi-Center Studies 
Data will not be summarized by study center or for groupings of study centers. 


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10.3 Multiple Comparisons/Multiplicity 
No formal statistical testing will be performed; therefore, no adjustments for multiple 
comparisons or multiplicity are planned. 
10.4 Examination of Subgroups 
No subgroup analyses are planned for this study. 
10.5 Interim Analysis and Data Monitoring 
No formal interim analysis will be performed in this study. After Part 1, the MTD for 
single agent USL311 will be determined, if achieved, by the Dose Escalation Committee 
(DEC). The DEC will also determine the RP2D. 
11 Pharmacokinetics/Pharmacodynamics 
11.1 Pharmacokinetic analyses 
Pharmacokinetic summaries and analyses will be performed according to a separate PK 
analysis plan and will be reported in a separate PK analysis report. Collection dates and 
times (both planned and actual) as well as PK concentrations at each timepoint will be 
listed by subject for all PK samples. 
11.2 Biomarker Samples (Pharmacodynamic Analyses) 
Blood and urine samples will be collected to evaluate biomarkers of target engagement 
(WBC and CD34+ cell counts) and phospholipidosis (BMP), respectively. 
Biomarkers will be summarized at baseline (the last assessment prior to the first dose of 
USL311) and at each scheduled post-baseline visit and time point using descriptive 
statistics. Results will be summarized by dose group and overall for each part of the 
study. Difference of BMP between cycle 2 day 1 and baseline for the overall part 1 safety 
population will be analysised using student’s paired t-test. 
Additional pharmacodynamic analyses may be performed as warranted following data 
exploration. If performed, the analyses will be conducted according to a separate 
pharmacodynamic analysis plan and will be reported in a separate report. 
Biomarker data will be presented by subject in a data listing. Collection dates and times 
(planned and actual) will be listed by subject for all biomarker samples. 
11.3 Exposure-Response Analyses 
Response data (i.e., efficacy, safety and biomarker data) may be explored for correlations 
with measures of USL311. If potential exposure-response relationships are suggested, 
additional analyses may be performed and may be included in the CSR or may be 
reported in a separate analysis report. Exposure-response analyses, if performed, are 
outside the scope of this SAP. 


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12 Safety Analysis 
The safety assessments include study drug exposure, adverse events (including DLTs and 
SAEs), vital signs, physical examinations, neurological examinations, clinical laboratory 
tests, electrocardiograms (ECG), and concomitant medications. Safety will be 
summarized by dose group and overall for each part of the study. All safety data will be 
included in data listings. 
12.1 Study Drug Exposure  
USL311 exposure will be summarized for the Safety population by dose group and 
overall for each part of the study. The following variables will be summarized for IV 
USL311 (part 1a): 
 Number of cycles each subject was dosed in. Patient received any dose at a given 
cycle will be considered as received dose for that cycle 
 Number of infusions 
 Total cumulative dose over the study (mg and mg/m2) 
 Duration of exposure in weeks, calculated (Date of Last Drug Administration – 
Date of First Drug Administration + 1 day) / 7 days) 
 Treatment compliance of IV USL311 is determined by total cumulative dose over 
the study/planned dose. Planned dose is equal to duration of exposure in weeks* 
assigned dose for that subject. 
The following variables will be summarized for oral USL311 (Part 1b): 
 Number of cycles each subject is dosed in. Patient received any dose at a given 
cycle will be considered as received dose for that cycle 
 Total cumulative dose over the study (mg) 
 Duration of exposure in weeks, calculated (Date of Last Drug Administration – 
Date of First Drug Administration + 1 day) / 7 days) 
 Treatment compliance of oral USL311 is determined by total cumulative dose 
over the study/planned dose. Planned dose is equal to duration of exposure in 
days* assigned dose for that subject. 
Study drug administration data, including BSA, will be presented by subject in a data 
listing. 
12.2 Adverse Events 
Adverse events (AEs) will be summarized for the Safety population by dose group and 
overall for each part of the study. All AEs will be summarized by MedDRA system organ 
class (SOC) and preferred term (PT). Adverse events will be graded according to the NCI 
CTCAE v 4.03. An AE that begins on or after the date of first dose of study drug will be 
considered a treatment-emergent adverse event (TEAE). 


