A Follow-Up Study to Add Whole Brain Radiotherapy (WBRT) to Standard Temozolomide Chemo-Radiotherapy in Newly Diagnosed Glioblastoma (GBM) Treated With 4 Weeks of Continuous Infusion Plerixafor
Phase: PHASE2
Conditions: Glioblastoma, Glioblastoma With Primitive Neuronal Component, Gliosarcoma, Malignant Glioma, Oligodendroglial Component Present
Sponsor: Lawrence D Recht

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NCT03746080 
A follow-up study to add whole brain radiotherapy (WBRT) to standard 
temozolomide chemo-radiotherapy in newly diagnosed glioblastoma (GBM) 
treated with 4 weeks of continuous infusion Plerixafor 
 
Coordinating Center 
Stanford Cancer Institute 
875 Blake Wilbur Drive 
Stanford, CA 94305 
 
Protocol Director  
Lawrence Recht, MD 
Professor of Neurology 
Stanford University Hospital 
875 Blake Wilbur Drive, 
 
Stanford, CA 94305 
Phone: (650) 725-8630 
Fax: (650) 498-4686 
lrecht@stanford.edu 
 
Co-Protocol Director 
Reena Thomas, MD PhD 
Clinical Assistant Professor 
Department of Neurology 
875 Blake Wilbur Drive, 
 
 Stanford, CA 94305 
Phone: 
 
Fax: 
 
reenat@stanford.edu 
 
 
Co-Investigators 
Martin Brown, PhD 
Professor Emeritus, Department of Neurology 
875 Blake Wilbur Drive, 
 
Stanford, CA 94305 
Phone: 
 
Fax: 
 
mbrown@stanford.edu 
 
Scott Soltys, MD 
Associate Professor of Radiation Oncology 
875 Blake Wilbur Drive, 
 
Stanford, CA  94305 
Phone: 
 
Fax:
 
 

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Seema Nagpal, MD 
Clinical Assistant Professor 
Department of Neurology 
875 Blake Wilbur Drive, 
 
Stanford, CA 94305 
Phone: (650) 725-8630 
Fax: (650) 498-4686 
 
 
Michael Iv, MD 
Assistant Professor of Radiology 
300 Pasteur Drive, 
 
Stanford, CA 94305 
Phone: 
 
Fax: 
 
miv@stanford.edu 
 
Biostatistician 
 M.P.H 
Biostatistician, QSU Department 
1070 Arastradero Road 
Stanford, CA  94305 
Phone: 
 
Fax: 
 
 
 
Study Coordinators 
 
Phone: 
 
 
Phone: 
 
 
Study Coordinators’ Address 
800 Welch Road, 
 
Palo Alto, CA  94305 
 
Study Coordinators’ Fax: 
 
 
 
 

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TABLE OF CONTENTS 
 
PROTOCOL SYNOPSIS ............................................................................................................. 5 
SCHEMA ....................................................................................................................................... 6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .............................................. 7 
1. OBJECTIVES ........................................................................................................................ 8 
1.1. PRIMARY OBJECTIVE ......................................................................................................... 8 
2. BACKGROUND .................................................................................................................... 8 
2.1 INTRODUCTION AND RATIONALE FOR FOLLOW-UP STUDY................................................... 8 
2.2 STUDY AGENT/DEVICE/PROCEDURE ................................................................................... 9 
2.3 RATIONALE ....................................................................................................................... 10 
2.4 STUDY DESIGN ................................................................................................................. 10 
2.5 CORRELATIVE STUDIES BACKGROUND ............................................................................. 10 
3. PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES ....................... 23 
3.1 INCLUSION CRITERIA ........................................................................................................ 23 
3.2 EXCLUSION CRITERIA ....................................................................................................... 24 
3.3 INFORMED CONSENT PROCESS .......................................................................................... 24 
3.4     RANDOMIZATION PROCEDURES ........................................................................................ 25 
3.5 STUDY TIMELINE .............................................................................................................. 25 
4. TREATMENT PLAN .......................................................................................................... 25 
4.1 GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES .................. 27 
4.2 CRITERIA FOR REMOVAL FROM STUDY ............................................................................. 27 
4.3 ALTERNATIVES ................................................................................................................. 28 
5. INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION ................ 28 
5.1 
 INVESTIGATIONAL AGENT/DEVICE/PROCEDURE .............................................................. 28 
5.2 AVAILABILITY .................................................................................................................. 29 
5.3 AGENT ORDERING ............................................................................................................ 29 
5.4 AGENT ACCOUNTABILITY ................................................................................................. 29 
5.5      RADIATION THERAPY PLANNING………………………………………………………..29 
6. DOSE MODIFICATIONS .................................................................................................. 31 
6.1 INFUSION REACTIONS ....................................................................................................... 31 
7. ADVERSE EVENTS AND REPORTING PROCEDURES ............................................ 32 
7.1 POTENTIAL ADVERSE EVENTS .......................................................................................... 32 
7.2 ADVERSE EVENT REPORTING............................................................................................ 34 
8. CORRELATIVE/SPECIAL STUDIES ............................................................................. 36 
8.1 LABORATORY CORRELATIVE STUDIES .............................................................................. 36 
9. STUDY CALENDAR .......................................................................................................... 37 
10. MEASUREMENT.............................................................................................................. 39 
10.1  PRIMARY  MEASURE ....................................................................................................... 39 
10.2  SECONDARY OUTCOME .................................................................................................. 40 
10.3  SECONDARY OUTCOME TOXICITIES ............................................................................... 40 

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10.4  SECONDARY OUTCOME PATTERN OF FAILURE ............................................................... 41 
    10.5     Secondary Outcome Neuro-cognitive and quality of life outcomes…………………..41 
11. REGULATORY CONSIDERATIONS ........................................................................... 42 
11.1 INSTITUTIONAL REVIEW OF PROTOCOL ........................................................................... 42 
11.2 DATA AND SAFETY MONITORING PLAN .......................................................................... 42 
11.3 DATA MANAGEMENT PLAN ............................................................................................ 42 
12. STATISTICAL CONSIDERATIONS ............................................................................. 42 
12.1 STATISTICAL DESIGN ...................................................................................................... 42 
12.2 INTERIM ANALYSES ......................................................................................................... 43 
12.3 DESCRIPTIVE STATISTICS AND EXPLORATORY DATA ANALYSIS .................................... 43 
12.4 PRIMARY ANALYSIS ........................................................................................................ 43 
12.5 SECONDARY ANALYSIS ................................................................................................... 44 
12.6  SAMPLE SIZE .................................................................................................................. 44 
12.7 CRITERIA FOR FUTURE STUDIES ...................................................................................... 44 
13. REFERENCES ................................................................................................................... 46 
APPENDICES ............................................................................................................................. 51 
APPENDIX A: PARTICIPANT ELIGIBILITY CHECKLIST ............................................................. 51 
 

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PROTOCOL SYNOPSIS 
 
 
TITLE 
A follow-up study to add whole brain 
radiotherapy (WBRT) to standard 
temozolomide chemo-radiotherapy in 
newly diagnosed glioblastoma (GBM) 
treated with 4 weeks of continuous infusion 
Plerixafor 
STUDY PHASE 
II 
INDICATION 
Newly diagnosed glioblastoma 
INVESTIGATIONAL PRODUCT OR 
PROCEDURE 
Continuous infusion of Plerixafor 
PRIMARY OBJECTIVE(S) 
Efficacy as measured by progression free 
survival at 6 months from the start of 
Chemoradiation 
SECONDARY OBJECTIVE(S) 
(i) Overall survival 
(ii) Toxicity 
(iii) Recurrent tumor patterns of failure 
EXPLORATORY OBJECTIVE 
 Neurocognitive outcomes & 
Patient-reported health-related QOL 
TREATMENT SUMMARY 
Patients will be treated within a 
conventional framework of maximal safe 
surgical resection followed by a 6 week 
course of irradiation administered 
concomitantly with 75 mg/m2 
temozolomide x 42 days with two 
additions: (i) Plerixafor will be 
administered at 400 micrograms per 
kilogram per day for four weeks beginning 
one week before the end of radiation; and 
(ii) Whole brain radiotherapy (WBRT) – 
Radiotherapy consists of standard 30 Gy of 
IMRT to the tumor bed followed by 30 Gy 
to the whole brain. Plerixafor infusion will 
begin during this WBRT component.  After 
completion of Plerixafor infusion, patients 
will be administered six cycles of monthly 
TMZ 
SAMPLE SIZE  
20 patients 
STATISTICAL CONSIDERATIONS 
For efficacy, a greater than 50% PFS at 6 
months will be considered a positive signal 
and warrant further study. A secondary 
endpoint will consider a median survival 
greater than 32 months as a measure of 
especially meaningful significance. 

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SCHEMA 
 
 
 
 
 
 
 
 
 
 
Resection 
Chemoradiation (XRT) 
 
42 days 
 
PICC line placed prior to starting 
Plerixafor 
Start continuous Plerixafor infusion 
7 days before end of XRT  
4 weeks (+/-
3 days) 
  
Start monthly TMZ 
35 days post XRT 
Initiation of WBRT, 
fraction 16 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ABW 
Actual Body Weight 
ADL 
Activities of daily living 
AE 
Adverse event 
CBC 
Complete blood count 
CMAX 
Maximum concentration of drug 
CNS 
Central nervous system 
CRF 
Case report/Record form 
CR 
Complete response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DSMB 
Data Safety Monitoring Board 
GBM 
Glioblastoma 
GI 
Gastrointestinal 
HIV 
Human Immunodeficiency Virus 
IBW 
Ideal Body Weight 
IMRT 
Intensity Modulated Radiation Therapy 
IRB 
Institutional Review Board 
IV 
Intravenous 
KPS 
Karnofsky Performance Score 
MTPI 
Modified Toxicity Probability Interval 
OS 
Overall survival  
PLT 
Platelet 
PD 
Progressive disease 
PFS 
Progression free survival  
PR 
Partial response 
QOL 
Quality of Life 
RANO 
Revised Assessment in Neuro-oncology 
RR 
Response rate 
RT 
Radiotherapy 
SAE 
Serious adverse event 
SD 
Stable disease 
SOC 
Standard of care 
SLD 
Sum of the longest diameter 
SPD 
Sum of the products of the diameter 
TMZ 
Temozolomide 
TTP 
Time to progression 
ULN 
Upper limit of normal 
UNK 
Unknown 
WBC 
White blood cell 
WBRT 
Whole brain radiotherapy 
XRT 
Chemoradiation 
 
 

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1. 
OBJECTIVES 
 
1.1. 
Primary Objectives  
• To assess the 6 month PFS (post initiation of radiation) of continuous infusion Plerixafor 
beginning one week prior to the end of concurrent chemotherapy with Temozolomide and a 
modified radiation regimen that includes a component of whole brain radiation therapy 
(WBRT) in patients with newly diagnosed GBM. 
 
1.2  
Secondary Objectives 
• To assess the median survival of patients treated with continuous infusion Plerixafor/WBRT 
• To assess the toxicities both short and long term of continuous infusion Plerixafor/WBRT. 
• To assess the patterns of failure (in and out of irradiated brain field, out of brain) of 
continuous infusion Plerixafor/WBRT. 
 
1.3        Exploratory Objectives 
• To assess the neurocognitive outcomes and patient-reported health-related quality of life 
after continuous infusion Plerixafor/WBRT. 
 
2. 
BACKGROUND 
 
2.1 
Introduction and Rationale for Follow-up Study of Continuous Infusion Plerixafor 
in Glioblastoma 
Although radiotherapy delays the recurrence of most glioblastomas (GBMs), these 
tumors invariably regrow and prove fatal by two years after diagnosis in more than half the 
patients. Importantly, 80% of first recurrences occur within the field of high dose radiation, 
underscoring the importance of local control in improving survival [1-4].  
Our preclinical work demonstrated that brain cancer recurrence after irradiation resulted 
in large part through vasculogenesis rather than angiogenesis (which is significantly inhibited by 
RT). Vasculogenesis, the growth of tumor blood vessels from circulating bone marrow-derived 
cells, is fueled in large part by SDF-1 (CXCL12), which is secreted by the injured tumor bed and 
results in recruitment of peripheral monocytes that promote vascularization. As described below, 
blocking SDF-1 with Plerixafor prevented this repopulation and resulted in cures of several 
different models of experimental glioblastoma. 
In July 2014, with the generous assistance of Sanofi, we launched a Phase I/II study that 
assessed the effects in newly diagnosed GBM patients of a 4-week continuous infusion of 
Plerixafor that started one week prior to the end of standard focal radiotherapy (i.e. 6 weeks 
radiation, 60 Gy to a field encompassing the original tumor bed plus a 2 cm margin). The timing 
of initiation was chosen based on experimental evidence that SDF-1 levels were highest in the 
immediate post-RT period. Enrollment criteria allowed us to enroll patients between 18 and 75 
years old who only needed biopsy confirmation of diagnosis and whose KPS was 60 or better; 
criteria that were quite liberal relative to other studies that examined treatments for GBM.  
We determined in Phase I that a four-week infusion of 400 µg/kg/day was well tolerated 
without any Grade 3 toxicities and resulted in a consistent elevation of Plerixafor levels and 
intravascular myeloid cells.  An additional 20 patients were evaluated in the Phase II companion 

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study.  All 29 patients have met their primary and secondary endpoints with the following 
observations:  
 
(i) We have noted a marked decrease in cerebral 
blood volume and blood flow as determined by 
dynamic susceptibility contrast (DSC)-MRI in the 
irradiated field that extends out to six months after 
irradiation. This decrease is noted only in the field 
that received at least 95% of the maximal RT 
dosage. CBV’s outside of this area as well as 
CBV’s within the 95% fields of non-Plerixafor 
infused treated controls are not impacted (Graph 
1);  
(ii) Our estimated median overall survival as 
assessed by Kaplan Meier analysis is 20 months 
(compared to the historical control figure of 14 
months), despite the fact that the entry criteria into 
this study were very liberal (i.e., age up to 75, 
KPS of 60 or greater), and that there was biopsy 
only in over 20% of the patients; and; 
(iii) While the KM estimate alone is encouraging, 
it is even more compelling in light of a high 
incidence of first recurrences occurring out of the 
irradiated field and in the meninges (10/12 to date 
compared to a standard expectation that 80% of 
recurrences will occur within the irradiation field). This is an unprecedented result and 
suggests that widening the radiation field may be a key element in markedly improving 
overall survival using this strategy. 
 
