Conditions: Brain Tumors Spinal Cord Tumors
Keywords: Brain Tumor Central Nervous System CNS Spinal Cord Tumor Anaplastic Ependymoma Supratentorial Ependymoma Infratentorial Ependymoma Spinal Cord Ependymoma Lapatinib GW572016 Temozolomide Temodar
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 58
Healthy volunteers: no

Brief summary:
The goal of this clinical research study is to learn if lapatinib when given in combination with temozolomide can help to control ependymoma that has come back after treatment. The safety of this combination will also be studied.

Detailed description:
The Study Drugs:

Temozolomide is designed to kill cancer cells by damaging deoxyribonucleic acid (DNA) (the genetic material of cells). This could cause the tumor cells to die.

Lapatinib is designed to prevent or slow down the growth of cancer cells by blocking proteins inside the cancer cell, called the human epidermal growth factor receptor 2 (Her2/neu) receptor and the epidermal growth factor receptor (EGFR).

Study Drug Administration:

If you are found to be eligible to take part in this study, every day, you will take lapatinib by mouth once a day in the morning. You should take lapatinib 1 hour before or 1 hour after eating, with at least 1 cup (about 8 oz.) of water.

On Days 1-7 and 15-21 of each cycle, you will take temozolomide by mouth 1 time each day. You will start to take a lower dose of temozolomide for the first 2 cycles, then take a higher dose for Cycles 3 and beyond if you tolerate the treatment. It should be taken at least 2 hours before and 2 hours after eating with 1 cup (about 8 oz.) of water.

You should swallow temozolomide and/or lapatinib whole, one right after the other, without chewing either of the study drugs. If you vomit while taking temozolomide and lapatinib, you cannot take more capsules before the next scheduled dose. You should report any missed pills or trouble you have with taking the pills to your study doctor. Your study doctor will give you a form (patient diary) to fill out to keep track of your treatment. You will be asked to return your completed diary and pill bottles at each visit with your doctor.

Each study "cycle" is 28 days.

Study Visits:

Every 2 weeks, blood (about 2-3 teaspoons) will be drawn for routine tests and to check your blood's ability to clot.

Every 8 weeks, the following tests and procedures will be performed:

* You will have a physical exam, including measurement of your vital signs.
* You will have a neurological exam.
* Your performance status will be recorded.
* You will be asked about any drugs you may be taking and if you have experienced any side effects.
* You will complete the quality of life questionnaire.
* You will have an magnetic resonance imaging (MRI) scan to check the status of the disease.
* You will have either a multi-gated acquisition scan (MUGA) scan (if the doctor thinks it is needed) or an echocardiogram.

Length of Study:

You will be on study treatment for up to 2 years. You will be taken off study treatment early if the disease gets worse or you experience intolerable side effects.

After you are off study, you may be able to continue taking lapatinib for as long as the doctor thinks it is in your best interest. Your doctor will discuss this with you.

End-of-Study Visit:

After you go off study treatment, you will have an end-of-study visit. At this visit, the following tests and procedures will be performed:

* You will have a physical exam.
* Your performance status will be recorded.
* You will be asked about any drugs you may be taking and if you have experienced any side effects.
* You will have a neurological exam.
* Blood (about 3 teaspoons) will be drawn for routine tests and to check your blood's ability to clot.
* You will complete the questionnaire.
* You will have an MRI scan to check the status of the disease.
* You will have either a MUGA scan (if the doctor thinks it is needed) or an echocardiogram.

Long-Term Follow-up Visit:

If you go off treatment (having completed the maximum 24 months on study drug treatment) and have stable disease or response, you will have an MRI scan to check the status of the disease every 2 months for first year after you are off study, then every 3 months for the second year, then every 4 months for the third year, and then every 6 months from then on.

If you continue taking lapatinib after you have completed up to 24 months on study treatment, you will have a clinic visit and an MRI scan to check the status of the disease every 2 months for as long as the doctor thinks it is needed. At the clinic visits, you will be asked how you are doing.

If you went off study treatment because the disease got worse or you experienced intolerable side effects, after the end-of-study visit, the study staff will call you every 3 months from then on to check how you are doing. Each phone call will take about 5 minutes.

This is an investigational study. Temozolomide is Food and Drug Administration (FDA) approved or commercially available for the treatment of tumors of the nervous system. Lapatinib is FDA approved and commercially available for the treatment of breast cancer. However, lapatinib is not FDA approved for the treatment of brain tumors. The use of lapatinib with temozolomide in the treatment of brain tumors and spinal tumors is investigational.

Up to 50 patients will take part in this multicenter study. Up to 30 will be enrolled at MD Anderson.

Arms:
arm 1: Temozolomide starting dose 125 mg/m\^2 daily by mouth on days 1-7 \& 15-21 of a 28 day cycle. Lapatinib starting dose 1250 mg daily by mouth.

Interventions: intervention 1: Temozolomide intervention 2: Lapatinib
Intervention descriptions: intervention 1: Starting dose 125 mg/m\^2 daily by mouth on days 1-7 \& 15-21 of a 28 day cycle. intervention 2: Starting dose 1250 mg daily by mouth.

Protocol document:
Prot_SAP_000.pdf: 
Abbreviated Title: Ph II Recurrent Ependymoma 
Version Date: 07/21/17 
 
1 
 
CC Protocol #:  16CN005 
Previous CERN Protocol# 08-02 
Amendment Letter: A 
Version Date: 07/21/2017 
NCT Number:  NCT00826241 
 
Title:  A Phase II Study of Dose-Dense Temozolomide and Lapatinib for Recurrent Low-
Grade and Anaplastic Supratentorial, Infratentorial and Spinal Cord Ependymoma 
 
Principal Investigator: 
 
Mark Gilbert, MD, NOB, CCR, NCI E 
9030 Old Georgetown Road, 82/225  
Bethesda, MD 20892  
Tel:  301-402-6298  
Fax: 301-480-2246 
Email: mark.gilbert@nih.gov 
 
NCI Associate Investigators: 
Terri S. Armstrong, PhD, ANP-BC, NOB, CCR, NCI E 
 
 
Christine Bryla, RN, OCD, CCR, NCI E 
 
 
Ann McCoy, RN, OCD, CCR, NCI E 
 
 
Referral Contact: 
 
 
Christine Bryla, RN, OCD, CCR, NCI E  
 
CCR Study Coordinator: 
 
Christine Bryla, RN, OCD, CCR, NCI E 
 
 
Non-NIH Associate  
Investigators: 
Alvina Acquaye, MS, (Contractor) Columbus Technologies 
& Services E,F 
Elizabeth Vera, MS, (Contractor) Columbus Technologies 
& Services E,F 
Miranda Brown, RN, (Contractor) Leidos Biomed E, F 
 
 
 
Non-NIH  
Collaborator(s): 
 
 
Ying Yuan, PhD, Biostatistician, MDACC F, G 
 
 
 
 
 
Tito Mendoza, PhD, Biostatistician, MDACC F, G 
 
 
 
 
 
 


Abbreviated Title: Ph II Recurrent Ependymoma 
Version Date: 07/21/17 
 
2 
 
Investigator Roles: 
A. Obtain information by intervening or interacting with living individuals for research 
purposes 
B. Obtaining identifiable private information about living individuals 
C. Obtaining the voluntary informed consent of individuals to be subjects 
D. Makes decisions about subject eligibility 
E. Studying, interpreting, or analyzing identifiable private information or data/specimens 
for research purposes 
F. Studying, interpreting, or analyzing de-identified data or specimens for research 
purposes 
G. Some/all research activities performed outside NIH 
 
 
Commercial Agents: 
Temozolomide and Lapatinib are commercially available.


Abbreviated Title: Ph II Recurrent Ependymoma 
Version Date: 07/21/17 
 
3 
 
 
Participating Centers and Principal Investigators: 
 
Institution
al PI: 
Marta Penas-Prado, 
MD 
Elizabeth R. 
Gerstner, MD 
Antonio Omuro, 
MD 
Tobias Walbert, 
MD 
Frances Collichio, 
M.D. 
H. Ian Robins MD 
Institution:  MD Anderson Cancer 
Center 
Massachusetts 
General Hospital/ 
Dana Farber Cancer 
Institute 
Memorial Sloan 
Kettering Cancer 
Center 
Henry Ford Health 
System 
University of 
North Carolina at 
Chapel Hill 
 
University of 
Wisconsin School of 
Medicine & Public 
Health 
Institution 
FWA# 
FWA00000363 
FWA00001121 
FWA00004998 
FWA00005846 
FWA00004507  
FWA00005399 
Address: 
1515 Holcombe 
Blvd, Houston, TX 
77030 
55 Fruit Street, 
Yawkey 9E 
Boston, MA 02114 
1275 York 
Avenue, New 
York, NY 10065 
2799 W. Grand 
Blvd, Pallister 
Place T-139, 
Detroit, MI  48202 
UNC Healthcare 
101 Manning Dr 
Chapel Hill, NC 
27514 
 
K4/534, Box5664 
Clinical Science 
Center 
600 Highland Ave 
Madison, WI 53792 
Phone 
Number: 
713-745-2164 
617-724-8770 
212- 639-2000 
313-916-1784 
919-966-7890 
608- 265-0861 
Email: 
mpenaspr@mdanders
on.org  
egerstner@mgh.harva
rd.edu  
OmuroA@mskcc.
org  
Tmikkel1@hfhs.or
g 
collich@med.unc.
edu  
hirobins@wisc.edu 


Abbreviated Title: Ph II Recurrent Ependymoma 
Version Date: 07/21/17 
 
4 
 
PRÉCIS  
Background: 
• Although relatively uncommon, ependymoma can occur at any age group although 
the tumors of the posterior fossa are much more common in the pediatric population 
and spinal cord tumors are more common in young to middle age adults.  
Anaplastic ependymomas are more common in adults 
• There have only been a limited number of reports describing chemotherapy 
treatments for patients with recurrent ependymoma, either low grade or anaplastic.  
As a consequence, optimal therapy for this group remains unknown.  Traditionally, 
combination chemotherapy regimens have been used, often containing either 
carboplatin or cisplatin.  Many of these treatment programs were associated with a 
high incidence of moderate to severe toxicity 
• Given the paucity of established treatments for recurrent ependymomas in adults, 
we propose a study that uses a combination of an established cytotoxic agent, 
temozolomide with a small molecule tyrosine kinase inhibitor.  Temozolomide was 
chosen because it has an established track record in treating primary brain tumors, it 
has a good safety profile and recent data suggest that certain dosing schedules may 
modulate tumor cell resistance via the MGMT mechanism.  Given the recent 
studies in glioblastoma that correlate MGMT methylation status with outcome, 
modulating MGMT activity may have a significant impact on response 
• Additionally, we plan to target the ERBB1 and the ERBB2 pathways using 
lapatinib on a continuous daily dosing schedule 
Objectives: 
• To determine the efficacy of the combination of temozolomide and lapatinib in 
recurrent brain ependymoma and anaplastic ependymoma as measured by median 
progression-free survival. 
Eligibility: 
• Histologically proven ependymoma or anaplastic ependymoma. There must be 
pathologic or imaging confirmation of tumor progression or regrowth.  
• Patients must be on a steroid dose that has been stable or decreasing for at least 5 
days.  
• Karnofsky performance status ≥ 70 
• Age ≥ 18 
• No severe, active comorbidity  
• No condition that impairs ability to swallow pills  
Design: 


Abbreviated Title: Ph II Recurrent Ependymoma 
Version Date: 07/21/17 
 
5 
 
• This is a phase II study to determine the efficacy of the combination of 
temozolomide and lapatinib in recurrent brain ependymoma and anaplastic 
ependymoma as measured by median progression-free survival. 
• Eligible patients will receive 2 cycles of the combination of temozolomide and 
lapatinib.  The temozolomide will be administered at a dose of 125 mg/m2 as a 
single daily dose on days 1-7 and 15-21 of a 28-day cycle.  The lapatinib will be 
given as a single daily dose of 1250 mg orally. Patients who do not experience any 
grade 1 or greater myelotoxicity will be eligible to have the temozolomide dose 
increased to 150 mg/m2 as a single daily dose on days 1-7 and 15-21 of a 28-day 
cycle.  The lapatinib dose will not be increased.  
• Patients who exhibit response to protocol therapy and have not experienced any 
significant or intolerable toxicities may continue to receive protocol therapy up to a 
maximum number of 24 cycles.  
• Patients that are showing sustained Complete Response (CR), Partial Response 
(PR) or Stable Disease (SD) may continue post protocol single agent therapy with 
lapatinib.  Post-protocol lapatinib supply may be obtained through Glaxo Smith-
Kline (GSK).  Patients on post protocol single agent lapatinib will have follow up 
visits every 2 months for survival assessment and radiographic evaluation of 
disease per MRI or CT scan.  
 
 


Abbreviated Title: Ph II Recurrent Ependymoma 
Version Date: 07/21/17 
 
6 
 
STUDY SCHEMA   
 
REGISTRATION
STEP 2
Cycle 1 and 2 of 
Lapatinib 1250MG, PO daily  for 28 days, Q28 Day Cycle
and 
Temodar 125mg/m2 po QD, Days 1-7 & 15-21 Q28 Day Cycle 
Cycle 3-24
Lapatinib 1250MG, PO daily for 28 days, Q28 Day Cycle
and 
Temodar 150mg/m2 po QD, Days 1-7 & 15-21 Q28 Day Cycle 
Clinical Evaluations 
(Schedule per Section 11.1.9)
Cycle 3-24
Lapatinib1250MG, PO daily for 28 days, Q28 Day Cycle
and 
Temodar 125mg/m2 po QD, Days 1-7 & 15-21 Q28 Day Cycle 
Continue Therapy 
for up to 24 cycles
OFF PROTOCOL
OFF TREATMENT
(Follow Patient per 
protocol F/U Schedule)
CONSENT 
PATIENT
Scans & Tests for Eligibility
Baseline Measurements (not for Eligibility)
 Research Specimens
Central Pathology Review
Baseline MDASI
PATIENT NOT 
ELIGIBLE
STOP
(Discuss other options 
with the patient)
PATIENT 
ELIGIBLE
Yes, Continue, 
No Myelotoxicity
Clinical Evaluations 
(Schedule per Section 11.1.9)
Response Evaluation (Q8 Weeks)
MDASI (Q8 Weeks)
Yes, Continue, 
Yes Myelotoxicity
Yes, Continue
No.Discontinue.
Meets Off 
Treatment Criteria
REGISTRATION
STEP 1
 
 
 


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Abbreviated Title: Ph II Recurrent Ependymoma 
Version Date: 07/21/17 
 
10 
 
The causes of ependymoma are not known.  Although relatively uncommon, the disease can 
occur at any age group although the tumors of the posterior fossa are much more common in 
the pediatric population and spinal cord tumors are more common in young to middle age 
adults.  Anaplastic ependymomas are more common in adults.  A series of genetic changes 
have been reported in these tumors, although a wide variability between tumors has been 
reported. Furthermore, patients can be initially diagnosed with an anaplastic ependymoma or 
these malignant tumors can develop from the malignant transformation of the lower grade 
ependymoma. This underscores the importance of genetic changes in the formation of the 
disease, the biologic behavior including malignant transformation and the potential utilization 
of these characteristic molecular changes as treatment targets. The variable patterns of 
histology and clinical presentation of ependymoma, and the separation of pediatric and adult 
oncology services, have hindered efforts to coordinate clinical trials in this disease.  As a 
result, no new therapeutic approaches have been identified to treat ependymoma during last 20 
years and up to 40% of patients remain incurable](Brandes, Cavallo et al. 2005; Merchant and 
Fouladi 2005).   
Currently, the standard therapy for newly diagnosed low-grade ependymoma includes total 
surgical excision followed by radiation therapy. Complete surgical resection is often not 
possible because of the location of the tumor and the concern for damage to surrounding 
eloquent brain during surgery.  The situation is even more critical for patients with anaplastic 
ependymomas because of the higher proliferative rate and greater propensity for tumor 
infiltration into surrounding normal brain, preventing any possibility of complete tumor 
removal by surgery. For patients with the more aggressive anaplastic ependymoma, 
chemotherapy is often administered either before or after the radiation in the hope that 
infiltrating tumor cells will be eliminated.  Unfortunately, even for patients with low-grade 
ependymoma, survival can be poor when the tumor is not totally surgically resected.   
1.2.2 Treatment of recurrent ependymoma 
There have only been a limited number of reports describing chemotherapy treatments for 
patients with recurrent ependymoma, either low grade or anaplastic.  As a consequence, 
optimal therapy for this group remains unknown.  Traditionally, combination chemotherapy 
regimens have been used, often containing either carboplatin or cisplatin.  Many of these 
treatment programs were associated with a high incidence of moderate to severe toxicity.   
A recent publication by Brandes and colleagues underscores some of the limitations in 
determining the optimal treatment for recurrent disease(Brandes, Cavallo et al. 2005).   They 
report on the treatment of 28 adults who had recurrent ependymoma (n = 17) or anaplastic 
ependymoma (n = 11) after initial treatment with surgery and radiation.  Half of the patients 
had undergone multiple tumor resections.  A wide variety of regimens were used ranging from 
single agent temozolomide to the “8 in 1” regimen that combines 8 different chemotherapy 
agents.  For their analyses, they looked at the composite group as well as a comparison of 
patients treated with or without cisplatin.  No overall differences were noted based on the use 
of cisplatin.  Furthermore, the overall objective response rate was 20% (CR and PR).  The 12 
month progression free survival rate was 44% (95% CI, 29-68%).  The median time to 
progression was 9.9 months.  These data provide a benchmark for subsequent clinical trials 
evaluating treatments for adults with recurrent ependymomas. 