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Adverse event severity will be classified into 5 categories based on NCI CTCAE 4.03 
toxicity grades: Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe or medically 
significant but not immediately life-threatening, Grade 4 = life threatening or debilitating, 
and Grade 5 = death related to AE.  
The relationship of the AE to USL311 will be classified into 5 categories: related, 
probably related, possibly related, probably not related, and not related. Treatment-related 
adverse events are defined as a relationship of related, probably related, or possibly 
related. 
12.2.1 
Overview of Treatment-Emergent Adverse Events 
An overview summary table of TEAEs will include number and percentage of subjects in 
each of the following categories, summarized by dose group and overall for each part of 
the study: 
 Subjects reporting at least one TEAE 
 Subjects reporting at least one TEAE with CTCAE Grade ≥3 
 Subjects reporting at least one TEAE related to USL311 
 Subjects reporting at least one treatment-emergent serious AE (SAE) 
 Subjects reporting at least one TESAE related to USL311 
 Subjects with at least one dose-limiting toxicity (DLT) as defined in the protocol 
 Subjects with AE resulting in death on study 
12.2.2 
Treatment-Emergent Adverse Events 
The number and percentage of subjects with the following categories of AEs will be 
summarized in tables by dose group and overall for each part of the study by system 
organ class (SOC) and preferred term (PT), with SOCs sorted by decreasing frequency 
based on the overall populatin, and PTs sorted alphabetically within a SOC by decreasing 
frequency based on the overall population. 
 Any TEAE by SOC and PT. 
 Any TEAE by SOC, PT and CTCAE grade  
 Any TEAE with CTCAE Grade ≥3 by SOC and PT 
 Any TEAE by SOC, PT, and relationship to USL311 
  Any treatment-emergent SAE by SOC and PT 
 Any treatment-emergent AE resulting in treatment discontinuation by SOC and 
PT 
Each subject will contribute at most one count per summarization category. In other 
words, if a subject has more than one AE with same SOC or PT, the subject will be 
counted only once for that SOC or PT. Similarly, if a subject reports multiple toxicity 


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grades or relationship categories for a PT, only the highest toxicity grade or strongest 
relationship will be summarized. Missing toxicity grades and relationships will not be 
imputed. 
By-subject listings also will be provided for the following: all AEs, AEs with toxicity 
grade 3 or above, treatment-related AEs, AEs resulting in death, serious AEs, and DLTs. 
12.3 Clinical Laboratory Data 
Quantitative clinical laboratory results (hematology [except biomarker white blood cells, 
which are part of the pharmacodynamics analysis]), coagulation, serum chemistry, and 
other laboratory tests collected throughout the course of the study) will be summarized at 
baseline (the last assessment prior to the first dose of study drug), each scheduled post-
baseline visit, and change from baseline to each scheduled post-baseline visit using 
descriptive statistics (number of subjects, mean, median, standard deviation, range, and 
inter-quartile range). Results will be summarized by dose group and overall for each part 
of the study. 
Shift tables that present changes from baseline to worst on-study values relative to NCI 
CTCAE v 4.03 classification ranges will be produced by dose group and overall for each 
part of the study for laboratory parameters. For some lab values, both shift high and shift 
low are applicable to CTCAE grade. 
Hematology 
 hemoglobin 
 lymphocytes (absolute) 
 platelet count 
 neutrophils (absolute) 
 white blood cells 
 
Coagulation  
 activated partial thromboplastin time 
 INR 
 
Serum chemistry  
 albumin 
 alkaline phosphatase 
 ALT 
 AST 
 calcium 
 creatinine 
 magnesium 
 glucose 
 potassium 
 sodium 


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Values of laboratory tests with NCI-CTCAE Severity ≥ Grade 3 will be listed by subject; 
the listing will contain all of a subject’s values for parameters meeting the criteria. 
All laboratory parameters will be included in data listings, and values outside of the 
reference range will be flagged in data listings. 
12.4 Physical and Neurological Examination  
Physical and neurological examination data will be listed by subject.  
12.5 Vital Signs  
Vital signs data will include systolic blood pressure, diastolic blood pressure, pulse rate, 
temperature, respiration rate, weight, and BSA. Results will be summarized by dose 
group and overall for each part of the study at baseline (the last assessment prior to first 
dose of study drug), at each scheduled post-baseline visit, and change from baseline to 
each scheduled post-baseline visit using descriptive statistics (mean, median, standard 
deviation, range, and inter-quartile range). 
On the dosing day, vital sign will be summarized pre-dose, post dose and change from 
pre-dose descriptively. 
Vital signs data will be listed by subject. 
12.6 Electrocardiogram 
12.6.1 Safety Electrocardiograms 
Safety ECG data collected at the investigative sites and entered into the eCRF will 
include heart rate, PR and QRS intervals, QT interval, QT interval corrected for heart rate 
using Bazett method (QTcB), and QT interval corrected for heart rate using Fridericia 
method (QTcF). ECG data will be summarized for baseline (pre-dose), each scheduled 
post-baseline visit, and change from baseline to each post-baseline visit using descriptive 
statistics (number of subjects, mean, median, standard deviation, range, and inter-quartile 
range) by dose group and overall for each part of the study. All parameters will be based 
on ECG triplicate averages (or if fewer, average of ECGs available). 
Shift tables will be prepared for the overall interpretation of the ECG. Both the baseline 
and the worst on study results will be classified into 1 of 3 categories: normal, abnormal 
– not clinically significant, or abnormal – clinically significant. Baseline will be the worst 
value at Screening.  
The number and percentage of subjects meeting each of the following criteria (based on 
NCI-CTCAE 4.03) for QTc value will be summarized. 
 < 450 msec 
 450  - 480 msec 
 481  - 500 msec 
 > 500 msec 


