Clinical trial NCT02186509
Conditions: Adult Anaplastic Astrocytoma Adult Anaplastic Ependymoma Adult Anaplastic Oligodendroglioma Adult Brain Stem Glioma Adult Diffuse Astrocytoma Adult Giant Cell Glioblastoma Adult Glioblastoma Adult Gliosarcoma Adult Mixed Glioma Adult Oligodendroglioma Adult Pilocytic Astrocytoma Adult Pineal Gland Astrocytoma Adult Subependymal Giant Cell Astrocytoma Recurrent Adult Brain Tumor
Sponsor: Sidney Kimmel Cancer Center at Thomas Jefferson University
Start date: 2015-01-30; Completion date: 2018-12-31
Enrollment: 17 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase I trial studies the side effects and best dose of alisertib when combined with fractionated stereotactic radiosurgery in treating patients with high-grade gliomas that have returned after previous treatment with radiation therapy (recurrent). Alisertib may stop the growth of tumor cells by blocking an enzyme needed for the cells to divide. Radiation therapy uses high energy x rays to kill tumor cells. Stereotactic radiosurgery uses special positioning equipment to send a single high dose of radiation directly to the tumor and cause less damage to normal tissue. Delivering stereotactic radiosurgery over multiple doses (fractionation) may cause more damage to tumor tissue than normal tissue while maintaining the advantage of its accuracy.

Detailed description:
PRIMARY OBJECTIVES:

I. Evaluate the safety and tolerability of the study treatment. II. To determine the maximum tolerated dose (MTD) of daily oral alisertib when combined with fractionated stereotactic radiation treatment for recurrent high grade glioma.

SECONDARY OBJECTIVES:

I. To estimate 6 month progression free survival rate. II. To estimate the median time to progression. III. To estimate overall survival. IV. To estimate the impact on quality of life (QoL).

OUTLINE: This is a dose-escalation study of alisertib.

CONCURRENT PHASE: Patients undergo fractionated stereotactic radiosurgery once daily (QD) every weekday for 10 days and receive alisertib orally (PO) twice daily (BID) concurrently with radiation therapy for 10 days.

MAINTENANCE PHASE: Patients receive alisertib PO BID on days 1-7. Treatment repeats every 21 days for up to 18 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year and then every 4-6 months thereafter.

Arms: arm 1: CONCURRENT PHASE: Patients undergo fractionated stereotactic radiosurgery QD every weekday for 10 days and receive alisertib PO BID concurrently with radiation therapy for 10 days.

MAINTENANCE PHASE: Patients receive alisertib PO BID on days 1-7. Treatment repeats every 21 days for up to 18 courses in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Hyperfractionated radiation therapy intervention 2: Stereotactic radiosurgery intervention 3: Alisertib intervention 4: Quality-of-life assessment
Intervention descriptions: intervention 1: Undergo hyperfractionated radiation therapy intervention 2: Undergo stereotactic radiosurgery intervention 3: Given PO intervention 4: Ancillary studies

Protocol documents:
Prot_SAP_000.pdf: 
 
1 
Protocol #13P.528, 
v5.4(13September2017) 
THOMAS JEFFERSON UNIVERSITY 
Kimmel Cancer Center 
 
PHASE I STUDY OF ALISERTIB WITH CONCURRENT FRACTIONATED 
STEREOTACTIC RADIATION TREATMENT FOR RECURRENT HIGH GRADE 
GLIOMAS 
 
Principal Investigators: 
Wenyin Shi, MD, PhD 
Department of Radiation Oncology 
111 S 11st, Suite G301 
Philadelphia, PA 19107 
(215) 955-6702 
Fax: (215) 955-0412 
Co-Principal 
Investigator: 
David Andrews, MD 
Rani Anne, MD Voichita 
Bar-Ad, MD Adam 
Dicker, MD James 
Evans, MD Christopher 
Farrell, MD Jon Glass, 
MD 
Kevin Judy, MD 
Lyndon Kim, MD  
Maria Werner-Wasik, MD  
Nina Martinez, MD 
Funding Sponsor: 
Millennium 
Regulatory Sponsor: 
Thomas Jefferson University 
IND Number: 
119975 
Study Product: 
Alisertib 
Protocol Number: 
Jefftrial# 3007 
CCRRC# 2012-12 
IRB# 13P.528 
 
Version: 
Date: 
1.0 
9/16/2013 
3.0 
2/17/2014 
4.0.1 
9/03/2014 
5.0 
4/16/2015 
5.1 
02/16/2016 
5.2 
07/20/2016 
5.3 
08/08/2017 
5.4 
9/13/2017 
 


 
2 
Protocol #13P.528, 
v5.4(13September2017) 
CONFIDENTIAL 
This document is confidential and the property of THOMAS JEFFERSON 
UNIVERSITY.  No part of it may be transmitted, reproduced, published, or used by 
other persons without prior written authorization from the study sponsor. 
 


 
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Protocol #13P.528, 
v5.4(13September2017) 
3 
S
3.1 
TUDY DESIGN ..............................................................................................................................................19 
GENERAL DESIGN......................................................................................................................................19 
3.2 
PRIMARY STUDY ENDPOINTS ....................................................................................................................19 
3.3 
SECONDARY STUDY ENDPOINTS ...............................................................................................................19 
3.4 
PRIMARY SAFETY ENDPOINTS ...................................................................................................................20 
4 
SUBJECT SELECTION AND WITHDRAWAL..........................................................................................20 
4.1 
INCLUSION CRITERIA.................................................................................................................................20 
4.2 
EXCLUSION CRITERIA ...............................................................................................................................20 
4.3 
GENDER/MINORITY/PEDIATRIC INCLUSION FOR RESEARCH......................................................................21 
4.4 
SUBJECT RECRUITMENT AND SCREENING .................................................................................................21 
4.5 
EARLY WITHDRAWAL OF SUBJECTS ..........................................................................................................22 
4.5.1 
When and How to Withdraw Subjects ..................................................................................................22 
4.5.2 
Data Collection and Follow-up for Withdrawn Subjects .....................................................................22 
5 
STU 
5.1 
Y DRUG/THERAPY .............................................................................................................................22 
DESCRIPTION .............................................................................................................................................22 
5.2 
TREATMENT REGIMEN ..............................................................................................................................22 
5.3 
RISKS ........................................................................................................................................................23 
5.4 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ..................................................................24 
5.5 
PREPARATION AND ADMINISTRATION OF STUDY DRUG/THERAPY ............................................................24 
5.6 
SUBJECT COMPLIANCE MONITORING ........................................................................................................24 
5.7 
PRIOR AND CONCOMITANT THERAPY ........................................................................................................24 
5.8 
PACKAGING ...............................................................................................................................................25 
5.9 
BLINDING OF STUDY DRUG .......................................................................................................................25 
5.10 
RECEIVING, STORAGE, DISPENSING AND RETURN .....................................................................................25 
5.10.1 
Receipt of Drug Supplies .....................................................................................................................25 
5.10.2 
Storage .................................................................................................................................................25 
5.10.3 
Dispensing of Study Drug ....................................................................................................................25 
5.10.4 
Return or Destruction of Study Drug ...................................................................................................25 
6 
STUD Y PROCEDURES..................................................................................................................................26 
Table of Contents 
STUDY SUMMARY ...................................................................................................................................................7 
1 
INTR
1.1 
ODUCTION............................................................................................................................................10 
SPECIFIC AIMS AND HYPOTHESIS ..............................................................................................................11 
1.1.1 
Hypothesis ...........................................................................................................................................11 
1.1.2 
Primary Aims .......................................................................................................................................11 
1.1.3 
Secondary Aims ...................................................................................................................................11 
1.2 
BACKGROUND ...........................................................................................................................................11 
1.2.1 
Recurrent Glioma ................................................................................................................................11 
1.2.2 
Fractionated Stereotactic Radiation Therapy (FSRT) .........................................................................12 
1.2.3 
Aurora A Kinase and Aurora A Kinase Inhibitor Alisertib (MLN8237) ..............................................13 
1.2.4 
Rationale .............................................................................................................................................14 
1.3 
STUDY THERAPY .......................................................................................................................................14 
1.3.1 
FRST ...................................................................................................................................................14 
1.3.2 
Aisertib Treatment ...............................................................................................................................15 
1.4 
PRECLINICAL DATA...................................................................................................................................15 
1.4.1 
In Vitro Studies ...................................................................................................................................15 
1.4.2 
In Vivo Studies .....................................................................................................................................16 
1.5 
CLINICAL DATA TO DATE..........................................................................................................................17 
1.6 
DOSE RATIONALE AND RISK/BENEFITS .....................................................................................................18 
2 
STUDY OBJECTIVES ....................................................................................................................................19 
2.1 
PRIMARY OBJECTIVE .................................................................................................................................19 
2.2 
SECONDARY OBJECTIVE(S) .......................................................................................................................19 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
D 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.1 
STUDY VISIT SCHEDULE............................................................................................................................26 
6.2 
DEFINITION OF DOSE LIMITING TOXICITIES ..............................................................................................26 
6.3 
DOSE DELAYS AND DOSE MODIFICATIONS. ..............................................................................................27 
 


 
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6.4 
DOSE DELAYS AND DOSE MODIFICATIONS ..................................................................................28 
6.5 
QUALITY OF LIFE MEASUREMENTS ................................................................................................29 
6.6 
DEFINE PROGRESSION ........................................................................................................................29 
7 
S
7.1 
TATISTICAL PLAN .....................................................................................................................................29 
SAMPLE SIZE DETERMINATION .................................................................................................................29 
7.2 
STATISTICAL METHODS.............................................................................................................................30 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ..................................................................................................30 
8 
SAFETY AND ADVERSE EVENTS .............................................................................................................30 
8.1 
DEFINITIONS..............................................................................................................................................30 
8.2 
RECORDING OF ADVERSE EVENTS.............................................................................................................32 
8.3 
UNBLINDING PROCEDURES........................................................................................................................33 
8.4 
STOPPING RULES .......................................................................................................................................33 
8.5 
DATA AND SAFETY MONITORING PLAN ....................................................................................................33 
8.5.1 
Medical Monitoring and AE/SAE Reporting .......................................................................................33 
8.5.2 
Data and Safety Monitoring Committee ..............................................................................................35 
8.6 
PRODUCT COMPLIANTS .....................................................................................................................36 
9 
DATA HANDLING AND RECORD KEEPING ..........................................................................................36 
9.1 
CONFIDENTIALITY .....................................................................................................................................36 
9.2 
SOURCE DOCUMENTS ................................................................................................................................37 
9.3 
CASE REPORT FORMS ................................................................................................................................37 
9.4 
RECORDS RETENTION................................................................................................................................37 
10 
STUDY MONITORING, AUDITING, AND INSPECTING .......................................................................38 
10.1 
STUDY MONITORING PLAN .......................................................................................................................38 
10.2 
AUDITING AND INSPECTING.......................................................................................................................38 
10.2.1 
Independent External and Internal Audits ...........................................................................................39 
11 
ETHICAL CONSIDERATIONS ....................................................................................................................39 
12 
STUDY FINANCES.........................................................................................................................................39 
12.1 
FUNDING SOURCE .....................................................................................................................................39 
12.2 
CONFLICT OF INTEREST .............................................................................................................................40 
12.3 
SUBJECT STIPENDS OR PAYMENTS ............................................................................................................40 
13 
PUBLICATION PLAN....................................................................................................................................40 
14 
REFERENCES .................................................................................................................................................40 
15 
APPENDIX .......................................................................................................................................................43 
 


 
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Protocol #13P.528, 
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AE 
adverse event 
ALT 
alanine aminotransferase/glutamic pyruvic transaminase/GPT 
ANC 
absolute neutrophil count 
ASCO 
American Society of Clinical Oncologists 
AST 
aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
AUC 
area under the curve 
BUN 
blood urea nitrogen 
CIS 
carcinoma in-situ 
Cmax 
maximum concentration of drug 
CNS 
central nervous system 
CR 
complete response/remission 
CTCAE 
NCI common terminology criteria for adverse events 
CV 
coefficient of variation 
DLT 
dose-limiting toxicity 
DNA 
deoxyribose nucleic acid 
ECG 
12 lead electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
food and drug administration 
GBM 
Glioblastoma 
Gy 
Gray (unit of radiation) 
H3, H4 
histones H3, H4 
HIV 
human immunodeficiency virus 
i.v. 
intravenous(ly) 
IRB 
institutional review board 
LLN 
lower limit of normal 
LVEF 
left ventricular ejection fraction 
mg/m2 
milligrams per square meter 
MTD 
maximum tolerated dose 
MUGA 
multiple uptake gated acquisition scan 
MWF 
monday, wednesday, Friday 
NCI 
national cancer institute 
NHL 
non-hodgkin’s lymphoma 
NIH 
national institutes of health 
PD 
Pharmacodynamic 
P-gp 
p-glycoprotein 
PK 
Pharmacokinetic 
PLT 
Platelet 
PR 
partial response 
SAE 
serious adverse event 
QoL 
Quality of life 
SD 
stable disease 
FSRT 
Fractionated stereotactic radiation therapy 
T4 
Thyroxine 
TSH 
thyroid stimulating hormone 
List of Abbreviations 
 


 
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Protocol #13P.528, v5.24(13September2017) 
 
 
 
 
ULN 
upper limit of normal 
WBC 
white blood cell 
WNL 
within normal limits 
WOCBP 
women of childbearing potential 
 


 
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Protocol #13P.528, v5.24(13September2017) 
Study Summary 
Title 
Phase I study of Alisertib with concurrent fractionated stereotactic radiation 
treatment for recurrent high grade gliomas 
Short Title 
Safety study of Alisertib and radiation for recurrent glioma 
Protocol Number 
JeffTrial# 3007 
CCRRC# 2013-12 
IRB# 13P.528 
Phase 
1 
Methodology/Stu 
dy Design 
This is an open label phase I clinical trial. Alisertib will be administered 
twice daily by mouth on days of radiation treatment. The radiation dose and 
fractionation are pre-determined. Alisertib dose will escalate according to 
the protocol. There is no intra-patient dose escalation. 
Study Duration 
18 months 
Study Center(s) 
Single-center. 
 