Abbreviated Title: Ph II Recurrent Ependymoma 
Version Date: 07/21/17 
 
11 
 
There have been anecdotal reports of response of ependymoma to temozolomide.  The study 
by Brandes included 4 patients who received this either as single agent (n = 3) or in 
combination with cisplatin (n = 1)(Brandes, Cavallo et al. 2005).  All patients were reported to 
have stable disease as their best response.  A single case report describes a patient with 
recurrent anaplastic ependymoma with a greater than 10 year response to temozolomide 
therapy(Rehman, Brock et al. 2006).  There is no published literature on the use of signal 
transduction modulating agents, save for a recent phase I study of the farnesyltransferase 
inhibitor lonafarnib in patients with recurrent primary pediatric brain tumors(Kieran, Packer et 
al. 2007).  A single patient with a recurrent ependymoma did achieve stable disease with this 
regimen. 
Recent correlative laboratory studies have carefully examined the molecular profiles of both 
pediatric and adult ependymomas.  Distinct profiles of gene expression were uncovered that 
were primarily based on tumor location, with less difference in expression pattern noted 
between the pediatric and adult tumor samples.   
1.2.3 Potential molecular targets in ependymoma 
Several studies have been performed examining the spectrum of molecular profiles in 
ependymoma. These studies often examine a wide variety of tumors including grade II and III 
ependymomas, myxopapillary ependymomas.  These series often include pediatric and adult 
tumors as well as those from spinal cord, posterior fossa and supratentorial locations.  Most 
studies demonstrate specific molecular patterns that distinguish tumors by location with the 
largest differences noted between tumors arising within the spinal cord compared with those of 
brain origin.  There are reports that find some distinct changes in comparing supra- from 
infratentorial tumors however this is much less striking. 
Cytogenetic studies report aberrations on chromosome 22 in a high percentage of tumors, with 
either monosomy or 22q deletion (Lamszus, Lachenmayer et al. 2001; Suarez-Merino, Hubank 
et al. 2005).  Intracranial tumors are reported to have a gain of 1q and chromosomal losses on 
6q, 9 and 13(Korshunov, Neben et al. 2003).  In comparison, spinal cord ependymomas have 
been reported to have gains on chromosome 7(Korshunov, Neben et al. 2003).  Specific 
microarray analysis has shown increased expression of putative oncogenes such as WNTSA, as 
well as genes involved in cell cycle regulation, cell adhesion and proliferation(Suarez-Merino, 
Hubank et al. 2005).  More recently, promoter methylation analysis has been performed on 
ependymoma cells uncovering that genes involved in apoptosis, such as TRAIL, are frequently 
methylated(Michalowski, de Fraipont et al. 2006).  However, these studies also show that the 
MGMT gene is not commonly methylated, which may impact sensitivity of ependymoma to 
alklyating agent chemotherapies.   
Recent, comparative genomic hybridization studies demonstrated that 90% of ependymomas 
had increased expression of EGFR(Gilbertson, Bentley et al. 2002).  Furthermore, 
immunohistochemical analysis showed increased levels of intracellular EGFR in nearly 60% of 
intracranial ependymoma and this was highly correlated with a poorer prognosis (P = 0.002).  
Interestingly, although the rate of high expression of EGFR was the same in spinal cord 
tumors, there was no correlation with outcome.  These studies suggest that EGFR may be a 
suitable target for treating intracranial ependymomas. 
Additional studies have shown increased expression of ERBB2 and ERBB4 in pediatric 
intracranial ependymomas(Gilbertson, Bentley et al. 2002).  Also, a polymorphism has been 


Abbreviated Title: Ph II Recurrent Ependymoma 
Version Date: 07/21/17 
 
12 
 
detected in the promoter region of the PDGFRα gene that alters the binding of the transcription 
factor, ZNF-148, suggesting that the PDGFR pathway may be important in the development of 
some ependymomas(De Bustos, Smits et al. 2005).  Therefore, the PDGFR pathway may also 
be a potential therapeutic target. 
1.2.4 Study proposal 
Given the paucity of established treatments for recurrent ependymomas in adults, we propose a 
study that uses a combination of an established cytotoxic agent, temozolomide with a small 
molecule tyrosine kinase inhibitor.  Temozolomide was chosen because it has an established 
track record in treating primary brain tumors, it has a good safety profile and recent data 
suggest that certain dosing schedules may modulate tumor cell resistance via the MGMT 
mechanism.  Given the recent studies in glioblastoma that correlate MGMT methylation status 
with outcome, modulating MGMT activity may have a significant impact on response.   
Prolonged dosing of temozolomide using a dose-dense schedule has been shown to reduce 
MGMT activity in peripheral blood mononuclear cells(Tolcher, Gerson et al. 2003).  
Therefore, this strategy which has shown potential benefit in recurrent malignant glioma, may 
enhance the activity of temozolomide in ependymoma.  In recurrent glioblastoma, response (as 
measured by 6-month progression free survival)l to conventional dosing of temozolomide was 
21% (Yung, Albright et al. 2000).  In comparison, a “week-on, week-off” schedule resulted in 
a 46% 6-month progression free survival rate(Wick, Felsberg et al. 2007).  A similar dosing 
schedule is proposed for this study. 
Additionally, we plan to target the ERBB1 and the ERBB2 pathways using lapatinib on a 
continuous daily dosing schedule.  Given the recent results described above demonstrating a 
high percentage of ependymomas expressing high levels of EGFR (ERBB1) as well as 
ERBB2, these are logical targets.  The concept of potential additive or synergistic benefit of 
combining a cytotoxic agent with a cytostatic agent has been established in brain tumor 
treatments.  Conventional dosing of temozolomide shows better response when combined with 
either isotretinoin (6-month PFS = 31%) or marimastat (6-month PFS = 42%)(Groves, 
Puduvalli et al. 2002; Jaeckle, Hess et al. 2003). 
Recently, studies have been performed on tumor tissues from patients with glioblastoma who 
were treated with EGFR inhibitors (either erlotinib or gefitinib).  Two studies demonstrated a 
correlation of response with either EGFR overexpression or the presence of the EGFRVIII 
mutation, but only when the PTEN gene or protein was present(Haas-Kogan, Prados et al. 
2005; Mellinghoff, Wang et al. 2005).  It is not known whether these results are translatable to 
ependymoma.  Therefore, in addition to the clinical trial, a correlative study will be performed.  
Tumor tissue will be analyzed for the following markers: 
MGMT methylation status 
EGFR amplification 
EGFR vIII mutation 
PI3K pathway activation 
This correlative study may help define the tumors that are optimally treated with the 
combination of temozolomide and lapatinib.  Furthermore, this study will further define the 
frequency of these molecular changes in adult ependymoma. 


Abbreviated Title: Ph II Recurrent Ependymoma 
Version Date: 07/21/17 
 
13 
 
1.2.5 Temozolomide overview 
Temozolomide, an oral alkylating agent with good penetration of the central nervous system, 
has been evaluated in patients with glial malignancies.  Initial studies evaluated the efficacy of 
temozolomide in patients with recurrent glioblastoma and anaplastic glioma.  A large, 
randomized phase II study by Yung and colleagues treated patients with recurrent glioblastoma 
with either temozolomide (200 mg/m2 days 1-5 of a 28-day cycle) or procarbazine (150 mg/m2 
28 day-on, 28-day off schedule) (Yung, Albright et al. 2000).  The study demonstrated only a 
modest objective response rate for both regimens (approximately 5%), but a superior 6-month 
progression-free survival rate for temozolomide (21% vs. 9%) was found. In the pre-radiation 
setting, a phase II study demonstrated a good objective response rate (complete plus partial 
response = 41%) in patients with glioblastoma during the four monthly cycles of treatment, 
using 200 mg/m2 on days 1 to 5 of a 28-day cycle. However, the responses were not durable in 
many cases and the median progression-free survival rate was 3.8 months.  Overall survival for 
patients on this study was 13.1 months, similar to most reports of treatment in newly diagnosed 
patients.  This suggests that the neoadjuvant temozolomide chemotherapy likely had little 
overall benefit.  However, these results did demonstrate definite activity of temozolomide for 
glioblastoma.(Gilbert, Friedman et al. 2002) 
Stupp and colleagues performed a phase III trial in patients with newly diagnosed 
glioblastoma, administering a daily lower dose (75 mg/m2) of temozolomide every day during 
the course of radiation therapy, followed by 6 months of adjuvant chemotherapy at the 
standard single-agent dose of 200 mg/m2 for days 1 to 5 of a 28-day cycle.(Stupp, Mason et al. 
2005)  This study, performed by the EORTC and the NCIC, randomized patients with newly 
diagnosed glioblastoma to receive either radiation therapy alone or concurrent radiation and 
temozolomide followed by 6 months of adjuvant temozolomide.  The study demonstrated a 
statistically significant improvement in median survival for the combination treatment arm 
(12.1 vs. 14.6 months) as well as a significant increase in 2-year survival (10% vs 26%). 
Eighty-eight percent of the patients received the full course of concurrent temozolomide with 
radiation.  Approximately 40% of patients received the full 6 cycles of temozolomide after the 
completion of the radiation (adjuvant therapy).  Tumor progression was the most prominent 
cause of treatment cessation.  The chemoradiation treatment was well tolerated, with an 
incidence of grade 3 or 4 hematologic toxicity of < 4%.  This chemoradiation regimen has been 
widely accepted as the new standard of care for patients with newly diagnosed glioblastoma.  
As described above, incorporation of a dose-dense strategy for recurrent primary brain tumors 
is supported by the results of a recently reported clinical trial that treated patients with 
recurrent malignant glioma with the week on/week off dosing schedule of temozolomide at a 
dose of 150 mg/m2 /day.  This study reported a 6-month progression free survival rate of 46%, 
which compares favorably with the 6-month PFS rate of 21% reported with conventional 5 day 
of a 28 day cycle of temozolomide (Yung, Albright et al. 2000; Wick, Felsberg et al. 2007).  
1.2.6 Lapatinib overview 
Lapatinib acts as a dual inhibitor of both ErbB1(EGFR) and ErbB2 (HER2) tyrosine kinase 
activity. As a member of the 4-anilinoquinazoline class of kinase inhibitors, Lapatinib is thought 
to react with the ATP binding site of EGFR/ErbB2, resulting in inhibition of autophosphorylation 
and subsequent proliferative signaling (Shewchuk, Hassell et al. 2000). The ErbB family consists 
of four closely related growth factor receptor tyrosine kinases. The family is comprised of ErbB1 


Abbreviated Title: Ph II Recurrent Ependymoma 
Version Date: 07/21/17 
 
14 
 
(EGFR/HER), ErbB2 (HER2/neu), ErbB3 (HER3), and ErbB4 (HER4).  All members of the 
ErbB family share a common extracellular ligand-binding domain, a single membrane-spanning 
region and a cytoplasmic tyrosine kinase domain (reviewed in (Yarden and Sliwkowski 2001) and 
(Burgess, Cho et al. 2003)).  A ligand for ErbB2 has not been identified, while ErbB3 lacks 
tyrosine kinase activity.  Ligand binding to EGFR, ErbB3 or ErbB4 induces these inactive 
monomers to undergo an array of homo- or heterodimerization with other members of the ErbB 
family.  ErbB2 is the preferred heterodimeric partner for all ErbB receptors, resulting in a 
complex that is endocytosed at one half to one third the rate of other EGFR dimers (Graus-Porta, 
Beerli et al. 1997; Hendriks, Opresko et al. 2003).  ErbB dimerization leads to receptor 
autophosphorylation and subsequent activation of the tyrosine kinase domain.  The signaling 
characteristics of the ErbB family are thought to be strongly interdependent.  
EGFR expression by tumor cells has been linked with aggressive tumor growth, disease 
progression, poor survival, and poor response to therapy.  Overexpression of EGFR has been 
reported in a number of epithelium-derived carcinomas including head and neck, colorectal, lung, 
esophageal, gastric, and breast carcinoma.  In a similar manner, ErbB2 has been reported to be 
overexpressed in 15-30% of invasive ductal breast cancer and has been associated with increased 
proliferation, poor clinical outcome, and altered responsiveness to various adjuvant therapies 
(Allred, Mohsin et al. 2001)  Activation of either EGFR or ErbB2 initiates a series of signaling 
cascades that includes mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase 
(PI3K), Akt, and p70S6K.  
1.2.6.1 Mechanism of Action 
Lapatinib has been shown to be a potent and selective dual inhibitor of EGFR (ErbB1) and ErbB2 
tyrosine kinase activity with IC50 values of 10.2 and 9.8 nM, respectively(Rusnak, Lackey et al. 
2001).  Lapatinib has demonstrated selective growth inhibition of human cell lines (head and 
neck, breast, and gastric) in vitro (IC90 values <2.26 µM or 1313 ng/mL) with no outgrowth 
observed up to 18 days following cessation of treatment.  Growth inhibition corresponded with 
the ability of Lapatinib to inhibit phosphorylation of Akt.  
These studies suggested that inhibition of EGFR by Lapatinib resulted preferentially in cell 
growth arrest, while inhibition of ErbB2 led to cell growth arrest and apoptosis after 72 hours.  
Treatment with Lapatinib leads to arrest of tumor cell growth and/or apoptosis, even in the 
presence of saturating concentrations of epidermal growth factor (EGF).  Treatment of tumor 
xenografts resulted in inhibition of activation of EGFR, erbB2, Erk1/2, and Akt (Xia, Mullin et 
al. 2002).  
1.2.6.2 Preclinical Studies 
The ability of Lapatinib to inhibit the growth of EGFR-overexpressing cell lines (IC50 <0.16 µM) 
was observed to be equal to that of other EGFR inhibitors being tested in clinical trials (e.g. 
gefitinib/IressaTM or erlotinib/TarcevaTM).  With the exception of ErbB4, Lapatinib was >300-fold 
more selective towards ErbB2 and EGFR kinase inhibition than to other kinases tested.  Lapatinib 
demonstrated potent growth inhibition of human breast ductal (BT474) and head and neck (HN5) 
tumor xenografts in mice.  A dose response inhibition was observed in both models receiving 
Lapatinib (30 or 100 mg/kg twice daily orally for 21 days).  Complete inhibition of tumor growth 
was seen in mice receiving 100 mg/kg (Rusnak, Lackey et al. 2001).  