These results are promising and suggest that the incorporation of end-of-treatment 
Plerixafor may represent a “one size fits all” radiation amplifier that may apply not only to GBM 
but also to other solid cancers. Furthermore, specific to malignant glioma, it leads to the crucial 
next experiment: given that local tumor control within the irradiation field is seen with 
Plerixafor, what are the outcomes if the entire brain is included in the irradiation field?  
We are therefore proposing to treat an additional 20 newly diagnosed GBM patients with 
a four-week Plerixafor infusion that will begin one week after a modified irradiation regimen that 
will be designed to administer whole brain irradiation during the last three weeks of a six week 
treatment. It is our hope that this increased field will significantly decrease out of field 
recurrences in the brain and believe that this will markedly increase survival, a result that can be 
established with even this small cohort. Furthermore, it is important to note that widening the 
field does not necessarily mean that this will be associated with increased neurotoxicity; we and 
others have previously shown that the same treatment that blocks macrophages and produces 
radiation enhancement of tumor response not only produces no enhancement of normal skin and 
GI tract reactions to irradiation but produces a significant radioprotection including 
radioprotection against neurocognitive dysfunction [5-7]. 
 
Normalized MRI rCBV Ratios in 95% isodense regions:
Control vs. Plerixafor Patients
Pre-RT
1 mo p-RT
6 mo p-RT
Y Data
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Control RT/TMZ
Plerixafor infusion
NS
P < 0.02
P < 0.001
 
Graph 1. Normalized rCBV in tissue receiving 95% of 
maximum RT in controls and Plerixafor treated patients. 
Note values for 1 and 6 mo. are significantly lower in the 
Plerixafor group. Areas outside the 95% field were not 
significantly different.  
 
 

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2.2 
Plerixafor 
Plerixafor is a reversible inhibitor of the binding of stromal cell derived factor - 1α (SDF-1α), 
also known as chemokine (C-X-C motif) ligand 12 (CXCL12) to its cognate receptor chemokine 
(C-X-C motif) receptor 4 (CXCR4).   
 
The FDA has not approved the drug or biologic for treatment of this indication to date.  
 
2.3 
Rationale 
Our experimental studies suggest that post-irradiation tumor recurrences can be prevented or 
markedly delayed by blocking the influx of circulating proangiogenic cells including CD11b+ 
monocytes and endothelial cells into the tumor [5, 8].  Plerixafor is a reversible inhibitor of SDF-
1 binding that prevents or markedly delays the influx of proangiogenic cells thereby preventing 
post-irradiation tumor recurrences in glioblastoma.   
 
2.4 
Study Design 
For clinicaltrials.gov and Stanford Clinical Trials Directory compliance  
 
This is an open-label, non-randomized, single-arm trial.   
 
The primary purpose of this Phase II study is to evaluate the efficacy of Plerixafor 
administered with a modified radiation regimen that includes a component of WBRT. The 
primary endpoint is 6-month progression free survival post initiation of Chemoradiation..  
 
The secondary endpoints are the rate of patients surviving 32 months; toxicity of 
treatment; patterns of treatment failure; and cognitive outcome.   
 
 
2.5 
Correlative Studies Background 
Using transplanted glioblastoma tumors in mice, we have developed and validated a new 
paradigm to enhance the therapeutic effect of radiation: Namely that post-irradiation tumor 
recurrences can be prevented or markedly delayed by blocking the influx of circulating 
proangiogenic cells- CD11b+ monocytes and endothelial cells into the tumor [5, 8]. The 
significance of our findings and therapeutic strategy to prevent GBM recurrence has been 
highlighted in recent commentaries in prominent biomedical journals [9]. Our findings of the 
importance of CD11b+ monocytes and/or macrophages in a tumor response to irradiation have 
now been confirmed by others [10]. 
 
Our findings of relevance to the present proposal are summarized as follows: 
• We have shown that the clinically approved drug Plerixafor (AMD3100), which inhibits the 
interaction of stromal cell-derived factor-1 (SDF-1, CXCL-12) with its receptor, CXCR4, on 
bone marrow derived, proangiogenic, CD11b+ monocytes [11] both inhibits the radiation-
induced influx of the CD11b+ monocytes and prevents tumor recurrence following single or 
fractionated doses of irradiation (Figure 1A,C). We have confirmed the importance of the SDF-

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1/CXCR4 pathway for tumor recurrences by demonstrating that neutralizing antibodies to 
CXCR4 also inhibit tumor recurrence after irradiation (Figure 1D). In addition we have shown 
that neutralizing antibodies to CD11b+ monocytes can inhibit the recurrence of a human head 
and neck cancer in nude mice, as well as demonstrating that tumors in mice genetically deficient 
in CD11b+ cells are radiosensitive [8]. 
 
• We have demonstrated that blockage of angiogenesis following irradiation with the anti-
VEGFR2 neutralizing antibody DC101 is not as effective in potentiating the response to 
irradiation as is AMD3100 either by tumor recurrence or by inhibition of tumor blood flow 
following irradiation (Figure 1E, F). 
 
• We have shown that radiation selectively depletes the tumor vasculature thereby inducing 
tumor hypoxia and upregulating the transcription factor hypoxia inducible factor-1 (HIF-1), 
which in turn trans activates SDF-1, the key chemokine responsible both for the mobilization of 
bone marrow derived proangiogenic cells and their retention in the irradiated tumor. [5, 8]. 
 
• We have demonstrated the importance of CD11b+ monocytes in tumor recurrences after 
irradiation in patients by showing that, as in mice, GBM recurrences in patients following 
Irradiation have higher levels of CD11b+ monocytes than prior to therapy (Figure 2). 
 
• We have demonstrated that irradiated tumors express elevated levels of SDF-1 and this 
Chemokine is found at higher levels in the plasma of rats and patients with irradiated 
Brain tumors. 
 

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Because the CXCR4 serves as a co-receptor, along with CD4, for the binding of human 
immunodeficiency virus type 1 (HIV-1) [12], initial Plerixafor clinical trials were conducted for 
the treatment of HIV-1 infection [13]. In follow-up to the observation that Plerixafor given to 
healthy volunteers and HIV-1 infected patients elicited increases in white blood cell counts, 
studies have been done in healthy volunteers to assess the effect on circulating peripheral blood 
stem cells (PBSCs) [14]. Coincidentally, data emerged demonstrating that homing of CXCR4-
expressing stem cells to bone marrow is regulated, at least in part, through a chemoattractant 
effect of SDF-1α that is produced locally by bone marrow stromal cells [15]. In fact, disruption 
of the SDF-1α/CXCR4 through G-CSF exposure [16] or with chemotherapy, results in the 
appearance of both mature and pluripotent cells in the systemic circulation. Unlike the modes of 
action of either chemotherapy or cytokine growth factors, however, Plerixafor exerts its effect on 
PBSC mobilization as a direct consequent of its antagonism of CXCR4 [17]. Subsequent PBSC 
mobilization studies have shown Plerixafor to have a synergistic effect on the number of 
circulating progenitor cells when administered with G-CSF in patients with non-Hodgkin 
lymphoma (NHL) and multiple myeloma (MM) [18, 19]. 
 
Pharmacokinetics of Plerixafor 
The kinetics of dosing of Plerixafor was first explored in humans in a phase I 
bioavailability study in 17 healthy volunteers; 12 by intravenous (IV) infusion (three subjects 
each at 10, 20, 40, and 80 µg/kg), 5 by subcutaneous (SC) injection (two subjects at 40 µg/kg 
and three at 80 µg/kg) [20]. In this study, the Cmax and AUC0-∞ demonstrated dose 
proportionality across the four dose levels. However, a higher Cmax for IV administration was 
noted compared to SC administration (IV: 292.8 ± 67.0 and 503.9 ± 29.6, SC: 123.5 ± 27.9 and 
238.3 ± 17.3) for the 40 and 80 µg/kg dose levels, respectively. The bioavailability of Plerixafor 
was determined to be 80-90%. The pharmacokinetic behavior of Plerixafor is characterized by 
elimination from the plasma in a bi-exponential manner with a terminal elimination half-life of 
approximately 3.5-5 hours following a single dose. Plerixafor absorption following subcutaneous 
administration is rapid and essentially complete, with peak plasma levels occurring within 0.5–1 

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hour of dosing. The exposure-response relationship of Plerixafor in mobilizing CD34 + cells 
when administered as a single agent was also independently explored at doses ranging from 80-
320 µg/kg in 32 healthy volunteers [21] and from 40–320 µg/kg in 29 additional healthy 
volunteers [22]. In both studies, Plerixafor exhibited linear pharmacokinetics (PK) over the 
tested dose range (up to 320 µg/kg), consistent with previously reported PK results. Plerixafor is 
extensively protein bound to both human serum albumin and 1-acid glycoprotein; however, 
protein binding does not appear to have a major influence on either antiviral activity, effect on 
stem cell mobilization or toxicity. Saturation of protein binding sites may occur at plasma 
Plerixafor concentrations in excess of those likely to be achieved in any ongoing or planned 
clinical studies.  
The safety and the pharmacokinetics and pharmacodynamics of Plerixafor with G-CSF in 
patients with non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) was also evaluated in 
a phase II, open-label, single-arm study [23]. The patients were given G-CSF (10 µg/kg/day SC) 
for 4 days in the morning and Plerixafor 240 µg/kg SC on the evening before each day of 
apheresis. The PK profile of Plerixafor was characterized in 13 patients (5 with NHL and 8 with 
MM) and, overall, parameters were comparable in the patients with NHL and those with MM. 
Plerixafor was rapidly absorbed after SC administration with no observable lag time, with peak 
plasma concentrations occurring 0.5 hour after administration in most patients. Plerixafor was 
rapidly cleared, with a median terminal half-life of 4.6 hours. The median maximum increase in 
the number of circulating cells from baseline was 4.2-fold (range, 3.0- to 5.5-fold); with the 
maximum fold increase occurring approximately 10 hours after Plerixafor injection for all 
patients. The Plerixafor PK and PD profiles in the study patients were consistent with those in 
healthy volunteers and support the current dosing regimen and timing of apheresis.  
The primary route of elimination of Plerixafor is through the kidneys. A Phase I open-
label study in healthy subjects was conducted to evaluate the pharmacokinetic characteristics of 
Plerixafor in subjects with renal impairment [24]. All subjects received a single 240 µg/kg 
subcutaneous dose of Plerixafor. Subjects were stratified into 4 cohorts based on creatinine 
clearance determined from a 24-hour urine collection: control (>90 mL/min), mild renal 
impairment (51-80 mL/min), moderate renal impairment (31-50 mL/min), and severe renal 
impairment (<31 mL/min, not requiring dialysis). Eleven women (48%) and 12 men (52%), 
ranging in age from 35 to 73 years, were enrolled. Plerixafor clearance was reduced in subjects 
with renal impairment and was positively correlated with creatinine clearance. The mean area 
under the concentration-versus-time curve from time 0 to 24 hours post dose of Plerixafor in 
subjects with mild, moderate, and severe renal impairment was 7%, 32%, and 39% higher, 
respectively, than that in subjects with normal renal function. Renal impairment had no effect on 
maximal plasma concentrations. The safety profile was similar among subjects with renal 
impairment and controls. No renal impairment-related trends in the incidence of adverse events 
(AEs) were apparent. A Plerixafor dose reduction to 160 µg/kg in patients with a creatinine 
clearance value <or= 50 mL/min is expected to result in exposure similar to that in patients with 
normal to mildly impaired renal function, and became the basis for this dose recommendation in 
the FDA approved indication in NHL and MM, when added to G-CSF for mobilization. 
In a phase I trial evaluating single dose IV Plerixafor in healthy donors for stem cell 
harvest and use in allogeneic transplant, pharmacokinetic evaluation demonstrated that Cmax 
following the 320 μg/kg IV dose remained below 1.0 µg/mL whereas 400 μg/kg (N = 3) and 480 
μg/kg (N = 3) doses resulted in Cmax levels of 1.8-2.2 µg/mL.  

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Finally, chronic administration of Plerixafor has 
also been evaluated by continuous infusion for 10 days in 
HIV patients in an open-label dose escalation study with 
doses ranging from 2.5 to 160 µg/kg/h [25]. In this study, 
a 10-day infusion was administered via infusion pump at 
40 mL/hour (daily solutions prepared by dilution of a 10 
mg/mL solution of Plerixafor in 0.9% saline). Note that 
the total dose infused in this study was much higher 
than those doses proposed here (i.e., the highest dose 
over 4 weeks for our protocol will be 11,200 mcg/kg 
compared to 38,400 mcg/kg total for the highest 
cohort in the cited study). The median terminal 
elimination half-life was 8.6 hours (range: 8.1-11.1 
hours). Cardiac toxicities were observed in the HIV+ 
patients dosed to achieve Cmax levels above 2 µg/mL.  
 
