Clinical trial NCT02781792
Conditions: Glioma Glioblastoma Multiforme
Sponsor: Washington University School of Medicine
Start date: 2016-08-11; Completion date: 2024-07-18
Enrollment: 42 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Temozolomide (TMZ) is the chemotherapy drug approved by the FDA to increase survival in glioblastoma (GBM) patients beyond surgical resection and radiation therapy alone. Give its activity in astrocytomas, TMZ is commonly used in grade III anaplastic astrocytoma (AA) as well. Both grade III AA and grade IV GBM are high grade gliomas (HGG). The short half-life of this drug and known oscillations in DNA damage repair make it an ideal candidate for chronotherapy.

Chronotherapy is the improvement of treatment outcomes by minimizing treatment toxicity and maximizing efficacy through delivery of a medication according to the timing of biological rhythms within a patient. Chronotherapy has improved outcomes through the reduction of side effects and increase in anti-tumor activity for a variety of cancers, but has never been applied to the treatment of gliomas.

Based on the preliminary preclinical data for chronotherapeutic TMZ treatment of intracranial glioma xenografts and the success of chronotherapy in the treatment of other cancers, the investigators hypothesize that the timing of TMZ treatment will alter its efficacy and toxicity.

Detailed description:

Arms: arm 1: * Temozolomide will be given as per standard of care. Typical dosing is 150 to 200 mg/m\^2 on Days 1 through 5 of a 28-day treatment cycle. Patients will be randomized to take their temozolomide doses in the morning (before 10:00).
* FACT-Br quality of life at baseline, at the beginning of each cycle of chemotherapy, and 1 month after the final chemotherapy treatment arm 2: * Temozolomide will be given as per standard of care. Typical dosing is 150 to 200 mg/m2 on Days 1 through 5 of a 28-day treatment cycle. Patients will be randomized to take their temozolomide doses in the evening (after 20:00).
* FACT-Br quality of life at baseline, at the beginning of each cycle of chemotherapy, and 1 month after the final chemotherapy treatment
Interventions: intervention 1: Temozolomide intervention 2: Functional Assessment of Cancer Therapy - Brain intervention 3: ActTrust Condor Instrument Watch
Intervention descriptions: intervention 1: -Given standard of care intervention 2: * 23-item questionnaire that can be completed in 5 to 10 minutes with little or no assistance in patients who are not neurologically incapacitated. This brain subscale is usually used along with the core (general) questionnaire \[2\] that includes 27 items.
* Patients rate all 5 items using a five-point Likert scale ranging from 0 "not at all" to 4 "very much." Overall, higher ratings suggest higher QOL. Items are totaled to produce the following subscales, along with an overall QOL score: physical well-being (7 items); social/family well-being (7 items); emotional well-being (6 items); functional well-being (7 items); and concerns relevant to patients with brain tumors (23 items)
* The sleep portion of this questionnaire consists of 17 questions about sleeping patterns and the ability to rate severity of insomnia. intervention 3: -Will be required to wear 24 hours per day and will only be removed at specified data collection time points

Protocol documents:
Prot_SAP_000.pdf: 
 
Version 09/20/22 
 
page 1 of 35 
 
 
 
A Randomized Feasibility Study Evaluating Temozolomide Chronotherapy for High Grade 
Glioma 
 
Washington University School of Medicine 
Division of Oncology 
660 South Euclid Avenue, Campus Box 8056 
St. Louis, MO  63110 
 
Protocol #: 201605081 
Version Date: 09/20/2022 
 
Principal Investigator: 
Milan Chheda, M.D. 
Phone:  (314) 747-2712 
E-mail:  mchheda@ wustl.edu  
 
 
Sub-Investigators 
 
 
 
 
Modality 
Katherine Weilbaecher, M.D.  
 
 
Medical Oncology 
Joshua Rubin, M.D., Ph. D.  
 
 
Pediatrics  
Emily Slat 
 
 
 
 
 
Clinical Trial Training Group  
Melissa Meyer 
 
 
 
 
Clinical Trial Training Group 
Beverly Riola  
 
 
 
 
Clinical Trial Training Group  
 
Yu Tao, Ph.D.  
 
 
 
 
Biostatistics 
 
 
Study Drug(s): 
 
Temozolomide (Temodar) 
 
 
ClinicalTrials.gov #: 
NCT02781792 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them 
 
 


 
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A Randomized Feasibility Study Evaluating Temozolomide Chronotherapy for High Grade 
Glioma 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
05/11/2016 
Amendment #1 Version 
 
 
 
 
 
 
09/29/2016 
Amendment #2 Version 
 
 
 
 
 
 
01/27/2017 
Amendment #3 Version 
 
 
 
 
 
 
08/23/2017 
Amendment #4 Version 
 
 
 
 
 
 
09/25/2018 
Amendment #5 Version 
 
 
 
 
 
 
11/09/2018 
Amendment #6 Version 
 
 
 
 
 
 
09/17/2020 
Amendment #7 Version 
 
 
 
 
 
 
08/02/2021 
Amendment #8 Version 
 
 
 
 
 
 
03/22/2022 
Amendment #9 Version 
 
 
 
 
 
 
09/20/2022 


 
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A Randomized Feasibility Study Evaluating Temozolomide Chronotherapy for High Grade 
Glioma 
 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment Plan 
Randomize patients to morning (before 10:00) or evening 
(after 20:00) temozolomide treatment.  
Eligible Patients 
Newly diagnosed and recurrent high grade gliomas (WHO grades III & IV) and high 
risk WHO grade II gliomas who are to begin treatment with monthly high dose 
temozolomide therapy See protocol Section 3.0 
At time of enrollment in study 
Baseline quality of life surveys 
During each cycle of treatment 
Quality of life surveys filled out at clinic visits 
Hematologic toxicity assessed by standard blood draws 
Long-term follow-up 
To assess progression-free and overall survival, patient charts 
will be followed by chart review or at follow up visits until 24 
months. Tumor progression or death will be recorded. 
Two months after final temozolomide treatment 
Final quality of life survey 
Screening and Enrollment 
Patients will be screened and enrolled prior to starting high dose temozolomide 
therapy. Patients will sign informed consent forms, have baseline labs completed 
and initial quality of life surveys. 


 
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Glossary of Abbreviations 
 
AE 
Adverse event 
CBV 
Cerebral Blood Volume 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DNA 
DOB 
Deoxyribonucleic acid 
Date of Birth 
DSM 
Data and Safety Monitoring  
HRPO 
Human Research Protection Office (IRB) 
HGG 
High Grade Glioma 
IRB 
MD 
Institutional Review Board 
Medical Doctor 
MLA 
Minimal lumen area 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
PFS 
Progressive disease 
Progression Free Survival 
PI 
Principal investigator 
PR 
Partial response 
QASMC 
QOL 
RANO 
Quality Assurance and Safety Monitoring Committee 
Quality of Life 
Response Assessment in Neuro-Oncology 
SAE 
SAP 
Serious adverse event 
Statistical analysis plan 
SD 
T2/FLAIR 
TEAE 
TMZ 
Stable disease 
T2-weighted Fluid Attenuated Inversion Recovery 
Treatment-emergent adverse events 
Temozolomide 
UPN 
Unique patient number 
WHO 
World Health Organization 
 
 