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Abbreviated Title: Ph II Recurrent Ependymoma 
Version Date: 07/21/17 
 
16 
 
2.1.1.4 Patients must be able to undergo brain or spine MRI scans with intravenous 
gadolinium, based on tumor location(s) within 14 days prior to registration. 
2.1.1.5 Patients must be on a steroid dose that has been stable or decreasing for at least 5 
days. If the steroid dose is increased between the date of imaging and registration, a 
new baseline MRI is required.  
2.1.1.6 Karnofsky performance status ≥ 70 
2.1.1.7 Age ≥ 18 
2.1.1.8 CBC/differential obtained within 14 days prior to registration, with adequate bone 
marrow function defined as follows:  
• Absolute neutrophil count (ANC) ≥ 1,500/mm3 
• Platelets ≥ 100,000 cells/mm3    
• Hemoglobin ≥ 10.0 gm/dL (Note: The use of transfusion or other intervention to 
achieve Hgb ≥ 10.0 is acceptable) 
• White blood cell count (WBC) ≥ 3,000/mcL.  
• Adequate liver function within 14 days prior to registration, defined as follows: 
SGPT (ALT) < 2.5 times the upper limit of normal, Bilirubin ≤ 1.6 mg/dL  
• Adequate renal function within 14 days prior to registration, defined as follows: 
Creatinine < 1.7 mg/dL 
2.1.1.9 Patients must have recovered from the toxic effects of prior therapy, and there must 
be a minimum time of:   
• 28 days from the administration of any investigational agent 
• 28 days from administration of prior cytotoxic therapy with the following 
exceptions: 
• 14 days from administration of vincristine 
• 42 days from administration of nitrosoureas 
• 21 days from administration of procarbazine  
• 7 days from administration of non-cytotoxic agents [e.g., interferon, tamoxifen, 
thalidomide, cis-retinoic acid, etc. (radiosensitizer does not count)]. 
• 28 days from prior radiation therapy.  
2.1.1.10 Patients must have recovered from the effects of surgery and a minimum of 14 days 
must have elapsed from the day of surgery to the day of registration.  For core or 
needle biopsy, a minimum of 7 days must have elapsed prior to registration. 
2.1.1.11 Residual disease following resection of recurrent tumor is not mandated for eligibility 
into the study.  To best assess the extent of residual disease post-operatively, an MRI 
should be done no later than 96 hours in the immediate postoperative period or at least 
4 weeks postoperatively, within 14 days prior to registration.  If the “within 96-hour 
of surgery” scan is more than 14 days before registration, the scan needs to be 


Abbreviated Title: Ph II Recurrent Ependymoma 
Version Date: 07/21/17 
 
17 
 
repeated.  
2.1.1.12 Patients must sign study-specific informed consent and authorization for the release of 
their protected health information prior to registration. Patients must be registered in 
the prior to treatment with study drug. 
2.1.1.13 Women of childbearing potential must have a negative β-HCG pregnancy test 
documented within 14 days prior to registration. 
2.1.1.14 Women of childbearing potential and male participants must practice adequate 
contraception. 
2.1.1.15 All patients must have an LVEF measurement of at least 50% by Echo or MUGA (if 
clinically indicated) within 14 days prior to registration. The method used for LVEF 
assessment in an individual subject must be the same throughout the trial 
2.1.2 Exclusion Criteria 
2.1.2.1 Prior invasive malignancy that is not the ependymoma (except non-melanomatous 
skin cancer or carcinoma in situ of the cervix) unless the patient has been disease free 
and off therapy for that disease for a minimum of 3 years. 
2.1.2.2 Severe, active comorbidity, defined as follows: 
• Transmural myocardial infarction or unstable angina within 3 months prior to study 
registration 
• Evidence of recent myocardial infarction or ischemia by the findings of S-T 
elevations of ≥ 2 mm using the analysis of an EKG performed within 14 days prior 
to registration 
• New York Heart Association grade II or greater congestive heart failure requiring 
hospitalization within 12 months prior to registration 
• History of stroke or transient ischemic attack within 3 months prior to registration. 
• Inadequately controlled hypertension (systolic blood pressure > 150 mm Hg and/or 
diastolic blood pressure > 90 mm Hg despite antihypertensive medication) 
• History of cerebral vascular accident (CVA) within 3 months prior to registration. 
• Serious and inadequately controlled cardiac arrhythmia 
• Significant vascular disease (e.g., aortic aneurysm, history of aortic dissection) 
• Acute bacterial or fungal infection requiring intravenous antibiotics at the time of 
registration 
• Acquired immune deficiency syndrome (AIDS) based upon current CDC definition; 
note, however, that HIV testing is not required for entry into this protocol. The need 
to exclude patients with AIDS from this protocol is necessary because the 
treatments involved in this protocol may be significantly immunosuppressive.   
2.1.2.3 Patients cannot be receiving HAART (Highly Active Anti-Retroviral Therapy) 
therapy. 
2.1.2.4 Pregnant or nursing women because of concern of fetal/infant exposure to these 


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Abbreviated Title: Ph II Recurrent Ependymoma 
Version Date: 07/21/17 
 
21 
 
3.3.1.2 Summary of dose modifications 
Dermatologic 
Rash – acne/acneiform 
• Intolerable Grade 2 & 
Grades 3-4 
 
 
Hold dose.   
• Re-evaluate at least weekly 
until AE resolved to < 1 or 
tolerable Grade 2.   
• Re-treat at a one dose level 
reduction 
• If AE persists > 4 weeks, 
remove patient from study 
Patients with Grade 4 AEs related 
to agent should be taken off study. 
 
Note: Grade 2 lapatinib related rash 
may not automatically require dose 
reduction.  However, for Grade≥ 3 
rash or recurrent intolerable Grade 
2 rash, reduce 1 dose level. 
 
Gastrointestinal 
Diarrhea 
• Grade 1 
 
•  Grade 2 
 
 
• Grade 3, 4 or 
intolerable Grade 2:   
 
 
 
 
 
 
No intervention required 
 
Loperamide (4 mg at first onset, 
followed by 2 mg every 2–4 hrs 
until diarrhea free for 12 hrs) 
 
• Hold dose.   
• Loperamide, hold agent until 
recovery to < Grade 1 and then 
reduce 1 dose level 
• If AE persists > 4 weeks, 
remove patient from study 
• Patients with Grade 4 AEs 
related to agent may be taken 
off study at investigator’s 
discretion. 
 
Ocular/Visual 
Keratitis 
 
• Grade 1 
 
 
 
 
 
 
 
 
 
• Preservative-free artificial tears, 
ointments, and/or other therapies 
as clinically indicated, with a 
follow-up examination within 
2 weeks1. 
• Dose reduction not required. 


Abbreviated Title: Ph II Recurrent Ependymoma 
Version Date: 07/21/17 
 
22 
 
 
 
 
• Grade 2 or 3 
 
 
 
 
 
 
 
• Manage as for Grade 1 keratitis1.   
• Grade 2 persistent (>14 days) or 
Grade 3:  Hold dose.  Re-treat at a 
reduced dose after resolution or 
amelioration of AE to < Grade 1 
at the discretion of the 
investigator. 
• Persistent Grades 2 or 3:  Remove 
patient from study for persistent 
Grade >2 keratitis after dose held 
for 14 days.  Ophthalmologic F/U 
should be scheduled at a 
frequency determined by the 
ophthalmologist 
Pulmonary/Upper Respiratory 
Signs and symptoms of 
Interstitial Pneumonitis 
 
Patient should be thoroughly 
evaluated, closely monitored, and 
supported as clinically indicated. 
 
Hold dose pending diagnosis 
 
Permanently discontinue lapatinib if 
diagnosis is confirmed and 
considered possibly related to 
lapatinib. 
All other non-hematologic adverse events  
 
Any Grade 2 of concern 
(e.g.,  prolonged cardiac,  
 
 
 
 
 
 
 
Hold dose. 
• Re-treat at a reduced dose after 
resolution or amelioration of AE 
to < Grade 1 
If AE persists > 4 weeks , remove 
patient from study 
 
 
 
 
Grade 3 or 4 
 
Hold dose.   
• Re-evaluate until AE 
resolved to < Grade 1 (or 
tolerable Grade 2).   
• If AE persists >4 weeks, 
remove patient from study 
• Patients with Grade 4 AEs 
related to agent may be 
taken off study at 
investigator’s discretion. 
 


Abbreviated Title: Ph II Recurrent Ependymoma 
Version Date: 07/21/17 
 
23 
 
3.3.1.3 Liver Chemistry Stopping and Follow-up Criteria 
3.3.1.3.1 Liver Chemistry Stopping Criteria 
3.3.1.3.1.1 Liver chemistry stopping and follow up criteria have been designed to assure 
subject safety and evaluate liver event etiology.  All subjects who meet liver 
chemistry criteria requiring permanent discontinuation of lapatinib must continue 
to be followed for the study assessments and procedures as defined in Section 
3.7.6and Appendix 12.5If a subject experiences ALT >3 × ULN and total bilirubin 
>2.0 × ULN (>35% direct; bilirubin fractionation required*), then the following 
actions must be taken: 
• immediately and permanently discontinue investigational product; 
• complete the SAE data collection tool, and the clinical evaluation CRF; 
• in addition to the liver event follow up assessments defined below, the following 
are suggested:  specialist or hepatology consultation; anti-nuclear antibody, anti-
smooth muscle antibody, and Type 1 anti-liver kidney microsomal antibodies; and 
liver imaging and/or liver biopsy to evaluate liver disease; 
• promptly report the event to NCI CCR within 24 hours of learning of its occurrence 
(refer to Section 7.4); 
• monitor every week until liver chemistries resolve, stabilize or return to within 
baseline values; 
• do not re-challenge with lapatinib. 
• NOTE:  bilirubin fractionation should be performed if testing is available.  If 
testing is unavailable and a subject meets the criterion of total bilirubin >2.0 × 
ULN, then the aforementioned actions must still be performed. 
3.3.1.3.1.2 If a subject experiences: 
• ALT >8 × ULN or 
• ALT >5 × ULN persisting for ≥2 weeks: retest within 3 days from the first 
occurrence and then weekly to determine if ALT elevation persists or 
• ALT >3 × ULN with signs or symptoms of hepatitis or hypersensitivity (the 
appearance or worsening of fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, or eosinophilia),  
• Total Bilirubin > 2 x ULN in absence of Gilbert’s Syndrome 
then hold investigational product for 2 weeks, repeat liver chemistry testing in 2 weeks, and 
then call the Study Chair (Dr. Mark Gilbert) to discuss the possibility of re-challenging with 
investigational product.   
3.3.1.3.1.3 If the treatment is exhibiting efficacy and the subject wants to continue for 
potential benefit of lapatinib therapy after being informed of the results of liver 
chemistry testing, then the lapatinib may be re-started at the reduced dose agreed 
upon by the investigator and the Study Chair.  The liver event CRF should be 
completed and liver chemistries and aforementioned signs and symptoms should 


Abbreviated Title: Ph II Recurrent Ependymoma 
Version Date: 07/21/17 
 
24 
 
be monitored at a minimum of every 2 weeks until resolution, stabilization, or a 
return to baseline values, at which point monitoring should be continued per 
protocol. 
3.3.1.3.1.4 If a subject experiences ALT >3 × ULN but <5 × ULN and total bilirubin ≤2 × 
ULN, without signs or symptoms of hepatitis or hypersensitivity, and who can be 
monitored weekly, then the following actions should be taken: 
• continue investigational product; 
• monitor weekly until liver chemistries resolve, stabilize, or return to within 
baseline, then monitor liver chemistries as per protocol assessment schedule; 
• if ALT >3 and < 5 × ULN for > 4 weeks , discontinue the treatment; 
• if at any time this subject meets any of the aforementioned liver chemistry stopping 
criteria, then proceed as described above. 
3.3.1.3.2 Liver Chemistry Follow up Criteria 
3.3.1.3.2.1 For all subjects who meet any of the liver chemistry criteria described above, make 
every attempt to carry out the liver follow up assessments described below:  
• Viral hepatitis serology including: 
• Hepatitis A IgM antibody; 
• Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); 
• Hepatitis C RNA; 
• Cytomegalovirus IgM antibody;  
• Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, 
obtain heterophile antibody or monospot testing); 
• Hepatitis E IgM antibody (if subject resides or has travelled 
outside USA or Canada in past 3 months); 
• Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH); 
• Complete blood count with differential to assess eosinophilia; 
• Record the appearance or worsening of clinical symptoms of hepatitis, or 
hypersensitivity, fatigue, decreased appetite, nausea, vomiting, abdominal pain, 
jaundice, fever, or rash as relevant on the AE report form; 
• Record use of concomitant medications, acetaminophen, herbal remedies, other 
over the counter medications, or putative hepatotoxins, on the concomitant 
medications report form; 
• Record alcohol use on the liver clinical evaluation case report form. 
• Refer to Appendix 12.5 for a liver safety algorithm detailing stopping and follow up 
criteria. 


Abbreviated Title: Ph II Recurrent Ependymoma 
Version Date: 07/21/17 
 
25 
 
3.3.1.4 Cardiac Assessments 
 
3.3.1.4.1 Cardiac Definitions 
3.3.1.4.1.1 Cardiac Death is defined as either: 
• Cardiac death due to heart failure, myocardial infarction, or arrhythmia. 
• Probable cardiac death defined as sudden, unexpected death within 24 hours of a 
definite or probable cardiac event. 
3.3.1.4.1.2 Severe symptomatic CHF is defined as New York Heart Association (NYHA) 
Class III or IV (Class III defined as being not capable of climbing one flight of 
stairs and class IV defined as having symptoms at rest) and a drop in LVEF of 
more than 10 points from the baseline and to below 50%. In these cases there is no 
need to perform a confirmatory second LVEF assessment. The method used for the 
LVEF assessment must be the same method as used for the baseline assessment. 
3.3.1.4.1.3 Asymptomatic (NYHA I) or mildly symptomatic (NYHA II) is defined as a 
significant drop in LVEF, confirmed by a second LVEF assessment within 
approximately three weeks showing also a significant drop in LVEF. A significant 
drop is defined as an absolute decrease of more than 10 points below the baseline 
LVEF and to below 50%. The method used for LVEF assessment must be the same 
method used for the first (baseline) assessment. 
New York Heart Association Functional Classification 
I 
No Symptoms and no limitations in ordinary physical activity. 
II 
Mild Symptoms and slight limitation during ordinary activity. 
Comfortable at rest. 
III 
Marked limitation in activity due to symptoms, even during 
less-than-ordinary activity. 
Comfortable at rest. 
IV 
Severe limitations. Experiences symptoms even while at rest. 
3.3.1.4.1.4 Stopping and holding rules 
• Stopping rule 
Treatment with any of the treatment regimens defined for this study will be permanently 
stopped if a patient develops a symptomatic cardiac event or an asymptomatic event confirmed 
by repeat evaluation. However, patients will remain in the study and all efforts will be made to 
complete all assessments as planned. 
• Treatment 
It is strongly recommended that patients who have symptomatic decreases in LVEF or those 
who meet the criteria for stopping treatment seek cardiologic consultation for advice on 
potential treatment for their cardiac dysfunction. 


Abbreviated Title: Ph II Recurrent Ependymoma 
Version Date: 07/21/17 
 
26 
 
3.3.2 Temozolomide 
3.3.2.1 Dosing is based on adverse events (AEs) during the prior treatment cycle. If multiple 
AEs are seen, the dose administered should be based on the dose reduction required 
for the most severe grade of any single AE.  
Dose Level 
Dose mg/m2 
Remarks 
- 2  
75 
Reduction if prior AE 
-1  
100 
Reduction if prior AE 
 0 
125 
Starting dose for cycle 1and 2, 
increase to 150 mg/m2 for cycle 3 
and beyond if non hematologic 
toxicity 
≤ 
grade 
2 
and 
hematologic toxicity ≤ grade 1 
+1 
150 
Highest possible dose level  
 
3.3.2.1.1 First and Second Cycle: Temozolomide will be started at a dose of 125mg/m2/day.  
3.3.2.1.2 Third Cycle: The dose of temozolomide will be determined according to: (1) 
treatment related non-hematologic AE during the preceding treatment cycle, as well 
as (2) the worst ANC and platelet counts. 
3.3.2.1.3 Delay: On day 1 of each cycle (within the prior 72 hours), ANC ≥ 1.5 x 109/L, 
platelet count ≥ 100 x 109/L and all grade 2, 3 or 4 non-hematologic AEs (except for 
alopecia, nausea, and vomiting) must have resolved (to grade ≤ 1).  
3.3.2.1.4 If AEs persists, treatment should be delayed by 1 week for up to 4 consecutive 
weeks. If, after 4 weeks of delay, all treatment related AEs have still not resolved (to 
grade ≤ 1): then any further treatment with temozolomide should be stopped.  
3.3.2.1.5 Dose Escalations and Reductions: If, during the first and second cycle, all 
hematologic AEs observed were ≤ grade 1 and treatment related non-hematologic 
AEs observed were grade ≤ 2 (except alopecia, lymphopenia, nausea and vomiting) 
then the temozolomide dose should be escalated to dose level 1 and this dose should 
be used as the starting dose for subsequent cycles. If treatment after cycles 1and 2 
temozolomide has to be delayed because of ongoing non-hematologic AEs of grade 
≥ 2, then no escalation is possible. If the dose was not escalated at cycle 3, then the 
dose should not be escalated in further cycles (4-24). 
3.3.2.1.5.1 Dose reductions: If any treatment related non-hematologic AE observed was grade 
> 2 (except alopecia, lymphopenia, nausea and vomiting) and/or if platelets < 50 x 
109/L and/or ANC < 1 x 109/L, then the dose should be reduced by one dose level. 
Patients who require more than two dose reductions will have treatment stopped. 
If any treatment-related non-hematologic AE observed was grade 4 (except alopecia, 
lymphopenia, nausea and vomiting) then temozolomide treatment should be stopped.  