 
 
 
 
 
Objectives 
Primary Objectives: 
1.   Evaluate the safety and tolerability of the study treatment 
2.   To determine the Maximum Tolerated Dose (MTD) of Alisertib 
when combined with fractionated stereotactic radiation treatment for 
recurrent high grade glioma. 
Secondary Objectives: 
1.   To estimate 6 month progression free survival rate 
2.   To estimate the median time to progression 
3.   To estimate overall survival 
4.   To estimate the impact on quality of life (QoL) 
Number of 
Subjects 
Up to 24 subjects 
 


 
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Protocol #13P.528, v5.4 
(13September2017) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnosis and 
Main Inclusion 
Criteria 
Patients with recurrent high grade glioma (grade III or IV). 
Main inclusion criteria: 
1. 
Patients must have a previously histologically or cytologically 
confirmed high grade glioma (astrocytic or oligodendroglial 
supratentorial tumors grade 3 or 4) that has been previously treated 
with fractionated radiation therapy and now shows evidence of 
recurrence. 
2. 
Patients must have recovered from the toxic effects of prior therapy. 
3. 
Patients must have recovered from the effects of surgery.  There must 
be a minimum of 21 days from the day of surgery to the day of 
protocol treatment. For core or needle biopsy, a minimum of 7 days 
must have elapsed prior to the day of protocol treatment. 
4. 
Prior treatment with cytotoxic and biological agents is permissible. 
There should be at least a 2-week break between prior treatment and 
the protocol treatment. 
5. 
Prior treatment with fractionated radiation therapy (up to 60Gy) is an 
eligibility criterion, however there should not have been a second 
course of fractionated radiotherapy to the supratentorial area. 
6. 
One prior single fraction radiosurgical procedure within the treatment 
field is acceptable if V12<5 cc (V12 is the volume of normal brain 
(outside GTV) receiving 12 or more Gy). Additional radiosurgical 
procedures outside of the treatment area are acceptable. 
7. 
Subject must be able to take oral medication and to maintain a fast is 
required for 2 hours before and 1 hour after MLN8237 administration. 
8. 
ANC > 1500/mm³, platelets > 100,000/mm³, Hgb > 9 g/dL. Values 
must be obtained without need for myeloid growth factor or platelet 
transfusion support within 14 days of registration. However, 
erythrocyte growth factor is allowed as per published ASCO 
guidelines. 
9. 
Total bilirubin ≤ ULN, SGOT (AST) and SGPT (ALT)< 1.5 x ULN, 
within 14 days of registration. 
10.  
clearance m 
-Gault), within 14 days 
of registration. 
11.  Age >18 years. 
12.  ECOG performance status <2 (see Appendix I). 
13.  Life expectancy of greater than 2 months. 
14.  Women of childbearing potential must have a negative β-HCG 
pregnancy test documented within 7 days prior to registration. 
15.  Women of child-bearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry and for 4 months after last dose. 
16.  Ability to understand and the willingness to sign a written informed 
consent document. 
 


 
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Protocol #13P.528, v5.4 
(13September2017) 
Study Therapy, 
Dose, Route, 
Regimen 
Alisertib (MLN8237) will be administered by mouth, twice daily. The dose 
of Alisertib will be defined by the protocol. 
Duration of 
administration 
and follow-up 
Concurrent with radiation treatment, then 30 days after finishing radiation 
therapy will receive twice daily from day 1-7, every 21 day cycle for up to 
18 cycles, or until tumor progression. 
Reference 
therapy 
None. This is a phase I study 
 
 
 
 
 
 
 
Statistical 
Methodology 
We will use a two-stage accrual design at each dose considered. We will 
initially enter 3 subjects at each dose. If none of the three experiences a dose-
limiting toxicity we will proceed to the next dose. If one of the three 
experiences toxicity at that level, we will accrue 3 more subjects at that dose. 
If at any time there are two or more dose-limiting toxicities (in the 3-6 
subjects) on a given dose, we will terminate accrual to the Phase I portion of 
that trial. No patient will be treated at a higher dose until the 3 or 6 patients 
have completed their toxicity evaluation period at the current dose. With this 
plan, a dose with a 50% or greater probability of causing a dose-limiting 
toxicity has at most a 12.5% chance of satisfying the conditions for dose 
escalation after the first 3 subjects and at least a 50% chance of stopping at 
3. With the two-stages (3-6) together, there is at most a 17.2% chance of 
escalation. 
 
 
 
 
 
 
 
 
 
 
Schema 
 
 


 
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Protocol #13P.528, v5.4 
(13September2017) 
1.0 Introduction 
This document is a protocol for a human research study. This study is to be conducted according 
to US and international standards of Good Clinical Practice (FDA Title 21 part 312 and 
International Conference on Harmonization guidelines), applicable government regulations and 
Institutional research policies and procedures. 
 
1.1 Specific Aims and Hypothesis 
1.1.1 Hypothesis 
Malignant gliomas are the most common primary brain tumors in adults [1]. The standard of care 
for newly diagnosed high grade glioma, especially glioblastoma multiforme (GBM), is maximal 
surgical resection, followed by radiation treatment (RT) and concurrent and adjuvant 
chemotherapy with temozolamide (TMZ) [2]. Nonetheless, 90% of the patients recur within 2 
years [2, 3]. There is no standard treatment for recurrent high grade glioma. Therapeutic options 
include repeat surgery, re-irradiation, cytotoxic agents, and target therapies. Fractionated 
stereotactic radiotherapy (FSRT) may offer some improvement in survival with minimal toxicity 
for patients with previously treated gliomas. Our institution published one of the largest single 
institution experiences of using FSRT in recurrent high grade glioma. The treatment is well 
tolerated with a favorable median survival of 11 months after FSRT. Aurora kinase A is 
overexpressed in many malignant tumors [4]. Overexpression of Aurora-A has a prognostic value 
in high grade glioma. Administration of Aurora-A kinase inhibitor can suppress the growth of 
GBM, as well as be synergistic to radiation treatment [5-8]. Alisertib (MLN8237) is a potent 
second generation Aurora-A kinase inhibitor [4, 9, 10]. Combining FSRT with Alisertib for patients 
with recurrent high glioma likely would result in improved local control and prolonged survival. 
The effect of combination therapy may be more than additive effect, as suggested by a 
preclinical study [7]. The current phase I study will assess the safety profile of combining 
different doses of Alisertib with FSRT. We will determine the MTD (maximum tolerated dose), 
as well as a recommended phase II trial dose of Alisertib when used concurrently with radiation 
treatment for recurrent glioma patients. 
 
1.1.2 Primary Aims: 
• Evaluate the safety and tolerability of the study treatment 
• To determine the Maximum Tolerated Dose (MTD) of Alisertib when combined with 
fractionated stereotactic radiation treatment for recurrent high grade glioma. 
 
1.1.3 Secondary Aims: 
• To estimate 6 month progression free survival rate 
• To estimate the median time to progression 
• To estimate overall survival 
• To estimate the impact on quality of life (QoL) 
 
1.2 Background and Rationale 
1.2.1 Recurrent glioma 
High-grade gliomas are the most frequent primary brain tumor seen in adults. The addition of 
temozolomide (concurrent and adjuvant) to radiation therapy in the upfront setting improved 
overall survival in a phase III trial from 12.1 to 14.6 months [2, 3]. Nonetheless, following 
radiation therapy, 90% of gliomas recur within 2 years. The aggressive nature of gliomas is 
 


 
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Protocol #13P.528, v5.4 
(13September2017) 
 
 
 
 
explained in terms of inappropriate activation of pro-survival pathways (esp. PI3 Kinase) [11, 12], 
aberrant DNA repair [13], prominent angiogenesis [14], and multiple aberrations in the epigenetic 
control of gene expression [15]. 
 
Gliomas frequently recur close to their site of origin, making re-treatment challenging; 
furthermore, gliomas become more aggressive over time [16-18]. Continued tumor growth 
produces neurological symptoms and eventual death. Poor prognostic factors include increased 
age, lower Karnofsky performance score (KPS), initial and on-study histologies of glioblastoma 
multiforme (GBM), corticosteroid use, shorter time from original diagnosis to recurrence, and 
tumor outside frontal lobe [19]. Overall survival for relapsed glioma is less than 8 months. 
 
There is no standard treatment for recurrent tumor; therapeutic options include repeat surgery [20- 
22], re-irradiation [23-29], cytotoxic agents [30-32] and anti-angiogenic therapy [33-37]. Bevacizumab is 
an FDA approved agent for recurrent glioma that produces a response rate of 30-40% and a 
median overall survival of 9 months [38]. Unfortunately, there is emerging evidence that tumors 
that progress on bevacizumab are extremely resistant to other therapies as well [39], suggesting 
that bevacizumab may be best reserved for after other modalities have been exhausted. 
 
1.2.2 Fractionated Stereotactic Radiation Therapy (FRST) 
Radiation therapy is thought to kill living cells through the induction of DNA damage, in 
particular DNA double strand breaks. Due to a variety of practical and technical reasons, normal 
tissue is often incorporated into the ‘target volume’. Early radiotherapists discovered that 
fractionating the treatment (i.e. delivering it in many small daily doses over a number of weeks) 
is a way of damaging tumor tissue more than normal tissues. In stereotactic radiosurgery (SRS) 
on the other hand, a large dose of radiation is delivered in a single session to a stereotactically 
defined intracranial volume. SRS avoids toxicity by its high degree of precision in target 
definition, thus avoiding radiating normal structures. 
 
Fractionated stereotactic radiotherapy combines the precision of stereotactic positioning with the 
radiobiologic advantage of fractionation. FSRT, as utilized in this trial, utilizes a frameless mask 
system with daily stereotactic images for precise localization. FSRT is delivered by a Novalis 
LINAC based teletherapy unit. 
 
The Jefferson FSRT program is headed by Dr. David Andrews, a pioneer in the field. 
Neurosurgeons, Radiation oncologists and neuro-oncologists work closely together to obtain 
consensus treatment decisions. Following the acquisition of CT and contrast enhanced MRI 
images (obtained with face mask in place) treatment is planned by a dedicated team of physicists 
and therapists. 
 
Early Jefferson experience determined that re-irradiation with FSRT was extremely well 
tolerated in recurrent glioma; there were no ≥ grade 3 toxicities in 20 patients [23]. Gross tumor 
volume (GTV) was defined by the gadolinium-enhanced tumor edge using T1 weighted series. 
The PTV was considered equivalent to the GTV and edema was not included in the treatment 
volume. Tumors were treated to the 85-90% isodose line and coverage of the target volume was 
reviewed on the planning system. 
 


 
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Protocol #13P.528, v5.4 
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A report on 147 patients with recurrent high grade gliomas (Grade 3 astroctoma or GBM) 
undergoing this treatment between 1994 and 2008 was recently published in the Journal of 
Clinical Oncology [29]. The median age at primary diagnosis was 53 years (range, 19 to 86 
years). Sixty-seven patients (45%) were female. At initial diagnosis, 105 patients (71%) were 
diagnosed with GBM and 42 were diagnosed with anaplastic astrocytoma. All patients received 
initial postoperative conformal fractionated RT to a mean and median dose of 60.0 Gy in daily 
2.0 Gy fractions. Eighty-four patients (60%) had surgical resection of their progressive glioma 
prior to salvage FSRT. Forty-eight of the 147 patients received various chemotherapy agents 
(mostly temozolomide) at recurrence together with FSRT. 
 
Toxicity was minimal; no patients demonstrated clinically significant acute morbidity and all 
patients were able to complete the prescribed radiation dose without interruption. No patient 
required hospitalization or surgery for early acute or delayed toxicity. 
 
The median time from diagnosis to H-SRT was 8 months (range 4-205 mo). Median survival time 
from the start of FSRT was 10 months (8, 12 mo) for patients with grade 3 tumors and 11 months 
(9, 14) in grade 4 patients. Three month follow up MRI scans following H-SRT indicated stable 
disease in 89 (60%). Minimal response as defined by Macdonald criteria was noted in 15 (10%) 
patients and progression was noted in 43 (30%) patients. 
 
The University of Heidelberg has published their experience of re-irradiation for recurrent 
gliomas in 172 patients. Fractionated stereotactic radiation therapy was performed with a median 
dose of 36 Gy in 2 Gy fractions. This regimen was well tolerated and resulted in modest survival 
(survival from re-irradiation for grade 3 and 4 patients was 16 months and 8 months 
respectively). The largest series of re-irradiation of recurrent gliomas examined 172 patients with 
recurrent gliomas of which 111 had high-grade gliomas [24]. Fractionated stereotactic radiation 
therapy was performed with a median dose of 36 Gy in 2 Gy fractions. This regimen was well 
tolerated and resulted in modest survival. Similar to our study age and extent of initial 
neurosurgical resection at diagnosis influenced survival and no relationship was found between 
time to progression and survival benefit from re-treatment. In contrast to our results, no 
relationship between volume at re-irradiation and post re-irradiation survival was identified. The 
role of second resection, chemotherapy with re-irradiation and influence of dose were not 
reported. Of note, survival from re-irradiation for grade 3 and 4 patients was 16 months and 8 
months respectively compared to 10 months and 11 months in our series. These differences are 
likely attributable to differences in patient populations, most notably age (median age was 41 
versus 53 in this report). 
 
The best reported survival for standard fractionated re-irradiation combined with chemotherapy 
was reported by an Italian group [40]. Thirty-one patients received external beam RT to a dose of 
34.5 Gy with concurrent lumustine (CCNU) and reported a 13.5-month MST after re-irradiation. 
Other studies combining re-irradiation with chemotherapy have demonstrated similar results [24, 
40, 41]. 
 
1.2.3 Aurora A Kinases and the Aurura A Kinase Inhibitor Alisertib (MLN8237) 
Alisertib is a selective small molecule inhibitor of Aurora A kinase that is being developed for 
the treatment of advanced malignancies. Aurora A kinase belongs to a highly conserved family 
 


 
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Protocol #13P.528, v5.4 
(13September2017) 
of serine/threonine protein kinases that also includes Aurora B and Aurora C. Aurora A and 
Aurora B are expressed in all actively dividing cells, while Aurora C expression is largely 
restricted to dividing germ cells [42]. Aurora A localizes to centrosomes and the proximal mitotic 
spindle during mitosis where it functions in a diverse set of mitotic processes. 
 
The evidence supporting Aurora A kinase as a therapeutic target for the treatment of 
malignancies comes from several sources. First, the Aurora A kinase gene is amplified and/or 
overexpressed in many tumors, including colon, breast, pancreatic, and bladder cancers, as well 
as certain lymphomas, leukemias, and myeloma [43-47]. Aurora A overexpression in human 
cancers has been correlated with increased aneuploidy and centrosome amplification [48]. Second, 
forced overexpression of Aurora A kinase in experimental models results in the transformation 
of normal cells, suggesting that Aurora A overexpression may be oncogenic [43]. Lastly, in a 
number of different experimental systems, Aurora A inhibition leads to mitotic delays and severe 
chromosome alignment and segregation defects, followed by cell death [49-52]. Overall, the 
essential role of Aurora A in mitotic progression and its dysregulation in certain cancers makes it 
an attractive therapeutic target. 
 
Given the obligatory role of mitosis in tumor proliferation, an Aurora A inhibitor would be 
expected to have potential applications across a broad range of human tumors, including GBM. 
Indeed, MLN8237 has demonstrated activity against a variety of nonclinical solid tumor and 
hematological malignancy models grown in vitro and in vivo [53, 54]. 
 