Our own studies in the Phase I component of this 
study’s predecessor indicate that a four week infusion of 
Plerixafor at 400 µg/kg/d is well tolerated and achieves 
the target value necessary to ensure adequate bone 
marrow mobilization and prevent tumor entry (Figure 3). 
Furthermore, we noted a sustained elevation of 
monocytes that was sustained through the entire infusion, 
consistent with their being maintained in the circulation 
(Figure 4). 
 
Plerixafor for Stem Cell Mobilization 
Plerixafor is a bicyclam small molecule that 
selectively and reversibly inhibits CXCR4.  In preclinical 
and clinical studies, it was found to lead to a rapid 
increase in circulating hematopoietic progenitor cells and 
mature lymphocytes. 
 
In a phase I clinical trial conducted in healthy volunteers, a single dose of Plerixafor by 
SC injection (160 or 240 μg/kg) given alone or added to a mobilization regimen of daily G-CSF 
(10 μg/kg) for four days was shown to be generally safe and well-tolerated, as compared to a 
mobilization regimen consisting of G-CSF alone [26]. The most frequently reported AEs were 
injection site reactions, GI effects, paresthesias, and headaches. Plerixafor augmented CD34+ 
cell mobilization by G-CSF on average 3.8 fold. More recently, the safety of Plerixafor 
administered as a single agent by injection was further explored in healthy volunteers at doses up 
to 480 μg/kg [27]. No dose limiting toxicity was observed, and common adverse events were 
diarrhea, injection site erythema, perioral numbness, sinus tachycardia, headache, nausea, 
abdominal distention and injection site pain.  
 
Similar to the experience in healthy volunteers, phase I evaluation of a single injection of 
Plerixafor (160 or 240 μg/kg) given to 13 cancer patients (MM, n=7; NHL, n=6) was well 
tolerated and only grade 1 toxicities were observed [28]. A rapid and statistically significant 
increase in the total WBC and PB CD34+ counts at both 4 and 6 hours following a single 
injection were noticed. The absolute CD34+ cell count increased from a baseline of 2.6 +/- 0.7/ 
Plerixafor Serum Levels in Phase I Cohort
Days After Infusion Start
0
5
10
15
20
25
30
35
Serum Plerixafor Level
0
100
200
300
400
500
200 g/kg/d
400 g/kg/d
 
Figure 3. 
Monocytes, Absolute Counts
Screening
D1
D4
D8
D15
D22
D29
P-1
P-2
Monocytes/l (x 1000)
0.0
0.5
1.0
1.5
2.0
2.5
P < 0.001, one wayANOVA
 
 
Figure 4. Sustained elevation of monocyte counts 
during Plerixafor infusion. 

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μL (mean +/- SE) to 15.6 +/- 3.9/ μL and 16.2 +/- 4.3/ μL at 4 hours (P=.002) and 6 hours after 
injection (P =.003), respectively. The absolute CD34+ cell counts observed at 4 and 6 hours 
following Plerixafor were higher in the 240 μg/kg group (19.3 +/- 6.9/ μL and 20.4 +/- 7.6/ μL, 
respectively) compared with the 160 μg/kg group (11.3 +/- 2.7/ μL and 11.3 +/- 2.5/ μL, 
respectively).  
Plerixafor was then studied for hematopoietic stem cell mobilization coupled with G-CSF 
for autologous stem cell transplantation. In a phase II, open label, crossover study in 25 patients 
with NHL and MM, patients received 3 days of G-CSF run-in, and then underwent mobilization 
with one regimen of either: (A) up to 4 days of 10 μg/kg of G-CSF or (B) up to 4 days of 
10 μg/kg of G-CSF plus 160 μg/kg of Plerixafor [29].  Patients were apheresed one hour after the 
dose of G-CSF alone or 6 hours after the morning G-CSF plus Plerixafor dose for up to 4 days to 
achieve a target of 5 x 106 cells/kg. After a rest period, patients received 3 days of G-CSF run-in, 
followed by the opposite regimen (A after B or B after A) and were apheresed in the same 
manner. The purpose was to determine safety, apheresis yields, and transplantation success. 
After the initial 8 patients were dosed at 160 μg/kg, the protocol was amended to increase the G-
CSF run-in from 3 to 4 days, and the Plerixafor dose to 240 μg/kg. Later, the protocol was 
further amended such that the G-CSF alone regimen was always used first. There was no drug-
related SAE or unexpected AE. More patients achieved ≥5 × 106 CD34+ cells/kg after 
mobilization with Plerixafor plus G-CSF compared to G-CSF alone. Nine patients (8 NHL and 1 
MM patient) who mobilized CD34+ cells poorly with G-CSF alone (<1.6 × 106 CD34+ cells/kg) 
improved when mobilized with Plerixafor plus G-CSF, with all patients achieving >2 × 106 
CD34+ cells/kg (range: 2.78 to 13.6 CD34+ cells/kg). The median day of polymorphonuclear 
leukocyte (PMN) engraftment was Day 10 and Day 17 for platelets, when using cells collected 
by Plerixafor plus G-CSF.  Durability of engraftment has been measured up to one year. 
 
Two phase III, multi-center, randomized, double-blind, placebo-controlled, comparative 
trials examined the ability of Plerixafor (240 μg/kg) plus G-CSF (10 μg/kg) vs. placebo plus G-
CSF (10 μg/kg) to mobilize CD34+ stem cells for autologous hematopoietic stem cell 
transplantation in patients with NHL (protocol 3101) and MM (protocol 3102), respectively. 
Patients were excluded if they previously attempted stem cell mobilization or received a prior 
stem cell transplant. 
 
In protocol 3101, the addition of Plerixafor to a G-CSF regimen significantly increased 
the proportion of patients with NHL who were able to mobilize minimum (2 x 106 cells/kg) and 
target (5 x 106 cells/kg) numbers of CD34+ cells for autologous transplant and allowed both 
targets to be reached in significantly fewer apheresis days [30]. In 3102, the addition of 
Plerixafor to a G-CSF regimen, compared with G-CSF alone, significantly increased the 
proportion of patients with MM who were able to mobilize the target (6 x 106 cells/kg) number 
of CD34+ cells needed for autologous transplant and allowed this target to be reached in 
significantly fewer apheresis days [31]. In both trials, hematopoietic stem cells mobilized with 
Plerixafor + G-CSF were equally capable of prompt and durable PMN and PLT engraftment, 
compared to cells mobilized with G-CSF alone.   
In the controlled Phase III studies in patients with NHL and MM (3101 and 3102), a total 
of 301 patients were treated in the G-CSF plus Plerixafor 240 μg/kg SC group and 292 patients 
were treated in the G-CSF plus placebo group. The safety profile of Plerixafor was consistent 
with that observed in previous mobilization studies and adverse events that occurred more 
frequently with Plerixafor than placebo were: insomnia, headache, dizziness, diarrhea, nausea, 
flatulence, abdominal pain, vomiting, abdominal distention, dry mouth, stomach discomfort, 

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constipation, dyspepsia, hypoesthesia oral, arthralgia, musculoskeletal pain, hyperhidrosis, 
erythema, injection site reactions, fatigue, and malaise [30, 31]. Overall, the AE data, combined 
with the laboratory and vital sign findings, indicate that Plerixafor 240 μg/kg, in conjunction 
with G-CSF for the mobilization and collection of CD34+ cells, is well-tolerated in patients with 
NHL or MM undergoing autologous stem cell transplant. No notable differences in the incidence 
of AEs were observed across treatment groups from chemotherapy/ablative treatment through 12 
months post-transplantation.  
Plerixafor has been studied in over 2000 human subjects in over 78 clinical trials, which 
have encompassed healthy volunteers, HIV infected patients, multiple myeloma patients, 
lymphoma patients, and patients with a variety of other malignancies.  Mozobil® (Plerixafor 
injection) has been approved by the FDA in combination with G-CSF to mobilize hematopoietic 
stem and progenitor cells (HSPCs) for collection and subsequent autologous transplantation in 
patients with non-Hodgkin’s lymphoma (NHL) and multiple myeloma (MM) based on phase III 
studies. Several reports have recently indicated that Plerixafor can also be safely administered 
with G-CSF in the context of a chemotherapy-based mobilization regimen [32-36]. Finally, 
based on favorable pharmacokinetic observations in healthy volunteers, the impact of 
intravenous Plerixafor in stem cell mobilization for cancer patients is now under investigation. In 
a phase I/II study, escalating doses of intravenous Plerixafor (up to 400 μg/kg) alone or added to 
G-CSF were administered to 25 patients with NHL (n=15) or HL (n=10). In the phase I portion 
of the study, one dose-limiting toxicity (grade 2 chest pain) was observed at 320 μg/kg and no 
grade 3/4 toxicities occurred at 400 μg/kg. A total of 24 of 25 patients (96%) met the goal 
collection of ≥ 2.0 x 106 CD34+ cells/kg and 21 of 25 patients (84%) collected ≥ 5.0 x 106 
CD34+ cells/kg in a median 1 day of pheresis, including 6 of 6 patients in the 400 µg/kg cohort.   
 
Impact on Graft Composition and Transplant Outcomes 
Although collectively referred to as CD34+ progenitor or stem cells, the full repertoire 
and relative abundance of each cell type collected during PBSC harvest is thought to be 
governed by selection of the mobilization regimen. The relative importance of blood graft 
composition on hematopoietic reconstitution following autologous transplant has been recently 
reviewed [37]. A number of small studies indicate that cells mobilized with Plerixafor are 
phenotypically distinct from those derived through other mobilization approaches. In macaque, 
for instance, gene and micro-RNA expression profiling of Plerixafor-mobilized CD34(+) cells 
include more B-, T-, and mast cell precursors, whereas G-CSF-mobilized cells have more 
neutrophil and mononuclear phagocyte precursors [38]. When evaluated in both healthy donors 
and lymphoma patients, Plerixafor alone mobilizes more precursors of the plasmacytoid 
dendritic cell (pDC) lineage, relative to mobilization with G-CSF + Plerixafor or G-CSF alone . 
Authors hypothesize that stem cell products enriched in pDCs may lead to improved immunity in 
the recipient after transplant and reduced incidence of CMV. The impact of Plerixafor on DC 
graft composition was corroborated in MM and NHL patients mobilized according to the 
approved indication. In terms of DC subsets, grafts mobilized with P+G contained similar % of 
myeloid (MDC, Lin-CD11c+HLA-DR+CD123-) and BDCA3+ DCs. The percentage of 
plasmacytoid DCs (PDC; CD123+BDCA2+HLADR+) was significantly increased in the P+G 
grafts (median, 0.87% vs. 0.30%; p=0.002), leading to a significantly higher PDC/MDC ratio in 
the P+G group, 2.08 vs. 1.01, p<0.0001). It was also found that there were significantly more 
CD8+ IFN-gamma and TNF-alpha secreting T cells in the P+G group as compared to the G 
group (median, 12.3% vs. 5.3%, p=0.01; and 5.9% vs. 2.8%, p=0.02, respectively). Again, more 

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pDC cells, as well as CD34+CD45RA-CD123hi cells of unknown function, were also noted 
when Plerixafor was given intravenously at high doses with G-CSF, relative to G-CSF alone. 
Lastly, the addition of Plerixafor to G-CSF not only potentiates CD34+ peripheral stem cell 
yields, but also significantly increases the proportion of more primitive CD34+ CD38- subsets 
relative to G-CSF alone mobilization [39-41], the latter speculated to potentially promote 
superior engraftment after high-dose chemotherapy [42]. 
The functional consequence of qualitative differences in graft composition emerging 
from inclusion of Plerixafor in stem cell mobilization is not known. Human progenitor cells 
mobilized with Plerixafor were shown to more robustly repopulate NOD/SCID recipient mice, 
relative to cells derived through G-CSF mobilization in the same donors [43]. In the clinic, a 
higher median of absolute lymphocyte counts harvested through addition of Plerixafor to G-CSF 
mobilization compared with a control group mobilized with G-CSF alone (4.16 x 109 
lymphocytes/kg vs. 0.288 x 109 lymphocytes/kg; P < 0.0001) correlated with better outcomes in 
progression-free survival after autologous transplant in NHL patients [44]. With a median 
follow-up of 20 months (range, 4-24 months), no relapses were reported in the AMD3100 
(Plerixafor) group compared with 15 of 29 in the control group (P < 0.02). Despite various 
studies pointing to Plerixafor impacting the graft composition, meaningful differences in 
engraftment from cells mobilized with Plerixafor + G-CSF vs placebo + G-CSF were not 
apparent in either the NHL [30] or MM [31] phase III trials. In fact, absolute CD34+ cell dose 
transplanted, rather than qualitative differences that may have resulted from either mobilization 
approach, was associated with better long-term platelet recovery after ASCT in those trials [45].  
 
Leukemia Stromal Interactions 
Similar to normal hematopoietic stem cells, leukemic blasts express many of the same 
adhesion molecules such as CXCR4, VLA-4, VLA-5, and CD44 which allow them to interact 
with the marrow stroma [46-48]. The interaction of leukemic blasts with the marrow 
microenvironment is postulated to be important in mediating disease resistance, a process 
commonly referred to as cell-adhesion mediated drug resistance (CAM-DR) [49] which 
eventually promotes relapse. CAM-DR can provide protection from cell cycle-dependent 
chemotherapy through induction of quiescence of tumor cells, as well as through exposure to 
SDF-1  which activates the prosurvival PI3K/Akt and MAPK pathway, preventing apoptosis in 
cancer cells. The role of the SDF-1α/CXCR4 axis in mediating CAM-DR in malignancies is 
currently under investigation and provides a rationale for evaluating the potential activity of 
Plerixafor in chemo sensitization.    
 