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Furthermore, subjects meeting the following criteria for change from baseline within each 
of the above category will also be summarized. 
 ≤ 30 msec increase from baseline 
 > 30 - 60 msec increase from baseline 
 ≥ 60 msec increase from baseline 
In addition, a listing of subjects with values meeting each criterion any time after the first 
dose of study drug will be provided. The listing will contain all of a subject’s values for 
parameters meeting the criteria.  
All safety ECG results will be listed by subject. 
12.6.2 Extracted Electrocardiograms  
Quantitative analysis of the ECG extractions from the holters will be performed and 
reported separately by the ECG vendor. 
ECG data including heart rate, PR and QRS intervals, QT interval, QTcB, and QTcF with 
respect to the Holter monitor will be listed by subject and summarized similaly as the 
safety ECG data. In  addition, time match change will be listed and summarized for the 
above extracted ECG data. 
12.6.3 Real-Time Bedside ECG and Heartrate Monitoring 
Real-time bedside ECG will be monitored by clinic staff from start of USL311 infusion 
through clinic discharge (up to approximately 6 hours post start of infusion) on days 
where continuous telemetry monitoring is required. Date of assessment will be captured 
on the eCRF and will be presented in a data listing. 
12.7 Karnofsky Performance Status (KPS) Scale 
Performance status will be measured using the KPS Scale (Table 2). The KPS Scale 
allows subjects to be classified as to their functional impairment. Lower scores represent 
more impairment.  
The number and percentage of subjects with each KPS score will be summarized for 
baseline (the last assessment prior to first dose of study drug) and for each scheduled 
post-baseline assessment by dose group and overall for each part of the study. 
KPS data will be listed by subject.  
Table 1: Karnofsky Performance Status Scale 
Karnofsky Performance Status Scale 
Percent 
Description 
100 
Normal, no complaints, no evidence of disease 
90 
Able to carry on normal activity; minor signs or symptoms of disease 
80 
Normal activity with effort; some signs or symptoms of disease 


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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 
50 
Requires considerable assistance and frequent medical care 
40 
Disabled, requires special care and assistance 
30 
Severely disabled, hospitalization indicated 
Death not imminent 
20 
Very sick, hospitalization indicated 
Death not imminent 
10 
Moribund, fatal processes progressing rapidly 
0 
Dead 
 
12.8 Other Safety and Pharmacodynamic Assessments 
Any safety and pharmacodynamics assessments not previously described will be 
presented in data listings. Additional analyses may be performed if warranted. 
13 Quality Control 
All data displays and analyses will adhere to the International Conference on 
Harmonisation (ICH) Harmonized Tripartite Guideline: Structure and Content of Clinical 
Study Reports (ICH Topic E3). 
All analyses will be performed using SAS® Version 9.3 (or later). Covance will follow 
its standard operating procedures in the creation and quality control of all tables, listings, 
figures, and analyses. The Sponsor or its designee will review all tables, listings, and 
figures prior to final database lock. All final SAS programs and associated output files 
will be transferred to the Sponsor in agreed-upon format at project completion. 
14 Changes in Conduct or Planned Analyses from the Protocol 
Study P311-201 was terminated early, for non-safety reasons, during Part 1b prior to the 
determination of the MTD. As a result, the SAP for the protocol has been revised from 
version 1.0, dated 29Apr2020, of the SAP to report endpoints to support an abbreviated 
clinical study report focusing on safety.  The analyses will include summary tables, 
supported by listings, for study demographics and safety. Summary tables related to 
evaluation of efficacy have been removed from the final analysis. A summary of changes 
to reflect the change in scope of the protocol analyses are as follows: 
 


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1. Section 5 Analysis Population: Only Full Analysis data set, Safety Analysis data set, 
and MTD-Evaluable Data set will be determined.  
2. Section 9 Efficacy Variables and Analysis: As there are limited number of patients 
per dose level in the dose escalation, no efficacy analysis will be completed. Tumor 
assessment and responses will be included in listings. 
3. Section 12.7: Karnofsky Performance Status (KPS) Scale: KPS Scale will only be 
presented in a listing.