Abbreviated Title: Ph II Recurrent Ependymoma 
Version Date: 07/21/17 
 
27 
 
3.3.2.1.5.2 Subsequent cycles (4-24): Any dose reductions of temozolomide will be 
determined according to: (1) non-hematologic AE during the preceding treatment 
cycle, as well as (2) the lowest ANC and platelets observed. No dose escalation 
should be attempted. The same dose reductions as for the second cycle should be 
applied. Important: If the dose was reduced or delayed for AEs, there will be no 
dose re-escalation in subsequent treatment cycles.  
3.3.2.2 Summary of Dose Modifications or Discontinuation for Temozolomide-Related 
Adverse Events 
 
Worst Treatment-Related Non-Hematologic AE (except for alopecia, nausea, 
and vomiting) During the Previous Cycles 
Grade 
Dose Modification 
0-2 
No dose modifications for non-hematologic AEs. Dose reductions based on 
ANC and platelet counts are applicable.  
3 
Reduce by one dose level (except alopecia, nausea, and vomiting).  
4 
Stop (except alopecia, nausea, and vomiting). Dose modifications based on 
ANC and platelet counts are not applicable.  
 
3.3.2.3 Worst Treatment-Related Hematologic AE During the Previous Cycle 
Worst AE 
Platelets 
 
≥100 x 109/L  
50 – 99 x 109/L  
< 50 x 109/L  
 
≥ 1.5 x 109/L  
Dose unchanged  
Dose unchanged  
Reduce by 1 dose 
level  
ANC  ≥1 & <1.5 x 
109/L  
Dose unchanged  
Dose unchanged  
Reduce by 1 dose 
level  
 
< 1 x 109/L  
Reduce by 1 dose 
level  
Reduce by 1 dose 
level  
Reduce by 1 dose 
level  
Note: A complete blood count must be performed on days 14 and 28 (± 72 hours) after the first 
daily dose of each treatment cycle.  
Hematologic AE on Day 1 of Each Cycle (within the prior 72 hours 
before Day 1) 
AE 
Delay 
ANC< 1.5 x 109/L 
and/or Platelet count < 
100 x 109/L 
Delay up to 4 weeks until all resolved. If 
unresolved after 4 weeks then stop. If resolved, 
dose delay/reductions based on non-hematologic 
AEs are applicable. If treatment has to be delayed 
for AEs, then no escalation is possible.  
 
Non-Hematologic AE (except for alopecia, nausea, and vomiting)  
On Day 1 of Each Cycle (within the prior 72 hours) 
Grade 
Delay 


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Abbreviated Title: Ph II Recurrent Ependymoma 
Version Date: 07/21/17 
 
32 
 
It will be documented whether or not each patient completed the clinical study. If for 
any patient study treatment or observations were discontinued the reason will be 
recorded on the appropriate case report form. Reasons that a patient may discontinue 
participation in a clinical study are listed below: 
Any patient who receives at least one dose of trial medication will be included in the 
safety analysis. 
3.8.1.1 Evidence of recurrent or progressive disease 
3.8.1.2 Second malignancy 
3.8.1.3 Development of unacceptable toxicity during treatment 
3.8.1.4 Non-adherence to the protocol 
3.8.1.5 Refusal of therapy 
3.8.1.6 Pregnancy 
3.8.1.7 At 2 years of protocol therapy 
 
3.8.2 Off Study Criteria 
3.8.2.1 Death 
3.8.2.2 Lost to follow-up 
3.8.2.3 Withdrawal of consent for continued follow-up 
3.8.2.4 Protocol defined follow-up completed 
3.8.2.5 Withdrawal of consent 
 
3.8.3 Off study procedure 
 
For participating CERN sites: 
When a subject is taken off-study, notify CCR study coordinator via encrypted email. 
(Christine Bryla email: christine.bryla@nih.gov ) 
 
 
3.8.4 POST PROTOCOL THERAPY AND FOLLOW UP 
3.8.4.1 Post Protocol Single Agent Lapatinib 
Patients that are showing sustained Complete Response (CR), Partial Response (PR) or Stable 
Disease (SD) may continue Post protocol single agent therapy with lapatinib.  Post 
protocol lapatinib supply may be obtained through Glaxo Smith-Kline (GSK), using the same  
drug ordering mechanism as detailed in section 10.2.12 (Agent Ordering/Requests). 
 


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Abbreviated Title: Ph II Recurrent Ependymoma 
Version Date: 07/21/17 
 
35 
 
5.1.2 Rationale 
The purpose of analyzing the tissue samples is to confirm the diagnosis of ependymoma, as 
well as to determine the status of key molecular markers.  As described below, such markers 
will be examined in an effort to further characterize other factors that may be predictive of 
response and prognosis using the treatment regimens that are undergoing evaluation in this 
clinical trial.  Furthermore, in the case where frozen tumor tissue is also available, more 
extensive genetic testing will be performed so that correlative profiles of gene expression to 
response and outcome can be made in this carefully studied, uniformly treated group of 
patients.  
5.1.3 Specimen Collection: Tissue specimens should be taken from pre-study diagnostic 
open biopsy or surgical resection. 
5.1.3.1 To be eligible for this study, the patient must have an ependymoma.  Features of a 
grade II or III ependymoma according to WHO guidelines must be present.   
5.1.3.2 The following materials will be required for tissue evaluation: 
5.1.3.2.1 Representative tissue blocks that contain diagnostic tumor.  As a guide, at least 1 
cubic centimeter of tissue composed primarily of tumor is desired.  If tissue block is 
not available, 15 unstained slides from a representative tumor block is required. 
5.1.3.2.2 If a representative tissue block is submitted, an accompanying H&E is encouraged 
for rapid diagnosis but not required.  If an H&E is included, Dr. Aldape will use this 
for the review.  If not included, Dr. Aldape will cut a section from the paraffin 
block, stain this with H&E, and use that slide for the review. 
5.1.3.2.3 A Pathology Report documenting that the submitted material contains tumor; the 
report must include the protocol number, patient case number, and the patient’s 
initials. The patient’s name and/or other identifying information should be removed 
from the report. The surgical pathology numbers and information must NOT be 
removed from the report. 
5.1.3.2.4 Tissue evaluation will be required for every case before study registration Step 2. 
Send pathology material by overnight mail directly to: 
Ken Aldape, MD 
MacFeeters- Hamilton Centre for Neuro-Oncology, 
101 College St, Room 14-701 
Princess Margaret Cancer Centre, 
Toronto Medical Discovery Tower (TMDT), 
Toronto, ON  M5G 1L7 
Canada 
kaldape@gmail.com  


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Abbreviated Title: Ph II Recurrent Ependymoma 
Version Date: 07/21/17 
 
37 
 
 
Sites will enter data on paper Case Report Forms; then transfer study data to NCI via fax, mail 
or Secure E-mail and File Transfer Service (SEFT).  Contracted Data Managers will enter the 
data into a secure research database.   
 
End of study procedures: Data will be stored according to HHS, FDA regulations and NIH 
Intramural Records Retention Schedule as applicable.  
 
Loss or destruction of data: Should we become aware that a major breach in our plan to 
protect subject confidentiality and trial data has occurred, the IRB will be notified.  
 
 
 
6.1.1 Confidentiality  
All documents, investigative reports, or information relating to the patient are strictly 
confidential. Any patient specific reports (i.e., Pathology Reports, MRI Reports, Operative 
Reports, etc.) submitted to the NCI must have the patient’s full name & social security number 
“blacked out” and the assigned patient ID number, protocol accession number, and protocol 
number written in. Patient initials may be included or retained for cross verification of 
identification. 
 
6.1.2 Certificate of Confidentiality 
As part of study efforts to provide confidentiality of subject information, this study has 
obtained a Certificate of Confidentiality, which helps to protect personally identifiable research 
information. The Certificate of Confidentiality allows investigators on this trial to refuse to 
disclose identifying information related to the research participants, should such disclosure 
have adverse consequences for subjects or damage their financial standing, employability, 
insurability or reputation. The informed consent includes the appropriate coverage and 
restrictions of the Certificate of Confidentiality. 
6.1.3 Safety Data  
All patients receiving study agents will be evaluated for safety.  The safety parameters include 
all laboratory tests and hematological abnormalities, CNS observations, physical examination 
findings, and spontaneous reports of adverse events reported to the investigator by patients.  
All toxicities encountered during the study will be evaluated according to the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 and recorded prior to each 
course of therapy.  Life-threatening toxicities that are unexpected and assessed to be possibly 
related to the study agent/s should be reported immediately to the study Coordinator and 
Institutional Review Board (IRB).   
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other 
means, will be collected and recorded on the Adverse Event Case Report Form and followed as 
appropriate. An adverse event is any undesirable sign, symptom or medical condition occurring 


Abbreviated Title: Ph II Recurrent Ependymoma 
Version Date: 07/21/17 
 
38 
 
after starting study drug (or therapy) even if the event is not considered to be related to study 
drug. 
Medical conditions/diseases present before starting study treatment are only considered 
adverse events if they worsen after starting study treatment (any procedures specified in the 
protocol). Adverse events occurring before starting study treatment but after signing the 
informed consent form are recorded on the Baseline Evaluations Adverse Events Case Report 
Form. Abnormal laboratory values or test results constitute adverse events only if they induce 
clinical signs or symptoms or require therapy, and are also recorded on the Adverse Events 
Case Report Form. 
 


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Abbreviated Title: Ph II Recurrent Ependymoma 
Version Date: 07/21/17 
 
42 
 
• 
Is associated with death or another serious adverse event, including hospitalization.  
• 
Is judged by the Investigator to be of significant clinical impact 
• 
If any abnormal laboratory result is considered clinically significant, the investigator 
will provide details about the action taken with respect to the test drug and about the 
patient’s outcome. 
7.2.2 Suspected adverse reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 
7.2.3 Unexpected adverse reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in 
the investigator brochure or is not listed at the specificity or severity that has been observed; 
or, if an investigator brochure is not required or available, is not consistent with the risk 
information described in the general investigational plan or elsewhere in the current 
application. "Unexpected” also refers to adverse events or suspected adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of drugs or as anticipated from 
the pharmacological properties of the drug, but are not specifically mentioned as occurring 
with the particular drug under investigation. 
7.2.4 Serious  
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a 
Serious Adverse Event or if it compromises the safety, welfare or rights of subjects or others. 
7.2.5 Serious Adverse Event 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
• 
Death, 
• 
A life-threatening adverse drug experience 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect. 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. 
7.2.6 Disability 
A substantial disruption of a person’s ability to conduct normal life functions. 


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Abbreviated Title: Ph II Recurrent Ependymoma 
Version Date: 07/21/17 
 
47 
 
The trial will be stopped early if, based on the current data, Pr ( QE > QS +3.5| 
data)  <  0.065.  That is, the trial will be stopped early if, it is very unlikely that the median 
time to progression with the experimental therapy (temozolomide and lapatinib) is less than the 
historical median time to progression for the standard treatment as described in the 
literature.  The rule will be applied every 2 months, with the probability criterion recomputed 
based on the most recent data available at that time.  Based on an anticipated accrual rate of 2.5 
patients per month, the trial is expected to complete accrual in 40 months.   
To obtain operating characteristics of the early stopping rule, the trial was simulated under 
three scenarios, which we have summarized in the Table below. The design’s operating 
characteristics are as follows.  Each entry in the table is the mean from 2000 simulated trials: 
Table Operating Characteristics.  Maximum sample size 50 
 
Case 
Median 
Time to 
Progression 
 
Pr(Stop Early) 
 
# Patients 
(25%,75%) 
 
 
 
 
Scenario 1 
2.0 
1 
   16.435 ( 13, 19 ) 
Scenario 2 
7.0 
0.896 
36.694 ( 27, 50 ) 
Scenario 3 
10.5 
0.173 
47.354 ( 50, 50 ) 
Scenario 4 
14.0 
0.034 
49.054 ( 50, 50 ) 
We also summarize the median lower and median upper credible intervals for this trial on an 
assumption of that the data follows an exponential distribution (with median survivals 
summarized in the Table below).  To calculate the expected lower and expected upper credible 
intervals we simulated progression free survival data (1000 simulations) from exponentially 
distributed data and assuming observations without events were censored at 48 months (40 
months of accrual and 8 months of additional follow-up). For each simulation we recorded the 
lower (1st decile) and upper (9th  decile) credible sets from the posterior distribution of the 
median PFS parameter.  At the end of the simulation we then calculated and recorded below 
the median 1st decile and median 9th deciles from the vector of recorded deciles obtained from 
our simulation.   
True Median Survival Median 1st decile and Median 9th decile Credible Limits 
10.5 Months 
(8.72, 12.50) 
14 Months 
(11.52, 16.66) 
 
Secondary Efficacy Analysis 
The secondary endpoint of this trial is anti-tumor activity as determined by the overall response 
(CR or PR) rate.  MacDonald criteria will be used to determine the overall response. Patients 
must have completed at least 4 weeks of treatment to be considered evaluable for overall 
response, unless treatment is stopped for neurologic progression.  Patients with neurologic 
progression will be scored as non-responders regardless of duration of treatment. 
Safety Analysis 


Abbreviated Title: Ph II Recurrent Ependymoma 
Version Date: 07/21/17 
 
48 
 
All patients will be considered evaluable for safety after the first dose of therapy. AEs and 
clinically significant laboratory abnormalities with associated incidence rates and severities 
will be tabulated. 
Deaths and Serious Adverse Events 
Serious adverse events and deaths will be listed. Data from the adverse event page that specify 
the event is serious will be used to generate the listing. 
Summaries of serious unique adverse events will include: 
• all serious treatment emergent adverse events, 
• all serious treatment emergent adverse events by sex, 
• all serious treatment emergent adverse events by race, 
• all serious treatment emergent adverse events by the worst grade, 
• all related serious treatment emergent adverse events by the worst grade. 
Neurological Symptoms and Signs 
Neurological symptoms and signs collected on the neurological examination CRFs will be 
summarized at the baseline and by scheduled visit. 
Laboratory Tests 
Changes from baseline in laboratory measurements will be summarized by study visit. 
The worst post-baseline laboratory measurements up to (1) 30 days after the permanent 
discontinuation of the study medication or (2) the initiation of subsequent anti-ependymoma 
therapy will be summarized. Marked laboratory toxicity (baseline grade 0 to post-baseline 
grade 3 or 4, or baseline grade 1 to post-baseline grade 4) will also be summarized. 
Vital Signs, Weight and Karnofsky Performance Status 
Descriptive statistics will be used to summarize vital signs, weight, and Karnofsky 
performance status. For continuous outcomes the mean, standard deviation, median, 25% 
percentile, 75% percentile, minimum, and maximum will be reported for change from baseline 
at each scheduled visit. For discrete (i.e., Karnofsky performance status) outcomes, descriptive 
analyses will be based on the distribution of this outcome and will be reported as percentages 
and patient counts by category. 
MDASI-BT 
The sample size for this trial was based on the primary end point of the study. 
Received MDASI-BT and MDASI-SP forms will be checked versus the timing schedule and 
considered as valid if they fall within one week of the scheduled assessment.  Compliance rates 
will be calculated as the number of received valid forms over the number of expected forms. 
Differences between groups in compliance will be tested by use of Fisher’s exact test at every 
time point. 
We will use descriptive statistics to describe how patients rate symptom severity and 
interference with function at each time point.  Error bar graphs for each of the symptoms will 
be constructed at each time point.  The proportion of patients rating their symptoms to be 7 or 


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Abbreviated Title: Ph II Recurrent Ependymoma 
Version Date: 07/21/17 
 