Pre-Clinical Studies of Chemo sensitization with Plerixafor 
In preclinical models of leukemia, targeting the microenvironment with CXCR4 
antagonists was sufficient to overcome resistance to cytarabine [50] and also provided 
responsiveness to antibody-mediated cytotoxicity [51]. Similarly, the addition of Plerixafor in a 
mouse model of APL was able to enhance the efficacy of cytarabine therapy compared with mice 
leukemic treated with cytarabine alone, which resulted in reduced tumor burden and improved 
survival [52]. The median overall survival for the untreated control, Plerixafor alone, cytarabine 
alone, and cytarabine + Plerixafor cohorts were 18, 19, 23 and 30 days, respectively (cytarabine 
vs cytarabine + Plerixafor cohorts: p < 0.0006). A survival advantage was also noted in two 
xenograft models of ALL exposed to a CXCR4 antagonist followed by chemotherapy 

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(vincristine or nilotinib), compared to chemotherapy alone [53]. Plerixafor alone had no 
detectable anti-tumor effect in these experiments. 
In BCR-ABL(+) leukemia (CML), Plerixafor was able to inhibit tumor cell chemotaxis 
and confer added sensitivity to the tyrosine kinase inhibitors Imatinib and Nilotinib [54]. Using a 
functional mouse model of progressive and residual disease of CML, Plerixafor was also able to 
mobilize leukemic cells in vivo, such that when added to nilotinib, the leukemia burden in mice 
was significantly reduced below the baseline level suppression achieved by nilotinib alone [55]. 
Overall, these results support the notion that CXCR4 inhibition in conjunction with targeted 
tyrosine kinase therapy may overcome drug resistance in CML and potentially suppress or 
eradicate residual disease. 
Disrupting the interaction of tumor cells to bone marrow niches also confers added 
sensitivity to therapy in multiple myeloma (MM). In a xenograft model, bortezomib-treated mice 
showed reduction in tumor progression compared with control (P = .041), and the mice treated 
with the combination of Plerixafor and bortezomib showed significant tumor reduction compared 
with control (P = .001) and bortezomib alone (P = .021) [56]. Tumor involvement in different 
organs was also evaluated in the treated groups. The Plerixafor alone group was similar to that of 
the control group in the BM, liver and spleen, indicating that mobilization of MM cells by 
Plerixafor does not lead to engraftment of MM cells into extra medullary sites. However, there 
was a significant decrease of tumor cells present in BM, liver and spleen in the bortezomib-
treated group, and a significant decrease was further obtained in the group treated with the 
combination of Plerixafor and bortezomib [56]. 
Collectively these data suggest a pivotal role for the CXCR4/SDF-1 axis in sustaining 
viability of hematologic malignancies through interaction with the marrow microenvironment 
and provide a basis for evaluating Plerixafor as sensitization agent in the clinic.  
 
Clinical Experience with Plerixafor for Sensitization to Leukemia Treatment 
Elevated levels of CXCR4 expression on leukemic cells are associated with worse 
outcomes including shorter overall survival in AML [57-59]. Plerixafor has been shown to 
mobilize leukemic cells in humans [60] and was first reported to be used for sensitization in 
combination with reinduction chemotherapy in an AML patient who had relapsed from prior 
allogeneic transplant [61].  
 
Formal clinical trial evaluation of Plerixafor given prior to salvage chemotherapy in 
relapsed or refractory AML patients has been evaluated in a phase I/II study [62].  A test dose of 
Plerixafor was administered SC followed by a 24 hour observation period to analyze its effects 
on AML blasts in the absence of chemotherapy. Plerixafor was then given 4 hours prior to MEC 
chemotherapy (mitoxantrone 8 mg/m2/d, etoposide 100 mg/m2/d and cytarabine 1,000 mg/m2/d) 
daily for 5 days.  
Forty patients have been enrolled in the study with median age of 49 yrs. (range 19-71). 
Baseline characteristics include 6 patients (15%) with secondary AML, 4 (10%) with prior 
transplant, 24 (60%) with intermediate and 10 (25%) with poor risk cytogenetics. Thirty-six 
patients (90%) received Plerixafor + MEC as their 1st salvage regimen for relapsed disease with 
21 (53%) having a CR1 duration of < 12 months and 9 patients (6%) for primary refractory 
disease. The remaining four patients (10%) received the regimen as their 2nd salvage regimen. 
Three dose levels of Plerixafor: 80 , 160 and 240 µg/kg were tested in the phase I dose 
escalation. In the phase II, a total of 34 patients have been treated at the 240 µg/kg dose level. 
Common grade 3 adverse events consisted primarily of cytopenias and infections. No evidence 

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of hyper leukocytosis or significant delays in neutrophil recovery (ANC >500/mm3, median 27d, 
range 21-37) or platelet recovery (plt >50k/mm3, median 26d, range 20-40d) were observed. Of 
the 32 patients evaluable for response at the 240 µg/kg dose level, a complete remission 
(CR+CRi) has been achieved in 50% of patients (CR=13, CRi=3) which compares favorably to 
historical CR rates of 25-35%. Treatment failure was due to persistent disease in 14 patients 
(44%) and early death due to complications from infection in 2 patients (6%). One year KM 
estimate of overall survival is currently 56%.  
Correlative studies demonstrated that Plerixafor mobilizes AML blasts (mean 2.5-fold 
increase, range 0.9-7.3 fold) into the peripheral circulation peaking at 6-8 hours after 
administration. FISH performed in patients with informative cytogenetic abnormalities indicates 
that mobilization occurs equally in both non-leukemic and leukemic populations. Higher baseline 
surface CXCR4 expression correlated with increased mobilization of AML blasts (Pearson's 
r=0.53, p=0.023) into the PB at 6 hrs. post-Plerixafor. It was concluded that Plerixafor can be 
safely administered in combination with cytotoxic chemotherapy in patients with AML [62].  
A phase I study is also being conducted to determine the MTD and safety of Plerixafor 
when combined with cytarabine and daunorubicin  (7+3 regimen) for newly diagnosed adult 
AML [63]. Plerixafor was given as a 30-min IV infusion, 4–5 hours before daunorubicin 
beginning on day 2 and repeated every day until day 7. Dose levels were from 240, 320, and 400 
to 480 µg/kg. Three to 12 evaluable patients were enrolled in each cohort in a modified 3+3 
design. Twenty-three patients (median age 57 years) have been enrolled in 4 cohorts. Plerixafor 
infusion on day 2 caused a rise in PB AML blasts (mean 3.01-fold increase) peaking at 2–4 hours 
after administration. On day 7, there was a mean 1.51-fold increase in PB AML blasts but far 
fewer total cells were detected.  
Eighteen (86%) patients experienced adverse events (AEs) that were reported as at least 
possibly related to Plerixafor. The majority was grade 1/2 in severity and mainly included 
gastrointestinal disorders. Four (19%) patients experienced Grade 3 Plerixafor-related AEs 
including febrile neutropenia (n=3), neutropenia (n=1), nausea (n=1), infections (n=2) and 
decreased appetite (n=1) commonly observed with 7+3 regimen. One (5%) patient (480 µg/kg 
cohort) experienced Grade 4 related AEs of thrombocytopenia and asymptomatic pulmonary 
embolism (while receiving medroxyprogesterone); the latter was the only possibly-related SAE 
reported. The median time to neutrophil (  0.5 x 109/L) and platelet ( 100 x 109/L) recovery for 
responders was 19.5 (range 13–35) and 21 (range 17–37) days, respectively. There were 4 (17%) 
Plerixafor unrelated deaths (240 µg/kg): 1 within 30 days post induction due to an AE of acute 
respiratory distress syndrome and 3 due to disease progression > 3 months post induction. No 
DLTs have been reported.  
Of 21 patients with available data, 14 (67%) had complete response (CR), 2 had CR with 
incomplete count recovery (CRi), 2 had residual leukemia (RL), 2 had treatment failure (TF) due 
to resistant disease and 1 was not evaluable (NE) due to early death. Sixteen of 21 patients, 
majority of who had intermediate or poor risk cytogenetics, achieved a CR or CRi, with 
responses observed across all Plerixafor doses. Twice daily Plerixafor dosing and addition of G-
CSF to augment mobilization are being currently explored. 
Plerixafor is also being investigated as sensitization agent to conditioning chemotherapy 
in AML and MDS patients undergoing allogeneic transplantation [48]. In this Phase I/II study, 
G-CSF is administered at a standard dose beginning on day -9 daily for 6 days, and Plerixafor 
from day -7 at one of the 4 dose levels 0 (control), 80, 160, or 240 µg/kg, 8 hours prior of each 

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four daily doses of a standard preparative regimen consisting of 40 mg/m2 Fludarabine and 
130mg/m2 IV Busulfan, days -6 through -3.  
To date, twenty seven patients have been enrolled in the study to date with a median age 
of 48 years (range 25-65).  Baseline characteristics include 13 patients (48%) with de novo 
AML, 6 (22%) with secondary AML, 5 with MDS and 3 with CML. Among the 24 AML/MDS 
patients, 14 (58%) had intermediate and 10 (42%) poor risk cytogenetics. Twelve patients (50%) 
had primary refractory AML, 5 were in 1st or 2nd relapse, 2 were untreated, and 3 were in CR1 
and 2 in CR2. The source of stem cells was sibling donor in 16 and unrelated donor in 11. After 
phase I Plerixafor dose escalation in 16 patients, 11 patients received 240 µg/kg in Phase II. 
Common grade ≥ 3 adverse events which consisted primarily of neutropenic fever, infections, or 
rash were seen in 24/27 (89%) patients. There were no toxicities ascribed to the G-
CSF/Plerixafor component of the regimen.  No evidence of significant delays in neutrophil 
(ANC >500/mm3, median 12.5d, range 10-19) or platelet recovery (plt >20k/mm3, median 12d, 
range 9-74d) were observed.  Grade I-II GVHD was seen in 10/27 patients (37%), with no 
occurrences of Grade III-IV GVHD. Of the 19 patients with active disease at study entry, 18 
achieved a CR. Treatment failure was due to persistent disease in 1 pt (4%), relapsed disease in 
10 patients (37%) and early death due to complications from intracranial hemorrhage in 1 patient 
(4%). Median progression-free survival (PFS) for all patients was 26.6 wks (95%CI: 18.1-33.9 
wks) and 15.7 wks (95% CI: 12.1-26.6 wks) in relapsed patients. Median follow-up for all study 
patients was 19.14 wks (range: 0.7-54.6 wks).  
Correlative studies analyzed from 16 patients enrolled in the Phase I portion of the trial 
demonstrate that G-CSF/Plerixafor mobilizes CD34+ cells, with the mean fold increase of 5.9-
fold at 80 µg/kg Plerixafor; at 160 µg/kg, 13-fold; and at 240 µg/kg, 14.2-fold. Over time, the 
relative increase of FISH+ cells was significantly higher than that of FISH- cells, indicating 
preferential mobilization of cytogenetically abnormal leukemic over normal  cells (p=0.005). 
The objective of the ongoing Phase II study is to determine if the combination of G-
CSF/Plerixafor with busulfan/fludarabine improves PFS compared to historical controls 
receiving busulfan/fludarabine alone.  
Another study is aiming to establish the maximum tolerated dose (MTD) of Plerixafor in 
combination with bortezomib in patients who have active relapse/refractory MM [64]. Patients 
with active disease received Plerixafor at the recommended dose SC on days 1-6 of every cycle. 
Planned dose levels include 160, 240, 320, 400, and 480 µg/kg. Bortezomib was given at the 
recommended dose twice a week on days 3, 6, 10, and 13 every 21 days. Dose levels include 1.0 
and 1.3 mg/m2, 60-90 minutes after Plerixafor. Patients who had response or stable disease went 
on to receive a total of 8 cycles without planned maintenance therapy. The median number of 
cycles on therapy was 3 (1–11). Dose limiting toxicities including insomnia, restlessness, and 
psychosis were observed in two patients at dose level 6 (Plerixafor 400 µg/kg and bortezomib 
1.3 mg/m2). To further explore the safety of maximum tolerated dose, three additional patients 
were enrolled at dose level 5b (Plerixafor 320 µg/kg and bortezomib 1.3 mg/m2). Overall, the 
combination proved to be well tolerated. There were no grade 4 toxicities. Grade 3 toxicities 
included lymphopenia (40%), hypophosphatemia (20%), anemia (10%), hyponatremia (10%), 
hypercalcemia (10%), and bone fracture due to myeloma bone disease (10%). One patient came 
off treatment due to grade 2 painful neuropathy at cycle 5. Twenty-three patients were evaluable 
for response, including 1 (4%) complete response (CR), 1 (4%) very good partial response 
(VGPR) and 3 (13%) MR, with an overall response rate (including MR) of 5 (22%) in this 
relapsed and refractory population. In addition, 15 (65%) patients achieved stable disease (SD), 

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with just 3 (13%) having progressive disease (PD) as their best response. The combination of 
Plerixafor and bortezomib is generally well tolerated with minimal neuropathy or other toxicities 
seen to date. The responses observed are encouraging in this relapsed and refractory population. 
Plerixafor was able promote transient de-adhesion of MM cells and accessory cells in vivo in 
most of the patients, indicating that chemo sensitization can potentially be achieved in patients 
with MM using this approach. 
The toxicities and pharmacokinetics of the combination of Plerixafor and rituximab in 
previously treated patients with chronic lymphocytic leukemia (CLL) are being investigated in a 
phase I dose escalation study (Andritsos et al. 2010). Rituximab was administered three times a 
week as a 100 mg dose on day 1, followed by 375 mg/m2 IV for 12 total doses.  Plerixafor was 
administered beginning with the 4th dose of Rituximab, 4 hours prior to the rituximab, in 4 
cohorts of patients receiving various doses: (1) 80 µg/kg, (2) 160 µg/kg, (3) 240 µg/kg, and (4) 
320 µg/kg.  Preliminary results from the study demonstrated that CLL cells were mobilized to 
the peripheral blood in a dose-dependent fashion by Plerixafor. The combination of Plerixafor + 
rituximab in CLL patients with WBC < 50×109/L was well tolerated, and no dose limiting 
toxicities were reported. The most common adverse events that were reported were nausea, 
fatigue, chills, and diarrhea. CLL cells were mobilized following Plerixafor, and partial 
remissions were seen in a proportion of patients. In some cases, maximum responses were seen 
several months after completion of rituximab, consistent with single agent therapy. Higher 
Plerixafor doses and IV administration are now being investigated in an amendment to the 
ongoing clinical trial.   
 