1.2.4 Rationale 
Aurora A is expressed in many types of cancer in which polyploid cells containing multiple 
centrosomes are observed. Aurora-A localizes to the centrosomes, where it is required for their 
maturation and separation, thereby promoting mitotic entry and spindle assembly. In mitosis, 
Aurora-A associates with the spindle poles and is involved in both centrosomal assembly and 
acentrosomal spindle assembly. The gene encoding Aurora-A lies within a region of 
chromosome 20q13, which is amplified in many epithelial malignant tumors, including breast, 
gastric, colon, ovarian, glioma and pancreatic cancers. Furthermore, overexpression of an active 
mutant of Aurora-A in rat1 cells induced neoplastic transformation, indicating that Aurora-A is 
an oncogene. Overexpression of Aurora-A contributes to genetic instability and tumorigenesis by 
disrupting the proper assembly of the mitotic checkpoint complex. In addition, this kinase is a 
key regulatory component of the p53 pathway and its overexpression leads to an increase in p53 
degradation, which again facilitates oncogenic transformation. Overexpression of aurora kinase 
appears to have prognostic value in high grade glioma. Administration of aurora kinase inhibitor 
can suppress the growth of glioblastoma model [8]. Moreover, inhibition of aurora-A kinase is 
found to synergize with radiation in glioblastoma cells [55, 56]. Alisertib (MLN8237) is a second 
generation AURKA inhibitor and has recently entered phase I/II clinical trials. Early clinical 
studies showed promising result against multiple types of cancers when used alone. Combining 
Alisertib with FSRT in patients with recurrent GBM likely would result in enhanced therapeutic 
effects. The current phase I study will assess the safety profile of combining different doses of 
Alisertib with standard dose FSRT in patients with recurrent GBM. We will determine the MTD 
(maximum tolerated dose), as well as a recommended phase II trial dose of Alisertib. 
 


 
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1.3 Study Therapy 
1.3.1 FSRT 
Fractionated stereotactic surgery (FSRT) will be administered once daily, every weekday for a 
total of 10 daily treatments. All subjects will receive the 30-35 Gy in 10 daily fractions, as 
determined by the treating physician. Radiation treatment interruptions for up to 3 days are 
permitted for any reason. Interruptions of 4 to 7 treatment days will be considered an acceptable 
protocol violation. For interruptions of 8 days or greater, an unacceptable deviation will be 
assigned. 
 
All patients will have CT simulation and high resolution MRI with contrast for radiation 
treatment planning. The gross tumor volume (GTV) will be defined by the contrast-enhanced T1 
abnormality on the post-operative MRI scan. This will generally include the surgical cavity 
margins from the most recent surgical procedure as well. There is no clinical target volume 
(CTV) or planned target volume (PTV) expansion. 
 
All patients will receive 35 Gy in 3.5 Gy fractions. This dose maybe reduced to 30 Gy in 10 
fractions per the treating physician if the GTV is large (> 50 cc) or close to critical structures 
(such as brainstem, optic nerves, or chiasm). The dose is prescribed to the highest isodose line 
that covers >99% of the GTV. 
 
1.3.2 Alisertib treatment 
Alisertib will be administered by mouth, twice daily on days of radiation treatment during the 
course of FSRT. All patients will receive 10 days of Alisertib, concurrent with 10 daily radiation 
treatments. The first dose should be administered on the day of, but prior to, the first radiation 
treatment. The dose of Alisertib will be determined according to the protocol. 
 
During the maintenance therapy period, Alisertib will be administered by mouth, at 50 mg twice 
daily from day 1 to day 7 of a 21-day cycle. All patients will receive up to 18 cycles, or until 
tumor progression. 
 
1.4 Preclinical Data 
1.4.1 In Vitro Studies 
Alisertib is an adenosine triphosphate (ATP)-competitive and reversible inhibitor of Aurora A 
kinase in vitro with an inhibition constant (Ki) of 0.43 nM. In cultured HCT-116 human 
colorectal tumor cells, Alisertib produces 50% inhibition of Aurora A kinase activity at a 
concentration of 6.7 nM. It is approximately 200-fold more selective for Aurora A kinase than 
the structurally related family member, Aurora B kinase (half maximal inhibitory concentration 
[IC50] = 1534 nM). Moreover, in enzyme assays, Alisertib is selective for Aurora A kinase when 
compared to other kinases and receptors. Alisertib has affinity for the gamma acid alpha 1 
(GABAA α1) receptor benzodiazepine (BZD) binding site (Ki = 290 nM). The consequences of 
GABAA binding in rat and dog safety pharmacology studies are discussed below. 
 
Consistent with the mechanism of action for an Aurora A kinase inhibitor, Alisertib treatment 
results in formation of abnormal mitotic spindles, an accumulation of mitotic cells, and a 
decrease in the proliferation of a broad range of tumor cell lines grown in culture [49, 57, 58]. 
 


 
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The in vitro antiproliferative effect of Alisertib was quantified in tumor cell lines derived from a 
variety of malignancies, including colon (3 cell lines), breast (1 cell line), lung (1), ovary (1), 
prostate (1), pancreas (1), and lymphoid (1). Alisertib inhibited proliferation with lethal 
concentrations for 50% cell-growth inhibitor concentrations (GI50 values) ranging from 16 to 
469 nM, demonstrating that Alisertib is a potent inhibitor of proliferation in diverse human 
tumor cell lines. 
 
1.4.2 In Vivo Studies 
Alisertib has demonstrated broad antitumor activity in a diverse array of experimental human 
tumor xenografts when dosed QD or BID. These include 2 colon models (HCT-116 and DLD-1), 
2 lung models (H460 and Calu-6), 1 breast model (MDA-MB-231 FP4), 1 prostate model 
(CWR22 RV-1 Luc1.17) and 4 DLBCL models (Ly19, WSU, Ly7, PHTX 22-06). Statistically 
significant tumor growth inhibition (TGI) was observed with Alisertib given at 30 mg/kg QD or 
less in all models but the Calu-6 model. At 20 mg/kg BID or less, statistically significant TGI 
was observed in all models tested, including Calu-6. Taken together, these results demonstrated 
that Alisertib has broad antitumor activity in many experimental human tumor models. 
 
Alisertib also demonstrated robust antitumor activity when combined with docetaxel in 
preclinical models. Alisertib dosed daily at 3, 10 or 20 mg/kg QD was tested with docetaxel 
dosed weekly at 5 or 10 mg/kg in mice bearing breast (MDA-MB-231), primary breast (PHTX- 
02), lung (H522) or prostate (CWR22 RV-1 Luc1.17) human tumor xenografts. The various 
combinations of these agents at these doses were well tolerated, and resulted in synergistic or 
additive antitumor activity relative to the single agent activity of either Alisertib or docetaxel 
alone. In several of these models, the combination of Alisertib and docetaxel led to regression in 
tumor size and a dramatic prolongation in survival after termination of treatment. When the 
taxane was delivered in a regimen that overlapped Alisertib exposure during the first week of 
dosing, major enhanced antitumor activity was observed when Alisertib was administered over a 
shorter (9-day) time period, and the magnitude of response and disease control was comparable 
to results obtained with a longer (21-day) dosing schedule. In the prostate cancer model (CWR22 
RV1), the combination Alisertib (10 mg/kg QD) and docetaxel (10 mg/kg Q7D x 3) led to 
regression in tumor size and a dramatic prolongation in overall survival after termination of 
treatment. 
 
Clinical pharmacokinetic data available as of 20 April 2012 are summarized in Section 5.2 of the 
IB. Upon oral administration of PIC formulation to patients with advanced nonhematologic 
malignancies, absorption of Alisertib was fast, with peak plasma concentrations generally 
achieved by 2 hours post-dose. Negligible urinary excretion of Alisertib was observed in 
humans. The renal clearance of Alisertib in humans was less than 0.1% of apparent oral 
clearance. Steady-state plasma exposures of Alisertib increased in an approximately dose- 
proportional manner over the range of 5 to 200 mg/day in patients with advanced solid tumors. 
Overall mean steady-state terminal half-life following multiple-dose administration in patients 
with nonhematologic malignancies was approximately 22 hours. The overall mean peak/trough 
ratios were 2.6 and 5.0 for BID and QD dosing, respectively. The overall mean accumulation 
ratios were 2.8 and 1.9 for BID and QD dosing, respectively. Pharmacokinetic steady-state 
conditions were approximately achieved by Day 7 following daily oral administration. 
 


 
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Based on the results of a population PK analysis in 294 adult cancer patients, the apparent oral 
clearance of MLN8237 CL/F was unaffected by age, body weight, BSA, or the UGT1A1 
genotype (number of *28 alleles). These results support the use of a common fixed starting dose 
of MLN8237 independent of UGT1A1 genotype status, age or body size in the adult patient 
population, in the ongoing and planned clinical trials. 
 
Results from the relative BA study in 14 patients indicated that systemic exposures achieved 
following administration of the enteric-coated-tablet (ECT) and powder-in-capsule (PIC) 
formulations of MLN8237 are generally similar, based on relative BA of ECT in reference to 
PIC of approximately 90% (90% confidence interval: 74.4%-108.8%), supporting transition from 
the PIC to ECT in clinical development. 
 
The absolute bioavailability of Alisertib in humans has not been determined; however, the 
single-dose pharmacokinetics of a prototype oral solution formulation of Alisertib (25-mg dose) 
were characterized in reference to the PIC (50-mg dose) in a cross-over relative bioavailability 
evaluation in Study C14010 in 15 patients with nonhematologic malignancies. Following 
administration as an oral solution, Alisertib was rapidly absorbed, with a median Tmax of 1 hour. 
Based on preliminary PK data, the dose-normalized geometric mean of Alisertib Cmax and 
AUCinf achieved following administration of the oral solution were approximately 78% and 
35% higher, respectively, than those observed following PIC dosing. 
 
The effect of a standardized high-fat meal on the PK of single dose Alisertib administered as a 
50-mg strength ECT formulation was evaluated in 14 patients with advanced solid tumors. The 
lack of an effect of food on Alisertib AUCinf observed in this study supports the conclusion of 
the lack of a clinically meaningful effect of food on the PK of Alisertib ECT. The results of this 
study, therefore, support a recommendation that Alisertib may be dosed without regard to the 
timing of meals in future clinical studies employing the ECT formulation, unless otherwise 
specified in the clinical study protocol. 
 
1.5 Clinical Data to Date 
Clinical experience with Alisertib includes phase 1 and 2 studies in both solid tumors and heme- 
lymphatic malignancies, described below. 
 
Alisertib for clinical studies is being developed in 3 dosage formulations:  powder-in-capsule 
(PIC), enteric-coated-tablet (ECT), and oral solution (OS: for pediatric use). The initial studies 
employed the PIC formulation, and more recent studies have evaluated safety, PK, relative 
bioavailability (in reference to the PIC), and antitumor activity after administration of the ECT 
formulation. 
 
Using the ECT formulation, the dose-escalation, phase 1 portion of an ongoing study, C14007, 
has evaluated multiple dose levels from 10 to 60 mg BID for 7 days in repeat, 21-day cycles and 
50 mg BID has been determined to be the MTD. 
 
In Study C14007, which includes a phase 1 dose escalation using the same ECT formulation 
employed in this study, multiple dose levels up to 840 mg total cycle dose (60 mg BID for 
7 days) were evaluated. At the maximum administered dose of 60 mg BID for 7 days 
 


 
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administered to patients with advanced solid tumors, 3 patients (out of 3 enrolled) developed 
myelosuppression during the treatment-free period which was considered intolerable and above 
the MTD of 50 mg BID. In summary, 700 mg total cycle dose (e.g., 50 mg BID administered 
daily for 7 days) represents the ceiling for dose escalation in these combinations with Alisertib 
planned for this current study. 
 
The predominant toxicities reflect the mechanism of action in proliferating tissue (bone marrow, 
GI epithelium, and hair follicles). The suggested management of these toxicities is based on 
standard clinical paradigms for an anti-proliferative chemotherapeutic agent. Using a treatment- 
free period for recovery between each cycle of drug administration, the clinical experience from 
multiple phase 1 through 2 studies indicate that major toxicities can be managed to allow repeat 
treatment cycles over periods extending beyond 12 months. 
 
Alisertib is structurally related to the benzodiazepines (BZD) (e.g., diazepam, lorazepam) and 
also has activity against the GABAAα1 BZD receptor. BZD-like effects (e.g., somnolence, 
confusion, memory loss) have been observed to be associated with the onset of maximal plasma 
concentration (e.g., Tmax [time to maximum plasma concentration]). CNS effects associated 
with peak plasma levels have been generally managed by administration of divided doses (e.g., 
BID administration), although dose reductions have sometimes been required. While CNS 
effects attributed to Alisertib were also generally reversible and manageable by dose delay or 
reduction, the causal relationship, and thus optimal approach to management, were sometimes 
confounded by diverse causes including, but not limited to, concomitant medications (e.g., 
narcotic analgesics, antianxiety medications), comorbidities (e.g., infection, anemia, electrolyte 
abnormalities), and progressive malignancy (e.g., brain metastases). 
 
1.6 Dose Rationale and Risk/Benefits 
The safety risks of Alisertib treatment are: (1) leukopenia, neutropenia, febrile neutropenia, and 
lymphopenia with a potential increased susceptibility to infection; (2) thrombocytopenia with a 
potential increased risk of bleeding; (3) anemia; (4) gastrointestinal (GI) toxicity resulting in 
stomatitis/mucositis, nausea, vomiting, anorexia, abdominal pain, dyspepsia, diarrhea, 
dehydration, and potentially mucosal/GI bleeding, and sepsis; (5) alopecia; (6) asthenia/fatigue; 
(7) fever; and (8) benzodiazepine-like effects including sedation, somnolence, sleep disorders, 
confusion, disorientation and associated memory loss and gait disturbances (which were 
reversible in clinical studies with cessation of treatment or dose reduction).  Skin changes 
including hand-foot syndrome have been reported in some patients. Clinical safety data includes 
experience from patients who received multiple cycles followed by treatment-free periods 
between each cycle, and from patients who reduced or discontinued treatment. Based on the 
available clinical data, drug abuse, dependency, and withdrawal were not observed. 
 
While these toxicities are potentially associated with risk or discomfort to the patient, they are 
anticipated to be reversible. Alisertib has not led to major neurotoxicities or fluid retention as a 
single agent. However, because there is only limited human experience with Alisertib, it is 
possible that Alisertib will have other toxicities that have not been observed in, or predicted 
based on, rat, dog, and human studies. Alisertib has a low potential to prolong the QT interval in 
vivo based upon its extremely weak in vitro binding to hERG (IC50 and Ki both > 100 µM). 
 


 
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Protocol #13P.528, v5.4 
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To mitigate the inherent risks in clinical studies of Alisertib, patients are evaluated frequently 
while they are receiving treatment. 
 
Because Alisertib inhibits Aurora A kinase, it is possible that Alisertib may interfere with cancer 
growth and cause cancer cell death through a potentially non-cross resistant pathway as 
compared to other agents that patients may have received. The clinical utility of these effects will 
be investigated in current and future studies. 
 
2.0 Study Objective 
2.1 Primary Objectives: 
1.   Evaluate the safety and tolerability of the study treatment 
2.   To determine the Maximum Tolerated Dose (MTD) of daily oral ALISERTIB when 
combined with fractionated stereotactic radiation treatment for recurrent high grade 
glioma. 
 