 
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Table of Contents 
SCHEMA ........................................................................................................................................ 3 
1.0 
BACKGROUND AND RATIONALE ............................................................................... 6 
1.1 
Glioblastoma Multiforme................................................................................................ 6 
1.2 
Temozolomide (Temodar) .............................................................................................. 7 
1.3 
Chronotherapy................................................................................................................. 7 
1.4 
Circadian Clock .............................................................................................................. 8 
1.5 
Anti-Tumor T Cell Activity and Circadian Rhythms ................................................... 10 
1.6 
Quality of Life............................................................................................................... 10 
1.7       Study Rationale ............................................................................................................. 10 
2.0 
OBJECTIVES ................................................................................................................... 11 
2.1 
Primary Objective ......................................................................................................... 11 
2.2 
Secondary Objectives.................................................................................................... 11 
3.0 
PATIENT SELECTION ................................................................................................... 12 
3.1 
Inclusion Criteria .......................................................................................................... 12 
3.2 
Exclusion Criteria ......................................................................................................... 12 
3.3 
Inclusion of Minorities .................................................................................................. 12 
4.0 
REGISTRATION PROCEDURES .................................................................................. 12 
4.1 
Confirmation of Patient Eligibility ............................................................................... 12 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database ......................... 13 
4.3 
Assignment of UPN ...................................................................................................... 13 
4.4 
Randomization .............................................................................................................. 13 
5.0 
STUDY PLAN .................................................................................................................. 13 
5.1 
Study Procedures .......................................................................................................... 13 
5.2 
Study Assessments ........................................................................................................ 13 
5.3 
Duration of Study Participation .................................................................................... 14 
5.4 
Definition of Evaluability ............................................................................................. 14 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS ................................................................... 14 
7.0 
CORRELATIVE STUDIES ............................................................................................. 14 
7.1 
Quality of Life Surveys ................................................................................................. 14 
7.2 
Wrist Actimetry and Sleep Questionnaire .................................................................... 15 
8.0 
REGULATORY AND REPORTING REQUIREMENTS .............................................. 15 
9.0 
STUDY CALENDAR ...................................................................................................... 16 
10.0 
DATA SUBMISSION SCHEDULE ................................................................................ 16 
11.0 
MEASUREMENT OF EFFECT....................................................................................... 16 
11.1 
Antitumor Effect – Solid Tumors ................................................................................. 16 
11.2 
Disease Parameters ....................................................................................................... 19 
11.3 
Methods for Evaluation of Measurable Disease ........................................................... 19 
12.0 
DATA AND SAFETY MONITORING ........................................................................... 22 
13.0 
STATISTICAL CONSIDERATIONS.............................................................................. 23 
13.1 
Endpoints ...................................................................................................................... 23 
13.2 
Data Analysis ................................................................................................................ 23 
14.0 
REFERENCES ................................................................................................................. 27 
Appendix A: Karnofsky Performance Status Scale ...................................................................... 30 
Appendix B: FACT-BR Quality of Life Survey ........................................................................... 31 
 
 


 
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1.0 
BACKGROUND AND RATIONALE 
 
1.1 
Glioblastoma Multiforme 
 
Glioblastoma multiforme (GBM) is the most aggressive and most common malignant 
primary brain tumor in adults (Ostrom et al., 2013). GBM accounts for 15.6% of all primary 
brain and central nervous system (CNS) tumors and 54.4% of all gliomas (Ostrom et al., 
2013; Central Brain Tumor Registry of the United States) (Figure 1).  
 
 
 
Figure 1. Distribution of primary brain and CNS tumors. (a) Distribution of primary and CNS based on 
histology. (b) Distribution of primary brain and CNS gliomas based on histology. Ostrom et al., 2013, 
modified. 
 
Standard therapy for treatment of GBM includes surgical resection followed by radiation 
a)
b)


 
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therapy with concomitant temozolomide.  
 
1.2 
Temozolomide (Temodar) 
 
The addition of the DNA alkylator temozolomide extended median survival by 2.5 months 
compared to surgical resection and radiation therapy alone (Stupp et al., 2005; figure 2).  
 
Figure 2. Progression-free survival (PFS) (left) and overall survival (OS) (right) of GBM patients receiving 
radiotherapy plus temozolomide versus radiotherapy alone. (Stupp et al, 2005, modified). 
 
Despite initial response to standard therapy, GBM has a poor prognosis, resulting in a 
median survival of 14.6 months (Ohka et al., 2012). Development of new therapies is 
important, but equally important is the optimization of currently available therapies for 
patients who are fighting to survive brain tumors now. 
 
1.3 
Chronotherapy 
 
Chronotherapy is the improvement of treatment outcomes by minimizing treatment toxicity 
and maximizing efficacy through delivery of a medication according to the timing of 
biological rhythms within a patient (Levi and Okyar, 2011). This concept has been applied 
to a variety of medications, including chemotherapeutics. Chronochemotherapy has 
successfully improved anti-tumor effect in the treatment of metastatic colon cancer (Levi 
et al., 1995, 2001; Innominato et al., 2010), improved survival rate in patients with ovarian 
cancer (Kobayashi et al., 2002), and decreased relapse rate for children with acute 
lymphoblastic leukemia (Rivard et al., 1993; Schmeigelow et al., 1997). Chronotherapy 
has the capacity to improve treatment outcomes for many other cancers, including GBM. 
 
In a mouse model of GBM, we have demonstrated greater anti-tumor efficacy of 
temozolomide during morning administration. Delivery of temozolomide by oral gavage 
at 7am showed a trend toward increased length of survival compared to delivery at 7pm 
(Figure 3).  
 


 
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Figure 3. Morning temozolomide (TMZ) treatment lengthens survival. Delivery of TMZ at 7am resulted in 
a longer median survival than 7pm TMZ delivery (11.2 vs 9.1 weeks, p=0.057).  
 
In a follow-up study with decreased tumor burden, intracranial GBM tumors shrank at a 
greater rate following 7am TMZ treatment compared to 7pm TMZ treatment. Tumor size 
was determined based upon weekly measurement of a bioluminescent reporter expressed 
by tumor cells. Figure 4 demonstrates a reduction in average tumor size for mice receiving 
TMZ. Mice receiving vehicle have continued tumor growth.  
 
 
Figure 4. Morning TMZ treatment results in greater reduction in tumor size compared to evening TMZ 
treatment.  
 
1.4 
Circadian Clock 
 
For decades, scientists have studied the regulation of daily oscillations in biological 
processes. At the end of the twentieth century, a regulator of these daily oscillations was 
discovered within individual cells, known as the molecular clock. Core clock genes form a 
molecular clock within cells to regulate a variety of cellular processes through the 
transcriptional control of gene expression (Reppert & Weaver, 2002). Reduced expression 
of several core clock genes, including Period2 and Period3, has been correlated with 
decreased survival in glioma patients (Repository for Molecular Brain Neoplasia Data, 
Figure 5).  
Treatment 


 
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Figure 5. Decreased survival is correlated with reduced core clock gene expression in gliomas. 
Downregulated expression of core clock genes Period2 and Period3 is linked to decreased survival in 343 
glioma patients (Repository for Molecular Brain Neoplasia Data).  
 
The molecular clock has also been linked to the DNA damage response pathway through 
protein-protein interactions of Period1 and Period3 with ATM, enhancing downstream 
phosphorylation of Chk2 in response to DNA double strand breaks (Figure 6; Gery et al., 
2006; Im et al., 2010). These discoveries suggest a role for the molecular clock in the 
cellular response to DNA damage. Therefore, DNA damaging agents like temozolomide 
may be most effective at the time when core clock proteins Period1 and Period3 are most 
abundant in the cell. 
 