51 
 
10.1.1 Formulation 
10.1.2 Other Names: - methazolastone; Temozolomide is supplied in white opaque, 
preservative-free, two-piece, hard gelatin capsules of the following p.o. dosage 
strengths: 5 mg, 20 mg, 100 mg, 180 mg and 250 mg.  Each capsule contains drug 
substance in combination with lactose, anhydrous NF, colloidal silicon dioxide NF, 
sodium starch glycolate NF, tartaric acid NF, and stearic acid NF.  The capsule shells 
contain gelatin NF, titanium dioxide USP, and sodium lautyl sulfate NF. 
10.1.3 Mode of Action:  Alkylating agent of imidazotetrazinone class. 
10.1.4 Storage and Stability 
The capsules are packaged in 30 cc, 28 mm, 48 Type I amber glass bottles (30 capsules/bottle) 
and should be stored at 25°C but temperatures between 15 and 30 degrees centigrade are 
permissible.  Capsules are stable for at least 30 months when stored in amber glass bottles at 
this temperature.   
10.1.5 Supply: Commercially available 
10.1.6 Pharmacokinetics 
Temozolomide is rapidly and completely absorbed after oral administration; peak plasma 
concentrations occur in 1 hour.  Food reduces the rate and extent of temozolomide absorption.  
Mean peak plasma concentration and AUC decreased by 32% and 9%, respectively, and Tmax 
increased 2-fold (from 1.1 to 2.25 hours) when temozolomide was administered after a 
modified high-fat breakfast. Temozolomide is rapidly eliminated with a mean elimination half-
life of 1.8 hours and exhibits linear kinetics over the therapeutic dosing range.  Temozolomide 
has a mean apparent volume of distribution of 0.4 L/kg (%CV=13%).  It is weakly bound to 
human plasma proteins; the mean percent bound of drug-related total radioactivity is 15%. 
10.1.7 Metabolism and Elimination 
Temozolomide is spontaneously hydrolyzed at physiologic pH to the active species, 3-methyl-
(triazen-1-yl)imidazole-4-carboxamide (MTIC) and to temozolomide acid metabolite.  MTIC 
is further hydrolyzed to 5-amino-imidazole-4-carboxamide (AIC), which is known to be an 
intermediate in purine and nucleic acid biosynthesis and to methylhydrazine, which is believed 
to be the active alkylating species.  Cytochrome P450 enzymes play only a minor role in the 
metabolism of temozolomide and MTIC.  Relative to the AUC of temozolomide, the exposure 
to MTIC and ACI is 2.4% and 23%, respectively.  About 38% of the administered 
temozolomide total radioactive dose is recovered over 7 days; 37.7% in urine and 0.8% in 
feces.  The majority of the recovery of radioactivity in urine is as unchanged temozolomide 
(5.6%), AIC (12%), temozolomide acid metabolite (2.3%), and unidentified polar 
metabolites(s) (17%).  Overall clearance of temozolomide is about 5.5 L/hr/m2. 
10.1.8 Special Populations 
10.1.8.1 Creatinine Clearance: Population pharmacokinetic analysis indicates that creatinine 
clearance over the range of 36-130 mL/min/m2 has no effect on the clearance of 
temozolomide after oral administration.  The pharmacokinetics of temozolomide have 
not been studied in patients with severely impaired renal function (CLcr < 36 
mL/min/m2). Caution should be exercised when temozolomide is administered to 


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52 
 
patients with severe renal impairment.  Temozolomide has not been studied in 
patients on dialysis. 
10.1.8.2 Hepatically Impaired Patients:  In a pharmacokinetic study, the pharmacokinetics of 
temozolomide in patients with mild to moderate hepatic impairment (Child’s-Pugh 
Class I-II) were similar to those observed in patients with normal hepatic function.  
Caution should be exercised when temozolomide is administered to patients with 
severe hepatic impairment.   
10.1.8.3 Gender: Population pharmacokinetic analysis indicates that women have an 
approximately 5% lower clearance (adjusted for body surface area) for temozolomide 
than men. Women have higher incidences of grade 4 neutropenia and 
thrombocytopenia in the first cycle of therapy than men. 
10.1.8.4 Population pharmacokinetic analysis indicates that age (range 19-78 years) has no 
influence on the pharmacokinetics of temozolomide. In the anaplastic astrocytoma 
study population, patients 70 years of age or older had a higher incidence of grade 4 
neutropenia and grade 4 thrombocytopenia in the first cycle of therapy than patients 
under 70 years of age.  In the entire safety database, however, there did not appear to 
be a higher incidence in patients 70 years of age or older. 
10.1.8.5 Drug-Drug Interactions:  
In a multiple dose study, administration of temozolomide 
with ranitidine did not change the Cmax or AUC values for temozolomide or MTIC. 
Population analysis indicates that administration of valproic acid decreases the 
clearance of temozolomide by about 5%.  The clinical implication of this effect is not 
known. Population analysis failed to demonstrate any influence of co-administered 
dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2-
receptor antagonists, or phenobarbital on the clearance of orally administered 
temozolomide. 
10.1.9 Known Potential Adverse Events  
Hematologic: Thrombocytopenia, leukopenia, myelodysplastic syndrome 
Gastrointestinal: Nausea, vomiting, anorexia 
Hepatic: Elevated liver enzymes (reversible) 
Skin: Rash 
Neurologic: Convulsions, weakness on one side of the body, abnormal coordination, paralysis 
Other: Constipation, diarrhea, stomatitis, fatigue, decreased performance status, headache 
Likely (occurring in more than 20% of patients) 
• fatigue  
• headache 
• seizures 
• alopecia 
• nausea 
• vomiting 
• constipation 
• anorexia 
Common (occurring in 3-20% of patients) 
 


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53 
 
• dizziness 
• abnormal muscle 
movements/ coordination 
• abnormal gait 
• hemiplegia or partial 
paralysis 
• upper and/or lower 
extremity edema 
• weakness (such as 
weakness on one side of the 
body) 
• tickling/tingling sensation 
• pain (such as in the 
abdomen, joints, back, 
and/or muscles) 
• breast pain in females 
• confusion 
• memory problems 
• anxiety 
• depression  
• difficulty sleeping 
• drowsiness 
• skin rash 
• pruritus 
• dry skin 
• mucositis  
• dysphagia 
• dysgeusia or taste changes 
• diarrhea  
• excess steroid in the body 
(possible bruising and/or 
increase in size of the face 
and/or neck) 
• viral infection 
• weight gain 
• loss of urinary control  
• urinary tract infection  
• frequent urination 
• abnormal vision 
• blurry vision  
• diplopia or double 
vision 
• fever 
• head cold 
• cough 
• sore throat 
• sinusitis  
• dyspnea 
• allergic reaction  
 
Temozolomide may commonly cause low blood cell counts (white blood cells, 
red blood cells, and platelets). This means that while you take the drug, there is 
more of a chance of getting an infection, including pneumonia. You may 
become anemic and/or have problems with bleeding, bruising, fatigue, and/or 
shortness of breath. You may need a blood transfusion. 
Rare but serious (occurring in fewer than 3% of patients) 
 


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54 
 
• bone marrow disease where 
not enough blood cells are made 
•  hallucinations 
•  nervous system disease 
(possible pain and/or weakness) 
•  neuropathies (nerve 
damage- possible numbness, 
tingling, and pain) 
• hyperglycemia (possible 
diabetes) 
• hypokalemia (possible 
weakness) 
• severe allergic reaction 
 
• new occurrence of 
cancer (including myeloid 
leukemia) 
• allergic skin reaction 
• severe skin damage with 
loss of a large portion of 
skin  
• weight loss 
• fever due to low white 
blood         
     cell counts 
• bruising 
•  hemorrhage 
•  Steven-Johnson 
Syndrome 
• damage from 
radiation (such as skin 
damage) 
• pneumonitis (lung 
inflammation) 
• flu-like symptoms 
• injection site 
reactions (skin redness, 
irritation, pain, itching, 
swelling, and/or warmth) 
• opportunistic 
infection 
• herpes infection 
causing painful skin rash 
(shingles) 
 
 
The following side effects have been reported in research studies with 
temozolomide. It is unclear if these side effects were caused by temozolomide, 
but they may be: 
• BUN blood level increase 
• creatinine blood elevated 
• lymphopenia 
• thrombocytopenia 
• neutropenia 
• death 
• hypoxia 
• weight loss 
• epistaxis 
• sepsis 
• cholecystitis 
• pancreatitis 
• GI perforation 
• dehydration 
 
10.1.10Temozolomide is potentially mutagenic and should be handled with appropriate 
precautions by both staff and patients.  Capsules should not be opened.  If capsules are 
accidentally opened or damaged, rigorous precautions should be taken with the capsule 
contents to avoid inhalation or contact with the skin or mucous membranes.  Procedures 
for proper handling and disposal of anticancer drugs should be considered. 
10.1.11Contraindications: Temozolomide is contraindicated in patients who have a history of a 
hypersensitivity reaction to any of its components or to DTIC. 
10.1.12Pregnancy Category D  
Temozolomide may cause fetal harm when administered to a pregnant woman.  There are no 
adequate and well-controlled studies in pregnant women.  If this drug is used during 
pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be 
apprised of the potential hazard to the fetus.  Women of childbearing potential should be 
advised to avoid becoming pregnant during therapy with temozolomide.   
Treatment of a man with temozolomide may increase the risk of birth defects if he causes a 
woman to become pregnant while he is taking temozolomide.   Men treated with temozolomide 
may have difficulty causing a woman to become pregnant after their treatment is completed.  
Men receiving temozolomide should be directed to use effective contraception while they are 


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Abbreviated Title: Ph II Recurrent Ependymoma 
Version Date: 07/21/17 
 
56 
 
deliberately formulated to be dispersible tablets; however, in circumstances where dosing of 
whole tablets is not possible, such as patients being unable to swallow or being fed through 
nasogastric tubes, tablets may be administered as a dispersion in water.   Liquids other than water 
should not be used.   Care should be taken to ensure that the whole dose is administered.  
10.2.11 Supplier 
Lapatinib is supplied to investigators by GlaxoSmithKline (GSK). 
The lapatinib supplied for this study will be commercial grade lapatinib labeled for commercial 
use. Each pharmacy must re-label the bottles for investigational use. 
10.2.12 Agent Ordering  
All regulatory document requirements prior to requesting study agents. GlaxoSmithKline (GSK) 
requires a copy of each Principal Investigator’s CV and Medical license to be forwarded to GSK. 
This information will be forwarded to GSK by the NCI upon protocol activation for each site. After 
this is done lapatinib may be requested directly from GlaxoSmithKline by the Principal 
Investigator (or their authorized designees) at each participating institution.  NCI policy requires 
that the agent be shipped directly to the institution where the patient is to be treated.  NCI does not 
permit the transfer of agents between institutions.  
Requests for drug supply should be sent to Mary Jo Penna at: 
 
Mary Jo Penna 
North America Medical Affairs, GSK Oncology 
1250 S. College Rd., UP4440 
Collegeville, PA 19426-0989 
E-mail:  mary-jo.q.penna@gsk.com   
Telephone: 610-917-5109 
10.2.13 Agent Accountability  
The Investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the inventory and disposition of all agents received. 
10.2.14 Investigational Drug Disposition Policy 
Investigational Agent Destruction or Returns 
Investigators/Designees should make every effort to minimize the amount of agent ordered and 
returned or destroyed unused, (e.g. limit inventories to an 8 week supply or less). 
Investigators/Designees must return or destroy unused supplied agent as directed by the 
protocol when:  
• The agent is no longer required because the study is completed.  
• Agent is outdated. Investigators/designees should only return or destroy outdated 
agents with a firm expiration date or if they have received written notification that 
an agent has expired and should be returned or destroyed.  
• The agent is damaged or unfit for use. Investigators/designees should contact the 
supplier prior to returning or destroying investigational agents because of stability 
concerns, (e.g. loss of refrigeration or exposure to elevated temperatures). Do NOT 


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57 
 
return broken vials. Broken vials should be destroyed at the clinical site. Follow the 
appropriate agent accountability guidelines. 
The destruction of the study agent should be carried out in accordance with the local 
institutions policies and procedures. The destruction of the agent must be documented on the 
DARF.  
10.2.15 Drug Interactions  
In vitro studies with human liver microsomes indicate that CYP3A4 and CYP3A5, and to a lesser 
extent CYP2C19, may be the enzymes primarily responsible for Lapatinib metabolism.  
Therefore, compounds known to modulate CYP3A4 activity may therefore affect metabolism of 
Lapatinib.  Inhibitors of CYP3A4 may decrease the metabolism and increase Lapatinib levels, 
while inducers of CYP3A4 may increase the metabolism and decrease Lapatinib levels. 
Ketoconazole, a CYP3A4 inhibitor, has been shown to elevate Lapatinib plasma concentrations 
3.5-fold.  Carbamazepine, a CYP3A4 inducer, has been shown to reduce Lapatinib plasma 
concentrations by 72%. Therefore, co-administration of Lapatinib with known inhibitors or 
inducers of CYP3A4 should be avoided.  If there is no medically acceptable alternative 
coadministration should proceed with caution.  
There may be a potential interaction between Lapatinib and warfarin.  Patients have experienced 
elevated INRs and bleeding with warfarin and quinazolines.  Patients on warfarin and Lapatinib 
should have more frequent INR/PT determinations after starting Lapatinib (e.g. weekly for the 
first month and weekly for a minimum of 2 weeks following discontinuation of Lapatinib. 
Alternatively, to avoid this interaction, it is strongly advised to switch patients to low molecular 
weight heparin, e.g. 5000 units of deltaparin subQ daily, or Lovenox 40mg sub Q daily.  
In addition, Lapatinib may inhibit CYP3A4 and increase concentrations of drugs metabolized by 
CYP3A4.  
Glucocorticoids: should be used at lowest effective dose of dexamethasone.  Note that 
dexamethasone equivalent dose > 1.5 mg/day, may alter metabolism of Lapatinib (see chart below 
for conversion). Glucocorticoid Conversion Table  
Glucocorticoid 
Equivalent Dose (mg) 
Cortisone 
25 
Hydrocortisone 
20 
Prednisone 
5 
Methylprednisolone 
4 
Dexamethasone 
0.75 
In human in vitro systems, Lapatinib showed minimal induction potential of CYP3A activity and 
was shown to have varying inhibitory potential towards CYPs 3A4, 1A2, 2C9, 2C19, and 2D6 at 
concentrations above those observed clinically in human plasma.  
Gastric pH Modifiers may modify the absorption of lapatinib.  Therefore, the administration of 
H2 inhibitors, proton pump inhibitors should be noted on the CRF. Antacids should not be given 
within 1 hour before and after dosing with Lapatinib.  
One should attempt to maximize the time interval between Lapatinib and proton pump inhibitors 
(aim for a 12hr interval if possible)  Schedule Lapatinib at least one hr prior to the PPI or H2 
blocker. It may help to take Lapatinib with a coke or pepsi drink.  


Abbreviated Title: Ph II Recurrent Ependymoma 
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58 
 
See Appendix 18.6 for a partial list of medications that induce or inhibit CYP3A4.  
10.2.16 Lapatinib Prohibited Medication List  
10.2.16.1 Inhibitors of CYP3A4  
The following drugs are prohibited beginning at least seven (7) days prior to registration Step 2 
and for the duration of the study:  
• Antibiotics: clarithromycin, erythromycin, troleandomycin, telithromycin, 
ciprofloxacin, norfloxacin  
• Antifungals: itraconazole, ketoconazole, voriconazole, fluconazole (doses up to 150 
mg/day are permitted)  
• Antidepressants: nefazodone, fluvoxamine  
• Calcium channel blockers: verapamil, diltiazem  
• GI: cimetidine, aprepitant  
• Miscellaneous: Grapefruit or its juice, amiodarone*; Bitter Orange  
• *Amiodarone use should have been discontinued at least 6 months prior to the 
administration of the first dose of study medication and for the duration of the 
study.  
10.2.16.2 Inducers of CYP3A4  
The following drugs are prohibited beginning at least fourteen (14) days prior to registration Step 
2 and for the duration of the study. 
• Anticonvulsants: phenytoin, carbamezepine, Barbiturates (e.g. Phenobarbital), 
oxcarbazepine 
• Antibiotics: all rifampin class agents (e.g. rifampin (rifampicin), rifabutin, rifapentene) 
• Miscellaneous: St. John’s Wort, modafinil 
10.2.16.3 Gastric pH Modifiers (not to be administered within 1 hour before and after 
Lapatinib dosing)  
• H2 blockers (ranitidine, nizatidine, famotidine), proton pump 
inhibitors(omeprazole, esomeprazole, rabeprazole, pantoprazole, lansoprazole), 
antacids  
10.2.17Pre-clinical Toxicology 
A range of toxicology studies has been conducted to support the oral administration of Lapatinib 
to humans.  Repeat oral dose toxicity studies have been completed in rats and dogs for up to 6 and 
9 months, respectively.  The effects of Lapatinib on fertility in the rat and embryofetal 
development in the rat and rabbit have been investigated.  A range of genetic toxicity studies has 
been performed in vitro and in vivo.  The significant findings from the toxicology studies are 
summarized below.  
Following single oral administration, Lapatinib was well-tolerated by both CD-1 mice and Wistar 
Han rats at doses up to 2000 mg/kg.  Treatment-related findings consisted of reversible changes in 