2.2 Secondary Objectives: 
1.   To estimate 6 month progression free survival rate 
2.   To estimate the medial time to progression 
3.   To estimate overall survival 
4.   To estimate the impact of quality of life (QoL) 
 
3.0 STUDY DESIGN 
3.1 General Design 
 
 
3.2 Primary Study Endpoints 
1.   Evaluate the safety and tolerability of the study treatment 
2.   To determine the Maximum Tolerated Dose (MTD) of daily oral ALISERTIB when 
 


 
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Protocol #13P.528, v5.4 
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combined with fractionated stereotactic radiation treatment for recurrent high grade 
glioma. 
 
3.3 Secondary Study Endpoints 
1.   To estimate 6 month progression free survival rate 
2.   To estimate the medial time to progression 
3.   To estimate overall survival 
4.   To estimate the impact of quality of life (QoL) 
 
3.4 Primary Safety Endpoints 
To determine the Maximum Tolerated Dose (MTD) of daily oral ALISERTIB when combined 
with fractionated stereotactic radiation treatment for recurrent high grade glioma. 
 
4.0 SUBJECT SELECTION AND WITHDRAWAL 
4.1 Inclusion Criteria 
1.   Patients must have a previously histologically or cytologically confirmed high grade 
glioma (astrocytic or oligodendroglial supratentorial tumors grade 3 or 4) that has been 
previously treated with fractionated radiation therapy and now shows evidence of 
recurrence. 
2.   Patients must have recovered from the toxic effects of prior therapy. 
3.   Patients must have recovered from the effects of surgery. There must be a minimum of 21 
days from the day of surgery to the day of protocol treatment. For core or needle biopsy, 
a minimum of 7 days must have elapsed prior to the day of protocol treatment. 
4.   Prior treatment with cytotoxic and biological agents is permissible. There should be at 
least a 2-week break between prior treatment and the protocol treatment. 
5.   Prior treatment with fractionated radiation therapy (up to 60Gy) is an eligibility criterion, 
however there should not have been a second course of fractionated radiotherapy to the 
supratentorial area. 
6.   One prior single fraction radiosurgical procedure within the treatment field is acceptable 
if V12<5 cc (V12 is the volume of normal brain (outside GTV) receiving 12 or more Gy). 
Additional radiosurgical procedures outside of the treatment area are acceptable. 
7.   Subject must be able to take oral medication and to maintain a fast, is required for 2 hours 
before and 1 hour after MLN8237 administration. 
8.   ANC > 1500/mm³, platelets > 100,000/mm³, Hgb > 9 g/dL. Values must be obtained 
without need for myeloid growth factor or platelet transfusion support within 14 days of 
registration. However, erythrocyte growth factor is allowed as per published ASCO 
guidelines. 
9.   Total bilirubin ≤ ULN, SGOT (AST) and SGPT (ALT)< 1.5 x ULN, within 14 days of 
registration. 
10. Adequate renal function as defined by: calculated creatinine clearance must be ≥40 
mL/minute (Cockcroft-Gault), within 14 days of registration. 
11. Age >18 years. 
12. ECOG performance status <2 (see Appendix I). 
13. Life expectancy of greater than 2 months. 
14. Women of childbearing potential must have a negative β-HCG pregnancy test 
documented within 7 days prior to registration. 
 


 
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15. Women of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and for 4 
months after last dose. 
16. Ability to understand and the willingness to sign a written informed consent document. 
 
4.2 Exclusion Criteria 
1.   Known history of uncontrolled sleep apnea syndrome and other conditions that could 
result in excessive daytime sleepiness such as severe chronic obstructive pulmonary 
disease requiring supplemental oxygen. 
2.   Systemic infection requiring IV antibiotic therapy within 14 days preceding the first dose 
of study drug, or other severe infection. 
3.   Myocardial infarction within 6 months prior to enrollment, New York Heart Association 
(NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled 
ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active 
conduction system abnormalities. Prior to study entry, any ECG abnormality at Screening 
has to be documented by the investigator as not medically relevant. 
4.   Female subject is pregnant or breast-feeding. Confirmation that the subject is not 
pregnant must be established by a negative serum -human chorionic gonadotropin ( 
-
hCG) pregnancy test result obtained during screening. Pregnancy testing is not required 
for post-menopausal or surgically sterilized women. 
5.   Patient has received other investigational drugs within 14 days before enrollment 
6.   Serious medical or psychiatric illness likely to interfere with participation in this clinical 
study. 
7.   Other severe acute or chronic medical or psychiatric condition, including uncontrolled 
diabetes, malabsorption, resection of the pancreas or upper small bowel, requirement for 
pancreatic enzymes, any condition that would modify small bowel absorption of oral 
medications, or laboratory abnormality that may increase the risk associated with study 
participation or investigational product administration or may interfere with the 
interpretation of study results and, in the judgment of the investigator, would make the 
patient inappropriate for enrollment in this study. 
8.   Treatment with clinically significant enzyme inducers, such as the enzyme-inducing 
antiepileptic drugs phenytoin, carbamazepine or phenobarbital, or rifampin, rifabutin, 
rifapentine or St. John's wort within 14 days prior to the first dose of MLN8237 and 
during the study. 
9.   Known history of human immunodeficiency virus (HIV) infection, hepatitis B, or 
hepatitis C.  Testing is not required in the absence of clinical findings or suspicion. 
10. Patients have a history of any other malignancy from which the patient has been disease- 
free for less than 2 years, with the exception of adequately treated basal or squamous cell 
carcinoma of skin, superficial bladder cancer or carcinoma in situ of cervix, AJCC 
(version 7.0) stage 0 or I breast cancer, AJCC (version 7.0) stage I, or II prostate cancer. 
11. Radiation therapy to more than 25% of the bone marrow. Whole pelvic radiation is 
considered to be over 25%. 
12. Patients who cannot swallow whole tablets (i.e. medication tablets) 
 
4.3 Gender/Minority/Pediatric Inclusion for Research 
This study includes both genders and minority patients. Pediatric patients are excluded. 
 


 
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Protocol #13P.528, v5.4 
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4.4 Subject Recruitment and Screening 
Patients who are 18 years of age or older with high grade gliomas are eligible for the study. 
Patients can be recruited from PI or co-investigators’ clinical practices. Principal Investigator 
and research nurses/research associates should be notified of potential study subjects. 
Appropriate laboratory or diagnostic testing necessary to meet any noted inclusion or exclusion 
criteria will be ordered through the recruiting physician. PI of the study or study designated 
research nurse/research associate will screen and determine the final eligibility of the subject for 
enrollment. 
 
4.5 Early Withdrawal of Subjects 
4.5.1 When and How to Withdraw Subject 
Patients will be informed that they have the right to withdraw from the study at any time for any 
reason, without prejudice to their medical care. The investigator also has the right to withdraw 
patients from the study for any of the following reasons: 
1.   Intercurrent illness 
2.   Occurrence of an unacceptable adverse event 
3.   A treatment delay >3 weeks 
4.   Patient request 
5.   Protocol violations based on the judgment of PI 
6.   Non-compliance 
7.   Administrative reasons 
8.   Failure to return for follow-up 
9.   General or specific changes in the patient’s condition that make it unacceptable to 
continue treatment, in the judgment of the investigator 
10. Progressive disease 
 
At the time of withdrawal, all study procedures outlined for the End of Study visit should be 
completed. The primary reason for a patient’s withdrawal from the study is to be recorded in the 
source documents. 
 
4.5.2 Data Collection and Follow-Up for Withdrawn Subjects 
According to FDA regulations, when a subject withdraws from the study, the data collected on 
the subject to the point of withdrawal remains part of the study database and may not be 
removed. 
 
A subject who discontinues study treatment needs to state whether he/she wishes to continue 
participating in the study and allow further data collection as part of long term follow-up. 
Subjects who choose to continue with the study will participate in follow-up visits and 
evaluations according to the protocol. Subjects who refuse to participate in follow-up will be 
withdrawn from the study. 
 
Study data collected prior to a subject’s withdrawal from the study will be included in the study 
analysis. 
 


 
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5.0 Study Drug 
5.1 Description 
Alisertib is supplied as the ECT dosage form in 10 mg strength, with dose strength expressed as 
the milligrams of active drug (free acid). 
 
5.2 Treatment Regimen 
Alisertib will be administered by mouth, twice daily on days of radiation treatment during the 
course of FSRT. All patients will receive 10 days of Alisertib, concurrent with 10 daily radiation 
treatments. The first dose should be administered on the day of, but prior to, the first radiation 
treatment. The dose of Alisertib will be determined according to the protocol. 
 
During the maintenance therapy period, Alisertib will be administered by mouth, at 50 mg twice 
daily from day 1 to day 7 of a 21-day cycle. All patients will receive up to 18 cycles, or until 
tumor progression 
 
5.3 Risks 
Most Common (≥ 30%) 
• Nausea, diarrhea 
• Decreased number of white blood cells, which may increase risk of infection 
• Damaged mucous membranes in the mouth (mouth blisters) 
• Decreased number of red blood cells (or anemia) which may cause feelings of tiredness 
• Weakness or feeling tired 
• Hair loss 
 
Very Common (10% and <30%) 
• Pain, including muscle pain, chest pain, and pain from cancer 
• Fever with or without decreased white blood cells 
• Sleepiness or feeling drowsy 
• Bleeding events with or without decreased number of blood platelets 
• Cough 
• Shortness of breath 
• Rash/skin eruption 
• Constipation 
• Vomiting 
• Decrease in weight or loss of appetite 
• Fluid retention and swelling (e.g., hands, feet, legs) 
• Headache 
• Dehydration (decreased body fluids) 
• Dizziness 
 
Common (>1% and <10%) 
• Confusion and mental status changes 
• Imbalance which can lead to falling 
• Anxiety or depression 
• Difficulty sleeping 
 


 
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Protocol #13P.528, v5.4 
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• High or low blood pressure 
• Itchy or dry skin 
• Bruises 
• Inflamed or dry eyes, blurred vision 
• Dry mouth 
• Difficulty or painful when swallowing, altered taste 
• Upset stomach, flatulence 
• Difficult or blocked bowel movements 
• Hemorrhoids 
• Runny nose, sinus or voice problems 
• Numbness or tingling in hands or feet 
• Abnormal heart rhythm 
• Ringing in the ears 
• Muscle spasms/weakness 
• Fluid around the lungs or abdomen 
• Increased sweating or chills 
• Abnormal kidney function 
• Abnormal liver function test 
• Abnormal levels of blood sugar, chemistry, protein or blood clotting time 
• Bacterial, fungal or viral infection 
• Increased blood bilirubin 
• Blood clot (usually in the legs) 
• Loss of bladder control 
 
Uncommon (< 1%) 
Serious and treatment-related adverse events include: rhabdomyolysis (muscle breakdown that 
can damage kidneys), bone fracture, blistering skin reaction, multiple organ failure, deafness, 
shock, hepatic veno-occlusive disease (also known as sinusoidal obstruction syndrome), heart 
problems, agitation or irritability, and injury to one or more organs that may be life-threatening 
or fatal. 
 
5.4 Method of Assigning Subjects to Treatment Groups 
This is an open label phase I study. 
 
5.5 Preparation and Administration of Study Drug 
Alisertib will be administered on an empty stomach with the patient remaining NPO (nothing by 
mouth), except for water and prescribed medications, for 2 hours before and 1 hour after each 
dose. Patients will be instructed to take each oral dose of Alisertib with 8 ounces (1 cup, 240 
mL) of water. 
 
Alisertib will be supplied as 10 mg ECT, with the dose strength expressed as milligrams of 
active drug (free acid). All tablets are to be ingested whole; patients who have difficulty 
swallowing tablets will be excluded from the study. 
 


 
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Protocol #13P.528, v5.4 
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5.6 Subject Compliance Monitoring 
Records of study medication used, dosages administered, and intervals between visits will be 
recorded during the study. The radiation treatment record will be reviewed and recorded. 
 
5.7 Prior and Concomitant Therapy 
Anti-emetogenic agents may be administered at the discretion of the investigator. Although not 
prohibited, the use of benzodiazepines for the prophylaxis or treatment of nausea or vomiting is 
discouraged because of the potential benzodiazepine-like effects of Alisertib. 
 
Other medications, such as PPIs, H2 antagonists, growth factors, glucocorticoids, anti-emetics, 
and anti-epileptics are permitted at the treating physician’s discretion. 
 
All patients will receive concurrent FSRT to the recurrent glioma. 
 
5.8 Packaging 
Alisertib will be supplied as 10 mg ECT, with the dose strength expressed as milligrams of 
active drug (free acid). 
 
5.9 Blinding of Study Drug 
 
5.10 Receiving, Storage, Dispensing, and Return 
5.10.1 Receipt of Drug Supplies 
Millennium will provide Alisertib. 
 
Upon receipt of the study treatment supplies, an inventory must be performed and a drug receipt 
log filled out and signed by the person accepting the shipment. It is important that the designated 
study staff counts and verifies that the shipment contains all the items noted in the shipment 
inventory. Any damaged or unusable study drug in a given shipment (active drug or comparator) 
will be documented in the study files. The investigator must notify study sponsor of any 
damaged or unusable study treatments that were supplied to the investigator’s site. 
 
5.10.2 Storage 
Alisertib must be stored in a secure area according to local regulations. 
 
The investigator must ensure that it is stored in accordance with the environmental conditions as 
determined by Millennium and defined in the Investigator Brochure or SmPC/reference label. 
Alisertib must be stored at room temperature. 
 
5.10.3 Dispensing of Study Drug 
It is the responsibility of the investigator to ensure that Alisertib is only dispensed to study 
subjects. The Alisertib must be dispensed only from official study site by authorized personnel 
according to local regulations. 
 
5.10.4 Return or Destruction of Study Drug 
It is the responsibility of the investigator to ensure that a current record of Alisertib disposition is 
maintained at each study site where Alisertib is inventoried and disposed of. Records or logs 
 


 
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Protocol #13P.528, v5.4 
(13September2017) 
must comply with applicable regulations and guidelines and should include: 
• Amount received and placed in storage area. 
• Amount currently in storage area. 
• Label ID number or batch number and use date or expiry date. 
• Non-study disposition (e.g., lost, wasted, broken). 
 
At the completion of the study, there will be a final reconciliation of drug shipped, drug 
consumed, and drug remaining. This reconciliation will be logged on the drug reconciliation 
form, signed and dated. Any discrepancies noted will be investigated, resolved, and documented 
prior to return or destruction of unused study drug. Drug destroyed on site will be documented in 
the study files. 
 
6.0 STUDY PROCEDURES 
6.1 Study Visit Schedule 
Please see Appendix II for study calendar. 
 
6.2 Definition of Dose-Limiting Toxicities 
Dose-limiting toxicities (DLTs) will be graded in severity according to the guidelines outlined in 
the NCI- CTCAE version 4.0. Dose-limiting hematologic and non-hematologic toxicities will be 
defined differently, and will be based on events that occur during study drug administration and 
for 30 days after the completion of the radiation therapy. In order to be declared a dose-limiting 
toxicity, an adverse experience must be related (definitely, probably, or possibly) to study 
therapy. 
 
If a patient experiences a DLT during the radiation phase or the 30 day post radiation observation 
period, the patient will be permanently discontinued from study. 
 