Plerixafor in Gliomas 
Prior to our study, the presence and activity of the CXCR4 was also found to be critical 
for the growth of both malignant neuronal and glial tumors. In an intracranial xenograft of U87 
glioma, antagonism of CXCR4 alone resulted in inhibition of tumor growth and increased 
apoptosis, compared to saline [65]. The anti-tumor effect of AMD3100 on glioma cells was 
associated with the drug’s ability to attenuate the AKT and MAPK pathways downstream of 
CXCR4 signaling. In another orthotopic model of glioblastoma multiforme, inhibition of 
CXCR4 was found to synergize with BCNU by inducing tumor regression in vivo, as a result of 
both increased apoptosis and decreased proliferation, and despite sub therapeutic doses of 
chemotherapy [66].  
In addition to directly conferring tumor cell responsiveness to therapy, a new mechanism 
of action for Plerixafor in tumor abrogation has recently emerged. A common pathway for tumor 
invasion or metastasis, as well as disease recurrence, is the appearance of new blood vessels 
forming as a consequence of hypoxic conditions in the tumor microenvironment.  
Revascularization at sites of hypoxia results from the recruitment and stimulation of 
CXCR4-positive bone marrow-derived progenitor cells through local upregulation of SDF1-α, 
which is in turn under positive regulation by HIF-1α [9, 67]. Of relevance, the process of 
vasculogenesis initiated after radiation therapy in an intracranial xenograft model of 
glioblastoma was recently shown to be a potential mechanism for disease recurrence [8]. In this 
model, Plerixafor was given chronically over a period that slightly overlapped with and extended 
beyond radiotherapy until hypoxia-induced SDF-1α levels resolved to baseline. In treated 
animals, disease recurrence was prevented, likely due to the mitigating effect of Plerixafor on the 
influx of bone marrow-derived cells to the brain. Effective abrogation of revascularization 
through CXCR4 antagonism was also recently demonstrated in xenograft models of lung and 

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breast, overcoming both the concomitant stimulation of angiogenesis by paclitaxel and G-CSF 
[68]. Taken together, these observations suggest a potential role for Plerixafor in directly 
sensitizing gliomas, and perhaps other solid cancers, to therapy or promote tumor cell apoptosis 
through deprivation of essential new vasculature.   
 
Dose Selection in Combination with Chemotherapy 
In preclinical animal toxicology studies, DLTs were primarily adverse neurologic events, 
including severe dyspnea, tremors, ventral recumbency, which, at higher dosages, progressed to 
convulsions.  The MTD for these effects was approximately 70 mg/m2, which correlates with a 
dose of approximately 1800 μg/kg in humans. Early evidence of adverse neurologic effects, 
including diarrhea, muscle twitches, tremor, and tachycardia, were seen at doses of 17.5 to 35 
mg/m2. This is thought to scale to an approximate human equivalent dose of 470 to 940 μg/kg. 
The effects tended to resolve within hours of the dose and appeared to be related to Cmax. 
Plerixafor has been given at doses of up to 480 μg/kg SC and IV in healthy volunteers 
and in cancer patients. A maximum tolerated dose has not been established. Higher doses of 
Plerixafor injection were evaluated in healthy volunteers in three cohorts of six subjects who 
each received two different doses of Plerixafor separated by at least 2 weeks to allow for 
adequate pharmacodynamic wash-out [27]. The dosing cohorts evaluated were: 240 and 320 
µg/kg (cohort 1); 320 and 400 µg/kg; (cohort 2); and 400 and 480 µg/kg (cohort 3). Plerixafor 
was considered reasonably safe with no dose-limiting toxicity and common adverse events that 
consisted of diarrhea, injection site erythema, perioral numbness, sinus tachycardia, headache, 
nausea, abdominal distention and injection site pain. No dose limiting toxicities occurred. Sinus 
tachycardia (all Grade 1) was observed in most subjects treated with 400 and 480 μg/kg doses of 
Plerixafor, which were usually associated with activity and resolved quickly following rest. 
Since these events occurred soon after Plerixafor administration, they may be related to the 400 
and 480 μg/kg doses of Plerixafor [27], which are higher than the 240 μg/kg dose used in the 
majority of other mobilization trials.   
 
Intravenous administration of Plerixafor has been evaluated in cancer patients to minimize 
discomfort, optimize normal and leukemia stem cell mobilization, and ease logistical problems in 
the timing of administration. The timing and magnitude of the peak leukemia cell mobilization in 
relation to the time of administration of the chemotherapeutic agents may be critical in the 
success of leukemia control.  Giving the Plerixafor IV may reduce the variability of the PK 
parameters and the range of peak leukemia cell mobilization, thus allowing better timing of 
chemotherapy administration.   
 
 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
 
Refer to the Participant Eligibility Checklist in Appendix A. Patients who do not meet 
our definition for the analysis population will be replaced.   
 
 
3.1 
Inclusion Criteria 
 

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3.1.1 Patients must have tissue confirmation of high grade (WHO Grade IV) glioma including 
but not limited to glioblastoma, gliosarcoma, glioblastoma with oligodendroglial features, and 
glioblastoma with PNET features. 
 
3.1.2 The patient must have post-operative contrast enhanced imaging (CT or MRI) unless only 
biopsy performed.  For patients having biopsy alone, post-operative imaging is not routinely 
obtained and therefore the preoperative study will serve as baseline.  
 
3.1.3 Patient should have surgery (biopsy, partial resection or gross total resection) and no 
additional anti-cancer therapy except the Chemo-radiation as specified in the protocol. 
 
3.1.4 Patients must be between the ages of 18 and 75 years old (inclusive).   
 
 
3.1.5 Patients must have Karnofsky Performance score ≥ 60.  
 
 
3.1.6 Adequate organ function is needed at time of screening visit including: 
1. ANC ≥ 1500  
2. Platelets ≥ 100,000 ml 
3. Serum Creatinine ≤ 1.5mg/dl; Cr clearance should be > 50 mL/min 
4. AST and ALT ≤ 3 times the upper limit of normal 
5. If female of childbearing potential, negative pregnancy test 
 
3.1.7 The patient or his/her legal representative must have the ability to understand and 
willingness to sign a written informed consent document.   
 
3.1.8 Patient agrees to use an effective method of contraception (hormonal or two barrier 
methods) while on study and for at least 3 months following the Plerixafor infusion 
 
3.2 
Exclusion Criteria 
Patients who meet any of the following criteria must not be permitted entry to the study 
 
3.2.1 Prior or concurrent treatment with Avastin (bevacizumab).   
 
3.2.2 Prior exposure to Plerixafor. 
 
3.2.3 Prior use of other investigational agents to treat the brain tumor.   
 
3.2.4 Recent history of myocardial infarct (less than 3 months) or history of active angina.   
 
3.2.5 Prior malignancy except for non-melanoma skin cancer and carcinoma in situ (of the 
cervix or bladder), unless diagnosed and definitively treated more than 3 years prior 
to 1st dose of investigational drug. 
 
3.2.6 Prior sensitivity to Plerixafor. 
 
3.2.7 Pregnant or patients who are breastfeeding.   

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3.3 
Informed Consent Process 
All participants will be provided a consent form describing the study with sufficient information 
for participants to make an informed decision regarding their participation.  Participants must 
sign the IRB approved informed consent prior to participation in any study specific procedure. In 
the event that a patient cannot sign due to writing impairment, the patient will make their mark 
and the person obtaining consent will print the patient’s name and date. All participants will 
receive a copy of the signed and dated consent document.  The original signed copy of the 
consent document must be retained in the medical record or research file.  
 
3.4       Randomization Procedures 
There is no randomization procedure. 
 
 
3.5 
Study Timeline 
Primary Completion: 
We estimate that the study will reach primary completion 36-42 months from the time the study 
opens to accrual. 
 
Study Completion: 
We estimate that the study, including the up to 5 year long term follow up, will reach study 
completion 8 years after the time the study opens to accrual. 
 
4. 
TREATMENT PLAN 
4.0.1 Screening 
 
The following procedures will be performed for all potential subjects at the Screening visit to be 
conducted within 10 days prior to the start of WBRT component (Fraction 16 of RT): 
• Written informed consent  must be obtained from the patient prior to performance of any 
study-specific tests or procedures within 35 days of the start of Fraction 16 of RT. 
• Confirm Eligibility Criteria 
• Demographics: birth date, race/ethnicity and gender at birth 
• Medical history 
• Cancer history 
• Physical Exam 
• KPS 
• Concomitant medications 
• Vital Signs (including height and weight) 
• Laboratory tests: CBC with differential, Comprehensive Metabolic Panel (including: 
sodium, potassium, chloride, CO2, glucose, creatinine, urea nitrogen, calcium, protein, 
albumin, total bilirubin, ALK Phosphatase, AST, ALT), Pregnancy Test (only for women 
of child bearing potential) Provided a patient's platelets meet screening requirements and 
day 1 requirements for the Plerixafor infusion, it is not necessary for them to be taking 

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the concurrent TMZ at that time, only necessary that they were given TMZ as intention to 
treat when they began RT/TMZ 
 
Fraction 16 of RT 
• Institution of whole brain irradiation (at Fraction 16, day 21 of radiation component) 
• Start tracking Adverse events 
 
Prior to start of Plerixafor infusion: 
• Placement of the PICC line and infusion pump  
• Neuro-cognitive assessment (HVLT-R, COWA, and Trail making Tests); quality of life 
surveys (MDASI-BT and EQ-5D-5L).  If patient is non-English speaking, this will be 
deferred on an ongoing basis. 
 
Day 1 must occur 7 days (+/- 3 days) prior to the completion of XRT: 
• Physical Exam  
• KPS 
• Vitals 
• Laboratory tests: CBC with differential, Complete Metabolic Panel (including: sodium, 
potassium, chloride, CO2, glucose, creatinine, urea nitrogen, calcium, protein, albumin, 
total bilirubin, ALK Phosphatase, AST, ALT) 
o Patients may proceed with the Plerixafor infusion even if the Day 1 ANC and 
platelets no longer meet inclusion criteria 3.1.7 due to the concurrent 
temozolomide and radiation and at the investigator’s discretion; 
Thrombocytopenia should be ≤ grade 2 
• Begin Plerixafor infusion in outpatient unit. 
 
Weekly following the start of the Plerixafor infusion through the end of infusion (+/- 3 
days) (Day 8, Day 15, Day 22): 
• Physical Exam 
• KPS 
• Vitals 
• Laboratory tests: CBC with differential, Complete Metabolic Panel (including: sodium, 
potassium, chloride, CO2, glucose, creatinine, urea nitrogen, calcium, protein, albumin, 
total bilirubin, ALK Phosphatase, AST, ALT) 
• Change infusion bag of Plerixafor 
• Review concomitant medications and adverse events 
 
 Day 29 (+/- 3 days): 
• Physical Exam 
• KPS 
• Vitals 
• Laboratory tests: CBC with differential, Complete Metabolic Panel (including: sodium, 
potassium, chloride, CO2, glucose, creatinine, urea nitrogen, calcium, protein, albumin, 
total bilirubin, ALK Phosphatase, AST, ALT) 
• Review concomitant medications and adverse events 

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Day 35 (+/- 7 days): 
• MRI brain with and without contrast 
• Start monthly TMZ 
 
Concomitant medications and adverse events will be followed up until 30 days after the end of 
the Plerixafor infusion.  
 
Investigator will manage monthly TMZ per their standard practice. Follow up MRIs will be done 
per standard of care (approximately every 8-12 weeks).  
 
6 months after the start of XRT (+/- 2 weeks): 
• MRI brain with and without contrast 
• Neuro-cognitive assessment; quality of life assessment if patients are being followed at 
Stanford in Palo Alto 
 
Long Term Follow-Up: 
Unless a patient has specifically withdrawn consent to be followed for survival, he or she will be 
contacted (by phone or clinic visit) every 12 weeks (+/- 2 weeks) after completion of the 
Plerixafor infusion to collect data regarding survival status and subsequent anticancer therapy.  
Follow up will continue either for 5 years or until death, withdrawal, lost to follow up, or study 
termination. 
 