 
 
Figure 6. Survival curves of patients with metastatic colorectal cancer according to the presence or absence 
of circadian disruption before chemotherapy start. The locomotor rhythm, recorded by a wrist-actigraph, was 
used as circadian biomarker. Circadian disruption was defined as being present in patients whose dichotomy 
index was in the lowest quartile (dashed grey line). The left panel shows data from 192 patients, receiving 
chronomodulated chemotherapy, as first or second line treatment. The right panel shows data from 130 


 
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previously untreated patients receiving either chronomodulated or conventional chemotherapy. (from 
Innominato et al, ADDR 2010). 
 
1.5 
Anti-Tumor T Cell Activity and Circadian Rhythms  
 
The immune response is an important predictor of glioma progression. Generally, the 
immune system and, more specifically, T lymphocytes are known to recognize tumor cells 
and target them for destruction. This action can initially restrain solid tumor growth. In 
support of this concept, glioma patients with lymphopenia have worse OS (Grossman et al, 
2011). Chemotherapy such as TMZ that targets highly proliferative populations affects T 
cell populations in addition to tumor cells. T lymphocyte populations experience rapid 
proliferation, especially after exposure to activating antigen, like that released when a 
tumor cells dies from chemotherapy. However, the rapid proliferation of the T lymphocytes 
could be inhibited by chemotherapy. Glioma patients given TMZ and radiation experience 
lymphopenia after two months of treatment and lymphocyte counts remain depressed 
during the entire course of treatment (Grossman et al 2011). It would be ideal to specifically 
target the tumor cells while allowing the anti-tumor T cells to remain. 
 
Like many other processes in the body, lymphocyte proliferation is dependent on circadian 
rhythms. Multiple studies have shown differential effects on lymphopenia depending on 
the time of day chemotherapy is administered. In a retrospective study, gemcitabine given 
at 9:00 am was less toxic to lymphocytes than gemcitabine given at 3:00 pm (Iwata K et 
al, 2011). In other studies, T cell progenitors in the bone marrow were found to be less 
proliferative at night. Due to the reduced proliferation, nighttime administration of 
docetaxel and irinotecan was found to reduce lymphocyte toxicity (Tampellini M et al 
1998, Ohdo S 1997). This would suggest administering chemotherapy at a time of less T 
cell proliferation would prevent lymphopenia and potentially support the T cell mediated 
anti-tumor immune response as well as allow patients to stay on treatment schedule. This 
could be an addition mechanism by which patients could benefit from chronotherapy.  
 
1.6 
Quality of Life 
 
Beyond patient outcome and measured biologic outcomes, it is also important to consider 
patient quality of life in response to treatment. Quality of life refers to the patient’s ability 
to conduct themselves as normal in reference to physical well-being, social interactions, 
emotional well-being, and ability to function normally. These qualities can be assessed 
through surveys administered to the patient throughout their disease and treatment (Piil et 
al 2015, Omuro et al 2014). Side effects and disease progression can influence quality of 
life significantly. In this study we will assess quality of life to determine how 
chronotherapy increases quality life experienced by some patients.  
 
1.7       Study Rationale 
 
Temozolomide (TMZ) is the chemotherapy drug approved by the FDA to increase survival 
in glioblastoma (GBM) patients beyond surgical resection and radiation therapy alone. 
Give its activity in astrocytomas, TMZ is commonly used in grade III anaplastic 
astrocytoma (AA) as well. Both grade III AA and grade IV GBM are high grade gliomas 


 
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(HGG). The short half-life of this drug and known oscillations in DNA damage repair make 
it an ideal candidate for chronotherapy. Chronotherapy has improved outcomes through 
the reduction of side effects and increase in anti-tumor activity for a variety of cancers, but 
has never been applied to the treatment of gliomas. Based on the preliminary preclinical 
data for chronotherapeutic TMZ treatment of intracranial glioma xenografts and the 
success of chronotherapy in the treatment of other cancers, we hypothesize that the timing 
of TMZ treatment will alter its efficacy and toxicity.  
 
These effects will be assessed by the following means: 
1. Randomized assignment of patients to one of two treatment time frames (before 
10:00 versus after 20:00).  
2. Measurement of hematologic toxicity throughout treatment. 
3. Assessment of QOL through surveys. 
4. Correlation of PFS and OS to chronotherapeutic treatment windows. 
5. Assessment of daily rest-activity rhythms as well as overall daily activity. 
 
 
2.0 
OBJECTIVES 
 
This exploratory study will collect pilot data for assessment of treatment outcomes in future glioma 
chronotherapeutic studies. 
 
2.1 
Primary Objective 
 
To determine the feasibility of treatment compliance and randomization of HGG patients 
to receive temozolomide between morning (before 10:00) or evening (after 20:00) 
treatment groups. Feasibility is defined as at least 80% compliance with assigned 
administration time.  
 
2.2 
Secondary Objectives 
 
1. To determine the number of HGG patients with grade 3 or 4 hematologic toxicity, 
including lymphopenia, thrombocytopenia, neutropenia and anemia, while receiving 
temozolomide when administered in the morning (before10:00) or evening (after 
20:00). 
2. To assess quality of life using quality of life surveys in HGG patients receiving 
temozolomide in the morning versus evening. 
3. To evaluate progression-free survival of HGG patients taking TMZ in the morning 
versus evening through chart view or patient visits. 
4. To determine overall survival of HGG patients taking TMZ in the morning versus 
evening through chart review or patient visits. 
5. To correlate the sleep-wake cycles of patients receiving temozolomide for treatment of 
HGG with treatment outcomes for morning versus evening TMZ treatments. 
 
 
 


 
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3.0 
PATIENT SELECTION 
 
3.1 
Inclusion Criteria 
 
1.    Newly diagnosed and recurrent high grade gliomas (WHO grades III & IV) and 
high risk WHO grade II gliomas who are to begin treatment with monthly high dose 
temozolomide therapy. 
 
2. At least 18 years of age. 
 
3. Karnofsky performance status ≥ 60%, see Appendix A 
 
4. Ability to understand and willingness to sign an IRB approved written informed 
consent document. 
 
3.2 
Exclusion Criteria 
 
1. Pregnant and/or breastfeeding.  Women of childbearing potential must have a negative 
pregnancy test within 14 days of study entry. 
 
3.3 
Inclusion of Minorities 
 
Women and members of all races and ethnicities are eligible for this trial. 
 
 
4.0 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility 
2. Registration of patient in the Siteman Cancer Center OnCore database 
3. Assignment of unique patient number (UPN) 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below: 
 
1. Registering MD’s name 
2. Patient’s race, sex, and DOB 
3. Three letters (or two letters and a dash) for the patient’s initials 
4. Copy of signed consent form 
5. Completed eligibility checklist, signed and dated by a member of the study team 
6. Copy of appropriate source documentation confirming patient eligibility 


 
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4.2 
Patient Registration in the Siteman Cancer Center OnCore Database 
 
All patients must be registered through the Siteman Cancer Center OnCore database. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  All data 
will be recorded with this identification number on the appropriate CRFs. 
 
4.4 
Randomization 
 
Eligible patients will be randomized on a 1:1 basis to receive temozolomide at one of two 
time points: before 10:00 or after 20:00. A computer-generated randomization scheme is 
used to assign subjects. It is maintained centrally by the study statistician.   
 
 
5.0 
STUDY PLAN 
 
5.1 
Study Procedures 
 
Temozolomide will be given as per standard of care.  Typical dosing is 150 to 200 mg/m2 
on Days 1 through 5 of a 28-day treatment cycle. Patients will be randomized to take their 
temozolomide doses in the morning (before 10:00) or evening (after 20:00). Compliance 
with dosing times will be verified by means of a medication diary (Appendix B).  Patients 
who miss taking their dose at the assigned time will be instructed to take the dose as soon 
as they can (as long as the next scheduled dose is at least 12 hours away) rather than 
omitting it. 
 