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59 
 
body weight and body weight gain as well as reversible GI effects.  
A 13-week oral dose ranging pilot carcinogenicity study in mice showed that treatment with 
Lapatinib at doses up to 200 mg/kg/day was generally well tolerated.  Microscopic changes 
attributable to treatment with Lapatinib were noted in the liver and preputial gland of males and 
large intestines (cecum and colon) of males and females. 
Administration of Lapatinib to rats and dogs for up to 6 months or 9 months resulted primarily in 
exaggerated pharmacologic effects and organ toxicities generally associated with degenerative 
and/or inflammatory epithelial changes (GI tract and accessory digestive organs, skin, mammary 
gland, liver and prostate).  Other treatment-related effects included clinical signs, decreased body 
weight and food consumption, organ weight changes and alterations in clinical pathology 
parameters.  Following the recovery period, treatment-related changes were either significantly 
improved or completely reversed.  
There were no effects on male or female rat gonadal function, mating, fertility or pregnancy nor 
were there any increases in the number or incidence of any malformations when rats or rabbits 
were given Lapatinib during the period of major organogenesis.  At maternally toxic doses (≥60 
mg/kg/day in rats and rabbits), Lapatinib treatment was associated with growth retardation and 
developmental variations.  
In genetic toxicity studies, Lapatinib was demonstrated to be non-mutagenic and nonclastogenic.    
Lapatinib was well tolerated in dogs at doses of <40 mg/kg/day (treated for 39 weeks). The No 
Observed Adverse Effect Level (NOAEL) in dogs was 10 mg/kg/day for both males and females. 
Inflammatory gastrointestinal toxicities were noted on repeated dosing along with changes in the 
epithelium of tissues that were considered related to EGFR inhibition.  Fertility studies in male  
and female rats demonstrated no Lapatinib-related effects at any dose tested.  No fetal 
malformations occurred when Lapatinib was given to pregnant, female rats or rabbits during the 
period of major organogenesis (Investigator’s Brochure, 2003).  At maternally toxic doses (60 
mg/kg/day in rats and rabbits), Lapatinib treatment was associated with growth retardation and 
developmental variations.  
Groups of 4 male and 4 female beagle dogs treated orally with Lapatinib at 10, 40, or 160 
mg/kg/day for up to 93 days resulted in mild leukocytosis (females only), mild decreases in 
albumin, total protein, and calcium, and mild increases in globulin, cholesterol, ALT, alkaline 
phosphatase, total bilirubin and total bile acids.  Improvement occurred in all parameters during 
the 29-day recovery period (Investigator’s Brochure, 2003).  
An additional study evaluated Lapatinib administered orally daily to groups of 4 male and female 
Beagle dogs at 0, 10, 40, or 100 mg/kg/day for 39 weeks.  The effects noted on the skin of males 
given 100-mg/kg/day and females given >40 mg/kg/day included ulceration with epidermal 
hyperplasia or epidermal hyperplasia with inflammation and follicular atrophy (Investigator’s 
Brochure, 2003).  
Lung alveolar histiocytosis and/or interstitial inflammation were seen in the 14-day and 3-month 
rat study and in the 3-month dog study.  This was seen at doses ≥180 mg/kg/day in rats and at 160 
mg/kg/day in dogs.  No lung changes were seen when Lapatinib was given chronically for 6 or 9 
months at lower doses (Investigator’s Brochure, 2003).  
Cardiac changes were seen at a low incidence (3 males and 1 female) only at the high dose in the 
rat 3-month study.   The lesions in the heart were identical to those observed with a spontaneous 


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age-related cardiomyopathy primarily seen in male Wistar rats.    In spite of a 7 fold greater 
exposure in female rats, the incidence was consistent with the natural history of this 
spontaneous lesion.   There were no cardiac changes in the rat 6-month study or in all dog 
studies indicating that Lapatinib is not directly cardiotoxic (Investigator’s Brochure, 2003).  
10.2.18  Clinical Studies and Toxicities  
As of November 2003, four trials in healthy volunteers had been completed, and five Phase 1 
studies and four Phase 2 studies in cancer patients were ongoing.  A phase 1 study of Lapatinib at 
doses of 175 to 1800 mg/day in heavily pre-treated patients (n=39) with solid tumors reported that 
the drug was well-tolerated and showed preliminary evidence of antitumor activity.  In this study, 
3 patients in each of the 175 and 375 mg/day cohorts; 4 in the 675, 900, and 1600 mg/day cohorts; 
6 in the 1200 mg/day and 9 in the 1800 mg/d were enrolled.  Six additional patients were 
administered 900 mg bid to compare safety of bid versus qday schedules.  Grade 1-2 rash, 
diarrhea, nausea, vomiting, constipation, fatigue, and anorexia were the most frequent adverse 
events in all qday dose cohorts.  Grade 3 toxicity was not observed in any of the qday dose 
cohorts.  Grade 3 diarrhea was observed in 2 of 6 patients at 900 mg bid, requiring dose 
reductions.  Eight patients (non-small cell lung cancer (NSCLC), carcinoma of unknown primary 
site, head and neck, colon, breast carcinomas) remained on study with stable disease (SD) of 4+ 
months duration.  Two NSCLC patients resistant to gefitinib (ZD1839, Iressa™) had minor 
responses (MRs) (3+ months, 12 months).  Patients continuing on therapy for more than 4 months 
had received Lapatinib at doses > 1200 mg/day.  Lapatinib was well tolerated when administered 
on a qday schedule, with preliminary evidence of anti-tumor activity in this heavily pre-treated 
population (Burris, Hurwitz et al. 2005).  
A Phase 1B trial evaluating tolerability and effects on biomarkers in tumor biopsies in heavily 
pre-treated patients with metastatic disease expressing EGFR or erbB2 reported that Lapatinib 
was well tolerated at all dose levels tested (500-1600 mg/day)(Burris, Hurwitz et al. 2005).  Of 33 
evaluable patients, 3 partial responses (PR) (10%) and 12 SD (36%) were reported.  An evaluation 
of tumor biopsies obtained prior to, and after 2-3 weeks of treatment with Lapatinib revealed that 
induction of apoptosis in tumor tissue and inhibition of intratumor expression of activated Erk1/2, 
Akt and cyclin D protein appeared to correlate with PR and SD (Burris, Hurwitz et al. 2005). 
Disease progression was associated with persistent, high levels of expression of these biomarkers. 
Treatment with Lapatinib was not effective when insulin growth factor receptor (IGFR) was 
highly expressed (Bacus, Gudkov et al. 2000). Tumor types in which objective response or stable 
disease were seen included: breast (7), colorectal (2), ovarian (2), lung (1), granular cell (1), and 
head and neck (1) carcinomas as well as adenocarcinoma of unknown primary (1).  Objective 
responses were observed in ErbB2-expressing breast cancer patients who had progressed after 
receiving prior trastuzumab (Herceptin™)-based regimens.  The most common adverse events 
included grade 1-2 rash (25%), diarrhea (27%), and nausea/vomiting (21%).  
10.2.19  Reported Adverse Events and Potential Risks  
Common Adverse Effects:  
• Constitutional Symptoms: fatigue (lethargy, malaise, asthenia), insomnia 
• Dermatology/Skin: rash (acne/acneiform), rash (desquamation) 
• Gastrointestinal: diarrhea, anorexia, nausea, vomiting 
Less Common Adverse Effects: 


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• Constitutional Symptoms:  weight loss 
• Dermatology/Skin: flushing, 
• Gastrointestinal: distension/bloating (abdominal), heartburn/dyspepsia, 
mucositis/stomatitis (clinical exam) - oral cavity, constipation, early satiety 
• Pain: head/headache 
• Syndromes: flu-like syndrome 
• Cardiac arrhythmia:  atrial fibrillation 
• Pulmonary/Upper respiratory:  pneumonitis/pulmonary infiltrates 
Uncommon Adverse Effects: 
• Blood/Bone Marrow:  hemoglobin, platelets* 
• Constitutional Symptoms: fever, weight loss 
• Cardiac General:  left ventricular systolic dysfunction, hypotension 
• Dermatology/Skin: pruritus 
• Gastrointestinal:  dehydration, taste alteration, flatulence 
• Lymphatics:  edema: limb 
• Metabolic/Laboratory:  bilirubin*, AST*, ALT* 
• Neurology: neurology - other* 
• Ocular/Visual:  blurred vision 
• Pain: abdomen NOS 
• Sudden Death 
• HepatoBiliary: Liver dysfunction/failure (clinical) 
*   These events were only reported in studies of Lapatinib in normal volunteers, a few of whom 
received a placebo.  
Also reported on Lapatinib trials but with the relationship to Lapatinib still undetermined:  
• leukocytes (total WBC) 
10.2.20 Recommended management for most common toxicities: 
Rash: Skin rash (usually grade 1-2) has been observed during the first several days of treatment 
with EGFR inhibitors and has been observed to diminish in severity after 4 weeks of treatment in 
many patients.  In some patients, this rash appeared to be treatable with standard acne therapies, 
including topical and oral antibiotics used to treat acne. Anecdotal reports of improvement have 
occurred with several agents.  In patients with severe rash, treatment may need to be discontinued 
or the dose reduced.  Anecdotal reports of improvement have occurred with any of the following: 
minocycline, topical tetracycline, topical clindamycin, topical silver sulfadiazine, 
diphenhydramine, oral prednisone (short course).  


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Diarrhea: Diarrhea has been seen with Lapatinib and with other EGFR inhibitors.   In general 
EGFR inhibitor-induced diarrhea has been transient, usually not of sufficient severity to 
hinder administration of the agents, and responsive to loperamide.    The recommended dose 
of loperamide is 4 mg at first onset, followed by 2 mg q 2-4 hr until diarrhea free for 12 hr.  
Nausea: Routine premedication for nausea is not necessary, but symptomatic patients should be 
treated with standard anti-nausea/antiemetic therapy as necessary.  
If the patient vomits after taking the tablets, the dose is replaced only if the tablets can actually be 
seen and counted.  
10.2.21  Safety Issues 
Due to the limited amount of experience in human subjects, there is only preliminary information 
available about the relationship of adverse events and administration of Lapatinib.  The following 
adverse events are included in the development core safety information for Lapatinib: diarrhea, 
which may lead to dehydration, nausea, fatigue, rash (including dermatitis acneiform), vomiting 
and anorexia.  At present, there are no known absolute contraindications with Lapatinib, with the 
exception of individuals who are hypersensitive to this compound.  
Congestive heart failure has been reported in the clinic with trastuzumab (Herceptin™), a 
monoclonal antibody directed against the ErbB2 receptor.  This cardiomyopathy has been seen at 
a higher incidence in patients that previously received anthracyclines and is characterized by 
dilatation and thinning of the ventricular walls with decreased left ventricular ejection fraction.  
As of 21 January 2004, a total of 10 patients in Phase I and II studies of Lapatinib have 
experienced a decrease in LVEF, 9 of which showed decreases ≥ 20% from baseline LVEF.  
In Phase I trials, 2 patients reported asymptomatic Grade 2 decreases in LVEF, and neither event 
met the criteria of an SAE.  For one patient (study EGF10003), the etiology of the LVEF decrease 
remains indeterminate, and a drug-related effect cannot be excluded.  The LVEF decrease in the 
other patient (study EGF10004) was not assessed as drug related, the patient having a prior history 
of cardiac disease.  Both patients withdrew from treatment because of progressive disease.  
A total of eight serious adverse event reports of decreased LVEF were received for patients 
participating in Phase II studies.  After the first two serious adverse events and possibly related 
cases, GSK instituted a ‘per protocol’ serious criterion of LVEF decreases ≥20% from baseline 
and below the institutions’ lower limit of normal.  For all eight cases the investigators considered 
there was a reasonable possibility that the LVEF decreases were associated with Lapatinib.  Two 
patients presented with symptoms (breathlessness and signs of cardiac failure) and were found as 
part of their examination to have LVEF reduction.  Both patients had co-morbidities, which could 
have contributed to the symptoms (pericardial and pleural effusions in one; diabetes, coronary 
artery disease, hypertension and hypercholesterolaemia in the other).  The remaining six Phase II 
reports were asymptomatic and discovered during the routine protocol specified cardiac 
monitoring. These events were reported as serious per the protocol specific requirement.  
Treatment with Lapatinib was stopped in all eight Phase II patients and the LVEF decrease 
resolved with the exception of one patient who died of disease progression before a follow-up 
assessment was completed. Because of the known effects of trastuzumab on cardiac function and 
the observed transient reductions of LVEF seen among patients receiving Lapatinib, only patients 
with normal LVEF are eligible for study and patients will undergo monitoring of LVEF while on 
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Interstitial pneumonitis/lung disease has been reported with the structurally similar 
anilinoquinazoline, gefitinib (ZD1839, Iressa™), which inhibits EGFR tyrosine kinase. The 
incidence and death rate has been reported to be 0.44% and 0.12% respectively world wide and 1-
2% and 0.4-0.5% respectively in Japan. At the time of the SAE data cut off, 30 January 2004, no 
cases of idiopathic interstitial pneumonitis (IP) has been reported in phase I monotherapy.  
However, one patient in study EGF10004 was diagnosed with interstitial pneumonia which the 
investigator attributed this event to disease under study and not related to Lapatinib.  Two reports 
of possible interstitial pneumonitis in studies of Lapatinib have been received, both occurring in 
the phase I combination study with the FOLFIRI regimen (EGF10011).  One report was 
considered possibly related to treatment with Lapatinib and one is unknown.  Both patients 
reported in this study were asymptomatic, had pulmonary metastases, and were diagnosed with 
interstitial pneumonitis after undergoing routine CT scanning for disease assessment.  Both cases 
resolved.  One report of possible interstitial pneumonitis has been reported from Phase II study 
EGF20002.  The event reported was an SAE of pulmonary pneumonitis and was ongoing at the 
time of the reporting.  Treatment was interrupted and the investigator considered the event 
unrelated to Lapatinib and related to disease under study, pericardial effusion and treatment 
failure.  Lapatinib should be withheld pending investigation and diagnosis in patients with 
symptoms and signs of suggestive pneumonitis.  Patients diagnosed with pneumonitis possibly 
related to Lapatinib should be removed from study.  
Fetal malformations were not observed when Lapatinib was administered to pregnant female 
rats or rabbits during the period of major organogenesis.  At maternally toxic doses, Lapatinib 
treatment was associated with growth retardation and developmental variations.  There has been 
no evidence of genotoxicity or clastogenicity in mutagenic studies. In healthy volunteers 
(EGF10013) receiving the CYP3A4 inhibitor ketoconazole at 200 mg twice daily for 7 days, 
plasma concentrations (AUC) of Lapatinib were increased approximately 3.5-fold, and half-life 
increased 1.7-fold.  In healthy volunteers (EGF10018) receiving the CYP3A4 inducer 
carbamazepine (CBZ) at 100 mg twice daily for 3 days and 200 mg twice daily for 17 days, 
plasma concentrations (AUC) of Lapatinib were decreased approximately 72%.  
These results are consistent with the strong dependence of Lapatinib elimination on CYP3A 
metabolism. Co-administration of Lapatinib with known inhibitors or inducers of CYP3A4 
should proceed with caution. The most common toxic effects of Lapatinib are diarrhea, which 
may lead to dehydration, nausea, fatigue, rash (including dermatitis acneiform), vomiting and 
anorexia.  
Co-administration of Lapatinib with known inhibitors of CYP3A4, and/or compounds 
metabolized by CYP3A4, should proceed with caution.  In vitro studies have shown that 
Lapatinib is metabolized predominantly by CYP3A4 and CYP3A5, and to a lesser extent by 
CYP2C19.  Lapatinib has also been shown to have inhibitory potential towards CYP3A4 
Investigator’s Brochure, 2003).  At this time, the effect of known inhibitors of CYP3A4 on 
Lapatinib metabolism or the effect of Lapatinib on drugs metabolized by CYP3A4 is unknown.  
As part of ongoing pharmacovigilance by GlaxoSmithKline, a review of all hepatobiliary events 
reported across the entire lapatinib clinical development programme has been performed.  Two 
hundred sixteen reports of hepatic events were retrieved from the GSK safety database as of 31 
December 2007 regardless of source (clinical trials, spontaneous/marketed use data).  In 39 of the 
216 cases, a causal association to lapatinib could not be ruled out: 38.5% (15/39) of these subjects 
received lapatinib monotherapy, 53.8% (21/39) of subjects received lapatinib in combination with 


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other chemotherapies, such as capecitabine, and 3 cases were still blinded. 
A total of 13 deaths were identified which contained hepatobiliary events.  In 3 of these cases, an 
association with lapatinib could not be excluded.  The remaining 10 cases were confounded by the 
patients underlying condition (progressive disease and/or progression of pre-existing liver 
metastases). 
Based on an additional sub-analysis, of 18 clinical studies of lapatinib in breast cancer, using Hy’s 
Law (defined as AST or ALT >3 x ULN, and total bilirubin >2 x ULN, with no initial findings of 
cholestasis i.e.: ALP <2 x ULN) as a predictor for potential drug induced liver injury, the liver 
injury associated with lapatinib seems to be the result of a prolonged exposure to the drug.  All the 
subjects whose events potentially met Hy’s Law received study medication for three months or 
longer.  The majority of these cases appeared reversible.  Most patients experienced a decline in 
liver enzymes with drug cessation. 
Based on the results of this review, GSK concluded a causal relationship between hepatobiliary 
disorders (specifically transaminase elevations) and lapatinib cannot be excluded.  As a 
consequence, hepatotoxicity was added to the core safety information (CSI) for lapatinib.  In 
addition, for ongoing clinical trials, the monitoring interval for hepatic function has been increased 
to every 4-6 weeks during treatment, and stopping rules have been added for severe hepatic events.  
Lapatinib dosing should be discontinued if changes in liver function are severe and patients should 
not be retreated. 
10.2.22 Pharmacokinetics 
Pharmacokinetic studies in healthy subjects receiving daily doses of Lapatinib (10-250 mg) found 
that the agent was well tolerated and resulted in moderate accumulation in systemic exposure 
(Bence, Anderson et al. 2005).  Peak concentrations (Cmax) occurred 3-4 hours following drug 
administration.  Drug accumulation of at least 50% was reported over an 8-day dosing period 
based on trough concentrations.  AUC values increased with increasing dose in a nearly 
proportional manner.  The average half life (t1/2) was 8 hours.  
The pharmacokinetics of Lapatinib are similar in healthy volunteers and patients, demonstrating 
oral absorption that is incomplete, highly variable, and sometimes delayed.  After dosing, plasma 
concentrations rise to a peak at approximately 4 h and thereafter decline with measured half-lives 
averaging up to 14 h.  However, accumulation with daily dosing achieves steady state in 6-7 days, 
which suggests a true elimination half-life on the order of 24 h.  Administration of the same daily 
dose in a BD schedule results in 2-fold greater systemic exposure than a OD schedule.  Despite 
this inconsistency, systemic exposure generally increases with increasing dose.  Absorption is 
increased by ingestion with food.  Elimination of Lapatinib is predominantly through metabolism 
by CYP3A4/5 with negligible renal excretion.  Significant changes in systemic exposure to 
Lapatinib result from co-administration of drugs that are potent inhibitors or inducers of CYP3A.  
10.2.23Human Toxicity  
Comprehensive Adverse Events and Potential Risks List (CAEPR) 
for 
Lapatinib (GW572016, NSC 727989) 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single, list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 


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Agent Specific Adverse Event List (ASAEL), appears in a separate column and is identified 
with bold and italicized text. This subset of AEs (ASAEL) contains events that are considered 
'expected' for expedited reporting purposes only. Refer to the 'CTEP, NCI Guidelines: Adverse 
Event Reporting Requirements' http://ctep.cancer.gov/reporting/adeers.html for further 
clarification. Frequency is provided based on 975 patients. Below is the CAEPR for lapatinib 
(GW572016). 
Version 2.2, March 5, 20081 
 
Adverse Events with Possible 
Relationship to Lapatinib (GW572016) 
(CTCAE v3.0 Term) 
[n=975 patients] 
 
 
 
'Agent Specific Adverse 
Event List' 
(ASAEL) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
CARDIAC ARRHYTHMIA 
 
 
 
Prolonged QTc 
interval 
Prolonged QTc interval 
CARDIAC GENERAL 
 
 
Left ventricular 
systolic dysfunction 
Left ventricular systolic 
dysfunction 
CONSTITUTIONAL SYMPTOMS 
Fatigue (asthenia, 
lethargy, malaise) 
 
 
Fatigue (asthenia, lethargy, 
malaise) 
 
Weight loss 
 
 
DERMATOLOGY/SKIN 
 
Flushing 
 
Flushing 
 
Pruritus/itching 
 
Pruritus/itching 
Rash/desquamation 
 
 
Rash/desquamation 
 
Rash: acne/acneiform 
 
Rash: acne/acneiform 
GASTROINTESTINAL 
 
Anorexia 
 
Anorexia 
 
Dehydration 
 
Dehydration 
Diarrhea 
 
 
Diarrhea 
 
Distension/bloating, 
abdominal 
 
Distension/bloating, 
abdominal 
 
Flatulence 
 
Flatulence 
 
Heartburn/dyspepsia 
 
Heartburn/dyspepsia 
 
Mucositis/stomatitis 
(clinical exam) - Select 
 
Mucositis/stomatitis (clinical 
exam) - Select 
 
Mucositis/stomatitis 
(functional/symptomatic) - 
Select 
 
Mucositis/stomatitis 
(functional/symptomatic) - 
Select 
Nausea 
 
 
Nausea 
 
Taste alteration (dysgeusia)  
Taste alteration (dysgeusia) 


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Vomiting 
 
Vomiting 
HEPATOBILIARY/PANCREAS 
 
 
Liver 
dysfunction/failure 
(clinical) 
Liver dysfunction/failure 
(clinical) 
METABOLIC/LABORATORY 
 
ALT, SGPT (serum 
glutamic pyruvic 
transaminase) 
 
ALT, SGPT (serum glutamic 
pyruvic transaminase) 
 
AST, SGOT (serum 
glutamic oxaloacetic 
transaminase) 
 
AST, SGOT (serum glutamic 
oxaloacetic transaminase) 
 
Bilirubin 
(hyperbilirubinemia) 
 
Bilirubin 
(hyperbilirubinemia) 
PAIN 
 
Pain - Abdomen NOS 
 
Pain - abdomen NOS 
 
Pain - Head/headache 
 
Pain - head/headache 
PULMONARY/UPPER RESPIRATORY 
 
 
Pneumonitis/pulmo
nary infiltrates 
 
SYNDROMES 
 
Flu-like syndrome 
 
Flu-like syndrome 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be 
distributed to all Principal Investigators at the time of revision.   
Also reported on lapatinib (GW572016) trials but with the relationship to lapatinib 
(GW572016) still undetermined: 
ALLERGY/IMMUNOLOGY - allergic reaction 
BLOOD/BONE MARROW - hemoglobin; leukopenia; lymphopenia; platelets; 
neutrophils/granulocytes 
CARDIAC ARRHYTHMIA - atrial fibrillation 
CARDIAC GENERAL - cardiac failure; cardiomyopathy; hypotension 
CONSTITUTIONAL SYMPTOMS - fever; insomnia 
DEATH - sudden death 
DERMATOLOGY/SKIN - dry skin; hand-foot skin reaction; nail changes; urticaria 
GASTROINTESTINAL - constipation; gastro-esophageal reflux disease (gastritis); intestinal 
obstruction 
HEMORRHAGE/BLEEDING - CNS hemorrhage; GI hemorrhage; nose hemorrhage 
(epistaxis);  
LYMPHATICS - limb edema 


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METABOLIC/LABORATORY - alkaline phosphatase; hyperglycemia; hypoglycemia; 
hypokalemia; hyponatremia; hypophosphatemia 
NEUROLOGY - coma; dizziness 
OCULAR/VISUAL - blurred vision 
PAIN - back pain; joint pain; pain NOS; muscle pain 
PULMONARY/UPPER RESPIRATORY - cough; dyspnea 
VASCULAR – hypovolemia; pulmonary embolism 
Note:  The following additional adverse events have been reported from all lapatinib studies 
(Periodic Safety Report to Investigators) as suspected and unexpected serious adverse 
reactions; acute respiratory failure, lung abscess, hemoptysis, laryngeal edema,dysphagia, 
odynophagia, hypertension,cardiac neoplasm, pericarditis, myocardial infarction, shock, GI 
infection, colitis, hematochezia, hematemesis, dehydration, renal failure, renal impairment, 
dysuria, facial swelling, hepatic failure, leukocytoclastic vasculitis, syncope, shingles, 
cellulitis, hypothyroidism, thyroiditis, alkaline phosphatase level increase, gamma-
glutamyltransferase level increase, hypercreatinemia, myocarditis, abnormal behavior, 
confusional state, coronary artery disease, atrial fibrillation, urinary tract infection, 
polyneuropathy, cerebrovascular ischemia, oral cavity hemorrhage, aplasia, anal fissure, deep 
vein thrombosis-limb, disseminated intravascular coagulation, hand-foot syndrome, viral 
infection, cardiac infection, respiratory tract infection, peripheral neuropathy, and chronic 
hepatitis.   
Note:  Lapatinib (GW572016) in combination with other agents could cause an exacerbation of 
any adverse event currently known to be caused by the other agent, or the combination may 
result in events never previously associated with either agent. 
Note:  There is a chemical that is present in lapatinib in small quantities.  This chemical by 
itself may cause changes to genes (DNA--the genetic material of cells) that may lead to an 
increased chance of developing new cancer or tumors. 
 
 


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Abbreviated Title: Ph II Recurrent Ependymoma 
Version Date: 07/21/17 
 
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Abbreviated Title: Ph II Recurrent Ependymoma 
Version Date: 07/21/17 
 
82 
 
 *Is this problem related or possibly related to participation in the research?  __YES __NO  Please explain: 
 
*Does the problem suggest the research places subjects or others at a greater risk of harm than was 
previously known or recognized?    __YES __NO      Please explain: 
 
 
Is this problem? (select all that apply) 
[  ] An Unanticipated Problem* that is:       [  ] Serious        [  ] Not Serious  
[  ] A Protocol Deviation that is:                [  ] Serious        [  ] Not Serious 
[  ] Non-compliance 
*Note if the 3 criteria starred above are answered, “YES”, then this event is also a UP. 
Is the problem also (select one)  [  ] AE  [  ] Non-AE 
Have similar problems occurred on this protocol at your site? __YES __NO       
If “Yes”, how many? ____      Please describe: 
Describe what steps you have already taken as a result of this problem: 
 
 
In addition to the NCI IRB, this problem is also being reported to: (select all that apply) 
[  ] Local IRB 
[  ] Study Sponsor 
[  ] Manufacturer : ____________________  
[  ] Institutional Biosafety Committee  
[  ] Data Safety Monitoring Board 
[  ] Other: ____________________________________  
[  ] None of the above, not applicable 
INVESTIGATOR’S SIGNATURE:  
 
DATE:   
 
 

ICF_001.pdf: 
July 21, 2017 
Page 1 of 11 
 
 
 
INFORMED CONSENT/AUTHORIZATION FOR PARTICIPATION IN RESEARCH 
 
A Phase II Study of Dose-Dense Temozolomide and Lapatinib for Recurrent Low-Grade and 
Anaplastic Supratentorial, Infratentorial and Spinal Cord Ependymoma 
 
Study Chair: (insert name of local PI) 
Participant’s Name 
 Medical Record Number 
You are being asked to take part in this clinical research study at (insert site name).  This 
consent form explains why this research study is being done and what your role will be if you 
choose to take part.  This form also describes the possible risks connected with being in this 
study.  After reviewing this information with the person responsible for your enrollment, you 
should know enough to be able to make an informed decision on whether you want to take 
part in the study. 
You are being asked to take part in this study because you have a brain or spinal cord tumor 
(ependymoma) that has returned after treatment. 
PURPOSE OF STUDY 
The goal of this clinical research study is to learn if lapatinib when given in combination with 
temozolomide can help to control ependymoma that has come back after treatment. The 
safety of this combination will also be studied. 
DESCRIPTION OF STUDY 
The Study Drugs 
Temozolomide is designed to kill cancer cells by damaging DNA (the genetic material of 
cells). This could cause the tumor cells to die. 
Lapatinib is designed to prevent or slow down the growth of cancer cells by blocking 
proteins inside the cancer cell, called the Her2/neu receptor and the epidermal growth factor 
receptor (EGFR). 
Screening Tests 
Signing this consent form does not mean that you will be able to take part in this study.  You 
will have "screening tests” to help the doctor decide if you are eligible to take part in this 
study.  If you have had some of them within the past 14 days, they may not need to be 
repeated.  The following tests and procedures will be performed: 
• You will be asked about any drugs you may be taking. 
• Your complete medical history will be recorded. 
• You will have a complete physical exam, including measurement of your vital signs 
(heart rate, temperature, breathing rate, and blood pressure), height, and weight. 
• You will be asked how well you are able to perform the normal activities of daily 
living (performance status). 


July 21, 2017 
Page 2 of 11 
• You will have a neurological exam (a test to check your level of brain and nerve 
function). 
• Blood (about 2-3 tablespoons) will be drawn for routine tests. This routine blood draw 
will also include a pregnancy test for women who are able to have children. If you are a 
woman who is able to have children, the pregnancy test must be negative in order for you 
to take part in this study.   
• Blood (about 1 teaspoon) will be drawn for tests to check your blood's ability to clot. 
• If you are taking anti-seizure drugs, blood (about 1 teaspoon) will be drawn to check 
the level of anti-seizure drug in your blood. 
• You will have an magnetic resonance imaging (MRI) scan to measure the tumor.  
• You will have an electrocardiogram (ECG--a test to measure the electrical activity of 
the heart). 
• You will have either a multigated acquisition (MUGA) scan (if the doctor thinks it is 
needed) or an echocardiogram to check your heart function.  
• You will be asked to complete a questionnaire about your quality of life. The 
questionnaire will take about 5 minutes to complete. 
• Samples of tumor tissue (such as disease diagnosis slides or tumor tissue leftover 
from a previous biopsy) is needed to verify your diagnosis.  If there is extra tumor tissue 
available, this will be used to test the biomarkers. Biomarkers are chemical "markers" in 
the blood/tissue that may be related to your reaction to the study drug. 
The study doctor will discuss the screening test results with you.  If the screening tests show 
that you are not eligible to take part in the study, you will not be enrolled.  Other treatment 
options will be discussed with you. 
Study Drug Administration 
If you are found to be eligible to take part in this study, every day, you will take lapatinib by 
mouth once a day in the morning. You should take lapatinib 1 hour before or 1 hour after 
eating, with at least 1 cup (about 8 oz.) of water. 
On Days 1-7 and 15-21 of each cycle, you will take temozolomide by mouth 1 time each 
day. You will start to take a lower dose of temozolomide for the first 2 cycles, then take a 
higher dose for Cycles 3 and beyond if you tolerate the treatment. It should be taken at least 2 
hours before and 2 hours after eating with 1 cup (about 8 oz.) of water.  
You should swallow temozolomide and/or lapatinib whole, one right after the other, without 
chewing either of the study drugs. If you vomit while taking temozolomide and lapatinib, you 
cannot take more capsules before the next scheduled dose.  You should report any missed 
pills or trouble you have with taking the pills to your study doctor.  Your study doctor will 
give you a form (patient diary) to fill out to keep track of your treatment.  You will be asked 
to return your completed diary and pill bottles at each visit with your doctor.  
Each study "cycle" is 28 days. 
Study Visits 
Every 2 weeks, blood (about 2-3 teaspoons) will be drawn for routine tests and to check your 
blood's ability to clot. 
Every 8 weeks, the following tests and procedures will be performed: 


July 21, 2017 
Page 3 of 11 
 You will have a physical exam, including measurement of your vital signs. 
 You will have a neurological exam. 
 Your performance status will be recorded. 
 You will be asked about any drugs you may be taking and if you have experienced 
any side effects. 
 You will complete the quality of life questionnaire.   
 You will have an MRI scan to check the status of the disease. 
 You will have either a MUGA scan (if the doctor thinks it is needed) or an 
echocardiogram. 
Length of Study 
You will be on study treatment for up to 2 years. You will be taken off study  treatment early 
if the disease gets worse or you experience intolerable side effects.    
After you are off study, you may be able to continue taking lapatinib for as long as the doctor 
thinks it is in your best interest.  Your doctor will discuss this with you. 
End-of-Study Visit 
After you go off study treatment, you will have an end-of-study visit.  At this visit, the 
following tests and procedures will be performed: 
• You will have a physical exam. 
• Your performance status will be recorded.   
• You will be asked about any drugs you may be taking and if you have experienced 
any side effects. 
• You will have a neurological exam. 
• Blood (about 3 teaspoons) will be drawn for routine tests and to check your blood's 
ability to clot. 
• You will complete the questionnaire.  
• You will have an MRI scan to check the status of the disease. 
• You will have either a MUGA scan (if the doctor thinks it is needed) or an 
echocardiogram. 
Long-Term Follow-up Visit 
If you go off treatment (having completed the maximum 24 months on study drug treatment) 
and have stable disease or response, you will have an MRI scan to check the status of the 
disease every 2 months for first year after you are off study, then every 3 months for the 
second year, then every 4 months for the third year, and then every 6 months from then on. 
If you continue taking lapatinib after you have completed up to 24 months on study 
treatment, you will have a clinic visit and an MRI scan to check the status of the disease 
every 2 months for as long as the doctor thinks it is needed.  At the clinic visits, you will be 
asked how you are doing. 
If you went off study treatment because the disease got worse or you experienced intolerable 
side effects, after the end-of-study visit, the study staff will call you every 3 months from 
then on to check how you are doing.  Each phone call will take about 5 minutes. 


July 21, 2017 
Page 4 of 11 
This is an investigational study.  Temozolomide is FDA approved or commercially 
available for the treatment of tumors of the nervous system. Lapatinib is FDA approved and 
commercially available for the treatment of breast cancer. However, lapatinib is not FDA 
approved for the treatment of brain tumors.  The use of lapatinib with temozolomide in the 
treatment of brain tumors and spinal tumors is investigational. 
While you are on study, lapatinib will be provided at no cost to you. If lapatinib becomes 
FDA approved for the treatment of ependymoma while you are on study, you may have to 
pay for the remaining doses. You and/or your insurance provider will be responsible for the 
cost of temozolomide. 
Up to 58 patients will take part in this multicenter study.  Up to (insert local accrual ceiling) 
will be enrolled at (insert site name). 
RISKS, SIDE EFFECTS, AND DISCOMFORTS TO PARTICIPANTS 
While on this study, you are at risk for side effects.  These side effects will vary from person 
to person.  The more commonly occurring side effects are listed in this form, as are rare but 
serious side effects that the drugs are known to cause.  You should discuss these with the 
study doctor.  You may also want to ask about uncommon side effects that have been 
observed in small numbers of patients but are not listed in this form.  Many side effects go 
away shortly after treatment is stopped, but in some cases side effects may be serious, long-
lasting or permanent, and may even result in hospitalization and/or death. 
Temozolomide Side Effects 
Likely (occurring in more than 20% of patients) 
• fatigue  
• headache 
• seizures 
• hair loss 
• nausea 
• vomiting 
• constipation 
• loss of appetite 
Temozolomide may likely cause low white blood counts. This means that while you take the 
drug, there is more of a chance of getting an infection, including pneumonia. 
Common (occurring in 3-20% of patients) 
• arm and/or leg swelling 
• weakness (such as weakness on 
one side of the body) 
• confusion 
• dizziness 
• fever 
• memory problems and/or loss 
• difficulty sleeping 
• drowsiness 
• anxiety 
• depression  
• abnormal muscle movements 
• itching 
• dry skin 
• excess steroid in the 
body (possible bruising 
and/or increase in size 
of the face and/or neck) 
• diarrhea  
• taste changes 
• sores in the mouth 
• difficulty swallowing 
• abdominal pain 
• weight gain 
• tickling/tingling 
sensation 
• unusual manner of 
walking 
• joint, muscle, and/or 
back pain 
• abnormal vision (such 
as  blurry and/or double 
vision) 
• head cold 
• cough 
• sore throat 


July 21, 2017 
Page 5 of 11 
Temozolomide may commonly cause low blood cell counts (red blood cells, and platelets). 
You may have problems with bleeding and /or bruising. You may become anemic, fatigued, 
and/or shortness of breath. You may need a blood transfusion.  
Rare but serious (occurring in fewer than 3% of patients) 
• hallucinations 
• nervous system disease (possible 
pain and/or weakness) 
• nerve damage (possible 
numbness, tingling, and pain) 
• damage from radiation (such as 
skin damage) 
• severe skin damage with loss of a 
large portion of skin 
• severe skin damage with 
inflammation of the bowel 
• allergic skin reaction 
• high blood sugar 
(possible diabetes) 
• low blood levels of 
potassium (possible 
weakness) 
• bone marrow disease 
where not enough blood 
cells are made 
• weight loss 
• fever due to low white 
blood cell counts 
• bruising 
• bleeding 
• lung inflammation 
• flu-like symptoms 
• injection site reactions 
(skin redness, irritation, 
pain, itching, swelling, 
and/or warmth) 
• opportunistic infection 
• herpes infection causing 
painful skin rash 
(shingles) 
• new occurrence of cancer 
(including myeloid 
leukemia) 
• severe allergic reaction 
The following side effects have been reported in research studies with temozolomide. It 
is unclear if these side effects were caused by temozolomide, but they may be: 
• hole in the stomach and/or 
intestines, which may cause the 
contents to leak  
• inflammation of the gallbladder 
• death 
• dehydration 
• inflammation of the 
pancreas 
• abnormal kidney test 
(possible decreased 
kidney function) 
• nosebleeds 
• deficient oxygen in the 
blood and tissues 
• presence of bacteria or 
their toxins in blood or 
tissues (sepsis) 
Lapatinib Side Effects 
Likely (occurring in more than 20% of patients)   
 
• pain, swelling, blistering, and/or 
redness of the hands/feet 
• skin rash  
• diarrhea  
• nausea  
• vomiting  
• abnormal liver test 
(possible liver damage)  
• jaundice (yellowing 
and/or darkening of 
skin) 
 
Lapatinib may likely cause low blood cell counts (red blood cells and white blood cells). This 
means that while you take the drug, there is more of a chance of getting an infection, 
/coordination 
• partial paralysis 
• skin rash 
• female breast pain  
• loss of urinary control  
• urinary tract infection  
• frequent urination 
• inflammation of the 
sinuses  
• difficulty breathing 
• allergic reaction  
• viral infection 


July 21, 2017 
Page 6 of 11 
including pneumonia. You may become anemic and/or have problems with bleeding, 
bruising, fatigue, and/or shortness of breath. You may need a blood transfusion.  
Common (occurring in 3-20% of patients)  
• fatigue  
• difficulty sleeping 
• flushing 
• dry skin 
• acne 
• itchy skin 
• abdominal pain 
• abdominal bloating 
• early satiety (feeling 
full) 
• inflammation of the 
mucus membrane 
• mouth sores  
• upset stomach  
• poor appetite 
• weight loss 
• gas 
• heartburn 
• taste change 
• arm and/or leg pain 
• general weakness 
• back pain  
• difficulty breathing 
• headache 
• flu-like symptoms 
Lapatinib may commonly cause low platelet counts. You may have problems with bleeding 
and/or bruising. You may need a blood transfusion if a problem with bleeding occurs.  
Rare but serious (occurring in fewer than 3% of patients) 
• decreased heart function 
• chest pain caused by a heart 
spasm  
• irregular heartbeat  
• liver damage 
• lung disease 
• lung inflammation 
 
The following side effects have been reported in research studies with lapatinib. It is 
unclear if these side effects were caused by lapatinib, but they may be:  
• heart failure  
• low blood pressure 
• enlarged heart  
• high blood pressure 
• tumor growth in the heart 
• inflammation of the membrane 
surrounding the heart 
• heart attack 
• blockage of a blood vessel that 
supplies blood to the heart 
• irregular heartbeat 
• infection of the heart 
• inflammation of the muscle of 
the heart 
• coma 
• bleeding in the brain 
• fever  
• dizziness 
• shock 
• abnormal behavior 
• confusion 
• low blood sugar 
• low blood levels of 
potassium (possible 
weakness) 
• high blood sugar 
(possible diabetes) 
• low blood level of 
sodium (possible 
headache, confusion, 
seizures, and/or coma) 
• low blood levels of 
phosphate (possible 
bone damage) 
• decreased thyroid 
hormones  
• inflammation of the 
thyroid gland  
• constipation 
• inflammation of the 
stomach lining 
• blockage of intestine 
• low volume of blood 
• inflammation of the 
blood vessels  
• liver failure 
• abnormal liver test 
(possible liver damage)  
• chronic inflammation of 
the liver 
• arm and/or leg swelling  
• general pain, joints and 
muscles 
• facial swelling 
• blurred vision 
• kidney failure 
• kidney impairment 
• increased creatinine 
blood level (possible 
kidney problems)  
• pulmonary embolism 
(blood clot to lung) 
• cough  


July 21, 2017 
Page 7 of 11 
• low blood supply to the brain 
tissue 
• fainting 
• degenerative nerve disease 
• painful fingers and feet/toes 
• skin changes including nail 
changes and/or hives 
• hand-foot syndrome (pain, 
swelling, blistering, and/or 
redness of the hands and/or feet) 
• shingles (painful skin rash) 
• inflammation of the tissue 
underneath the skin (cellulitis) 
• infection in stomach 
and/or intestines 
• inflammation of the 
large bowels 
• bloody stools 
• bloody vomit 
• break/slit of the tissue of 
the anus 
• mouth bleeding  
• dehydration 
• bleeding in the digestive 
system 
• painful urination 
• urinary tract infection 
• (DVT) a blood clot 
within a large vein (in 
the legs or pelvis) 
• (DIC) excessive clotting 
or bleeding throughout 
the body 
• nose bleeds 
• respiratory failure 
(inability to breathe) 
• pus-filled areas in the 
lung 
• coughing up blood 
• swelling of the throat or 
voice box 
• difficulty and/or painful 
swallowing 
• respiratory tract 
infection 
• allergic reaction 
• sudden death 
• viral infection 
• incomplete or faulty 
development of a body 
organ (aplasia) 
There is a chemical that is present in lapatinib in small quantities.  This chemical by itself 
may cause changes to genes (DNA--the genetic material of cells) that may lead to an 
increased chance of developing new cancer or tumors. 
Using the study drugs together may cause side effects that are not seen when each is given 
alone. 
Because certain other drugs can interact with temozolomide, review all drugs that you are 
taking with your healthcare provider, including those that you take without a prescription.  
Blood draws may cause pain, bleeding, and/or bruising.  You may faint and/or develop an 
infection with redness and irritation of the vein at the site where blood is drawn.  Frequent 
blood collection may cause anemia (low red blood cell count), which may create a need for 
blood transfusions. 
Questionnaires may contain questions that are sensitive in nature.  You may refuse to 
answer any question that makes you feel uncomfortable.  If you have concerns after 
completing the questionnaire, you are encouraged to contact your doctor or the study chair. 
Certificate of Confidentiality 
To help us protect your privacy, we have obtained a a Certificate of Confidentiality from the 
National Institutes of Health.  The Certificate protects against the involuntary release of 
information about subjects collected during the course of our covered studies.  The 
researchers involved in the studies cannot be forced to disclose the identity or any 
information collected in the study in any legal proceedings at the federal, state, or local level, 
regardless of whether they are criminal, administrative, or legislative proceedings.  However, 
the subject or the researcher may choose to voluntarily disclose the protected information 
under certain circumstances.  For example, if the subject or his/her guardian requests the 


July 21, 2017 
Page 8 of 11 
release of information in writing, the Certificate does not protect against that voluntary 
disclosure.  Furthermore, federal agencies may review our records under limited 
circumstances, such as a DHHS request for information for an audit or program evaluation or 
an FDA request under the Food, Drug and Cosmetics Act. The Certificate of Confidentiality 
will not protect against the required reporting by hospital staff of information on suspected 
child abuse, reportable communicable diseases, and/or possible threat of harm to self or 
others. 
This study may involve unpredictable risks to the participants. 
Pregnancy Related Risks 
Because taking part in this study can result in risks to an unborn or breastfeeding baby, you 
should not become pregnant, breastfeed a baby, or father a child while on this study.  You 
must use birth control during the study if you are sexually active. 
Birth Control Specifications:  Women who are able to become pregnant and men who are 
able to father a child must use birth control while on study and for 6 months after the last 
dose of study drugs. Acceptable forms of birth control include birth control pills and/or 
condoms. 
Males:  Tell the doctor right away if your partner becomes pregnant or suspects pregnancy. 
Females:  If you are pregnant, you will not be enrolled on this study. If you become pregnant 
or suspect that you are pregnant, you must tell your doctor right away. 
Getting pregnant may result in your removal from this study. 
POTENTIAL BENEFITS 
Treatment with lapatinib and temozolomide may help to control the disease.  Future patients 
may benefit from what is learned.  There may be no benefits for you in this study. 
ALTERNATE PROCEDURES OR TREATMENTS 
You may choose not to take part in this study.  You may choose to receive other treatments 
for ependymoma that has come back (such as chemotherapy, radiation therapy, or a 
combination of both). You may choose to receive other investigational therapy, if available.  
You may choose not to have treatment for cancer at all.  In all cases, you will receive 
appropriate medical care, including treatment for pain and other symptoms of cancer. 


July 21, 2017 
Page 9 of 11 
Additional Information 
You may ask the study chair any questions you have about this study.  You may contact the 
study chair, insert local PI name, at insert local PI contact information.  You may also contact 
the Chair of insert local IRB name (IRB - a committee that reviews research studies) at insert 
local IRB contact information with any questions that have to do with this study or your rights 
as a study participant.  
Your participation in this research study is strictly voluntary.  You may choose not to take part in 
this study without any penalty or loss of benefits to which you are otherwise entitled.  You may 
also withdraw from participation in this study at any time without any penalty or loss of benefits.  
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to the National Cancer 
Institute IRB or designated representatives. If you withdraw your consent and leave the trial, any 
samples of yours that have been obtained for the study and stored at the NCI can be destroyed 
upon request. However, any samples and data generated from the samples that have already been 
distributed to other researchers or placed in the research databases cannot be recalled and 
destroyed. 
If you decide you want to stop taking part in the study, it is recommended for your safety that 
you first talk to your doctor.   
This study or your participation in it may be changed or stopped at any time by the study 
chair, the U.S. Food and Drug Administration (FDA), the Office for Human Research 
Protections (OHRP - a regulatory agency that oversees research in humans), or the IRB of 
insert local IRB name.. 
You will be informed of any new findings that might affect your willingness to continue 
taking part in the study. 
This study is coordinated by The National Cancer Institute, Center for Cancer Research  
Dr. Mark R. Gilbert (Study Chair) has received compensation from GlaxoSmithKline as a 
Scientific Advisor.  The financial interests are within the limits of the conflict of interest 
policy. 
STUDY COSTS AND COMPENSATION 
(Tailor per local institution policy) 
If you suffer injury as a direct result of taking part in this study, insert site name health 
providers will provide medical care.  However, this medical care will be billed to your 
insurance provider or you in the ordinary manner. You will not be reimbursed for expenses or 
compensated financially by insert site name or the National Cancer Institute for this injury.  
You may also contact the Chair insert local IRB name and contact information with 
questions about study-related injuries. By signing this consent form, you are not giving up 
any of your legal rights. 


July 21, 2017 
Page 10 of 11 
Certain tests, procedures, and/or drugs that you may receive as part of this study may be 
without cost to you because they are for research purposes only.  However, your insurance 
provider and/or you may be financially responsible for the cost of care and treatment of any 
complications resulting from the research tests, procedures, and/or drugs, including 
hospitalization, nausea, vomiting, low blood cell counts, and dehydration.  Standard medical 
care that you receive under this research study will be billed to your insurance provider 
and/or you in the ordinary manner.  Before taking part in this study, you may ask about which 
parts of the research-related care may be provided without charge, which costs your insurance 
provider may pay for, and which costs may be your responsibility.  You may ask that a 
financial counselor be made available to you to talk about the costs of this study. 
There are no plans to compensate you for any patents or discoveries that may result from 
your participation in this research.  
You will receive no compensation for taking part in this study. 
WILL YOUR MEDICAL INFORMATION BE KEPT PRIVATE?  
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Organizations that may look at 
and/or copy your medical records for research, quality assurance, and data analysis include: 
• The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), which are involved in keeping research safe for people, or 
their agent(s) 
• Insert local IRB name 
• National Cancer Institute Institutional Review Board 
• Qualified representatives from GlaxoSmithKline, the pharmaceutical company who 
produces lapatinib. 
• All investigators participating in this protocol. 
A description of this clinical trial will be available on http://www.Clinicaltrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most the Web 
site will include a summary of the results.  You can search this Web site at any time.  
 
 
Notes to consent form authors: 
The NCI has recommended that HIPAA regulations be addressed by the local institution. 
Language pertaining to HIPAA compliance may or may not be included in the local consent 
form, depending on local institutional policy. 
 
 


July 21, 2017 
Page 11 of 11 
 
 
CONSENT/AUTHORIZATION 
I understand the information in this consent form.  I have had a chance to read the consent form 
for this study, or have had it read to me. I have had a chance to think about it, ask questions, and 
talk about it with others as needed. I give the study chair permission to enroll me on this study.  
By signing this consent form, I am not giving up any of my legal rights. I will be given a signed 
copy of this consent document. 
 
 
 
 
 
 
 
 
SIGNATURE OF PARTICIPANT 
DATE 
 
 
PERSON OBTAINING CONSENT 
I have discussed this clinical research study with the participant, using language that is 
understandable and appropriate.  I believe that I have fully informed this participant of the nature 
of this study and its possible benefits and risks and that the participant understood this 
explanation. 
 
 
 
SIGNATURE OF STUDY CHAIR OR PERSON AUTHORIZED TO 
OBTAIN CONSENT 
 
 
DATE