Neuro-cognitive and quality of life assessments will be administered at 12 months, twenty-four 
months after start of radiation (+/- 3 months) and then yearly (+/- 3 months) until progression  as 
long as patient is in follow-up if the patient is being followed at Stanford in Palo Alto. If a 
patient has definitive progression at any point during the long term follow up period, subsequent 
questionnaires will not be administered.  
4.1 
General Concomitant Medication and Supportive Care Guidelines 
The use of all standard supportive medication, including appropriate antimicrobial prophylaxis 
for chemotherapy, is permitted, although concurrent treatment with immunosuppressive or 
immunomodulatory agents is discouraged. Concomitant systemic corticosteroids are to be 
avoided if at all possible. If used, doses of steroids should be the minimum necessary for 
appropriate clinical management. 
 
The following are prohibited while on the infusion part of study: 
• Other investigational agents 
• Any concurrent chemotherapy, radiotherapy, hormonal therapy, immunotherapy, or other 
systemic therapy for cancer 
 
4.2 
Criteria for Removal from Study 
The investigator has the right to discontinue a patient from study drug or withdraw a patient from 
the study at any time. In addition, patients have the right to voluntarily discontinue study drug or 
withdraw from the study at any time, for any reason. Reasons for discontinuation or withdrawal 
include, but are not limited to: 

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• Patient withdrawal of consent 
• Progression of disease by RANO criteria, as determined by the investigator 
• Investigator decision (e.g., symptomatic/clinical deterioration or not in the patient’s best 
interest to continue in the study) 
• Patient is lost to follow up 
• Death 
• Non-compliance of the patient with protocol mandated procedures 
• Any unacceptable toxicity 
 
4.3 
Alternatives 
The study participant would be eligible for standard of care treatment protocols or any additional 
investigational trials (per eligibility requirements) should withdrawal from our study be 
warranted.   
 
5. 
INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION 
5.1 
 Investigational Agent/Device/Procedure   
The drug Plerixafor (AMD3100) will be supplied in infusion ready vials containing 10 ml of 20 
mg/ml solution (which is stable for several months at room temperature) by Sanofi.  There are no 
known incompatibilities of the agent with commonly used intravenous solutions.  There is no 
need to administer the agent with food and there are no pre-medications necessary. There are no 
restrictions against any medications and pre-medications may be used on an as needed basis. 
 
The dose will be 400 µg/kg per day for 4 weeks (+/-3 days)  
 
Dose will be based on weight at screening and will not be modified. Actual body weight will be 
used to calculate dose except in patients who are overweight (in which case adjusted body 
weight will be used). The dose of Plerixafor will be adjusted for patients who weigh > 30% over 
their Ideal body weight. IBW is calculated as follows: 
 
Males: IBW (kg) = 50.0 + [(2.3) (Height in inches – 60 inches)] 
= 50.0 + [(2.3) (Height in cm) (0.39370079) - 60)] 
 
Females: IBW (kg) = 45.5 + [(2.3) (Height in inches – 60 inches)] 
= 45.5 + [(2.3) (Height in cm)(0.39370079) – 60)] 
 
The ABW is calculated as follows: 
ABW (kg) = IBW + 0.4(actual weight - IBW) 
 
Plerixafor will be prepared weekly by the investigational pharmacy, with each dose being 
prepared no more than 4 hours prior to its use.  Per Stanford Investigational Pharmacy policy, the 
pharmacy will prepare sterile products in an environment that complies with USP 797 
parameters. The IV admixture area is kept clean and orderly and a demarcation line identifies the 
separation of the anteroom from the buffer area. Corrugated boxes are not allowed in the 
anteroom. A clean cart/dirty cart system is used to transfer inventory and compounding  

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supplies into and out of the cleanroom 
 
Infusion bags will be changed every week while the patient is coming for follow up.  Plerixafor 
will be infused using a 0.2 micron in-line filter that will be changed with each new dose for all 
administrations.  The volume prepared by the investigational pharmacy will be determined to 
allow a fixed infusion rate of 1.5 mL/hour.   
 
As per previously published technique, Plerixafor will be suspended in normal saline to the final 
solution [30].  The minimum rate will need to be 0.5 mL/hour to keep the Picc line patent 
however, the rate of infusion will be modified accordingly per the volume used in the diluent. 
 
 
Please see “Investigator’s Brochure” and section 2.5 above 
 
5.2 
Availability 
Plerixafor is supplied in open-label 2 mL glass vials containing 1.7 mL of a 20 mg/mL 
sterile solution. Each Plerixafor vial will be used to provide a single dose only. Remaining drug 
solution in each vial must not be used.  
 
The investigational product is shipped in cartons containing five (5) Plerixafor vials each. 
Each carton will also be affixed with a label describing the protocol number, contents of each 
carton, lot number, required cautionary statements or regulations, storage conditions, and the 
Sponsor’s name and address. 
The investigational product will be stored at room temperature (15-30oC) in a secure 
location accessible only by authorized personnel. All drug supplies are to be used only for this 
protocol and not for any other purpose. 
 
5.3 
Agent Ordering 
 
Plerixafor will be ordered using the Investigator Sponsored Trial (IST) portal at 
http://www.saists.com.   
 
5.4 
Agent Accountability 
 
All Plerixafor sent to the site will be accounted for.  In addition, the volume of Plerixafor 
dispensed for each patient will be recorded on an Investigational Product Accountability Log and 
the volume administered documented on the case report form (CRF). An accurate record of the 
date and amount of Plerixafor dispensed to each patient will be available for inspection at any 
time. Partially used vials may be destroyed per institutional guidelines and documented. All 
unopened and unused vials of Plerixafor will be destroyed upon completion of the study protocol 
or if drug expires unless otherwise directed by the Sponsor. The study site will document all 
receipt, complete destruction, and return (if applicable) of Plerixafor. 
 
5.5 
Radiation Therapy Planning 
 
Radiotherapy will consist of two sequential components. The first 30 Gy will be standard 

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conformal IMRT to the tumor/tumor bed. The second 30 Gy (total 60 Gy in 30 fractions) will be 
whole brain radiotherapy. 
 
Positioning, Immobilization and Simulation: 
1. The patient will be simulated in the supine position in most situations, 
immobilized typically with a thermoplastic mask. The treatment planning 
simulation CT scan will be acquired in the treatment position.  The treatment 
volumes will be defined by fusion with the pre- and post-resection MRI scans. 
2. CT contrast may be omitted if medically indicated.  The MRI sequences should 
include a T1-weighted post-contrast sequence (preferably stereotactic, thin slice, 
contiguous). Additionally, a T2/FLAIR sequence is helpful to identify non-
enhancing tumor. 
 
Equipment and Technique: 
1. Radiotherapy will be delivered with megavoltage equipment, typically of 4MV or 
greater energy. 
2. Intensity modulated radiotherapy (IMRT) via any method (e.g., VMAT, static 
field IMRT, tomotherapy) is preferred. 3D planning may be considered for the 
WBRT component. 
3. Daily image-guidance is recommended to allow smaller planning target volume 
(PTV) margins, but is not required. The PTV margin should reflect if image-
guided radiotherapy (IGRT) is used. 
 
Target Volume Delineation: 
 
Conformal RT Component– Treated from 2 to 30 Gy to the local tumor 
1. A gross tumor volume (GTV) will be defined using the CT and MRI images. 
The GTV includes any enhancing tumor, if present following resection, as well as 
the post-operative resection cavity. The GTV also includes any non-enhancing 
tumor as identified on T2/FLAIR. T2/FLAIR signal consistent with edema is not 
specifically included in the GTV.  Therefore, a distinction is made between T2 
edema (typically without mass effect, sparing the cortical ribbon, obeying the 
grey/white junction, etc.) and T2 tumor (mass effect with sulcal effacement, 
involvement of the grey/white junction, obliteration of the cortical ribbon). Fusion 
of the pre-operative MRI to determine initial extent of the tumor is helpful. 
2. The clinical target volume (CTV) is created by anatomically expanding the GTV 
by 15 to 20 mm, per physician preference.  The CTV should be trimmed at 
anatomic boundaries to rational tumor spread, such as the tentorium, falx if not 
near the corpus callosum, and skull.   At these boundaries, the CTV may be 0 mm. 
3. A geometric PTV expansion of 3 to 5 mm will be applied to the CTV that is 
justified based on image guidance and immobilization. For treatment utilizing 
IGRT techniques, the PTV may be as small as 3mm. For non-IGRT approaches, a 
5 mm expansion is recommended. 
 
Whole Brain Radiotherapy Component – Treated from 32 to 60 Gy to the 
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1. The CTV will consist of the intracranial compartment, including the brain, 
cisterns, and meninges.  
a. Note: Algorithms which ‘auto-contour’ the brain are not adequate, as 
this would not typically include the pre-pontine cistern and all 
meningeal surfaces 
2. The inferior extent of contouring will be the foramen magnum 
 
Organs at Risk (OAR) and OAR Constraints: 
1. OARs shall be contoured, including: optic nerves, optic chiasm, brainstem, 
lacrimal glands, retina, and cochlea and skin. 
2. A 3 mm PRV expansion shall be applied to the above. 
3. OAR Constraints to PRVs:  
1. Brainstem <55 Gy (except when the GTV involves the brainstem; Dmax 
may be 60.5 Gy in these circumstances) 
2. Chiasm and Optic nerves <55 Gy 
3. Retina < 45 Gy 
4. Cochlea < 40 Gy. This may be exceed to cover tumor per physician 
preference 
5. Lacrimal Gland <40 Gy 
6. Skin (defined as ‘Body’ – 4 mm) < 40 Gy if possible 
Dose: 
1. An initial dose of 30 Gy in 15 fractions of 2 Gy per day shall be delivered to the 
cover > 95% of the tumor PTV to > 30 Gy. Under coverage below 95% is 
acceptable to meet OAR constraints.  
2. A second plan of 30 Gy in 15 fractions of 2 Gy per day shall be delivered to cover 
>90% of the whole brain. Under coverage below 95% is acceptable to meet OAR 
constraints.  
1. A VMAT WBRT plan is preferable to allow modulation of dose to meet 
OAR constraints. 
2. Preferably, the VMAT WBRT plan is planned first, so that it may be used 
as the base plan for the VMAT conformal RT component, to meet OAR 
constraints 
3. A 3D opposed lateral WBRT is acceptable, but not preferred. The 3D plan 
should be used as the base plan upon which to design the initial 30 Gy of 
IMRT. 
3. IMRT plan heterogeneity should ideally be 110% (66 Gy Dmax) or less and 
preferably under 105% (63 Gy Dmax).  A Dmax of 114% (68.4 Gy) is an 
acceptable variation. It is preferable that the initial IMRT plan and the WBRT 
plan are planned concurrently, to account for heterogeneity between plans. 
4. Treatment shall be given daily. 
 
6. 
DOSE MODIFICATIONS 
There will be no dose modifications or delays for an individual patient’s dose except in the 
circumstance of moderate to severe renal impairment.  If a patient has a Creatinine clearance less 
than or equal to 50 mL/min, the dose of Plerixafor will be reduced by one-third. Plerixafor dose 
interruption is allowed for up to 3 business days to deal with possible adverse events, pump 

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malfunctions, abnormal clinically significant chemistries and or as per the physician’s discretion. 
If the interruption is more than the mentioned time frame, the participant will be withdrawn from 
the study. Subject who are not able to finish the 4-week (+/- 3 days) infusion will be replaced. 
 
6.1 Infusion Reactions 
All patients will be provided the contact information for the 24 hour on call pharmacist and 
neurology physician. 
 
For Grade 1 and 2 allergic reactions to Plerixafor infusion: oral steroids or antihistamine.  
Patients may be discontinued at investigator’s discretion 
For Grade 3 and higher allergic reactions: Standard allergy treatment could include intravenous 
solumedrol, intravenous Benadryl, and possibly epinephrine at the discretion of the treating 
physician. Plerixafor infusion will be discontinued. 
 
7. 
ADVERSE EVENTS AND REPORTING PROCEDURES 
7.1 
Potential Adverse Events 
Safety will be assessed by monitoring clinical and laboratory evaluations and AEs. 
 
Definitions 
 
Adverse Event 
An AE is any untoward medical occurrence associated with the use of the investigational 
product (active or placebo drug, biologic, or device) in a clinical investigation patient, which 
does not necessarily have a causal relationship with the investigational product. An AE can, 
therefore, be any unfavorable and unintended symptom, sign, disease or condition, or test 
abnormality whether or not considered related to the investigational product.  
 
AEs may include, but are not limited to: 
Subjective or objective symptoms spontaneously offered by the patient and/or observed by 
the investigator or medical staff 
Clinically significant laboratory abnormalities 
A significant worsening of the patient’s condition from study entry 
Disease signs and symptoms and/or laboratory abnormalities existing prior to the use of the 
study treatment that resolve but then recur after treatment 
Disease signs and symptoms and/or laboratory abnormalities existing prior to the use of the 
study treatment which increase in frequency, intensity, or a change in quality after 
treatment 
 
Serious Adverse Events (SAEs) 
A SAE is any adverse event that results in any of the following outcomes: 
• Death 
• A life-threatening experience 

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• Requires inpatient hospitalization or prolongs existing hospitalization 
• A persistent or significant disability/incapacity 
• A congenital anomaly/birth defect 
• Important medical events that may jeopardize the patient and may require medical or 
surgical intervention to prevent 1 of the outcomes listed above 
 
Hospitalizations that occur under the following circumstances are not considered to be SAEs: 
• were planned before entry into the clinical study; 
• are for elective treatment of a condition unrelated to the studied indication or its   
treatment; 
• Occur on an emergency or outpatient basis and do not result in admission (unless 
fulfilling the criteria above), are part of the normal treatment or monitoring of the studied 
indication and not associated with any deterioration in condition. 
 