Patients will be given an ActTrust Condor Instrument watch after signing the consent form. 
Patients will be required to wear the ActTrust Condor Instrument watch 24 hours per day; 
it should only be removed at specified data collection time points (see protocol calendar 
9.0). Actimetry data will be collected at corresponding time points with the return of the 
patient to clinic every 8 weeks. The ActTrust watch does not require the patient to charge 
the device, thus the patient will never have to remove the watch and a new, fully charged, 
watch will be provided to the patient at every collection time point.   
 
 
5.2 
Study Assessments 
 
5.2.1 Hematologic toxicity  
 
Hematologic toxicity will be assessed by standard blood collection.  Blood draws 
will occur within the same 4-hour window each cycle for each patient to take into 
account peripheral blood T cell numbers. (Timing of draws need not be 


 
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synchronized across patients, only consistent for each individual patient.) 
 
Hematologic toxicity will include grade 3 and 4 lymphopenia, thrombocytopenia, 
anemia and neutropenia. The criteria are summarized in the following chart: 
Toxicity 
Cell Type 
Grade III criteria 
Grade IV 
criteria 
Lymphopenia 
Lymphocytes 
<500-200/mm3 
<200/mm3 
Leukopenia 
Leukocytes 
<2000-1000/mm3 
<1000/mm3 
Neutropenia 
Neutrophils 
<1000-500/mm3 
<500/mm3 
Thrombocytopenia 
Platelets 
<50,000-
25,000/mm3 
<25,000/mm3 
Anemia 
RBC 
(Hemoglobin) 
<8.0-6.5 g/dL 
<6.5 g/dL 
 
5.3 
Duration of Study Participation 
 
Patients will be considered active participants from time of consent through 2 months 
following the last cycle of temozolomide. Patients will be followed after this time for 24 
months.  
 
5.4 
Definition of Evaluability 
 
Patients receiving a minimum of one full cycles of TMZ will be evaluable for the primary 
endpoint.  
 
 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS 
 
Dose delays or dose modifications will follow the standard of care. 
 
 
7.0 
CORRELATIVE STUDIES 
 
7.1 
Quality of Life Surveys 
 
Patient quality of life will be assessed using a standard quality of life survey specifically 
designed for brain cancer patients (the FACT-Br, see Appendix C). QOL assessments will 
be performed at the following time points: 
• baseline  
• at the beginning of each cycle of chemotherapy 
• 1 month after the final chemotherapy treatment. 
 
The QOL surveys will be administered during an office visit by the study coordinator.  
 
 
 


 
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7.2 
Wrist Actimetry and Sleep Questionnaire 
 
The ActTrust Condor Instrument watches are wrist actimetry/accelerometers. Large 
datasets from these devices can be accessed and analyzed through ActStudio (Condor 
Instruments). This technology has been used already by several groups at Washington 
University in St. Louis. 
 
Patients will wear an accelerometer on their wrist to measure activity level during the day 
and at night until two months after the end of treatment. The accelerometer will appear 
similar to an athletic wristwatch. Patients will be required to wear the accelerometer at all 
times starting at the beginning of treatment or as soon as they are enrolled in the study, 
whichever is later. Patients will remove the accelerometer only during situations when the 
accelerometer would be completely submersed in water or liquid. Wrist actigraphy will be 
quantified in one-minute bins for the duration of the recording (typically 60 days per 
patient). The data (counts per minute) will be quantified in terms of average activity per 
day, percent of activity during waking, percent of activity during sleep, chronotype 
(average time of daily mid-sleep), chronotype variability (e.g. cycle-to-cycle standard 
deviation of daily chronotype), sleep duration, nap duration, and number of naps per day. 
This data will be collected once every 2 months. Patients will not need to charge the watch 
and upon data collection, a new watch (that is fully charged) will be available for them to 
take.  Once data are collected, it will be analyzed for sleep/wake cycles and overall activity 
level. Total activity will be measured as average acceleration over 24 hours. Patterns of 
acceleration will also be noted relative to treatment times in 2 hour increments. 
 
At baseline and at the beginning of each cycle of TMZ, the patient will complete a sleep 
questionnaire that will be used in conjunction with the ActTrust watch. This qualitative 
data (sleep questionnaire) will be used with the quantitative data (collected via the ActTrust 
watch) to assess the level of disruption in sleep/wake cycles experienced by the patient 
while on study. This data will be collected up to 1 month after the last TMZ treatment. 
These sleep questionnaires will be administered during an office visit by the study 
coordinator.  
 
8.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
The Principal Investigator is responsible for ensuring the safety of subjects who have enrolled in 
the study.  The PI will monitor the study for adverse events directly attributable to participation in 
this study (i.e. events associated with the research specimen collections and QOLs, not events 
associated with routine administration of temozolomide). Because the care obtained while on trial 
is indicated and standard of care, no adverse events are likely to be attributable to enrollment.  If 
any breach of confidentiality were to occur, it would be reported according to the HRPO-
recommended guidelines. 
 


 
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9.0 
STUDY CALENDAR 
 
 
Baseline 
Beginning of each 
cycle of TMZ 
1 month after the last 
TMZ treatment3 
Follow-
up1 
Informed consent 
X 
 
 
 
ActTrust Condor 
Instrument watch 
Continuously beginning after the signing of consent but no 
more than 2 weeks prior to initiation of TMZ 
 
Sleep Questionnaire 
X 
X 
X 
 
FACT-Br 
X 
X 
X 
 
Randomization 
X 
 
 
 
Tracking of 
hematologic toxicity2 
 
X 
 
 
Review of medical 
record 
 
 
 
X 
1. Every 3 months by chart review looking for progression and survival. 
2. From SOC blood draws. 
3. To coincide with the patient’s SOC end of treatment follow up visit with treating physician.  
 
 
10.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
Registration Form 
Eligibility Form 
On-Study Form 
FACT-Br 
Randomization Form 
Quality of Sleep Questionnaire 
Prior to starting treatment 
Hematologic Toxicity Form 
Monthly 
Medication Diary 
End of every cycle 
FACT-Br 
Quality of Sleep Questionnaire 
Beginning of each cycle 
1 month after EOT 
Follow-Up Form 
Every 3 months until 24 months after 
active participation 
 
 
11.0 
MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 8 +/- 1 
weeks. After the first year, scans may go to every 12 weeks +/- 1 week. After the second year, 


 
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scans may go to every 16 weeks +/-1 week, depending on physician choice.  In addition to a 
baseline scan, confirmatory scans should also be obtained 8 weeks (not less than 4) weeks 
following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the updated response 
assessment criteria for high-grade gliomas: Response Assessment in Neuro-Oncology 
(RANO) working group guideline [JCO 28(11): 1963-1972, 2010]. 
 
Criteria for Determining First Progression Depending on Time from Initial Chemoradiotherapy 
First Progression 
Definition 
Progressive disease < 12 
weeks after completion of 
chemoradiotherapy 
Progression can only be defined using diagnostic imaging if there is new 
enhancement outside of the radiation field (beyond the high-dose region or 
80% isodose line) or if there is unequivocal evidence of viable tumor on 
histopathologic sampling (eg, solid tumor areas [ie, > 70% tumor cell nuclei 
in areas], high or progressive increase in MIB-1 proliferation index 
compared with prior biopsy, or evidence for histologic progression or 
increased anaplasia in tumor). Note: Given the difficulty of differentiating 
true progression from pseudoprogression, clinical decline alone, in the 
absence of radiographic or histologic confirmation of progression, will not 
be sufficient for definition of progressive disease in the first 12 weeks after 
completion of concurrent chemoradiotherapy.  
Progressive disease ≥ 12 
weeks after 
chemoradiotherapy 
completion 
1. New contrast-enhancing lesion outside of radiation field on 
decreasing, stable, or increasing doses of corticosteroids. 
2. Increase by ≥ 25% in the sum of the products of perpendicular 
diameters between the first postradiotherapy scan, or a subsequent 
scan with smaller tumor size, and the scan at 12 weeks or later on 
stable or increasing doses of corticosteroids.  
3. Clinical deterioration not attributable to concurrent medication or 
comorbid conditions is sufficient to declare progression on current 
treatment but not for entry onto a clinical trial for recurrence.  
4. For patients receiving antiangiogenic therapy, significant increase in 
T2/FLAIR nonenhancing lesion may also be considered progressive 
disease. The increased T2/FLAIR must have occurred with the 
patient on stable or increasing doses of corticosteroids compared 
with baseline scan or best response after initiation of therapy and 
not be a result of comorbid events (eg, effects of radiation therapy, 
demyelination, ischemic injury, infection, seizures, postoperative 
changes, or other treatment effects).  
 
Criteria for Response Assessment Incorporating MRI and Clinical Factors (Adapted from JCO 
2010) 
Response 
Criteria 
Complete 
response 
• Requires all of the following: complete disappearance of all enhancing 
measurable and nonmeasurable disease sustained for at least 4 weeks. 
• No new lesions; stable or improved nonenhancing (T2/FLAIR) lesions. 


 
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Response 
Criteria 
• Patients must be off corticosteroids (or on physiologic replacement doses 
only) and stable or improved clinically. Note: Patients with nonmeasurable 
disease only cannot have a complete response; the best response possible 
is stable disease.  
Partial response 
Requires all of the following:  
• ≥ 50% decrease compared with baseline in the sum of products of 
perpendicular diameters of all measurable enhancing lesions sustained for 
at least 4 weeks. 
• No progression of nonmeasurable disease. 
• Stable or improved nonenhancing (T2/FLAIR) lesions on same or lower 
dose of corticosteroids compared with baseline scan; the corticosteroid 
dose at the time of the scan evaluation should be no greater than the dose 
at time of baseline scan. 
• Stable or improved clinically. Note: Patients with nonmeasurable disease 
only cannot have a partial response; the best response possible is stable 
disease.  
Stable disease 
Requires all of the following:  
• Does not qualify for complete response, partial response, or progression. 
• Stable nonenhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared with baseline scan. In the event that the 
corticosteroid dose was increased for new symptoms and signs without 
confirmation of disease progression on neuroimaging, and subsequent 
follow-up imaging shows that this increase in corticosteroids was required 
because of disease progression, the last scan considered to show stable 
disease will be the scan obtained when the corticosteroid dose was 
equivalent to the baseline dose.  
Progression 
Defined by any of the following:  
• ≥ 25% increase in sum of the products of perpendicular diameters of 
enhancing lesions compared with the smallest tumor measurement 
obtained either at baseline (if no decrease) or best response, on stable or 
increasing doses of corticosteroids*. The absolute increase in any 
dimension must be at least 5mm when calculating the products. 
• Significant increase in T2/FLAIR nonenhancing lesion on stable or 
increasing doses of corticosteroids compared with baseline scan or best 
response after initiation of therapy not caused by comorbid events (e.g. 
radiation therapy, demyelination, ischemic injury, infection, seizures, 
postoperative changes, or other treatment effects). 
• Any new measureable lesion. 
• Clear clinical deterioration not attributable to other causes apart from the 
tumor (e.g. seizures, medication adverse effects, complications of therapy, 
cerebrovascular events, infection, and so on) or changes in corticosteroid 
dose. 


 
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Response 
Criteria 
• Failure to return for evaluation as a result of death or deteriorating 
condition; or clear progression of nonmeasurable disease.  
• 
NOTE. All measurable and nonmeasurable lesions must be assessed using the same 
techniques as at baseline. 
• 
Stable doses of corticosteroids include patients not on corticosteroids.  
11.2 
Disease Parameters 
 
Measurable disease:  Bi-dimensionally measurable lesions with clearly defined margins 
by MRI scan.  All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters).   
 
Non-measurable or evaluable disease:  Uni-dimensionally measurable lesions or lesions 
with margins not clearly defined such as areas of T2/FLAIR signal abnormality or poorly 
defined enhancing abnormality.  
 
Note: For cystic lesions, the only measurable part is any enhancement area around the cyst 
that is clearly defined and bi-dimensionally measurable. The cyst itself should not be 
considered measurable or non-measureable disease. 
 
Target lesions: All measurable lesions that are residual of the lesion treated with MLA 
should be identified as target lesions and recorded and measured.  Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), but in addition should 
be those that lend themselves to reproducible repeated measurements.  It may be the case 
that, on occasion, the largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion, which can be measured reproducibly should be 
selected.  When there are too many measurable lesions, choose the largest three lesions as 
target lesions to follow.  The other measurable lesions should be considered evaluable for 
the purpose of objective status determination. 
 
Non-target lesions:  All non-measurable lesions should be identified as non-target lesions 
and should also be recorded at baseline.  Measurements of these lesions are not required, 
but the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
11.3 
Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler.  All 
baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 2 weeks before the beginning of the treatment. 
 
Clinical lesions:  Clinical lesions will only be considered measurable on brain MRI when 
they are ≥ 5 mm diameter as assessed using a ruler. 
 


 
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Histology:  This technique can be used to differentiate between partial responses (PR) and 
complete responses (CR) in rare cases when biopsy or surgical resection of a measureable 
lesion is clinically indicated.  
 
Perfusion/CBV: This advanced brain MRI technique can be used as an adjunct test to 
determine treatment response or disease status.  However, it should not be used as the 
primary or sole method to determine response or disease status.  
 
Brain FDG-PET coupled with head CT or brain MRI: This advanced metabolic 
imaging technique can be used as an adjunct test to determine response or disease status. 
However it should be used as the primary or sole method of determining response or 
disease status. 
 
11.3.1 Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions. 
 
Partial Response (PR):  ≥ 50% decrease compared with baseline in the sum of 
products of perpendicular diameters of all target lesions sustained for at least 4 
weeks. 
 
Progressive Disease (PD):  At least a 25% increase in the sum of products of 
perpendicular diameters of at least 1 target lesion, taking as reference the smallest 
sum of products of perpendicular diameters on study (this includes the baseline sum 
if that is the smallest on study).  The absolute increase in any dimension must be at 
least 5mm when calculating the products of perpendicular diameters. 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum of products of 
perpendicular diameters while on study. 
 
11.3.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions.  
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s). 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions on stable or increasing doses 
of corticosteroids compared with baseline scan or best response after initiation of 
therapy* not caused by comorbid events (e.g. radiation therapy, demyelination, 
ischemic injury, infection, seizures, postoperative changes, or other treatment 
effects). Unequivocal progression should not normally trump target lesion status.  
It must be representative of overall disease status change, not a single lesion 
increase.     
 


 
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Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and the 
progression status should be confirmed at a later time by the review panel (or 
Principal Investigator). 
 
11.3.3 Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).  The 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
 
Summary of the RANO Response Criteria (Adapted from JCO 2010) 
Criterion 
CR 
PR 
SD 
PD 
T1 gadolinium 
enhancing disease 
None 
≥ 50% ↓ 
< 50% ↓ but < 25% ↑ ≥ 25% ↑* 
T2/FLAIR 
Stable or ↓ Stable or ↓ Stable or ↓ 
↑* 
New lesion 
None 
None 
None 
Present* 
Corticosteroids 
None 
Stable or ↓ Stable or ↓ 
NA† 
Clinical status 
Stable or ↑ Stable or ↑ Stable or ↑ 
↓* 
Requirement for 
response 
All 
All 
All 
Any* 
Abbreviations: RANO, Response Assessment in Neuro-Oncology; CR, complete response; PR, 
partial response; SD, stable disease; PD, progressive disease; FLAIR, fluid-attenuated inversion 
recovery; NA, not applicable.  
* Progression occurs when this criterion is present.  
† Increase in corticosteroids alone will not be taken into account in determining progression in the 
absence of persistent clinical deterioration.  
 
11.3.4 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first 
met for CR until the first date that progressive disease is objectively documented.  
 
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started, including the baseline 
measurements.  


 
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11.3.5 Neurological Exam and Performance Status  
 
Patients will be graded using the Karnofsky Performance Status scale and their 
neurological function evaluated as improved, stable or deteriorated in addition to 
objective measurement of tumor size. These parameters will be used to determine 
the overall response assessment. 
 
11.3.6 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression 
or death, whichever occurs first. 
 
 
12.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, the 
Principal Investigator will provide a Data and Safety Monitoring (DSM) report to the Washington 
University Quality Assurance and Safety Monitoring Committee (QASMC) semi-annually 
beginning six months after accrual has opened (if at least five patients have been enrolled) or one 
year after accrual has opened (if fewer than five patients have been enrolled at the six-month mark). 
 
The Principal Investigator will review all patient data at least every six months, and provide a 
semi-annual report to the QASMC. This report will include: 
• HRPO protocol number, protocol title, Principal Investigator name, data coordinator name, 
regulatory coordinator name, and statistician 
• Date of initial HRPO approval, date of most recent consent HRPO approval/revision, date 
of HRPO expiration, date of most recent QASMC audit, study status, and phase of study 
• History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 
error, or breach of confidentiality including start/stop dates and reason 
• Study-wide target accrual and study-wide actual accrual 
• Protocol activation date 
• Average rate of accrual observed in year 1, year 2, and subsequent years 
• Expected accrual end date and accrual by cohort 
• Objectives of protocol with supporting data and list the number of participants who have 
met each objective 
• Measures of efficacy 
• Early stopping rules with supporting data and list the number of participants who have met 
the early stopping rules 
• Summary of toxicities separated by cohorts 
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety or ethics of the study  
 
The study principal investigator and Research Patient Coordinator will monitor for serious 
toxicities on an ongoing basis. Once the principal investigator or Research Patient Coordinator 


 
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becomes aware of an adverse event, the AE will be reported to the HRPO and QASMC according 
to institutional guidelines. 
 
 
13.0 
STATISTICAL CONSIDERATIONS 
 
This study will include 40 patients with high grade glioma (WHO grades III or IV). Based on an 
extensive simulation regarding the sample size for translational and pilot studies, Piantadosi (2005) 
recommended that a sample size of 10 to 20 patients would provide a reasonable precision for 
estimating preliminary information. We therefore expect that the proposed sample size for this 
study will be adequate in estimating both safety and preliminary efficacy data. 
 
13.1 
Endpoints 
 
13.1.1 Primary Endpoint 
 
The feasibility of patient compliance to chronotherapy in HGG patients treated with 
TMZ will be the primary endpoint.  Feasibility is defined as at least 80% overall 
compliance (8 of 10 patients) with assigned administration time.  Compliance is 
defined as no more than one of five doses of temozolomide per cycle taken outside 
of the assigned administration time. 
 
13.1.2 Secondary Endpoints 
 
1. Number of patients experiencing lymphopenia, thrombocytopenia, neutropenia 
and anemia in each group as measured by standard blood draws. Thresholds for 
each event are listed in the table under Study Assessments below. 
 
2. Score on FACT-BR quality of life survey between morning and evening 
treatment to quantitatively measure quality of life. 
 
3. Progression-free survival as determined by chart review or patient visit. 
 
4. Overall survival as determined by chart review or patient visit.  
 
5. Correlation between sleep pattern and response to treatment in morning and 
evening groups. 
 
 
13.2 
Data Analysis 
 
13.2.1 General Considerations 
 
All data will be evaluated as observed, and no imputation method for missing 
values will be used. All data will be presented in a descriptive manner. Each cohort 
will be analyzed separately, and no multiplicity adjustment across cohorts will be 


 
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performed. All other analyses are considered as exploratory, even if statistical tests 
are used.  
 
Descriptive statistics will be used to summarize the trial results, i.e., statistics for 
continuous variables may include means, medians, ranges and appropriate 
measures of variability. Qualitative variables will be summarized by counts and 
percentages. The uncertainty of estimates will be assessed by confidence intervals. 
Unless otherwise specified, the calculation of proportions will be based on the 
sample size of the population of interest. Counts of missing observations will be 
included in the denominator and presented as a separate category if not otherwise 
specified in the statistical analysis plan (SAP). 
 
Duration of response, according to RANO, will be calculated for each subject and 
will be analyzed using the Kaplan-Meier method in the primary cohorts separately.  
 
PFS will be presented in subject listings and analyzed using the Kaplan-Meier 
method in the primary cohorts separately.   
Correlation analysis (significance at R2 ≥ 0.8) and slope analysis (Fisher’s Exact 
Test) of dependent variables (naps/day, nap duration, sleep duration, % activity 
during waking, % activity during sleep, chronotype, chronotype variability) and 
independent variables (tumor grade, time since TMZ administration, time of day of 
TMZ administration, time since diagnosis date, tumor size, immune health) will be 
carried out. Each variable will be calculated daily and averaged over the collection 
period. Daily calculation reveals stability, while the average reveals variability. 
 
13.2.2 Safety 
 
13.2.2.1 
Adverse Events 
 
All AEs will be listed. The focus of AE summarization will be on treatment-
emergent adverse events (TEAEs).   
 
AEs will be classified using MedDRA with descriptions by System Organ 
Class and Preferred Term. The severity of AEs will be graded by the 
investigator according to the CTCAE, Version 4.03, whenever possible. If 
a CTCAE criterion does not exist for a specific type of AE, the grade 
corresponding to the appropriate adjective will be used by the investigator 
to describe the maximum intensity of the AE: Grade 1 (mild), Grade 2 
(moderate), Grade 3 (severe), Grade 4 (life threatening), or Grade 5 (fatal). 
The relationship of the AE to the study drugs will be categorized as related 
or unrelated. 
 
Summary tables will be presented to show the number of subjects reporting 
TEAEs by severity grade and corresponding percentages. A subject who 


 
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reports multiple TEAEs within the same Preferred Term (or System Organ 
Class) is counted only once for that Preferred Term (or System Organ Class) 
using the worst severity grade. AE descriptions will be presented in order 
of decreasing frequency for System Organ Class, and by decreasing 
frequency in the overall or total column for a given Preferred Term. 
 
Separate listings and summaries will be prepared for the following types of 
AEs: 
• Study-drug-related AEs 
• AEs that are Grade ≥3, 4, or 5 in severity 
• AEs leading to study drug interruption and/or dose modification 
• AEs leading to study drug discontinuation 
• SAEs (with categorization of the primary reason that the AE is 
considered serious, eg, life-threatening, hospitalization) 
 
13.2.2.2 
Laboratory Evaluations 
 
All laboratory data will be listed. Summaries of laboratory data will be 
based on observed data and will be reported using conventional units. The 
focus of laboratory data summarization will be on treatment-emergent 
laboratory abnormalities. A treatment-emergent laboratory abnormality is 
defined as an abnormality that, compared to baseline, worsens by ≥1 grade 
in the period from the first study drug administration to 30 days after the 
last study drug administration. If baseline data are missing, then any graded 
abnormality (ie, an abnormality that is Grade ≥1 in severity) will be 
considered treatment-emergent.  
 
Test data will be programmatically graded according to CTCAE severity 
grade, when applicable. For parameters for which a CTCAE scale does not 
exist, reference ranges from the laboratory will be used to determine 
programmatically if a laboratory parameter is below, within, or above the 
normal range for the subject’s age, sex, etc. 
 
Test data will be summarized in tables and may be summarized in figures 
showing values over time, if informative. Summary tables will be presented 
for each relevant assay to show the number of subjects by CTCAE severity 
grade with corresponding percentages. For parameters for which a CTCAE 
scale does not exist, the frequency of subjects with values below, within, 
and above the normal ranges will be summarized. Subjects will be 
characterized only once for a given assay, based on their worst severity 
grade observed during a period of interest (eg, during the study or during a 
cycle). 
 
Shift tables for hematology and serum biochemistry will also be presented 
by showing change in CTCAE severity grade from baseline to each time 
point. For parameters for which a CTCAE scale does not exist, shift tables 


 
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will be presented showing change in results from baseline (normal, low and 
high [or abnormal]) to each time point (normal, low and high [or 
abnormal]). For selected variables of interest, tables may be prepared to 
show frequencies adjusted for baseline values; for these frequencies, 
subjects with the same or worse grade at baseline are not considered. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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14.0 
REFERENCES 
 
Courneya KS et al., A randomized trial of exercise and quality of life in colorectal cancer survivors. 
Eur J Cancer Care 2003;12(4):347-57. 
 
Gery, S., et al., The circadian gene per1 plays an important role in cell growth and DNA damage 
control in human cancer cells. Mol Cell, 2006. 22(3): p. 375-82. 
 
Grossman SA et al. Immunosuppression in patients with high-grade gliomas treated with radiation 
and temozolomide. Clin Cancer Res 2011;17:5473-5480. 
 
Horne JA, Ostberg O. A self-assessment questionnaire to determine morningness-eveningness in 
human circadian rhythms. Int J Chronobiol 1976;4(2):97-110. 
 
Im, J.S., et al., Per3, a circadian gene, is required for Chk2 activation in human cells. FEBS Lett, 
2010. 584(23): p. 4731-4. 
 
Innominato PF, et al., Circadian rhythm in rest and activity: a biological correlate of quality of life 
and a predictor of survival in patients with metastatic colorectal cancer. Cancer Res 2009 Jun 
1;69(11):4700-7. 
 
Innominato PF, Levi FA, and Bjarnason GA. Chronotherapy and the molecular clock: Clinical 
implications in oncology. Adv Drug Deliv Rev, 2010. 62(9-10): p. 979-1001. 
 
Iwata K et al. The relationship between treatment time of gemcitabine and development of 
hematologic toxicity in cancer patients. Biol Pharm Bull. 2011;34(11):1765-8. 
 
Jensen W, et al., Exercise training in patients with advanced gastrointestinal cancer undergoing 
palliative chemotherapy: a pilot study. Support Cancer Care 2014 Jul;22(7):1797-806. 
 
Kobayashi, M., P.A. Wood, and W.J. Hrushesky, Circadian chemotherapy for gynecological and 
genitourinary cancers. Chronobiol Int, 2002. 19(1): p. 237-51. 
 
Levi, F., et al., Chronomodulation of chemotherapy against metastatic colorectal cancer. 
International Organization for Cancer Chronotherapy. Eur J Cancer, 1995. 31A(7-8): p. 1264-70. 
 
Levi, F., et al., Chronotherapy of colorectal cancer metastases. Hepatogastroenterology, 2001. 
48(38): p. 320-2. 
 
Lévi, Francis; Okyar, Alper (2011): Circadian clocks and drug delivery systems: impact and 
opportunities in chronotherapeutics. In: Expert Opin Drug Deliv 8 (12), p. 1535–1541. 
 


 
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Mormont MC et al., Marked 24-h rest/activity rhythms are associated with better quality of life, 
better response, and longer survival in patients with metastatic colorectal cancer and good 
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Piil K, Jakobsen J, Christensen KB, Juhler M, Jarden M. Health-related quality of life in patients 
with high-grade gliomas: a quantitative longitudinal study. J Neurooncol. 2015 May [Epub ahead 
of print]. 
 
Ohdo S et al. Cell cycle-dependent chronotoxicity of irinotecan hydrochloride in mice. J 
Pharmacol Exp Ther. 1997 Dec;283(3):1383-8. 
 
Ohka, F., A. Natsume, and T. Wakabayashi, Current trends in targeted therapies for glioblastoma 
multiforme. Neurol Res Int, 2012. 2012: p. 878425. 
 
Omuro A, et al. Phase II study of bevacizumab, temozolomide, and hypofractionated stereotactic 
radiotherapy for newly diagnosed glioblastoma. Clin Cancer Res. 2014 Oct 1;20(19):5023-31. 
 
Ostrom, Q. T.; Gittleman, H.; Farah, P.; Ondracek, A.; Chen, Y.; Wolinsky, Y. et al. (2013): 
CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the 
United States in 2006-2010. In: Neuro-Oncology 15 (suppl 2), p. ii1. 
 
Reppert, S.M. and D.R. Weaver, Coordination of circadian timing in mammals. Nature, 2002. 
418(6901): p. 935-41. 
 
Rivard, G.E., et al., Circadian time-dependent response of childhood lymphoblastic leukemia to 
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Sancar, A., et al., Circadian clock control of the cellular response to DNA damage. FEBS Lett, 
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Schmiegelow, K. et al., Impact of morning versus evening schedule for oral methotrexate and 6-
mercaptopurine on relapse risk for children with acute lymphoblastic leukemia. Nordic Society for 
Pediatric Hematology and Oncology (NOPHO). J Pediatr Hematol Oncol, 1997; 19(2):102-9. 
 
Stupp, R., et al., Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N 
Engl J Med, 2005. 352(10): p. 987-96. 
 
Tampellini M et al. Docetaxel chronopharmacology in mice. Cancer Res. 1998;58(17):3896-904. 
 
Wee, R., Van Gelder RN. Sleep disturbances in young subjects with visual 
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Piantadosi S.  Translational clinical trials: an entropy-based approach to sample size. Clinical 
Trials 2005; 2: 1 82-1 92. 
 
 
We would like to thank the Alvin J. Siteman Cancer Center at Washington University School of 
Medicine and Barnes-Jewish Hospital in St. Louis, Missouri, for the use of the Clinical Trials Core 
which provided protocol development service. The Siteman Cancer Center is supported in part by 
an NCI Cancer Center Support Grant #P30 CA91842. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Appendix A: Karnofsky Performance Status Scale 
 
Definition 
Score 
Criteria 
Able to carry on normal activity 
and to work; no special care 
needed. 
100 
Normal, no complaints; no evidence of disease. 
90 
Able to carry on normal activity; minor signs or 
symptoms of disease. 
80 
Normal activity with effort; some signs or symptoms of 
disease. 
Unable to work; able to live at 
home and care for most personal 
needs; varying amount of assistance 
needed. 
70 
Cares for self; unable to carry on normal activity or to 
do active work. 
60 
Requires occasional assistance, but is able to care for 
most personal needs. 
50 
Requires considerable assistance and frequent medical 
care. 
Unable to care for self; requires 
equivalent of institutional or 
hospital care; disease may be 
progressing rapidly. 
40 
Disabled; requires special care and assistance. 
30 
Severely disabled; hospital admission is indicated 
although death not imminent. 
20 
Very sick; hospital admission necessary; active 
supportive treatment necessary. 
10 
Moribund; fatal processes progressing rapidly. 
0 
Dead. 
 
Oxford Textbook of Palliative Medicine, Oxford University Press. 1993;109. 


 
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   at all
bit 
what 
a bit 
muc
h
GS1 
I feel close to my friends .................................................... 
0 
1 
2 
3 
4 
GS2 
I get emotional support from my family ............................ 
0 
1 
2 
3 
4 
GS3 
I get support from my friends............................................. 
0 
1 
2 
3 
4 
GS4 
My family has accepted my illness .................................... 
0 
1 
2 
3 
4 
GS5 
I am satisfied with family communication about my 
illness.................................................................................. 
0 
1 
2 
3 
4 
GS6 
I feel close to my partner (or the person who is my main 
support) .............................................................................. 
0 
1 
2 
3 
4 
Q1 
Regardless of your current level of sexual activity, 
please answer the following question. If you prefer not 
GS7 
I am satisfied with my sex life ............................................ 
0 
1 
2 
3 
4 
Appendix B: FACT-BR Quality of Life Survey 
 
Below is a list of statements that other people with your illness have said are important. 
Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days. 
Not 
PHYSICAL WELL-BEING                                 at all 
A little 
bit 
Some- 
what 
Quite 
a bit 
Very 
much 
GP1 
I have a lack of energy ....................................................... 
0 
1 
2 
3 
4 
GP2 
I have nausea ...................................................................... 
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have trouble 
meeting the needs of my family ......................................... 
0 
1 
2 
3 
4 
GP4 
I have pain .......................................................................... 
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment ......................... 
0 
1 
2 
3 
4 
GP6 
I feel ill ............................................................................... 
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in bed ........................................ 
0 
1 
2 
3 
4 
SOCIAL/FAMILY WELL-BEING                     Not     A little    Some-    Quite     Very 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
please mark this box          and go to the next section.


 
Version 09/20/22 
 
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Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
 
 
EMOTIONAL WELL-BEING                             Not 
at all 
A little 
bit 
Some- 
what 
Quite 
a bit 
Very 
much 
GE1 
I feel sad .............................................................................. 
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping with my illness.......... 
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my illness .................. 
0 
1 
2 
3 
4 
GE4 
I feel nervous ....................................................................... 
0 
1 
2 
3 
4 
GE5 
I worry about dying ............................................................. 
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get worse ............................ 
0 
1 
2 
3 
4 
FUNCTIONAL WELL-BEING                           Not      A little    Some-    Quite     Very 
at all         bit        what      a bit      much 
GF1 
I am able to work (include work at home) .......................... 
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is fulfilling ..................... 
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life.......................................................... 
0 
1 
2 
3 
4 
GF4 
I have accepted my illness................................................... 
0 
1 
2 
3 
4 
GF5 
I am sleeping well ............................................................... 
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for fun ...................... 
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right now.............. 
0 
1 
2 
3 
4 


 
Version 09/20/22 
 
page 33 of 35 
ADDITIONAL CONCERNS 
Not 
at 
all 
A 
little 
bit 
Some
- 
what 
Quit
e a 
bit 
Very 
muc
h 
I am able to concentrate ...................................................... 
0 
1 
2 
3 
4 
I have had seizures (convulsions) ....................................... 
0 
1 
2 
3 
4 
I can remember new things ................................................. 
0 
1 
2 
3 
4 
I get frustrated that I cannot do things I used to.................. 
0 
1 
2 
3 
4 
I am afraid of having a seizure (convulsion)....................... 
0 
1 
2 
3 
4 
I have trouble with my eyesight .......................................... 
0 
1 
2 
3 
4 
I feel independent ................................................................ 
0 
1 
2 
3 
4 
I have trouble hearing.......................................................... 
0 
1 
2 
3 
4 
I am able to find the right word(s) to say what I mean ....... 
0 
1 
2 
3 
4 
I have difficulty expressing my thoughts ........................... 
0 
1 
2 
3 
4 
I am bothered by the change in my personality .................. 
0 
1 
2 
3 
4 
I am able to make decisions and take responsibility .......... 
0 
1 
2 
3 
4 
I am bothered by the drop in my contribution to the 
family ................................................................................. 
0 
1 
2 
3 
4 
I am able to put my thoughts together................................. 
0 
1 
2 
3 
4 
I need help in caring for myself (bathing, dressing, 
eating, etc.) ......................................................................... 
0 
1 
2 
3 
4 
I am able to put my thoughts into action ............................. 
0 
1 
2 
3 
4 
I am able to read like I used to ............................................ 
0 
1 
2 
3 
4 
I am able to write like I used to ........................................... 
0 
1 
2 
3 
4 
I am able to drive a vehicle (my car, truck, etc.)................. 
0 
1 
2 
3 
4 
I have trouble feeling sensations in my arms, hands, or 
legs ...................................................................................... 
0 
1 
2 
3 
4 
I have weakness in my arms or legs .................................... 
0 
1 
2 
3 
4 
I have trouble with coordination ......................................... 
0 
1 
2 
3 
4 
I get headaches ................................................................... 
0 
1 
2 
3 
4 
 
Please circle or mark one number per line to indicate your response as it applies 
to the past 7 days. 
 
 
 
 
 
Br1 
 
Br2 
  
Br3 
  
Br4 
  
Br5 
  
Br6 
  
Br7 
 
NTX6 
 
Br8 
  
Br9 
  
Br10 
  
Br11 
  
Br12 
 
 
 
Br13 
  
Br14 
 
 
 
Br15 
  
Br16 
  
Br17 
 
Br18 
  
Br19 
  
 
Br20 
  
Br21 
  
An10  


 
Version 09/20/22 
 
page 34 of 35 
Appendix C: Quality of Sleep Questionnaire 
 
1. What time do you typically go to bed on weekdays? ___:___ am/pm 
 
2. How long does it take you to fall asleep? _________(hours/min) 
 
3. What time do you typically wake up on weekdays? ___:___ am/pm 
a. Do you use an alarm clock/wake up call? YES NO 
b. Do you feel refreshed upon waking up? YES NO 
 
4. What time do you typically go to bed on the weekend/days off? ___:___ am/pm 
 
5. How long does it take you to fall asleep? _______(hours/min) 
 
6. What time do you wake up on the weekend/days off? ___:___ am/pm 
a. Do you use an alarm clock/wake up call? YES NO 
b. Do you feel refreshed upon waking up? YES NO 
 
7. How many times do you wake up on a typical night? _______ 
 
8. Do you have difficulty falling back to sleep? YES NO 
 
9. Check typical causes for awakening at night: 
a. Snoring 
b. Pain 
c. Full bladder 
d. Noise 
e. Nightmares 
f. Worry 
g. Thirst/hunger 
h. Bed partner/kids/pets 
i. Night sweats 
j. Headache 
k. Heartburn 
l. Choking/gasping 
 
 Please list other causes: __________________________________________________________ 
 
10. Do you nap intentionally? YES NO 
a. If yes, how many days per week? _______ 
b. What time of day? ____________ 
c. How long are naps? ____________ 
d. Do you feel refreshed upon waking up from the nap? YES NO 
 
 


 
Version 09/20/22 
 
page 35 of 35 
 
11. Do you have problems getting to sleep or staying asleep? YES NO 
 
12. Please rate the current, (i.e. the last 2 weeks) SEVERITY of your insomnia problem(s):