A dose-limiting toxicity (DLT) will be defined as follows: 
• All grade 3 or higher toxicities that occur during or within 30 days of completing 
radiation treatment will be considered “treatment related” with the exception of (1) 
symptoms that are clearly related to the cancer or other pathology (in the opinion of the 
treating physician), and (2) expected sequelae of the neurosurgical procedure or 
radiosurgery. All neurological symptoms will be considered “treatment related” unless 
they are present at study onset, expected sequelae of the neurosurgical procedure, or 
clearly related to disease progression. 
• Febrile neutropenia (even in the absence of  hospitalization) 
• Hematologic DLTs will be defined as either Grade 4 neutropenia lasting for ≥ 7 days in 
duration, any Grade 4 anemia, any Grade 4 thrombocytopenia, or any Grade 5 
hematologic toxicity. All patients will be evaluated for hematologic toxicity. 
• Any neurological toxicity of Grade 3, 4 or 5 will be considered a DLT, with the exception 
of 1) symptoms present prior to study enrollment, and 2) expected sequelae of the 
neurosurgical procedure. 
• Grade 3 event of hypocalcemia, hypophosphatemia, hypokalemia, or hypomagnesemia 
lasting more than 24 hours without responding to medical therapy; or responding to 
medical therapy and lasting more than 72 hours 
• Grade 3 transaminases elevation associated with ≥ grade 2 bilirubin elevation (Hy’s law) 
 


 
26 
Protocol #13P.528, v5.4 
(13September2017) 
will also be a DLT defining event. 
• Non-hematologic dose-limiting toxicity will be defined as any Grade 3, 4 or 5 non- 
hematologic toxicity, with the specific exception of: 
o Grade 3 nausea or Grade 3 vomiting that in the opinion of the Investigator occurs 
in the setting of inadequate compliance with supportive care measures and lasts 
for less than 48 hours. 
o Grade 3 diarrhea that in the opinion of the Investigator occurs in the setting of 
inadequate compliance with supportive care measures and lasts for less than 48 
hours. 
o Grade 3 dehydration that, in the opinion of the Investigator occurs in the setting of 
inadequate compliance with supportive care measures and lasts for less than 48 
hours. 
o Grade 3 acidosis or alkalosis which responds to medical intervention by returning 
to ≤ Grade 2 within 48 hours. 
o Isolated Grade 3 elevation of liver function tests (LFTs) without associated 
clinical symptoms, lasting for ≤ 14 days in duration. 
o Grade 3 hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia, or 
hyphosphatemia which responds to medical intervention. 
o Grade 3 hypercholesterolemia. 
o Grade 3 hypertriglyceridemia. 
o Grade 3 alopecia 
 
6.3 Dose escalation/de-escalation 
Dose escalation will proceed within each cohort according to a “3+3 design”, as explained in the 
following scheme. Dose-limiting toxicity (DLT) is defined above. The toxicity assessment 
period is 30 days after the completion of the radiation therapy. 
 
Dose Level 
Alisertib dose 
-1 
10 mg BID 
1 
20 mg BID 
2 
30 mg BID 
3 
40 mg BID 
4 
50 mg BID (final dose level) 
 
Number of Patients with 
DLT at a Given Dose 
Level† 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
>2 
Dose escalation will be stopped. This dose level will be 
declared the maximally administered dose (highest dose 
administered). Three (3) additional patients will be entered at 
the next lowest dose level if only 3 patients were treated 
previously at that dose. 
1 out of 3 
Enter at least 3 more patients at this dose level. 
•   If 0 of these 3 patients experience DLT, proceed to the next 
dose level. 
 


 
27 
Protocol #13P.528, v5.4 (13September2017)
 
 
 
 
 
•   If 1 or more of this group suffer DLT, then dose escalation is 
stopped, and this dose is declared the maximally 
administered dose. Three (3) additional patients will be 
entered at the next lowest dose level if only 3 patients were 
treated previously at that dose. 
<1 out of 6 at highest dose 
level below the maximally 
administered dose 
This is generally the recommended phase 2 dose. At least 6 
patients must be entered at the recommended phase 2 dose. 
†Dose escalation will be determined based on the occurrence of DLTs. For the purposes of 
determining whether to advance the Dose Level, DLTs will be counted by patient (i.e., a 
patient who experiences more than 1 DLT will be counted only once). 
 
6.4 Dose Delay and Dose Modification 
If a patient experiences DLT during the radiation phase or 30 day post radiation observation 
period the patient will be permanently discontinued from the study. 
 
Maintenance treatment with Alisertib will be repeated every 21 days. In order for a new cycle of 
therapy to begin, the patient’s ANC must be ≥ 1,500/mm3 and the platelet count must be ≥ 
75,000/mm3. In addition, any other toxicity considered by the investigator to be related to 
therapy with Alisertib must have resolved to ≤ Grade 1 or to the patient’s baseline value before a 
new cycle of therapy may begin. 
 
If the patient fails to meet the above-cited criteria for retreatment, then initiation of the next cycle 
of therapy will be delayed for up to 1 week. At the end of that week, the patient will be re- 
evaluated to determine whether the criteria for retreatment have been met. Should treatment need 
to be delayed for more than 1 week (i.e., a rest period of more than 21 days) because of 
incomplete recovery from treatment-related toxicity, the dose of Alisertib will be reduced 1 level 
when therapy resumes. A second dose reduction may occur should treatment need to be delayed 
for more than 1 week because of incomplete recovery from treatment-related toxicity on the 
reduced dosage. Should treatment need to be delayed for more than 2 weeks at any dose, therapy 
with Alisertib will be discontinued (Table 1). 
 
Table 1 Table of Dose Adjustments for Maintenance Therapy 
Dose Level 
Dose 
Schedule 
1 
50 mg 
PO BID 
-1 
40 mg 
PO BID 
-2 
30 mg 
PO BID 
-3 
Discontinue 
Level 1 is the standard maintenance dose of 50 mg BID. 
 
Dose Modifications for Hematological Toxicity 
If a patient experiences any of the following hematological toxicities during the dosing period, 
dosing will be discontinued for the remainder of that cycle and the dose will be decreased 1 level 
for all subsequent cycles of treatment. 
1.   
 
2.   Grade 4 thrombocytopenia (platelet count < 25,000/µL) lasting more than 7 consecutive 
 


 
28 
Protocol #13P.528, v5.4 (13September2017)
days 
3.   Grade 3 neutropenia with fever or infection, or both, where fever is defined as an oral 
temperature greater than 38.5°C 
4.   Grade 3 thrombocytopenia with clinically significant bleeding 
 
If a patient has a platelet count of less than 10,000/µl at any time, the patient will be removed 
from the study permanently. 
 
Hematopoietic growth factors are allowed for febrile neutropenia or prolonged neutropenia, or 
decided appropriate by the treating physician. The choice of growth factor, dose, and duration is 
up to the treating physician. CBC should be monitored no less than 2 times a week till the 
toxicity is resolved to grade 3 or less. 
 
Dose Modifications for Non-hematological Toxicities 
If a patient experiences any of the following toxicities during the dosing period, dosing will be 
discontinued for the remainder of that cycle and the dose will be decreased 1 level for all 
subsequent cycles of treatment, and treatment may resume after drug related toxicities have 
resolved to ≤ Grade 1 or to baseline. 
1.   Any Grade 2 or greater neurological toxicity 
2.   Any Grade 3 non-hematological toxicity that is considered by the investigator to be 
related to study drug other than: 
3.   Grade 3 arthralgias/ myalgias 
4.   Grade 3 or greater nausea or emesis, or both, that occurs in the absence of optimal 
antiemetic therapy (5-hydroxytryptamine 3 [5-HT3] serotonin receptor antagonist) 
5.   Grade 3 or greater diarrhea that occurs in the absence of optimal supportive therapy with 
loperamide 
6.   Grade 3 fatigue that lasts greater than 1 week  
7.   Grade 2 non-hematological toxicities that are considered by the investigator to be related 
to study drug and in the opinion of the investigator require dose reduction. 
 
In general, Alisertib treatment should be discontinued if a patient experiences a nonhematologic 
grade 4 toxicity. If, in the opinion of the investigator and study sponsor it is in the patient’s 
interest to continue therapy with Alisertib, then after recovery from the toxicity or toxicities in 
question to ≤ grade 1 or to baseline values, the dose of Alisertib should be reduced by at least 1 
dose level with subsequent cycles of therapy. 
 
When a dose reduction of Alisertib is required, no re-escalation of dose will be permitted. If a 
patient requires more than 2 dose reductions, therapy with Alisertib will be discontinued. 
 
6.5 Quality of Life Measurement 
The validated EORTC core quality of life questionnaire (QLQ-C30, version 3.0) supplemented 
by a brain cancer specific health-related quality of life questionnaire, QLQ-BN20, will be 
administered according to trial calendar. (Appendix V) 
 
6.6 Define Progression 
The progression of the glioma will be defined according to Updated Response Assessment 
 


 
29 
Protocol #13P.528, v5.4 (13September2017)
Criteria for High-Grade Gliomas: Response Assessment in Neuro-Oncology Work Group 
(RANO criteria) [59, 60]. 
 
7.0 STATISTICAL PLAN 
7.1 Sample Size Determination 
We use 3+3 design for this trial. We estimate up to 24 patients. 
 
7.2 Statistical Methods 
We will use a two-stage accrual design at each dose considered. We will initially enter 3 subjects 
at each dose. If none of the three experiences a dose-limiting toxicity we will proceed to the next 
dose.  If one of the three experiences that level of toxicity, we will accrue 3 more subjects at that 
dose. If at any time there are two or more dose-limiting toxicities (in the 3-6 subjects) on a given 
dose, we will terminate accrual to the Phase I portion of that trial. No patient will be treated at a 
higher dose until the 3 or 6 patients have completed their toxicity evaluation period at the current 
dose. With this plan, a dose with a 50% or greater probability of causing a dose-limiting toxicity 
has at most a 12.5% chance of satisfying the conditions for dose escalation after the first 3 
subjects and at least a 50% chance of stopping at 3. With the two-stages (3-6) together, there is at 
most a 17.2% chance of satisfying the conditions for dose escalation after the 6 subjects. 
 
The maximally tolerated dose (MTD) will then be the last dose studied or the previous dose, 
based on Investigator’s clinical judgment of the degree of toxicity seen at the last dose. While 
waiting for the 3 or 6 subjects accrued according to plan to complete their toxicity evaluation 
period, up to 3 additional subjects may be accrued at the current dose. These additional subjects 
will not count towards the formal plan of stopping at two or more toxicity occurrences, but will 
contribute to the judgment as to the MTD. 
 
We will also conduct some descriptive analyses that will help in the design of a possible phase-II 
trial. Among patients at the MTD in each arm, we will estimate the proportion with complete or 
partial response, as well as the median survival (through the Kaplan-Meier method). We will also 
compute associated 95% confidence intervals, although we realize that they will be very wide 
(given that we only anticipate 6-8 patients to be treated at the MTD in each arm). The estimates 
themselves, however, will help in the sample size calculations of possible future phase-II trials. 
 
Progression free survival and overall survival will be measured from the date of starting study 
treatment (first day of radiation treatment). Progression free survival will be assessed by the 
treating physician based on the brain MRI. 
 
7.3 Subject Population(s) for Analysis 
All subjects who received the radiation treatment per the protocol and concurrent Alisertib will 
be subjected to the study analysis – both for the primary analysis and any applicable secondary 
analyses. 
 
8.0 SAFETY AND ADVERSE EVENTS 
8.1 Definitions 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in 
 


 
30 
Protocol #13P.528, v5.4 (13September2017)
severity during the course of the study. Intercurrent illnesses or injuries should be regarded as 
adverse events.  Abnormal results of diagnostic procedures are considered to be adverse events if 
the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious. 
 
A serious adverse event is any AE that is: 
• fatal 
• life-threatening 
• requires or prolongs a hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly 
of major clinical significance. They may jeopardize the subject, and may require intervention to 
prevent one of the other serious outcomes noted above. For example, drug overdose or abuse, a 
seizure that did not result in in-patient hospitalization, or intensive treatment of bronchospasm in 
an emergency department would typically be considered serious. 
 
All adverse events that do not meet any of the criteria for serious should be regarded as non- 
serious adverse events. 
 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the period 
from the initiation of any study procedures to the end of the study treatment follow-up.  For this 
study, the study treatment follow-up is defined as 30 days following the last day of treatment 
(radiation treatment and/or Alisertib). 
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study. A preexisting condition 
should be recorded as an adverse event if the frequency, intensity, or the character of the 
condition worsens during the study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant findings or abnormalities that 
meet the definition of an adverse event must also be recorded and documented as adverse events. 
 


 
31 
Protocol #13P.528, v5.4 (13September2017)
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are 
resolved, the subject is lost to follow-up, or the adverse event is otherwise explained. At the last 
scheduled visit, the investigator should instruct each subject to report any subsequent event(s) 
that the subject, or the subject’s personal physician, believes might reasonably be related to 
participation in this study. The investigator should notify the study sponsor of any death or 
adverse event occurring at any time after a subject has discontinued or terminated study 
participation that may reasonably be related to this study. The sponsor should also be notified if 
the investigator should become aware of the development of cancer or of a congenital anomaly 
in a subsequently conceived offspring of a subject that has participated in this study. 
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of 
the following conditions is met: 
• The laboratory abnormality is not otherwise refuted by a repeat test to confirm the 
abnormality 
• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management; e.g. change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic 
investigation, etc. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed otherwise in 
this protocol. Any condition responsible for surgery should be documented as an adverse event if 
the condition meets the criteria for an adverse event. 
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an 
adverse event in the following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures 
for a preexisting condition. Surgery should not be reported as an outcome of an adverse 
event if the purpose of the surgery was elective or diagnostic and the outcome was 
uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy measurement for 
the study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of the study, 
unless it is a worsening or increase in frequency of hospital admissions as judged by the 
clinical investigator. 
 
8.2 Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse events by 
specific questioning and, as appropriate, by examination. Information on all adverse events 
should be recorded immediately in the source document, and also in the appropriate adverse 
event module of the case report form (CRF). All clearly related signs, symptoms, and abnormal 
diagnostic procedure results should be grouped under one diagnosis and recorded in the source 
document. 
 


 
32 
Protocol #13P.528, v5.4 (13September2017)
 
All adverse events occurring during the study period must be recorded (see Appendix III). 
 
The clinical course of each event should be followed until resolution, stabilization, or until it has 
been determined that the study treatment or participation is not the cause. Serious adverse events 
that are still ongoing at the end of the study period must be followed up to determine the final 
outcome. Any serious adverse event that occurs after the study period and is considered to be 
possibly related to the study treatment or study participation should be recorded and reported 
immediately. 
 
8.3 Unblinding Procedures 
This study is not blinded. 
 
8.4 Stopping Rules 
Enrollment will stop if there are two or more DLTs in any one dose cohort and the MTD will be 
defined as the next lowest dose. 
 
8.5 Data and Safety Monitoring Plan 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her 
site.  This safety monitoring will include careful assessment and appropriate reporting of adverse 
events as noted above, as well as the compliance and implementation of the KCC data and 
safety-monitoring plan (DSMP). Medical monitoring will include a regular assessment of the 
number and type of serious adverse events by both the assigned Medical Monitor and the KCC 
DSMC. 
 
8.5.1 Medical Monitoring and AE/SAE Reporting 
A Medical Monitor is assigned to this study at the Thomas Jefferson University. This is a 
physician or pharmacist who is not directly involved in the trial, and is not currently 
collaborating with the sponsor/investigator on any other trial. The role of the Medical Monitor is 
to review all reportable AEs and SAEs (in real-time) including grading, toxicity assignments, 
non-reportable AEs (quarterly), protocol violations/deviations, as well as all other safety data and 
activity data observed in the ongoing clinical trial occurring at Thomas Jefferson University. The 
Medical Monitor may recommend reporting of adverse events and relevant safety data, and may 
also recommend suspension or termination of the study to the DSMC and TJU IRB. 
 
Every KCC investigator initiated protocol includes requirements for reporting of adverse events 
based on CTC 4.0. All events are reported to the IRB and Medical Monitor using a password 
protected web-site. In addition all unexpected and serious adverse events (SAEs) are reported to 
the TJU IRB and to the Food and Drug Administration (FDA) if applicable. The investigator is 
required to submit all unexpected and serious adverse events to the TJU IRB and the Medical 
Monitor within the timeframes outlined in the below table. All AE/SAEs will be reported to the 
DSMC at the quarterly DSMC review meetings; however, if the Medical Monitor determines 
corrective action is necessary, an “ad hoc” DSMC meeting will be called. Fatal adverse events 
related to treatment which are unexpected must be reported within 24 hours to the TJU 
IRB and the DSMC. Fatalities not related to the study drug/device must be reported within 
5 days. A summary of the reporting requirements for KCC investigator initiated Phase I and 
 


 
33 
Protocol #13P.528, v5.4 (13September2017)
Phase II studies are presented below. 
 
Grade 1 
Grade 2 
Grade 2 
Grade 3 
Grade 3 
Grades 4 and 
5 
Unexpecte 
d and 
Expected 
Unexpect 
ed 
Expecte 
d 
Unexpect 
ed with 
Hospitali 
zation 
Unexpected 
without 
Hospitalizati 
on 
Expected 
with 
Hospitalizati 
on 
Expected 
without 
Hospitalizati 
on 
Unexpected 
and 
Expected 
Unrelate 
d 
Unlikely 
Reviewed 
at 
Quarterly 
DSMC 
Meeting 
and IRB 
Annual 
Review 
Reviewed 
at 
Quarterly 
DSMC 
Meeting 
and IRB 
Annual 
Review 
Reviewe 
d at 
Quarterl 
y 
DSMC 
Meeting 
and IRB 
Annual 
Review 
5 
Working 
Days 
Reviewed at 
Quarterly 
DSMC 
Meeting and 
IRB Annual 
Review 
5 Working 
Days 
Reviewed at 
Quarterly 
DSMC 
Meeting and 
IRB Annual 
Review 
Phase 1 - 
48 Hours 
(Death: 24 
Hours) 
Phase 2 - 
5 Working 
Days 
Possible 
Probable 
Definite 
Reviewed 
at 
Quarterly 
DSMC 
Meeting 
and IRB 
Annual 
Review 
5 
working 
days 
Reviewe 
d at 
Quarterl 
y 
DSMC 
Meeting 
and IRB 
Annual 
Review 
48 Hours 
(Death: 
24 
Hours) 
Phase 1 - 
48 Hours 
Phase 2 - 
5 Working 
Days 
48 Hours 
(Death: 24 
Hours) 
Reviewed at 
Quarterly 
DSMC 
Meeting and 
IRB Annual 
Review 
Phase 1 and 
Phase 2 - 
48 Hours 
(Death: 24 
Hours) 
**NOTE: This table is based on the NCI AE/SAE reporting Guidelines and the TJU IRB Policy and Procedures. 
Please follow the individual protocol AE/SAE reporting guidelines if more stringent reporting procedures are 
specified. 
 
In accordance with 21 CFR 212.32, sponsor-investigators of studies conducted under an IND 
must comply with following safety reporting requirements: 
 
Expedited IND Safety Reports: 
7 Calendar-Day Telephone or Fax Report: 
The Sponsor-Investigator is required to notify the FDA of any fatal or life-threatening adverse 
event that is unexpected and assessed by the investigator to be possibly related to the use of 
Alisertib. An unexpected adverse event is one that is not already described in the Investigator 
Brochure. 
 
Such reports are to be telephoned or faxed to the FDA within 7 calendar days and Millennium 
within 24 hours of first learning of the event. Each telephone call or fax transmission (see fax 
number below) should be directed to the FDA new drug review division in the Center for Drug 
Evaluation and Research or in the product review division for the Center for Biologics 
Evaluation and Research, whichever is responsible for the review of the IND. 
 
15 Calendar-Day Written Report: 
The Sponsor-Investigator is also required to notify the FDA and all participating investigators, in 
a written IND Safety Report, of any serious, unexpected AE that is considered possibly related to 
the use of Alisertib. An unexpected adverse event is one that is not already described in the 
Investigator Brochure. 
 


 
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Protocol #13P.528, v5.4 (13September2017)
Written IND Safety Reports should include an Analysis of Similar Events in accordance with 
regulation 21 CFR § 312.32. All safety reports previously filed with the IND concerning similar 
events should be analyzed. The new report should contain comments on the significance of the 
new event in light of the previous, similar reports. 
 
Written IND safety reports with Analysis of Similar Events are to be submitted to the FDA, 
Millennium, and all participating investigators within 15 calendar days of first learning of the 
event. The FDA prefers these reports on a MedWatch 3500A Form but alternative formats are 
acceptable (e.g. summary letter). 
 
FDA fax number for IND Safety Reports: 
 
1 (800) FDA - 0178 
 
All written IND Safety Reports submitted to the FDA by the Sponsor-Investigator must also be 
faxed to: 
 
Millennium Pharmacovigilance 
SAE and Pregnancy Reporting Contact Information: 
North America 
PPD, Inc. 
Safety and Medical Management, US 
Fax:  +1 888-488-9697 
Hotline number (available 24/7):  1-800-201-8725 
 
AND 
 
Thomas Jefferson University IRB 
 
Procedures for Reporting Drug Exposure during Pregnancy and Birth Events 
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, 
she must inform the investigator immediately and must permanently discontinue study drug(s). 
All pregnancies and suspected pregnancies must be reported to Millennium Pharmacovigilance 
(or designee) immediately. The pregnancy must be followed for the final pregnancy outcome 
(i.e., delivery, still birth, miscarriage) and Millennium Pharmacovigilance will request this 
information from the investigator. 
 
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, this must be reported to Millennium Pharmacovigilance (or designee) immediately. 
Every effort should be made to follow the pregnancy for the final pregnancy outcome. 
 
IND Annual Reports 
In accordance with the regulation 21 CFR § 312.32, the Sponsor-Investigator shall within 60 
days of the anniversary date that the IND went into effect submit a brief report of the progress of 
the investigation. Please refer to Code of Federal Regulations, 21 CFR § 312.32 for a list of the 
elements required for the annual report.  All IND annual reports submitted to the FDA by the 
 


 
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Protocol #13P.528, v5.4 (13September2017)
Sponsor-Investigator should be copied to Millennium.  Copies of such reports should be mailed 
to: 
 
Millennium Pharmacovigilance 
 
8.5.2 Data and Safety Monitoring Committee 
Data and Safety Monitoring Committee (DSMC) is the Data and Safety Monitoring Board 
(DSMB) for the KCC. The DSMC is a multidisciplinary committee charged with overseeing the 
monitoring of safety of participants in clinical trials, and the conduct, progress, validity, and 
integrity of the data for all clinical trials at the Thomas Jefferson University KCC. The 
committee meets quarterly to review the progress and safety of all active research protocols that 
are not monitored by another safety and data monitoring committee or board. 
• The DSMC meets quarterly. Additional DSMC meetings are scheduled based on the 
nature and number of trials being monitored over a specified time period. The DSMC 
meets (by conference call) within 24 hours following the notification of an unexpected 
adverse event felt to be related to the study drug. 
• Prior to each DSMC meeting, each board member, is provided a printout of all reported 
AEs and SAEs occurring during the reporting period for this clinical trial. The principal 
investigator provides a detailed and comprehensive narrative assessment of current 
adverse events to date, indicating their possible significance and whether these toxicities 
have affected the conduct of the trial. DSMC members are provided with the principal 
investigator’s assessment, a written report summarizing adverse events, safety data, and 
activity data observed during the specified time period described in each protocol, as well 
as recommendations from the Medical Monitor. A review of outcome results (response, 
toxicity and adverse events) and factors external to the study (such as scientific or 
therapeutic developments) is discussed, and the Committee votes on the status of each 
study. 
• A summary of the board’s action is sent to each investigator, the CCRRC and TJU IRBs. 
The DSMC actions may include recommendations and/or requirements that will lead to 
improved patient safety and/or efficacy, significant benefits or risks that have developed, 
or other changes determined to be necessary. The DSMC may also take note of slow 
accrual or lack of scientific progress, and refer such issues to the CCRRC. The DSMC 
provides the investigator with the rationale for any decision made. 
 
8.6 Product Compliance 
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product.  Individuals who 
identify a potential product complaint situation should immediately contact MedComm Solutions 
(see below) and report the event.  Whenever possible, the associated product should be 
maintained in accordance with the label instructions pending further guidance from a Millennium 
Quality representative. 
 
For Product Complaints, 
call MedComm Solutions at 
877-674-3784 (877 MPI DRUG) 
(US and International) 
 


 
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Protocol #13P.528, v5.4 (13September2017)
 
Product complaints in and of themselves are not AEs. If a product complaint results in an SAE, 
an SAE form should be completed and sent to PPD (refer to Section 8.2). 
 
9.0 DATA HANDLING AND RECOND KEEPING 
9.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). 
Those regulations require a signed subject authorization informing the subject of the following: 
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI. 
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at 
the end of their scheduled study period. 
 
9.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source 
data are contained in source documents. Examples of these original documents, and data records 
include: hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories, and at medico-technical departments involved 
in the clinical trial. 
 
9.3 Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study. All 
data requested on the CRF must be recorded. All missing data must be explained. If a space on 
the CRF is left blank because the procedure was not done or the question was not asked, write 
“N/D”. If the item is not applicable to the individual case, write “N/A”. All entries should be 
printed legibly in black ink. If any entry error has been made, to correct such an error, draw a 
single straight line through the incorrect entry and enter the correct data above it. All such 
changes must be initialed and dated. DO NOT ERASE OR WHITE OUT ERRORS. For 
clarification of illegible or uncertain entries, print the clarification above the item, then initial and 
date it. 
 
Please see Appendix VI for CRF. 
 
9.4 Records Retention 
It is the investigator’s responsibility to retain study essential documents for at least 2 years after 
 


 
37 
Protocol #13P.528, v5.4 (13September2017)
the last approval of a marketing application in their country and until there are no pending or 
contemplated marketing applications in their country or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period if required by an agreement with the sponsor. In such an 
instance, it is the responsibility of the sponsor to inform the investigator/institution as to when 
these documents no longer need to be retained. 
 
10.0 STUDY MONITORING, AUDITING AND INSPECTING 
10.1 Study Monitoring Plan 
The investigator will allocate adequate time for monitoring activities. The Investigator will also 
ensure that the medical monitor or other compliance or quality assurance reviewer is given 
access to all the above noted study-related documents and study related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.), and has adequate space to conduct the monitoring visit. 
 
KCC Investigator Initiated Phase I Studies 
Phase I studies require continuous monitoring by the PI of the study with quarterly safety and 
monitoring reports submitted to the CRMO and the DSMC. Each protocol is assigned to a 
medical monitor (a member of the Jefferson DSMC who is not directly involved in this trial, and 
who is a full voting member of the Jefferson DSMC). The medical monitor reviews all adverse 
events (in addition to unexpected adverse events), safety data and activity data observed in the 
ongoing clinical trial at each new dose level, prior to dose escalation. 
 
The PI provides a report to the DSMC of all AE/SAEs, safety and toxicity data, and any 
corrective action that occurred on a quarterly basis. The medical monitor also provides a 
summary of their review. The summary of all discussions of adverse events are submitted to the 
DSMC, and these reports are reviewed during the DSMC meetings that take place quarterly. 
Patients are only identified by initials, and no other personal health information (PHI) is included 
in the reports. 
 
The medical monitor may recommend reporting adverse events and relevant safety data not 
previously reported, and may recommend suspension or termination of the trial based on their 
review of AE/SAE data observed throughout the life of a clinical trial. In such circumstances, 
and “ad hoc” DSMC meeting will be called to discuss corrective action with the PI. If for any 
reason the PI of the trial disagrees with the conclusions of the Medical Monitor or DSMC, the 
issue will be referred to the Associate Director of Clinical Investigations, who will be 
responsible for dispute resolution. 
 
The summary of all discussions of adverse events are included in the KCC investigator’s reports 
to the TJU IRBs as part of its annual progress report. The DSMC and the TJU IRBs may, based 
on the monitor’s recommendation, suspend or terminate the trial. The quarterly safety and 
monitoring reports include a statement as to whether this data has invoked any stopping criteria 
in the clinical protocol. 
 
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections of all study related 
documents (e.g. source documents, regulatory documents, data collection instruments, study data 
 


 
38 
Protocol #13P.528, v5.4 (13September2017)
etc.) by the IRB, the funding sponsor, government regulatory bodies, and University compliance 
and quality assurance groups. The investigator will ensure the capability for inspections of 
applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality assurance 
offices. 
 
10.2.1 Independent External and Internal Audits 
In addition to review by the DSMC, all studies initiated by KCC investigators are audited by an 
independent auditor once they have achieved 10% of target accrual. However, a study can be 
audited at any time based on recommendations by the IRB, DSMC, CCRRC and/or the Director 
of Clinical Investigations, KCC. Studies are re-audited once they have achieved 50% of target 
accrual. Special audits may be recommended by the IRB, DSMC or CCRRC based on prior 
findings, allegations of scientific misconduct and where significant irregularities are found 
through quality control procedures. Any irregularities identified as part of this process would 
result in a full audit of that study. 
 
In addition to the audits at 10% and 50%, the CRMO randomly audits at least 10 percent of all 
patients entered into therapeutic KCC trials and other trials as necessary, on at least a bi-annual 
basis, to verify that there is a signed and dated patient consent form, the patient has met the 
eligibility criteria, and that SAEs are documented and reported to the TJU IRB. 
 
All audit reports are submitted to the DSMC for review and action (when appropriate). A copy of 
this report and recommended DSMC action is sent to the CCRRC and TJU IRB. The committee 
regards the scientific review process as dynamic and constructive rather than punitive. The 
review process is designed to assist Principal Investigators in ensuring the safety of study 
subjects and the adequacy and accuracy of any data generated. The TJU IRB may, based on the 
DSMC and auditor’s recommendation, suspend or terminate the trial. 
 
11.0 Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), 
applicable government regulations and Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent 
Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal 
approval of the study conduct.  The decision of the IRB concerning the conduct of the study will 
be made in writing to the investigator before commencement of this study. 
 
All subjects for this study will be provided a consent form that is compliant with local and federal 
regulations, describing this study and providing sufficient information for subjects to make an 
informed decision about their participation in this study. See Attachment for a copy of the 
Subject Informed Consent Form. This consent form will be submitted with the protocol for 
review and approval by the IRB for the study. The formal consent of a subject, using the IRB- 
approved consent form, must be obtained before that subject is submitted to any study procedure. 
 


 
39 
Protocol #13P.528, v5.4 (13September2017)
This consent form must be signed by the subject or legally acceptable surrogate, and the 
investigator-designated research professional obtaining the consent. 
 
12.0 STUDY FINANCES 
12.1 Funding Source 
This study is funded by Millennium. 
 
12.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the 
conflict reviewed by a properly constituted Conflict of Interest Committee with a Committee- 
sanctioned conflict management plan that has been reviewed and approved by the study sponsor 
prior to participation in this study. All Jefferson University Investigators will follow the TJU 
Conflicts of Interest Policy for Employees (107.03). 
 
12.3 Subject stipends or Payments 
There are no subject stipends or payments. 
 
13.0 Publication Plan 
Any formal presentation or publication of data from this trial may be published after review and 
comment by Millennium and prior to any outside submission. Millennium must receive copies of 
any intended communication in advance of publication (at least fifteen working days for 
presentational materials and abstracts and thirty working days for manuscripts). These 
requirements acknowledge Millennium’ responsibility to provide peer input regarding the 
scientific content and conclusions of such publications or presentations. Principal 
Investigation/Institution shall have the final authority to determine the scope and content of its 
publications, provided such authority shall be exercised with reasonable regard for the interests 
of Millennium and, in accord with the trial contract and shall not permit disclosure of 
Millennium confidential or proprietary information. 
 
Neither the complete nor any part of the results of the study carried out under this protocol, nor 
any of the information provided by the sponsor for the purposes of performing the study, will be 
published or passed on to any third party without the consent of the study sponsor. Any 
investigator involved with this study is obligated to provide the sponsor with complete test 
results and all data derived from the study. 
 
14.0 REFERENCES 
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racial disparities on premature cancer deaths. CA Cancer J Clin, 2011. 61(4): p. 212-36. 
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Stupp, R., et al., Radiotherapy plus concomitant and adjuvant temozolomide for 
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Stupp, R., et al., Effects of radiotherapy with concomitant and adjuvant temozolomide 
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Dar, A.A., et al., Aurora kinase inhibitors--rising stars in cancer therapeutics? Mol 
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5. 
Temme, A., et al., Giant cell glioblastoma is associated with altered aurora b expression 
and concomitant p53 mutation. J Neuropathol Exp Neurol, 2010. 69(6): p. 632-42. 
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Bie, L., et al., Kinesin family member 2C (KIF2C/MCAK) is a novel marker for 
prognosis in human gliomas. Clin Neurol Neurosurg, 2012. 114(4): p. 356-60. 
7. 
Tao, Y., et al., Enhancement of radiation response by inhibition of Aurora-A kinase using 
siRNA or a selective Aurora kinase inhibitor PHA680632 in p53-deficient cancer cells. 
Br J Cancer, 2007. 97(12): p. 1664-72. 
8. 
Lehman, N.L., et al., Aurora A is differentially expressed in gliomas, is associated with 
patient survival in glioblastoma and is a potential chemotherapeutic target in gliomas. 
Cell Cycle, 2012. 11(3): p. 489-502. 
9. 
Manfredi, M.G., et al., Characterization of Alisertib (MLN8237), an investigational 
small-molecule inhibitor of aurora A kinase using novel in vivo pharmacodynamic 
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10. 
Carol, H., et al., Efficacy and pharmacokinetic/pharmacodynamic evaluation of the 
Aurora kinase A inhibitor MLN8237 against preclinical models of pediatric cancer. 
Cancer Chemother Pharmacol, 2011. 68(5): p. 1291-304. 
11. 
Choe, G., et al., Analysis of the phosphatidylinositol 3'-kinase signaling pathway in 
glioblastoma patients in vivo. Cancer Res, 2003. 63(11): p. 2742-6. 
12. 
Ermoian, R.P., et al., Dysregulation of PTEN and protein kinase B is associated with 
glioma histology and patient survival. Clin Cancer Res, 2002. 8(5): p. 1100-6. 
13. 
Short, S.C., et al., DNA repair after irradiation in glioma cells and normal human 
astrocytes. Neuro Oncol, 2007. 9(4): p. 404-11. 
14. 
Brem, S.S., P.M. Gullino, and D. Medina, Angiogenesis: a marker for neoplastic 
transformation of mammary papillary hyperplasia. Science, 1977. 195(4281): p. 880-2. 
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Nagarajan, R.P. and J.F. Costello, Epigenetic mechanisms in glioblastoma multiforme. 
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Leighton, C., et al., Supratentorial low-grade glioma in adults: an analysis of prognostic 
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17. 
Huang, Q., et al., Glioma stem cells are more aggressive in recurrent tumors with 
malignant progression than in the primary tumor, and both can be maintained long-term 
in vitro. BMC Cancer, 2008. 8: p. 304. 
18. 
McCormack, B.M., et al., Treatment and survival of low-grade astrocytoma in adults-- 
1977-1988. Neurosurgery, 1992. 31(4): p. 636-42; discussion 642. 
19. 
Carson, K.A., et al., Prognostic factors for survival in adult patients with recurrent glioma 
enrolled onto the new approaches to brain tumor therapy CNS consortium phase I and II 
clinical trials. J Clin Oncol, 2007. 25(18): p. 2601-6. 
20. 
Young, B., et al., Reoperation for glioblastoma. J Neurosurg, 1981. 55(6): p. 917-21. 
21. 
Harsh, G.R.t., et al., Reoperation for recurrent glioblastoma and anaplastic astrocytoma. 
Neurosurgery, 1987. 21(5): p. 615-21. 
22. 
Ammirati, M., et al., Reoperation in the treatment of recurrent intracranial malignant 
gliomas. Neurosurgery, 1987. 21(5): p. 607-14. 
23. 
Hudes, R.S., et al., A phase I dose escalation study of hypofractionated stereotactic 
radiotherapy as salvage therapy for persistent or recurrent malignant glioma. Int J Radiat 
Oncol Biol Phys, 1999. 43(2): p. 293-8. 
24. 
Combs, S.E., et al., Efficacy of fractionated stereotactic reirradiation in recurrent 
gliomas: long-term results in 172 patients treated in a single institution. J Clin Oncol, 
 


 
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2005. 23(34): p. 8863-9. 
25. 
Fokas, E., et al., Hypofractionated stereotactic reirradiation of recurrent glioblastomas : a 
beneficial treatment option after high-dose radiotherapy? Strahlenther Onkol, 2009. 
185(4): p. 235-40. 
26. 
Patel, M., et al., Salvage reirradiation for recurrent glioblastoma with radiosurgery: 
radiographic response and improved survival. J Neurooncol, 2009. 92(2): p. 185-91. 
27. 
Cho, K.H., et al., Single dose versus fractionated stereotactic radiotherapy for recurrent 
high-grade gliomas. Int J Radiat Oncol Biol Phys, 1999. 45(5): p. 1133-41. 
28. 
Combs, S.E., et al., Stereotactic radiosurgery (SRS): treatment option for recurrent 
glioblastoma multiforme (GBM). Cancer, 2005. 104(10): p. 2168-73. 
29. 
Fogh, S.E., et al., Hypofractionated stereotactic radiation therapy: an effective therapy for 
recurrent high-grade gliomas. J Clin Oncol, 2010. 28(18): p. 3048-53. 
30. 
van den Bent, M.J., et al., Randomized phase II trial of erlotinib versus temozolomide or 
carmustine in recurrent glioblastoma: EORTC brain tumor group study 26034. J Clin 
Oncol, 2009. 27(8): p. 1268-74. 
31. 
Kappelle, A.C., et al., PCV chemotherapy for recurrent glioblastoma multiforme. 
Neurology, 2001. 56(1): p. 118-20. 
32. 
Schmidt, F., et al., PCV chemotherapy for recurrent glioblastoma. Neurology, 2006. 
66(4): p. 587-9. 
33. 
Vredenburgh, J.J., et al., Bevacizumab plus irinotecan in recurrent glioblastoma 
multiforme. J Clin Oncol, 2007. 25(30): p. 4722-9. 
34. 
Zuniga, R.M., et al., Efficacy, safety and patterns of response and recurrence in patients 
with recurrent high-grade gliomas treated with bevacizumab plus irinotecan. J 
Neurooncol, 2009. 91(3): p. 329-36. 
35. 
Kreisl, T.N., et al., Phase II trial of single-agent bevacizumab followed by bevacizumab 
plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol, 2009. 27(5): 
p. 740-5. 
36. 
Sorensen, A.G., et al., A "vascular normalization index" as potential mechanistic 
biomarker to predict survival after a single dose of cediranib in recurrent glioblastoma 
patients. Cancer Res, 2009. 69(13): p. 5296-300. 
37. 
Batchelor, T.T., et al., AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, 
normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell, 
2007. 11(1): p. 83-95. 
38. 
Friedman, H.S., et al., Bevacizumab alone and in combination with irinotecan in 
recurrent glioblastoma. J Clin Oncol, 2009. 27(28): p. 4733-40. 
39. 
Iwamoto, F.M., et al., Patterns of relapse and prognosis after bevacizumab failure in 
recurrent glioblastoma. Neurology, 2009. 73(15): p. 1200-6. 
40. 
Arcicasa, M., et al., Reirradiation and lomustine in patients with relapsed high-grade 
gliomas. Int J Radiat Oncol Biol Phys, 1999. 43(4): p. 789-93. 
41. 
Larson, D.A., et al., Phase II study of high central dose Gamma Knife radiosurgery and 
marimastat in patients with recurrent malignant glioma. Int J Radiat Oncol Biol Phys, 
2002. 54(5): p. 1397-404. 
42. 
Nigg, E.A., Mitotic kinases as regulators of cell division and its checkpoints. Nature 
Reviews Molecular Cell Biology, 2001. 2(1): p. 21-32. 
43. 
Bischoff, J.R., et al., A homologue of Drosophila aurora kinase is oncogenic and 
amplified in human colorectal cancers. EMBO Journal, 1998. 17(11): p. 3052-65. 
 


 
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44. 
Sen, S., et al., Amplification/overexpression of a mitotic kinase gene in human bladder 
cancer. Journal of the National Cancer Institute, 2002. 94(17): p. 1320-9. 
45. 
Camacho, E., et al., Analysis of Aurora-A and hMPS1 mitotic kinases in mantle cell 
lymphoma. International Journal of Cancer, 2006. 118(2): p. 357-63. 
46. 
Ikezoe, T., et al., A novel treatment strategy targeting Aurora kinases in acute 
myelogenous leukemia. Molecular Cancer Therapeutics, 2007. 6(6): p. 1851-7. 
47. 
Chng, W.J., et al., Clinical implication of centrosome amplification in plasma cell 
neoplasm. Blood, 2006. 107(9): p. 3669-75. 
48. 
Katayama, H., W.R. Brinkley, and S. Sen, The Aurora kinases: role in cell transformation 
and tumorigenesis. Cancer & Metastasis Reviews, 2003. 22(4): p. 451-64. 
49. 
Marumoto, T., et al., Aurora-A kinase maintains the fidelity of early and late mitotic 
events in HeLa cells. Journal of Biological Chemistry, 2003. 278(51): p. 51786-95. 
50. 
Glover, D.M., et al., Mutations in aurora prevent centrosome separation leading to the 
formation of monopolar spindles. Cell, 1995. 81(1): p. 95-105. 
51. 
Katayama, H., et al., Interaction and feedback regulation between STK15/BTAK/Aurora- 
A kinase and protein phosphatase 1 through mitotic cell division cycle. Journal of 
Biological Chemistry, 2001. 276(49): p. 46219-24. 
52. 
Hoar, K., et al., MLN8054, a small-molecule inhibitor of Aurora A, causes spindle pole 
and chromosome congression defects leading to aneuploidy. Molecular & Cellular 
Biology, 2007. 27(12): p. 4513-25. 
53. 
Maris, J.M., et al., Initial testing of the aurora kinase A inhibitor MLN8237 by the 
Pediatric Preclinical Testing Program (PPTP). Pediatr Blood Cancer, 2010. 55(1): p. 26- 
34. 
54. 
Gorgun, G., et al., A novel Aurora-A kinase inhibitor MLN8237 induces cytotoxicity and 
cell-cycle arrest in multiple myeloma. Blood, 2010. 115(25): p. 5202-13. 
55. 
Borges, K.S., et al., Inhibition of Aurora kinases enhances chemosensitivity to 
temozolomide and causes radiosensitization in glioblastoma cells. J Cancer Res Clin 
Oncol, 2012. 138(3): p. 405-14. 
56. 
Venkataraman, S., et al., Targeting Aurora Kinase A enhances radiation sensitivity of 
atypical teratoid rhabdoid tumor cells. J Neurooncol, 2012. 107(3): p. 517-26. 
57. 
Honda, R., R. Körner, and E.A. Nigg, Exploring the functional interactions between 
Aurora B, INCENP, and survivin in mitosis. Mol Biol Cell, 2003. 14(8): p. 3325-41. 
58. 
Giet, R., et al., Drosophila Aurora A kinase is required to localize D-TACC to 
centrosomes and to regulate astral microtubules. J Cell Biol, 2002. 156(3): p. 437-51. 
59. 
Quant, E.C. and P.Y. Wen, Response assessment in neuro-oncology. Curr Oncol Rep, 
2011. 13(1): p. 50-6. 
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15.0 Appendices 
Appendix I ECOG Performance status scale 
 
Appendix II Visit Schedule 
 
Appendix III SAE form 
 


 
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Appendix IV MMSE 
 
Appendix V QoL forms 
 
Appendix VI Case Report Forms 
 
 
 
Appendix I: ECOG Performance Status 
 
Grade Descriptions 
0 
Normal activity. Fully active, able to carry on all pre-disease performance 
without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., light 
housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to 
carry out any work activities. Up and about more than 50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to bed or 
chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self- care. Totally 
confined to bed or chair. 
5 
Dead 
 


 
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Protocol #13P.528, v5.4 (13September2017)
 
 
 
 
 
 
 
 
Appendix II: Visit Schedule 
 
Prior to 
Registration 
Pre- 
treatment 
Concurrent 
phase 
Observation 
phase 
Maintenance 
phase 
Recommended 
Follow up 
Time (day) 
-14 to -1 
-30 to -1 
1-7 
8-14 
Day 13-42 
From Day 43 
to 1 year 
Year 2 and 
onwards 
Informed 
consent 
X 
Demographics 
X 
Medical history X 
X 
H & P 
X 
X 
X7 
X7 
X5 
Q 2 months 
X6 
Neuro exam 
X 
X 
X8 
X7 
X5 
Q 2 months 
X6 
MMSE 
X 
X5 
Q 2 months 
X6 
QoL 
X 
X5 
Q 2 months 
X6 
Vitals 
X 
X7 
X7 
X5 
Q 2 months 
X6 
Weight 
X 
X7 
X7 
X5 
Q 2 months 
X6 
KP/ECOG 
X 
X 
X 
X7 
X5 
Q 2 months 
X6 
CBC w diff 
X 
X 
X7 
X7 
X5 
Weekly8 
X6 
CMP, Mg + 
X 
X 
X8 
X7 
X5 
Q 2 months 
X6 
PT/PTT/INR 
X 
Lipid Panel 
X7 
X7 
X5 
Q 2 months 
EKG 
X 
b-HCG 
X9 
MRI Brain 
X 
X1 
Q 2 months 
X6 
Treatment: 
RT 
X2 
X2 
MLN8237 
X3 
X3 
X4 
Q = every 
H & P = History & Physical 
 
NOTE: 
1. Brain MRI should be done between days 35-42, then every 2 months for 1st year. 
2. RT: daily on weekdays for a total of 10 treatments. 
3. Alisertib: BID on days of RT only. 
4. Alisertib: 50 mg BID on days 1-7 every 21 days, for up to 18 cycles or until progression. 
5. Between day 39 to day 45 (at the end of 30 day observation period), then every 2 months 
6. Every 3 months from year 1 to year 2, then every 4-6 months afterwards. 
7. All items only need to be done at least once during week 1 and at least once during week 2. 
8. Until discontinuation of Alisertib. 
9. Pregnancy test should be done within 7 days prior to registration, if applicable 
 


 
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Protocol #13P.528, v5.4 (13September2017)
 
 
Appendix III: SAE FORM 
 
 


 
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Protocol #13P.528, v5.4 (13September2017 
Appendix IV: MMSE 
 
 


 
Appendix V: QoL forms 
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Protocol #13P.528, v5.4 (13September2017 
 
Appendix VI: Case Report Form 
 
SCREENING 
 
 
VISIT DATE :   
 
 
Date Screening Informed 
Consent Signed:   
 
Not Applicable 
Screening Date: 
Not Applicable 
Is this participant a screen failure? 
Yes 
No (If Yes, complete Off Study form) 
If yes, specify primary reason for screen failure: 
Investigator decision 
Participant decision 
Did not meet eligibility criteria 
Other, specify: 
Comments: 
Who referred participant? 
Physician 
Health Care Provider 
Family/friend 
Self 
Other, specify: 
How did participant find out about the study? 
Physician Nurse 
Family/friend 
NCI web site 
Written material 
Unknown 
Other, specify: 
 


 
INCLUSION CRITERIA 
53 
Protocol #13P.528, v5.4 (13September2017) 
 
 
Criteria 
Yes 
No 
N/A 
 
1 
Patients must have a previously histologically or cytologically confirmed high grade 
glioma (astrocytic or oligodendroglial supratentorial tumors grade 3 or 4) that has been 
previously treated with fractionated radiation therapy and now shows evidence of 
recurrence. 
2 
Patients must have recovered from the toxic effects of prior therapy. 
 
3 
Patients must have recovered from the effects of surgery. There must be a minimum of 
21 days from the day of surgery to the day of protocol treatment. For core or needle 
biopsy, a minimum of 7 days must have elapsed prior to the day of protocol treatment. 
4 
Prior treatment with cytotoxic and biological agents is permissible. There should be at 
least a 2 week break between prior treatment and the protocol treatment. 
 
5 
Prior treatment with fractionated radiation therapy (up to 60Gy) is an eligibility criterion, 
however there should not have been a second course of fractionated radiotherapy to 
the supratentorial area. 
 
6 
One prior single fraction radiosurgical procedure within the treatment field is acceptable 
if V12<5 cc (V12 is the volume of normal brain (outside GTV) receiving 12 or more Gy). 
Additional radiosurgical procedures outside of the treatment area are acceptable. 
7 
Subject must be able to take oral medication and to maintain a fast is required for 2 
hours before and 1 hour after MLN8237 administration. 
 
8 
ANC > 1500/mm³, platelets > 100,000/mm³, Hgb > 9 g/dL. Values must be obtained 
without need for myeloid growth factor or platelet transfusion support within 14 days of 
registration, however, erythrocyte growth factor is allowed as per published ASCO 
guidelines. 
9 
Total bilirubin ≤ ULN, SGOT (AST) and SGPT (ALT)< 1.5 x ULN, within 14 days of 
registration. 
10 
Adequate renal 
mL/minute (Cockcroft-Gault), within 14 days of registration. 
11 
Age >18 years. 
12 
ECOG performance status <2 (see Appendix I). 
13 
Life expectancy of greater than 2 months. 
14 
Women of childbearing potential must have a negative β-HCG pregnancy test 
documented within 7 days prior to registration. 
 
15 
Women of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and for the 
duration of study participation. 
16 
Ability to understand and the willingness to sign a written informed consent document. 
 


 
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Protocol #13P.528, v5.4 (13September2017) 
EXCLUSION CRITERIA 
 
 
Criteria 
Yes No 
N/A 
 
2 
Known history of uncontrolled sleep apnea syndrome and other conditions that could 
result in excessive daytime sleepiness, such as severe chronic obstructive pulmonary 
disease; requirement for supplemental oxygen. 
3 
Systemic infection requiring IV antibiotic therapy within 14 days preceding the first 
dose of study drug, or other severe infection. 
 
 
 
4 
Myocardial infarction within 6 months prior to enrollment or has New York Heart 
Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe 
uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute 
ischemia or active conduction system abnormalities. Prior to study entry, any ECG 
abnormality at Screening has to be documented by the investigator as not medically 
relevant. 
 
5 
Female subject is pregnant or breast-feeding. Confirmation that the subject is not 
pregnant must be established by a negative serum β-human chorionic gonadotropin 
(β-hCG) pregnancy test result obtained during screening.  Pregnancy testing is not 
required for post-menopausal or surgically sterilized women. 
6 
Patient has received other investigational drugs within 14 days before enrollment 
7 
Serious medical or psychiatric illness likely to interfere with participation in this clinical 
study. 
 
 
 
8 
Other severe acute or chronic medical or psychiatric condition, including uncontrolled 
diabetes, malabsorption, resection of the pancreas or upper small bowel, requirement 
for pancreatic enzymes, any condition that would modify small bowel absorption of 
oral medications, or laboratory abnormality that may increase the risk associated with 
study participation or investigational product administration or may interfere with the 
interpretation of study results and, in the judgment of the investigator, would make the 
patient inappropriate for enrollment in this study. 
 
10 
Treatment with clinically significant enzyme inducers, such as the enzyme-inducing 
antiepileptic drugs phenytoin, carbamazepine or phenobarbital, or rifampin, rifabutin, 
rifapentine or St. John's wort within 14 days prior to the first dose of MLN8237 and 
during the study. 
11 Known history of human immunodeficiency virus (HIV) infection, hepatitis B, or 
hepatitis C. Testing is not required in the absence of clinical findings or suspicion. 
 
 
12 
Patients have a history of any other malignancy from which the patient has been 
disease-free for less than 2 years, with the exception of adequately treated basal or 
squamous cell carcinoma of skin, superficial bladder cancer or carcinoma in situ of 
cervix, AJCC (version 7.0) stage 0 or I breast cancer, AJCC (version 7.0) stage I, or II 
prostate cancer. 
13 Radiation therapy to more than 25% of the bone marrow. Whole pelvic radiation is 
considered to be over 25%. 
 


 
55 
Protocol #13P.528, v5.4 (13September2017) 
REGISTRATION 
Gender: 
Male 
Female 
Unknown 
Unspecified 
Date of Birth:   
 
Race: 
White 
(Check all that apply) 
Black or African 
American 
Native Hawaiian or 
Other Pacific Islander 
Asian 
American Indian or 
Alaska Native 
Unknown 
Ethnicity: 
Hispanic or Latino 
Not Hispanic or Latino 
Unknown 
Date Study Informed 
Consent Signed:   
 
Date of Registration:   
 
Does the participant satisfy all of the eligibility criteria? 
Yes 
No (If No, complete Off Study form) 
 
 


 
56 
Protocol #13P.528, v5.4 (13September2017) 
INTERVENTION ADMINISTRATION 
 
 
 
 
Agent 
# 
 
Agent 
Dose 
Dose 
Units 
Frequency 
Date Agent 
Provided (to 
Participant) 
Date Agent 
Started 
1 
2 
3 
 


 
57 
Protocol #13P.528, v5.4 (13September2017) 
 
BASELINE MEDICAL/SURGICAL HISTORY 
 
Check here if all body systems are normal: 
 
Body System 
Normal 
Abnormal 
Not 
Assessed 
Comments 
(Required if Abnormal; provide 
condition/diagnosis) 
H/E/E/N/T 
Neck 
Respiratory 
Cardiovascular 
Gastrointestinal 
Musculoskeletal 
Dermatologic 
Hematopoietic/Lymph 
Endocrine/Metabolic 
Genitourinary 
Breasts 
Neurologic 
Does the participant have any allergies? 
Yes 
No 
If Yes, specify: 
 


 
58 
Protocol #13P.528, v5.4 (13September2017) 
BASELINE SYMPTOMS 
 
Check here if none reported (no baseline symptoms): 
 
Symptom Description 
Onset Date 
Grade* 
Comments 
*Grade 
1 = Mild; 2 = Moderate; 3 = Severe; 4 = Life Threatening 
 


 
59 
Protocol #13P.528, v5.4 (13September2017) 
PHYSICAL EXAM 
 
Examination Date :   
 
Not Done 
Height:   
 
cm 
Not Obtained 
in 
Weight:   
 
kg 
Not Obtained 
lb 
Temperature:   
 
°C 
Not Obtained 
°F 
Pulse Rate:    
 
Not Obtained 
Respiration Rate:    
 
Not Obtained 
Blood Pressure:    
 
Not Obtained    Systolic (mm Hg) Diastolic (mm Hg) 
ECOG Performance Status: 
0 
1 
2 
3 
4 
Check here if NO body systems were examined: 
 
Body System/Site 
Normal 
Abnormal 
Not 
Examined 
Comments 
(Required if Abnormal; provide condition/diagnosis) 
Appearance* 
Skin* 
H/E/E/N/T* 
Thyroid 
Chest 
Lungs 
Breasts 
Heart 
Abdomen 
Musculoskeletal* 
Genitalia 
Pelvis 
Rectal 
Prostate 
Vascular 
Neurological* 
Lymph Nodes 
* Required Assessments 
All other Body Systems/Sites are to be done as clinically indicated. 
 


 
60 
Protocol #13P.528, v5.4 (13September2017) 
 
MMSE and QLQ result 
 
* Attach MMSE and QLQ result here. 
 


 
61 
Protocol #13P.528, v5.4 (13September2017) 
 
BASELINE IMAGING STUDY PRIOR TO RECEIVING PROTOCOL TREATMENT 
(Fill in what is applicable) 
 
 
 
* Please attached MRI, CT, PET/CT report here. 
 


 
62 
Protocol #13P.528, v5.4 (13September2017) 
 
CONCOMITANT MEDICATIONS/STEROIDS USE LOG 
(medications prescribed during study period) 
 
 
At end of study only: check this box if participant did not take any concomitant medications 
None 
 
 
Date 
Medication 
Dose 
Frequency Start Date 
Stop Date 
Continuing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
63 
Protocol #13P.528, v5.4 (13September2017) 
 
CLINICAL LABORATORY DATA 
 
* Attached blood test report here. 
* Attach EKG report here. 
 


 
64 
Protocol #13P.528, v5.4 (13September2017) 
 
PREGNANCY SPECIMEN DATA 
 
 
 
If “participant is male” or “participant is female and not of childbearing potential” and pregnancy 
specimen data was NOT COLLECTED please select the corresponding check-box below. 
Otherwise, if participant is female and is of childbearing potential, please complete the form by 
indicating results for all completed tests or check the “Not Obtained box” if a test was not 
performed. 
 
 
Reason pregnancy data was not collected: 
Participant is male 
Participant is female and not of childbearing potential 
 
Lab Test 
Pregnancy Test 
Type 
Result 
Date Specimen 
Collected 
Pregnancy 
Urine 
Serum 
Not Obtained 
Positive 
Negative 
 


 
65 
Protocol #13P.528, v5.4 (13September2017) 
 
TREATMENT INTERRUPTION / MODIFICATION FORM 
 
 
TREATMENT Interruptions: 
 
 
Stop Date 
Reason Stopped 
Specify Reason 
Stopped 
 
Investigator decision, specify 
1 
Participant decision, specify 
AE/SAE, specify 
Other, specify 
Investigator decision, specify 
2 
Participant decision, specify 
AE/SAE, specify 
Other, specify 
Investigator decision, specify 
3 
Participant decision, specify 
AE/SAE, specify 
Other, specify 
Investigator decision, specify 
4 
Participant decision, specify 
AE/SAE, specify 
Other, specify 
 
Was Agent 
Restarted? 
 
Yes 
No 
N/A 
 
Yes 
No 
N/A 
 
Yes 
No 
N/A 
 
Yes 
No 
N/A 
If Yes, 
date restarted 
 


 
66 
Protocol #13P.528, v5.4 (13September2017) 
 
AE log 
 
Attached AE log form here 
 


 
67 
Protocol #13P.528, v5.4 (13September2017) 
 
OFF STUDY* 
 
Date On Follow-up: 
Not Applicable 
Date Off Follow-up: 
Not Applicable 
Date Off Study: 
Date of Last Contact: 
Date Last Study Agent Taken: 
Not Applicable 
 
 
Reason Off Study  (Please mark only the primary reason. Reasons other than Completed 
Study require explanation below) 
Completed study 
Ineligible 
 
AE/SAE (complete AE CRF & SAE form, if applicable) 
 
Lost to follow-up 
 
Non-compliant participant 
Concomitant medication 
Medical contraindication 
Pregnancy 
Withdraw consent 
 
Death (complete Death Report CRF & SAE form) 
 
Other 
 
Reason Explanation: 
 
 
 
 
 
 
 
 
*This form must be completed for all participants that have signed an informed consent, 
including screen failures. 
 


 
68 
Protocol #13P.528, v5.4 (13September2017) 
 
DEATH REPORT 
 
 
 
Date of Death:   
 
Place of Death: 
Hospital (Submit discharge summary to NCI, 
DCP) 
Other, specify: 
Unknown 
Cause of Death: 
AE/SAE 
Other, specify:   
 
Unknown 
Autopsy performed? 
Yes (Attached autopsy report here) 
No 
Unknown 
 


 
69 
Protocol #13P.528, v5.4 (13September2017) 
 
VERIFICATION 
 
 
 
 
The Investigator signature on this form should be obtained after ALL the Case Report Forms for this 
participant have been completed. 
 
 
 
“I have reviewed all the Case Report Forms for the above participant and agree that they 
are accurate and complete.” 
 
 
 
 
 
 
Investigator’s Signature 
Date 
 
 
 
 
 
 
Investigator Name (PLEASE PRINT)