Severity 
The investigator will grade AEs using the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) (version 5.0, 27 Nov 2017). Grades refer to 
the severity of the AE. The CTCAE v 5.0 displays Grades 1 through 5 with unique clinical 
descriptions of severity for each AE based on this general guideline: 
 
Grade 
Description 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL) 
3 
Severe or medically significant but not immediately life-threatening hospitalization 
or prolongation of existing hospitalization indicated; disabling; limiting self-care 
ADL 
4 
Life-threatening consequences; urgent intervention indicated  
5 
Death related to AE 
 
Action taken 
The investigator should record what action, if any, was taken to the planned 
administration of the investigational product due to the AE (i.e., discontinuation, modification, or 
interruption of the treatment). 
 
Relationship to the investigational product 
When recording and reporting an AE or SAE, the investigator will provide an assessment 
of the relationship between the AE or SAE and the study drug(s) and/or study procedure.  
Related AEs or SAEs are those that are judged to be possibly or definitely related by the 
investigator.  Unrelated AEs or SAEs are those that are judged to be unlikely or not related to the 
study drug(s) by the investigator.  Definitions of relationship criteria are as follows: 
 
Related 
Definitely related: There is strong evidence that there is a causal relationship between exposure 
and AE 

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Possibly related: There is some evidence supporting the possibility of a causal relationship 
between exposure and AE   
 
Unrelated  
Remote/Unlikely related: There is no evidence of a causal relationship between exposure and 
AE; however, such a relationship cannot be ruled out 
 
Unrelated: There is no suspicion of a causal relationship between exposure and AE 
 
 
Describe all known or potential risks associated with this Investigational 
Drug/Device/Procedure.  Include Adverse Event description, grade, expectedness, and attribution 
to the study treatment. 
 
The most common adverse reactions (>=  10%) reported in patients who received 
Mozobil in conjunction with G-CSF regardless of causality and more frequent with Mozobil than 
placebo during hematopoietic stem cell mobilization and apheresis were diarrhea, nausea, 
fatigue, injections site reactions, headache, arthralgia, dizziness and vomiting.  Per label (USPI) 
serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have 
been life-threatening with clinically significant hypotension and shock, have occurred in patients 
receiving Plerixafor.  In randomized studies, 34% of patients with non-Hodgkin’s lymphoma and 
multiple myeloma had mild to moderate injection site reactions at the site of subcutaneous 
administration of Plerixafor. These included erythema, hematoma, hemorrhage, induration, 
inflammation, irritation, pain, paresthesia, pruritus, rash, swelling, and urticaria.  Mild to 
moderate systemic reactions were observed in less than 1% of patients approximately 30 min 
after Plerixafor administration. Events included one or more of the following: urticaria (n = 2), 
periorbital swelling (n = 2), dyspnea (n = 1) or hypoxia (n = 1). Symptoms generally responded 
to treatments (e.g., antihistamines, corticosteroids, hydration or supplemental oxygen) or 
resolved spontaneously.  Vasovagal reactions, orthostatic hypotension, and/or syncope can occur 
following subcutaneous injections. In Plerixafor oncology and healthy volunteer clinical studies, 
less than 1% of subjects experienced vasovagal reactions following subcutaneous administration 
of Plerixafor doses ≤ 240 mg/kg. The majority of these events occurred within 1 hour of 
Plerixafor administration. Other adverse reactions that occurred in < 5% of patients but were 
reported as related to Plerixafor during mobilization and apheresis included abdominal pain, 
hyperhidrosis, abdominal distention, dry mouth, erythema, stomach discomfort, malaise, 
constipation, dyspepsia, and musculoskeletal pain.  
In the study that assessed continuous infusion of Plerixafor over 10 days, four SAE’s 
were noted: thrombocytopenia, infection of a PICC line and arrhythmia (> 25 PVC’s/min) and 
panic attack associated with paresthesias [18]. 
 
7.2 
Adverse Event Reporting 
Adverse events will be graded according to CTCAE v5.0.  This is an off-label indication for 
Plerixafor. Investigators will reference safety information to assess expectedness: IB. All adverse 
events except those clearly attributable to the underlying disease will be reported, including 
definitely, probably and possibly related. Both Serious and Non-Serious Adverse Events will be 

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clearly noted in source documentation and listed on study specific Case Report Forms (CRFs).  
The Protocol Director (PD) or designee will assess each Adverse Event (AE) to determine 
whether it is unexpected according to the Informed Consent, Protocol Document, or 
Investigator’s Brochure, and related to the investigation. All Serious Adverse Events (SAEs) will 
be tracked until resolution or until 30 after the last dose of the study treatment.  
 
SAEs CTCAE Grade 3 and above, and all subsequent follow-up reports will be reported to the 
Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) using the study 
specific CRF regardless of the event’s relatedness to the investigation. Following review by the 
DSMC, events meeting the IRB definition of ‘Unanticipated Problem’ will be reported to the 
IRB using eProtocol within 10 working days of DSMC review, or within 5 working days for 
deaths or life-threatening experiences. 
 
In addition, within 24 hours (US) or one business day (EU) of first knowledge of such serious 
and related adverse event, we will notify Sanofi via fax, attention Sanofi Pharmacovigilance 
(PV), 908-203-7783 (US) or +1-908-203-7783 or via email at: USPVmailbox@sanofi-
aventis.com.   Additionally, the Investigator will transmit to Sanofi PV an information copy of 
any such report sent to the governing regulatory authority, prior to or at the time of authority 
filing. The Investigator will make available to Sanofi promptly such records as may be necessary 
and pertinent to investigate any such expedited adverse event, if specifically requested by Sanofi. 
 
Furthermore, the Investigator will inform Sanofi of the following: 
• Any events that result in protocol amendments for safety reasons, as well as any safety 
related regulatory action such as a clinical hold of the Research; 
• Any pregnancies occurring in patients who are exposed to the Product in connection with 
the Research. Please see section 10.2.1.3 for additional reporting guidance; 
• In addition, the Investigator will notify Sanofi within 24 hours (US) or one business day 
(EU) of first knowledge of any Product complaints (communication of dissatisfaction that 
alleges deficiencies related to the identity, quality, durability, effectiveness, safety, 
labeling, purity, stability, and appearance) by fax to 508-661-8771 (US)  or Sanofi 
Customer Services Europe, +31 (0)35 699 1222.  
• The Investigator will also inform Sanofi within 1 business day of becoming aware of any 
actions from any authority that may affect the performance of the Research  
 
Safety reporting rules are to be complied with, according to current PV specifications (QGSD-
007589).  Sponsor is to provide Sanofi with: results relevant to final diagnosis of any SAE; 
routine transmission of any overdose with Plerixafor; periodic reports; study report must contain 
section with safety review and conclusion –to be reviewed by Sanofi before finalization. 
 
Pregnancy reporting  
All patients must agree to an effective method of contraception while on study treatment 
and for at least 3 months following Plerixafor treatment (including both female patients of child-
bearing potential and male patients with partners of child-bearing potential). Effective birth 
control includes: a) birth control pills, depot progesterone, or an intrauterine device plus one 
barrier method, or b) two barrier methods. Effective barrier methods are: male and female 
condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm). 

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For patients using a hormonal contraceptive method, information about any interaction of 
Plerixafor with hormonal contraceptives is not known.  
The Investigator will inform Sanofi PV within 24 hours of the Investigator’s first 
knowledge of pregnancy in a female patient or the female partner of a male patient at any time 
after the first dose of Plerixafor.  Pregnant female patient(s) must not receive additional study 
treatment.  The pregnancy will be followed until the outcome is known (i.e., delivery, elective 
termination, spontaneous abortion).  The Investigator will obtain follow-up information no later 
than two months after the gestational period to obtain maternal, fetal, and neonatal outcome and 
any other relevant information.  If the pregnancy results in the birth of a child, additional follow-
up information may be requested.  The Investigator must complete as much information as 
possible on the relevant Pregnancy Notification Forms (PNF) A and B, and fax the forms to the 
Sanofi PV. 
 
8. 
CORRELATIVE/SPECIAL STUDIES  
During their pre-, post- and 6 month MRI’s, patients undergo rCBV analysis using standard 
sequencing. This will require no extra risk or time since these sequences are part of the standard 
clinical brain tumor protocols.  
 
8.1 
Laboratory Correlative Studies 
None are planned during this Phase II study.

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NCT03746080 
9. 
STUDY CALENDAR 
  
Screening 
(- 10 days 
from 
fraction 
16 of RT) 
Fraction 
16 of 
RT 
 
Pre-
Plerixafor 
Day 1 (- 7 
days from 
end of RT 
+/- 3)  
Day 8 
(+/- 3) 
Day 15 
(+/- 3) 
Day 22 
(+/- 3) 
Day 29 
(+/-3) 
Day 35 
(+/-7) 
30 days 
post 
Plerixafor 
6 months 
after 
start of 
XRT 
(+/- 2 
wks.) 
Every 12 
weeks 
after 
Plerixafor 
(+/- 2 
weeks) 
Consent  e 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
Medical/Cancer History 
X 
 
 
 
 
 
 
 
 
 
 
 
Vitals  
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
Height/Weight c 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
KPS 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
Hematology 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
Chemistry 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
Pregnancy a 
X 
 
 
 
 
 
 
 
 
 
 
 
Neurocognitive 
Assessments d 
 
 
X 
 
 
 
 
 
 
 
X 
Xb 
Quality of Life d 
 
 
X 
 
 
 
 
 
 
 
X 
Xb 
PICC Placement 
 
 
X 
 
 
 
 
 
 
 
 
 
Continuous Plerixafor 
400 mcg/kg/day 
 
 
 
X------------------------------------------------------| 
 
 
 
 
Whole Brain RT 
 
X------------------------------------------| 
 
 
 
 
 
 
 
MRI 
 
 
 
 
 
 
 
 
X 
 
X 
 
AEs 
 
X--------------------------------------------------------------------------------------------------------------------| 
 
 
Con Meds 
X---------------------------------------------------------------------------------------------------------------------------------| 
 
 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
X 
Subsequent anti-cancer 
therapy 
 
 
 
 
 
 
 
 
 
 
 
X 
a. females of childbearing potential only 
b. At 12 months, 24 months after start of radiation (+/- 3 months) and then yearly (+/- 3 months) until progression if patient is being 
followed at Stanford Palo Alto 
c. height only required at screening 

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d. only for English speaking patients 
e. Consent:  - 35 days from fraction 16 of RT 

26 January 2021 v 5.0 
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NCT03746080 
10. 
MEASUREMENTS 
For clinicaltrials.gov and Stanford Clinical Trials Directory compliance  
 
Primary Outcome Measure Definition: Six month progression free survival from the start of 
Chemoradiation 
Title: Rate of Six month PFS 
 
Time Frame: Six month progression free survival after the start of Chemoradiation 
Safety Issue: Is this outcome measure assessing a safety issue?  No 
10.1  Primary measure: Progression Free Survival  
Our primary objective in this Phase II study is to ascertain the six month progression free survival 
(PFS) rate in GBM patients treated with a 4 week (+/-3 days) infusion of Plerixafor at 400 
micrograms per kilogram per day layered onto a modified radiation therapy framework that includes a 
whole brain component.  
 
10.1.1 Relevant Subset 
• All patients who have completed the 28 day Plerixafor infusion will be included in the 
primary analysis. 
 
10.1.2 Measurement Definition 
• The primary outcome is progression free survival as determined by MR and clinical status at 
six months from start of the Chemoradiation.. 
 
10.1.3 Measurement Methods 
• MRI, which will be performed prior to RT onset, one month after RT (which will correlate to 
one week after Plerixafor completion) and six months after the start of Chemoradiation. 
 
Positive Response: Requires all of the following: 
• Stable or improved non-enhancing (T2/FLAIR) lesions 
• No new lesions 
• Stable or improved clinical status 
 
Progressive Disease (PD): Requires any of the following 
• ≥ 25% increase in the SPD of measurable enhancing target lesions plus >5 mm absolute 
increase in the sum of the longest diameters (SLD) of target lesions compared to the best 
response after initiation of therapy  
• Clear progression of enhancing non-target disease 
• Significant increase in T2/FLAIR non-enhancing disease not caused by co-morbid events (e.g. 
radiation therapy, demyelination, ischemic injury, infection, seizures, post-operative changes 
or other treatment effects) 

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• Any new lesions 
• Clear clinical deterioration not attributable to other causes apart from the tumor (e.g., seizures, 
medication adverse effects, complications of therapy, cerebrovascular events, infections etc.) 
• Increasing steroid doses alone do not constitute PD.  
 
10.1.4 Measurement Time Points 
• An MRI will be done 35 +/-3 days after the completion of XRT. Follow up MRIs will be done 
per standard of care (approximately every 8-12 weeks), with one occurring 6 months post the 
start of radiation, until progression or withdrawal of consent. 
 
10.1.5 Response Review 
•  A futility analysis will be performed after the first 16 patients have been followed for 6 
months (see Section 12.2 for details). 
 
 
10.2  Secondary Outcome: Median Survival 
10.2.1 Relevant Subset 
• All patients who have completed the 28 day Plerixafor infusion. 
  
10.2.2 Measurement Definition 
• Survival at date of last follow-up. 
 
10.2.3 Measurement Methods 
• Patients will be followed through course so status can be assessed. 
 
10.2.4 Measurement Time Points 
• Status at time of last follow-up will be recorded. The start of irradiation will be considered 
Day 0.  
 
 
10.3  Secondary Outcome: Toxicities 
10.3.1 Relevant Subset 
• All patients who have completed WBRT component, whether or not they receive Plerixafor 
infusion. 
 
10.3.2 Measurement Definition 
• 
All toxicities will be recorded and graded according to CTCAE.  
 
10.3.3 Measurement Methods 
• The CTCAE version 5.0 will be used to grade toxicities.  
 
10.3.4 Measurement Time Points 
• Adverse events/toxicities will be recorded as soon as they are reported. Patients in follow up 
will be queried for possible toxicities. 

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10.3.5 Response Review 
• 
Identification of adverse events will be made by the clinical coordinator and the primary 
treating doctor. In instances where the event is not clear, the Protocol Director will have the 
ultimate responsibility for calling and grading an adverse event. 
• 
All Gr.3 and above toxicities will be reviewed by the Protocol Director and Co-Director. 
 
10.4  Secondary Outcome: Pattern of Failure 
10.4.1 Relevant Subset 
• All patients who have completed WBRT component, whether or not they receive Plerixafor 
infusion, in adherence to the intent to treat principle. 
  
10.4.2 Measurement Definition 
• The 95% isodense field will be considered the maximal treatment field 
• When progressive disease defined, MR images will be co-registered with treatment planning 
imaging to determine whether the first progression occurs within the maximal treatment field, 
in the brain outside of the maximal treatment field, in the spine and outside the CNS.  
 
10.4.3 Measurement Methods 
• MR images from the MRI demonstrating progression will be co-registered with treatment 
planning imaging. 
 
10.4.4 Measurement Time Points 
• MRI’s are part of the standard of care and are done generally every two months or sooner if 
necessary.  
 
10.4.5 Response Review 
• The determination of failure pattern will be a consensus decision between Drs. Soltys, 
Thomas, Iv, Nagpal, and Recht. In cases where there is disagreement, the opinion of another 
Stanford neuroradiologist will be sought.  
 
10.5  Secondary Outcome: Neuro-Cognitive and Quality of Life Outcomes 
10.5.1 Relevant Subset 
• All patients who are competent in English and who have completed WBRT component, 
whether or not they receive Plerixafor infusion, in adherence to the intent to treat principle. 
  
10.5.2 Measurement Definition 
• 
A series of neurocognitive assessments in which it is possible to develop a score will be used 
to assess for cognitive effects and quality of life at various points in the clinical course.  
 
10.5.3 Measurement Methods 
• Patients will undergo neurocognitive assessment at the time they are receiving WBRT and 
then at 6, 12 and 24 months after start of radiation.  
• The neurocognitive assessments  will be administered by the study coordinator.  

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10.5.4 Measurement Time Points 
• Patients will undergo testing Pre Plerixafor and then 6, 12 and 24 months after the initiation of 
radiation. 
 
10.5.5 Response Review 
• At the end of the study, the collected data will be organized and first analyzed by the study 
team to assess changes in neurocognitive performance and QOL over time. 
 
11. 
REGULATORY CONSIDERATIONS 
11.1 
Institutional Review of Protocol 
The protocol, the proposed informed consent and all forms of participant information related to the 
study (e.g. advertisements used to recruit participants) will be reviewed and approved by the Stanford 
IRB and Stanford Cancer Institute Scientific Review Committee (SRC).  Any changes made to the 
protocol will be submitted as a modification and will be approved by the IRB prior to 
implementation.  The Protocol Director will disseminate the protocol amendment information to all 
participating investigators. 
 
11.2 
Data and Safety Monitoring Plan 
The Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) will be the 
monitoring entity for this study. The DSMC will audit study-related activities to determine whether 
the study has been conducted in accordance with the protocol, local standard operating procedures, 
FDA regulations, and Good Clinical Practice (GCP).  This may include review of the following types 
of documents participating in the study: regulatory binders, case report forms, eligibility checklists, 
and source documents.  In addition, the DSMC will regularly review serious adverse events and 
protocol deviations associated with the research to ensure the protection of human subjects.  Results 
of the DSMC audit will be communicated to the IRB and the appropriate regulatory authorities at the 
time of continuing review, or in an expedited fashion, as needed. 
 
11.3 
Data Management Plan 
The Protocol Director, or his designee, will prepare and maintain adequate and accurate participant 
case histories with observations and data pertinent to the study.  Study specific Case Report Forms 
(CRFs) will document treatment outcomes for data analysis.   Case report forms will be developed 
using the On Core database system and will be maintained by Sophie Bertrand. CRFs will be kept in 
a locked office, only accessible to the research team. 
 
12. 
STATISTICAL CONSIDERATIONS 
A Senior Biostatistician in the Quantitative Sciences Unit (QSU) will oversee all analyses and 
interpret the results. All analyses will be completed in the R statistical computing environment or 
SAS™ version 9. 
12.1 
Statistical Design 
A single arm (non-randomized trial). 

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Page 43 of 52
 
12.1.1 Randomization 
Not applicable. This is a single arm clinical trial 
 
 12.2 Interim analyses 
 We employ a Simon 2-stage design where the first 16 patients who have completed the 4 week(+/-3 
days) infusion are enrolled and assessed before completing our targeted enrollment of 20 patients. 
Thus, the interim analysis for futility will be performed on the first 16 patients. The trial will be 
stopped for futility if 6 or fewer subjects of the 16 achieve PFS by 6 months. The probability of 
stopping the trial for futility is 0.82 if the response rate is as low as 0.30.  
 
12.3 
Descriptive Statistics and Exploratory Data Analysis 
 Patient characteristics will be summarized using proportions for categorical variables, means and 
standard deviations for continuous variables (median and inter-quartile ranges where appropriate). 
 
12.4 
Primary Analysis  
For the Phase II component, the primary endpoint is 6-month progression free survival (PFS), as 
defined in Section 10.1.  
 
12.4.1 Analysis Population 
Our analysis population for assessing treatment efficacy consists of GBM patients treated with a 
4-week (+/-3 days) infusion of Plerixafor at 400 micrograms per kilogram per day layered onto a 
modified radiation therapy framework that includes a whole brain component, where the targeted 
enrollment for our study is 20 patients. Our safety population consists of all patients (at least 20 GBM 
patients) enrolled in the trial and exposed to any study drug. 
 
12.4.2. Analysis Plan 
Our Primary objective in the Phase II component is to assess progression free survival at 6 months. 
We consider the experimental treatment to be promising if it yields a response (ability to achieve PFS 
by 6 months) in 50% of subjects, and we consider the treatment to not be promising if the response 
rate is as low as 30%. To assess whether the regimen is promising, we utilize a Simon 2-stage design. 
In the first stage we evaluate the first 16 patients. If 6 or fewer subjects achieve a response, the trial 
will be stopped for futility. If more than 6 achieve PFS at 6 months, four more patients will be 
enrolled in the study. If a total of 8 or fewer achieve a response, the therapy will not be considered 
promising and will not warrant further study. If a total of 9 or more of the 20 achieve a response, the 
therapy will be a candidate for further study. Our design has adequate operating characteristics. 
Specifically, we have less than 0.10 probability of incorrectly concluding the therapy is promising if 
it is not (assuming a response rate of only 0.30). Further we have over 0.70 probability of correctly 
concluding the therapy warrants further study if the true response rate is 0.5. The probability of 
stopping the trial early for futility is 0.82 if the response rate is as low as 0.30.  
 
Our secondary objective is to characterize median survival time, with the expectation that median 
survival will exceed 20 months, the best GBM benchmark based on recent publications [69]. We will 
report and interpret the median survival and accompanying 90% lower confidence interval around the 

26 January 2021 v 5.0  
 
 
 
 
 
 
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Page 44 of 52
observed median. 
 
Although unexpected, it is possible that some patients drop out of the study prior to completing the 
treatment regimen. Although the analysis population for the primary outcome includes only patients 
that completed the Plerixafor infusion treatment, all patients will be included in descriptive statistics 
and Kaplan-Meier estimates (see Section 12.3). It should be noted that based on the ongoing trial, we 
expect at most 1 patient could fail to complete the treatment regimen. 
 
We will assess reported toxicities, pattern of failure (out-of-field occurrence or occurrence outside of 
the brain), and changes in neurocognitive measures and quality of life over time. Adverse events and 
qualifying DLT will be tabulated by cohort, site and severity.  Proportions of these patients in each 
response category will be tabulated; the combined proportion in categories CR (complete response), 
Cri (CR with incomplete count recovery), PR (partial response), SD (stable disease) will be computed 
along with an exact 90% confidence intervals.  Duration of response progression-free survival and 
median survival time will be computed from start of induction therapy and summarized with Kaplan-
Meier estimates. Other graphical tools will include a swimmer’s plot to view progression by patient, 
spaghetti plot for changes in neurocognitive assessments over time, and boxplots and histograms for 
continuous characteristics. Changes in neurocognitive outcomes will be analyzed with a linear mixed-
effect model, with a random effect for patient, to account for correlation over time within patient. 
 
12.5     Secondary Analysis 
         Included in the section Analysis Plan 12.4.2 
 
12.6  Sample Size 
12.6.1 Accrual estimates  
 
We expect to accrue the total number of 20 patients to complete the 4 weeks (+/-3 days) within the 
24-month timeline proposed. 
 
12.6.2 Effect size justification 
Based on positive results (> 80% who achieve a 6 month PFS) from an ongoing Phase I/II study using 
Plerixafor infusion, we hypothesize a true response rate of 50% or more.  
 
12.6.3 Sample size justification 
Our design that includes 20 subjects has adequate operating characteristics. Specifically, with our 
decision rule applied in the two stages as described above, we have less than 0.10 probability of 
incorrectly concluding the therapy is promising if it is not (assuming a response rate of only 0.30). 
Further we have over 0.70 probability of correctly concluding the therapy warrants further study if 
the true response rate is 0.5. The probability of stopping the trial early for futility is 0.82 if the 
response rate is as low as 0.30.  
   
 
 
12.7 
Criteria for future studies 
This Phase II study will provide additional data that should supplement that obtained with our prior 
Phase I/II protocol using Plerixafor as a continuous infusion. It is possible if our secondary endpoint 

26 January 2021 v 5.0  
 
 
 
 
 
 
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Page 45 of 52
of 32 month median survival is achieved, that this will justify incorporating this into the standard 
treatment framework. More likely, however, is that it will provide compelling data for a larger 
randomized study assessing this strategy with standard of care.  

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APPENDICES 
APPENDIX A: Participant Eligibility Checklist  
 
Protocol Title: 
A follow-up study to add whole brain radiotherapy (WBRT) 
to standard temozolomide chemo-radiotherapy in newly 
diagnosed glioblastoma (GBM) treated with 4 weeks 
continuous infusion Plerixafor 
Protocol Number: 
BRN0037 
Principal Investigator: 
Lawrence Recht, MD 
 
II. Subject Information: 
 
Subject Name/ID:   
 
Gender:    
 Male     
 Female 
 
III. Inclusion/Exclusion Criteria 
 
Inclusion Criteria 
(From IRB approved protocol) 
Yes 
No 
Supporting Documentation* 
1. Patients must have tissue 
confirmation of high grade (WHO 
Grade IV) glioma including but not 
limited to glioblastoma, 
gliosarcoma, glioblastoma with 
oligodendroglial features, 
glioblastoma with PNET features. 
 
 
      
2. The patient must have post-operative 
contrast enhanced imaging (CT or 
MRI) unless only biopsy performed 
(in which case post-operative 
imaging is not routinely obtained. In 
these patients, the preoperative study 
will serve as baseline). 
 
 
      
3. Patient should have surgery (biopsy, 
partial resection or gross total 
resection) and no additional anti-
cancer therapy except the 
Chemoradiation as specified in the 
protocol. 
 
 
      

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4. Patients must be between the ages of 
18 and 75 years old (inclusive) 
 
 
      
5. Patients must have Karnofsky 
Performance score ≥ 60. 
 
 
      
6. Adequate organ function is needed 
at time of screening visit including: 
1. ANC ≥ 1500 
2. Platelets ≥ 100,000 ml 
3. Creatinine  ≤ 1.5mg/dl; Cr 
clearance should be > 50 mL/min  
4. AST and ALT ≤ 3 times the 
upper limit of normal 
5. If female of childbearing 
potential, negative pregnancy 
test 
 
 
      
7.    The patient or his/her legal      
representative must have the ability to 
understand and willingness to sign a 
written informed consent document.   
 
 
      
8.   Patient agrees to use an effective 
method of contraception (hormonal or 
two barrier methods) while on study and 
for at least 3 months following the 
Plerixafor infusion 
 
 
      
Exclusion Criteria 
(From IRB approved protocol) 
 
1. Prior or concurrent treatment with 
Avastin (bevacizumab). 
 
 
      
2. Prior exposure to Plerixafor. 
 
 
      
3. Prior use of other investigational 
agents to treat the brain tumor.   
 
 
      
4. Recent history of myocardial infarct 
(less than 3 months) or history of 
active angina.   
 
 
      
5.   Prior malignancy except for non-
melanoma skin cancer and carcinoma in 
situ (of the 
cervix or bladder), unless diagnosed and 
definitively treated more than 3 years 
priorto 1st dose of investigational drug 
 
 
      
5. Prior sensitivity to Plerixafor.  
 
 
      

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6. Pregnant or patients who are 
breastfeeding 
 
 
      
*All subject files must include supporting documentation to confirm subject eligibility.  The 
method of confirmation can include, but is not limited to, laboratory test results, radiology test 
results, subject self-report, and medical record review.   
IV.  Statement of Eligibility 
This subject is [ 
 eligible / 
 ineligible ] for participation in the study. 
 
Treating Physician Signature: 
Date: 
Printed Name: 
 
 
Secondary Reviewer Signature: 
Date: 
Printed Name: 
 
Study Coordinator Signature: 
Date: 
Printed Name: