Clinical trial NCT01295944
Conditions: Ependymoma Anaplastic Ependymoma
Keywords: Chemotherapy Brain Tumor Spinal Cord Tumor Malignancy Neurologic
Sponsor: National Cancer Institute (NCI)
Start date: 2011-04-27; Completion date: 2021-05-14
Enrollment: 35 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical research study is to learn if the combination of bevacizumab and carboplatin can help to control recurrent ependymoma. The safety of this drug combination will also be studied.

Detailed description:
Background:

* Ependymomas are glial based tumors arising from the ependymal lining of the ventricular system and central canal of the spinal cord
* These tumors affect both adults and children and represent approximately 1.2%-7.8% of all intracranial cancers.
* Currently, the standard therapy for newly diagnosed low-grade ependymoma includes total surgical excision, when possible, 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.
* Extensive experience has been gathered with the use of bevacizumab in other neuroepithelial tumors such as malignant gliomas. Based on the interesting results observed in the reported small series of patients with recurrent ependymomas treated with bevacizumab, as well as on the evidence of vascular endothelial growth factor (VEGF)-promoted angiogenesis in these tumors, we designed a phase II study to test the efficacy of bevacizumab in patients with recurrent ependymoma. As results in most types of tumors have indicated that anti-angiogenesis therapies are more effective when given in combination with cytotoxic chemotherapy, in this study bevacizumab will be combined with carboplatin. The choice of carboplatin is justified by the fact that, as detailed above, this remains the most effective agent in this disease, and extensive toxicity data is available for the combination of bevacizumab and carboplatin in a variety of tumor types, including glioblastomas (GBMs).

Objective:

To evaluate the efficacy of carboplatin and bevacizumab for the treatment of recurrent low grade or anaplastic ependymoma. The primary endpoint will be progression-free survival (PFS) at one year.

Design:

* This is a phase II study to evaluate the efficacy of carboplatin and bevacizumab for the treatment of recurrent low grade or anaplastic ependymoma. This trial is designed utilizing a Simon optimal two-stage design.
* Carboplatin will be given on day 1 of each cycle. Bevacizumab will be administered on days 1 and 15 of each cycle. The total duration of treatment will be 6 cycles. After cycle 6, carboplatin should be discontinued, but bevacizumab may be continued at the discretion of the treating physician.
* Patients will be monitored for hematologic or serologic evidence of myelosuppression, hepatic injury, renal injury, and electrolyte disturbances and for clinical evidence of other toxicity.

Arms: arm 1: The total duration of treatment will be 6 cycles. After cycle 6, carboplatin should be discontinued, but bevacizumab may be continued at the discretion of the treating physician.
Interventions: intervention 1: Carboplatin intervention 2: Bevacizumab
Intervention descriptions: intervention 1: Carboplatin will be given on day 1 of each cycle; the carboplatin dose should be calculated using the Calvert formula: Carboplatin dose (mg) = target Area Under the Curve (AUC) x (Creatinine clearance (CrCl) + 25; The total duration of treatment will be 6 cycles. After cycle 6, carboplatin should be discontinued. intervention 2: Bevacizumab will be administered on days 1 and 15 of each cycle. Bevacizumab will be administered at a dose of 10 mg/kg; The total duration of treatment will be 6 cycles. After cycle 6, bevacizumab may be continued at the discretion of the treating physician.

Protocol documents:
Prot_SAP_004.pdf: 
Abbreviated Title: Ph II Ependymoma
Version Date: 07/22/2025
1
Abbreviated Title: Ph II Ependymoma
NIH Protocol #: 16C0009
Previous CERN Protocol#: 09-02
Version Date:    07/22/2025
NCT Number: NCT01295944
Title: Phase II trial of Carboplatin and Bevacizumab for the Treatment of Recurrent Low-grade and 
Anaplastic Supratentorial, Infratentorial and Spinal Cord Ependymoma in Adults: A Multi- Center Trial
Principal Investigator:
Kevin Camphausen, MD 
Radiation Oncology Branch (ROB)
Center for Cancer Research (CCR)
National Cancer Institute (NCI)
Bldg. 10, Rm B2-3500
9000 Rockville Pike
Bethesda, MD 20892
Phone:  240-760-6205
Email: camphauk@mail.nih.gov 
Coordinating Center: NOB, CCR, NCI
Commercial Agents: Bevacizumab and Carboplatin will be dispensed by the participating site’s 
pharmacy and will be charged to the patient’s medical insurance carrier. 


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STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Council for Harmonisation Good Clinical 
Practice (ICH GCP) and the following: 
1. United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 
46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are responsible 
for the conduct, management, or oversight of NIH-funded clinical trials have completed Human 
Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both the 
protocol and the consent form must be obtained before any participant is enrolled.  Any amendment to 
the protocol will require review and approval by the IRB before the changes are implemented to the 
study.  In addition, all changes to the consent form will be IRB-approved; an IRB determination will be 
made regarding whether a new consent needs to be obtained from participants who provided consent, 
using a previously approved consent form.


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PRÉCIS 
Background:
•
Ependymomas are glial based tumors arising from the ependymal lining of the ventricular 
system and central canal of the spinal cord
•
These tumors affect both adults and children and represent approximately 1.2%-7.8% of all 
intracranial cancers
•
Currently, the standard therapy for newly diagnosed low-grade ependymoma includes total 
surgical excision, when possible, 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.
•
Extensive experience has been gathered with the use of bevacizumab in other neuroepithelial 
tumors such as malignant gliomas. Based on the interesting results observed in the reported 
small series of patients with recurrent ependymomas treated with bevacizumab, as well as on 
the evidence of VEGF-promoted angiogenesis in these tumors, we designed a phase II study 
to test the efficacy of bevacizumab in patients with recurrent ependymoma. As results in 
most types of tumors have indicated that anti-angiogenesis therapies are more effective when 
given in combination with cytotoxic chemotherapy, in this study bevacizumab will be 
combined with carboplatin. The choice of carboplatin is justified by the fact that, as detailed 
above, this remains the most effective agent in this disease, and extensive toxicity data is 
available for the combination of bevacizumab and carboplatin in a variety of tumor types, 
including GBMs. 
Objective:
•
To evaluate the efficacy of carboplatin and bevacizumab for the treatment of recurrent low 
grade or anaplastic ependymoma. The primary endpoint will be progression-free survival 
(PFS) at one year.
Eligibility:
•
Histologically proven intra-cranial or spinal ependymoma or anaplastic ependymoma.  There 
must be pathologic or imaging confirmation of tumor progression or regrowth. 
•
Patients must be ≥18 years old.
•
Patients must have a Karnofsky performance status of ≥ 60.
•
Patients must have adequate bone marrow function, adequate liver function and adequate 
renal function before starting therapy. 
•
Patients must have recovered from the toxic effects of prior therapy: 


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•
Patients having undergone recent resection of recurrent or progressive tumor will be eligible
•
Patients must have failed prior radiation therapy and must have an interval of greater than or 
equal to 42 days from the completion of radiation therapy to study entry.
•
Women of childbearing potential must have a negative B-HCG pregnancy test documented 
within 14 days prior to registration.
•
Women of childbearing potential and male participants agree to practice adequate 
contraception.
•
Patients must not have any significant medical illnesses or active infection
•
Patients must not have history of any other cancer 
•
Patients must not be pregnant/breast feeding. 
•
Patients must not have received prior therapy with bevacizumab, or related drugs 
•
No active bleeding or pathological condition that carries a high risk of bleeding 
•
No major surgical procedure, open biopsy, or significant traumatic injury within 28 days. 
Design:
•
This is a phase II study to evaluate the efficacy of carboplatin and bevacizumab for the 
treatment of recurrent low grade or anaplastic ependymoma. This trial is designed utilizing a 
Simon optimal two-stage design.
•
Carboplatin will be given on day 1 of each cycle. Bevacizumab will be administered on days 
1 and 15 of each cycle. The total duration of treatment will be 6 cycles. After cycle 6, 
carboplatin should be discontinued, but bevacizumab may be continued at the discretion of 
the treating physician. 
•
Patients will be monitored for hematologic or serologic evidence of myelosuppression, 
hepatic injury, renal injury, and electrolyte disturbances and for clinical evidence of other 
toxicity.


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TABLE OF CONTENTS
STATEMENT OF COMPLIANCE.........................................................................................................2
PRÉCIS........................................................................................................................................................3
TABLE OF CONTENTS ............................................................................................................................5
1
INTRODUCTION ...............................................................................................................................7
1.1
Study Objectives..............................................................................................................................7
1.2
Background and Rationale...............................................................................................................7
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT ...................................................................11
2.1
Eligibility Criteria..........................................................................................................................11
2.2
Screening Evaluation.....................................................................................................................13
2.3
Registration Procedures.................................................................................................................14
2.4
Baseline Evaluation .......................................................................................................................16
3
STUDY IMPLEMENTATION .........................................................................................................16
3.1
Study Design..................................................................................................................................16
3.2
Drug Administration......................................................................................................................17
3.3
Questionnaires ...............................................................................................................................22
3.4
Study Calendar...............................................................................................................................23
3.5
On Study Evaluation......................................................................................................................24
3.6
Criteria for Removal from Protocol Therapy and Off Study Criteria ...........................................25
4
CONCOMITANT MEDICATIONS/MEASURES...........................................................................26
4.1
G-CSF Administration...................................................................................................................26
4.2
Supportive Care .............................................................................................................................26
5
BIOSPECIMEN COLLECTION.......................................................................................................27
5.1
Pathology Review..........................................................................................................................27
5.2
Laboratory Correlates ....................................................................................................................28
6
DATA COLLECTION AND EVALUATION .................................................................................28
6.1
Data Collection ..............................................................................................................................28
6.2
Data Sharing Plans.........................................................................................................................29
6.3
Response Criteria...........................................................................................................................30
6.4
Toxicity Criteria.............................................................................................................................32
7
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN.................32
7.1
Definitions .....................................................................................................................................32
7.2
OHSRP Office Of Compliance And Training / IRB Reporting ....................................................32
7.3
NCI Guidance for Reporting Expedited Adverse Events for Multi-Center Trials ........................32
8
Safety Reporting To Coordinating Center.........................................................................................32
8.1
Definitions .....................................................................................................................................32
8.2
Assessing Causality .......................................................................................................................34
8.3
Data and Safety Monitoring Plan ..................................................................................................34
9
STATISTICAL CONSIDERATIONS ..............................................................................................35
10
COLLABORATIVE AGREEMENTS..........................................................................................37
10.1
Multi-Institutional Guidelines .......................................................................................................38
10.2
Protocol Therapy Administration at a Non-Participating Site.......................................................38
11
HUMAN SUBJECTS PROTECTIONS........................................................................................39
11.1
Rationale for Subject Selection .....................................................................................................39
11.2
Participation of Children................................................................................................................39


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11.3
Participation of subjects unable to give Consent (CERN Sites)....................................................39
11.4
Evaluation of Benefits and Risks/Discomforts..............................................................................40
11.5
Risks/Benefits Analysis.................................................................................................................40
11.6
Consent and Assent Process and Documentation..........................................................................40
12
REGULATORY AND OPERATIONAL CONSIDERATIONS..................................................41
12.1
Quality Assurance And Quality Control........................................................................................41
12.2
Conflict Of Interest Policy.............................................................................................................41
12.3
Confidentiality And Privacy..........................................................................................................41
13
PHARMACEUTICAL INFORMATION .....................................................................................42
13.1
Rationale for IND Exemption........................................................................................................42
13.2
Drug Name: Bevacizumab.............................................................................................................43
13.3
Drug Name:   Carboplatin..............................................................................................................45
14
REFERENCES ..............................................................................................................................48
15
APPENDICES ...............................................................................................................................50
15.1
Karnofsky Performance Status and Neurological Function ..........................................................50
15.2
MD Anderson Symptom Inventory for Brain Tumors (MDASI-BT) ...........................................51
15.3
MD Anderson Symptom Inventory for Spine Tumors (MDASI-SP)............................................53
15.4
MRI Acquisition Protocol (Optional Procedure)...........................................................................55
15.5
Reliance Agreement.......................................................................................................................57
15.6
Local Physician Agreement...........................................................................................................60
15.7
Local Physician Information..........................................................................................................61
15.8
CCR PROBLEM REPORT FORM...............................................................................................62
15.9
Tissue Collection Shipping Form ..................................................................................................64


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1
INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Primary Objective
To evaluate the efficacy of carboplatin and bevacizumab for the treatment of recurrent low grade or 
anaplastic ependymoma. The primary endpoint will be progression-free survival (PFS) at one year.
1.1.2
Secondary Objectives
1.1.2.1
To evaluate response rates to this chemotherapy.
1.1.2.2
To evaluate overall survival in this population.
1.1.2.3
To evaluate toxicity profile of this combination.
1.1.2.4
To longitudinally evaluate patient reported outcome measures using self-reported symptom 
severity and interference with daily activities using the MDASI-BT and/or MDASI-SP instrument.
1.1.3
Exploratory Objectives
1.1.3.1
To evaluate safety and preliminary efficacy of this treatment in patients with recurrent 
Ependymomas according to anatomical location (supratentorial, posterior fossa and spinal cord).
1.1.3.2
To evaluate paraffin embedded tissue samples (and frozen samples, if available) utilizing gene 
expression profiling (Illumina technology), immunohistochemistry and/or RT-PCR. Analysis will focus 
on expression of genes involved in angiogenesis and hypoxia-related tissue factors. This component of 
the research will be overseen by Dr. Kenneth Aldape. 
1.2
BACKGROUND AND RATIONALE
1.2.1
Background on Ependymomas
Ependymomas are glial based tumors arising from the ependymal lining of the ventricular system and 
central canal of the spinal cord, and can therefore be found in the supratentorial, posterior fossa and 
spinal compartments. These tumors affect both adults and children and represent approximately 1.2%-
7.8% of all intracranial tumors. The WHO classifies ependymomas into low grade (WHO grade II) and 
the more malignant – anaplastic ependymomas (WHO grade III). Anaplastic ependymomas are more 
common in adults. 
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. 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.  Most reported regimens are based on platinum compounds (carboplatin or cisplatin) and have 
been developed in children.[1, 2] Many of these regimens are associated with a high incidence of 


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moderate to severe toxicity, and applying such treatments to adults can be challenging.[3] The largest 
experience with chemotherapy in adult ependymoma patients was reported by Brandes et al.[4]  That 
study included 28 adult patients who had recurrent ependymoma (n = 17) or anaplastic ependymoma (n 
= 11) after initial treatment with surgery and radiation.  One-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.  The overall objective response rate 
was 20% (complete response [CR] and partial response [PR]).  The 12 month PFS rate was 44% (95% 
CI, 29%-68%).  The median time to progression was 9.9 months and the median overall survival (OS) 
was 40.4 months. Analysis of outcomes in patients who received platinum-based chemotherapy 
regimens (N=13) in comparison to patients treated with regimens without platinum (N=15) showed that 
platinum-containing regimens are associated with higher response rates (30.8% vs. 13.3%), confirming 
the activity of platinum agents in this disease. However, there were no significant differences in PFS or 
OS between the two groups, although interpretation of these results is limited by the low number of 
patients. 
1.2.2
Rationale for bevacizumab and anti-angiogenesis strategies in ependymomas
Bevacizumab (AvastinTM, Genentech Inc., South San Francisco, CA) is a humanized monoclonal anti-
VEGF antibody with demonstrated efficacy in a variety of solid tumors. It was first approved by the 
FDA in 2004 for first line chemotherapy for colorectal cancer. Since then, FDA approval has been 
obtained for the treatment of advanced NSCLC and metastatic HER-2 negative breast cancer and, more 
recently, progressive glioblastoma (GBM). 
1.2.2.1
Pre-clinical data
A number of studies have investigated angiogenic patterns in ependymomas. The largest study evaluated 
paraffin embedded tissue in a series of 100 patients with ependymoma, obtained at the time of 
diagnosis.[5] This included 73% of patients with WHO grade II tumors and 27% with grade III tumors. 
In spite of the low prevalence of high grade tumors, microvascular proliferation could eventually be 
documented in 42% of patients in various patterns, whereas necrosis was present in 57% of patients. 
VEGF expression, as evaluated by in situ hybridization, was detected in 88% of patients. CA9 was 
expressed in 84% of patients, but HIF1-alpha was seen in only 42% of patients. This suggested that 
VEGF expression is frequent in ependymomas, and may not result from hypoxia (as in GBMs), but 
rather from oncogenic activation. In that same study, a high hypoxic score (defined as expression of 
more than two hypoxia-related tissue factors) was associated with worse prognosis on univariate, but not 
multivariate analysis, whereas elevated MIB-1 index remained a significant marker of poor prognosis in 
the multivariate setting. VEGF expression was associated with a trend in decreased OS (p= 0.06).[5]   In 
another study, VEGF expression in ependymomas was associated with tumor grade, and predicted 
shorter PFS (p=0.003).[6] In a smaller study, VEGF was found to be strongly expressed in 8/10 
ependymomas, all of them with extensive necrosis and vascular proliferation; VEGF expression was 
mainly observed around the necrotic areas, and most tumors also displayed strong expression of VEGFR 
(Flt-1 and KDR).[7] Taken together, these studies suggest that anti-VEGF treatments such as 
bevacizumab are an attractive strategy for the treatment of ependymomas, particularly in the recurrent 
setting where tumors are associated with a more aggressive behavior.
1.2.2.2
Clinical data
Clinical experience with bevacizumab in ependymomas is limited. A single, small, retrospective study 
has been reported.[8] That study reported on eight adult patients with recurrent ependymoma treated at 


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several different institutions. In three patients, bevacizumab was given in combination with CPT-11, in 
two patients with carboplatin, in one patient with temozolomide and in two patients as a single agent. 
Patients tolerated treatment well. Six of the 8 patients achieved a partial response, disease was stable in 
one patient and one patient progressed. The median TTP in that heavily pre-treated population was 6.5 
months and the overall survival was 9.4 months. 
Conversely, extensive experience has been gathered with the use of bevacizumab in other 
neuroepithelial tumors such as malignant gliomas and glioblastomas. After anecdotal experience 
suggested high response rates,[9] a phase II study was conducted in recurrent glioma.[10] Impressive 
response rates were confirmed, with 63% of the 32 enrolled patients demonstrating at least a PR. PFS, 
and to a lesser extent OS, were also increased in comparison to historical controls (GBM patients: 
median PFS- 20 weeks; median OS- 10 months; N=23). Preliminary results of a phase II randomized 
trial comparing single-agent bevacizumab versus the combination of bevacizumab with irinotecan 
indicate that both arms achieved superior outcomes in comparison to historical controls. The group 
receiving the combination of drugs achieved higher response rates (33% vs 20%) and 6 month-PFS 
(50% vs 35%), although OS was slightly longer in the single agent arm (8.9 vs 9.7 months).[11] Based 
on such results, bevacizumab was approved for the treatment of recurrent malignant gliomas. 
Importantly, such studies have demonstrated that bevacizumab can be safely given to patients with brain 
tumors, and that concerns of intracranial bleeding should not preclude their use, including in patients 
receiving anticoagulation.[12] 
1.2.3
Rationale for this study
Based on the interesting results observed in the reported small series of patients with recurrent 
ependymomas treated with bevacizumab, as well as on the evidence of VEGF-promoted angiogenesis in 
these tumors, we designed a phase II study to test the efficacy of bevacizumab in patients with recurrent 
ependymoma. As results in most types of tumors have indicated that anti-angiogenesis therapies are 
more effective when given in combination with cytotoxic chemotherapy, in this study bevacizumab will 
be combined with carboplatin. The choice of carboplatin is justified by the fact that, as detailed above, 
this remains the most effective agent in this disease, and extensive toxicity data is available for the 
combination of bevacizumab and carboplatin in a variety of tumor types, including GBMs.  The study 
will include a comprehensive translational component for the evaluation of treatment effects on 
advanced MRI imaging parameters (perfusion and spectroscopy) as well as serum levels of 
angiogenesis-related factors as potential biomarkers. 
A large number of manuscripts have been published outlining the toxicities associated with 
bevacizumab use in patients with cancer.  A recent publication by Armstrong, et al specifically describes 
the well-known toxicities and their incidence and management in the brain tumor patient population [24] 
These include hypertension which is refractory in a small percentage of patients, thromboembolic 
disease which occurs in the venous system in 8-10% of patients and arterial (mostly cerebral) in 1-2%, 
significant intracranial hemorrhage in less than 2%, renal dysfunction in less than 2% and wound 
dehiscence in less than 2% (partially dependent on time from craniotomy).  Intestinal perforation also 
occurs in less than 2%.
1.2.3.1
Rationale for the patient-reported outcomes:  
Although rare, ependymal tumors have a recognized impact on the patients physical and neurologic 
function[13, 14].  Despite aggressive therapy at diagnosis, many ependymomas recur [15].  Currently, 


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no standard therapy at recurrence has been established, and the impact of chemotherapy at recurrence 
has been limited[15].  
This study seeks to establish effective therapies at recurrence and improve on current clinical results.  
We hypothesize that using a combination of carboplatin and bevacizumab will result in improved 
survival.  However, given the intensive nature of this regimen, it will be important to determine whether 
if any determined survival benefit is associated with improvements in symptoms or does a worsening of 
these parameters offset the increase in survival. 
Precedence for measuring “non-therapeutic” endpoints exists in oncology research.  For example, 
Gemcitabine was approved by the FDA partially as a consequence of the decrease in pain reported in 
pancreatic patients who were treated, not on the basis of survival improvement which was modest, at 
best [16].  There have been efforts in neuro-oncology to evaluate secondary endpoints using validated 
instruments as an additional indicator of benefit. 
The M.D. Anderson Symptom Inventory-Brain Tumor Module or M.D. Anderson Symptom Inventory 
Spine Tumor Module (MDASI-BT or SP, respectively) allows the self-reporting of symptom severity 
and interference with daily activities.  The MDASI-BT or SP has demonstrated reliability and validity in 
the adult primary brain tumor patient population [17] [18]. This tool represents a modification of the 
widely used and validated MDASI, with particular attention to symptoms common in patients with brain 
tumors.   The availability of validated instruments provides an opportunity to prospectively assess the 
impact of treatment, both positive and negative, on patients.  This evaluation of symptom burden in this 
study will assist in finding the best possible treatment with the least toxicity.
1.2.4
Rationale for the correlative studies
Although bevacizumab has been extensively utilized for the treatment of GBM and several other types 
of cancer, to date, no predictive biomarker has been validated for selection of patients likely to benefit 
from treatment or that could be used for follow-up and to guide treatment decisions. In order to identify 
validate such potential biomarkers in this trial the following studies will be performed:
1.2.4.1
Baseline tumor expression of hypoxia-related factors
 In a recent retrospective study conducted by Sathornsumetee et al[19] in GBM patients undergoing 
treatment with bevacizumab, the authors found that high VEGF expression levels in the tumor was 
associated with radiographic responses but not OS. This finding is in line with the normalization of 
vasculature and decreased permeability observed with anti-VEGF strategies, which translates into 
radiographic response, but that may or may not be associated with anti-tumor effect. In contrast, 
expression of hypoxia-related factors CA9 and HIF-2 expression was associated with poor survival, 
suggesting that such factors may be better predictive markers for anti-angiogenic strategies. However, 
such findings may not be applicable in ependymomas, as the VEGF expression may not be dependent on 
hypoxia, but rather to oncogenic activation, as detailed above. To investigate these aspects in this study 
paraffin embedded tissue or frozen tissue from all patients will be evaluated for the expression of 
hypoxia-related and angiogenesis factors such as VEGF, VEGFR-2/KDR, CD31, CA9, HIF-2α and 
others, utilizing immunohistochemistry, RT-qPCR and gene expression profiling (Illumina technology). 
This component of the study will be performed by Dr. Kenneth Aldape (Section 5.1) who has extensive 
experience in the molecular characterization of ependymomas in the setting of prior CERN studies.  


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2
ELIGIBILITY ASSESSMENT AND ENROLLMENT
2.1
ELIGIBILITY CRITERIA
2.1.1
Inclusion Criteria
2.1.1.1
Histologically proven intra-cranial or spinal ependymoma or anaplastic ependymoma.  There 
must be pathologic or imaging confirmation of tumor progression or regrowth. The patient’s histologic 
diagnosis must be confirmed on Central Pathology Review prior to registration Step 2.
*If a patient has already had central pathology review at MDACC (for example, from a previous 
enrollment to protocol CERN08-02), the central pathology does not need to be repeated.  
Previous pathology confirmation can be utilized for this study’s pathology eligibility testing. 
2.1.1.2
The patient must have at least 1 block of tissue or 15 unstained slides at a minimum available   
for central pathology review and molecular profiling of the tissue sample.
2.1.1.3
All patients must sign an informed consent indicating that they are aware of the investigational 
nature of this study.  Patients must have signed an authorization for the release of their protected health 
information. 
2.1.1.4
Patients must be > 18 years old.
2.1.1.5
Patients must have a Karnofsky performance status of > 60.
2.1.1.6
Patients must have adequate bone marrow function (WBC > 3,000/µl, ANC > 1,500/mm3, 
platelet count of > 100,000/mm3, and hemoglobin > 10 gm/dl), adequate liver function (SGOT [AST 
<92.5 Units/L] and bilirubin < 1.5 mg/dL), and adequate renal function (creatinine < 1.5 mg/dL and 
calculated creatinine clearance > 60 cc/min) before starting therapy.  Eligibility level for hemoglobin 
may be reached by transfusion. 
2.1.1.7
Patients must have shown unequivocal radiographic evidence for tumor progression by MRI or 
CT scan  as defined by Section 6.3.1.6.  If an MRI is being obtained to verify eligibility, it is 
recommended that the MRI parameters follow the specifications detailed in Appendix 15.4 so that the 
patient will not require a repeat MRI prior to treatment start. 
2.1.1.8
At the time of registration:  Patients must have recovered from the toxic effects of prior 
therapy: > 28 days from any investigational agent, >28 days from prior cytotoxic therapy, >14 days from 
vincristine, >42 days from nitrosoureas, >21 days from procarbazine administration, and >7 days for 
non-cytotoxic agents, e.g., interferon, tamoxifen, thalidomide, cis-retinoic acid, etc. (radiosensitizer does 
not count).  Any questions related to the definition of non-cytotoxic agents should be directed to the 
Principal Investigator.
2.1.1.9
Patients having undergone recent resection of recurrent or progressive tumor will be eligible as 
long as all of the following conditions apply:
•
They have recovered from the effects of surgery. 
•
A minimum of 28 days have elapsed from the day of surgery to the day of registration Step 2.  
For core or needle biopsy, a minimum of 7 days must have elapsed prior to registration Step 
2.
•
Residual disease following resection of recurrent ependymoma is not mandated for eligibility 
into the study. To best assess the extent of residual disease post-operatively, a CT/ MRI 


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should be done no later than 96 hours in the immediate post-operative period or at least 4 
weeks post-operatively, within 14 days prior to consent.  If the “within 96-hour after surgery” 
scan is more than 14 days before consent the scan needs to be repeated.  If the steroid dose is 
increased between the date of imaging and consent, a new baseline MRI/CT is required on a 
stable steroid dosage for at least 5 days.
2.1.1.10 Patients must have failed prior radiation therapy* and must have an interval of greater than or 
equal to 42 days from the completion of radiation therapy to study entry.
*Note: Patients with an indication for craniospinal radiotherapy (i.e., extensive leptomeningeal disease) 
but have refused palliative craniospinal radiotherapy are eligible. 
2.1.1.11 Patients with prior therapy that included interstitial brachytherapy or stereotactic radiosurgery 
must have confirmation of true progressive disease rather than radiation necrosis based upon either PET 
or Thallium scanning, MR spectroscopy, or surgical/pathological documentation of disease.
2.1.1.12 Women of childbearing potential must have a negative B-HCG pregnancy test documented 
within 14 days prior to registration.
2.1.1.13 Women of childbearing potential and male participants agree to practice adequate 
contraception.
2.1.2
Exclusion Criteria
2.1.2.1
Patients with any significant medical illnesses that in the investigator’s opinion cannot be 
adequately controlled with appropriate therapy or would compromise the patient’s ability to tolerate this 
therapy.
2.1.2.2
Patients with a history of any other cancer (except non-melanoma skin cancer or carcinoma in-
situ of the cervix), unless in complete remission and off of all therapy for that disease for a minimum of 
3 years are ineligible.
2.1.2.3
Patients with an active infection or serious intercurrent medical illness.
2.1.2.4
Patients found to be pregnant/breast feeding. Patients must not be pregnant because animal 
studies show that carboplatin and bevacizumab are teratogenic
2.1.2.5
Patients with any disease that will obscure toxicity or dangerously alter drug metabolism.
2.1.2.6
Patients who have received prior therapy with bevacizumab, or related drugs (previous therapy 
with carboplatin is allowed).
2.1.2.7
Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg and/or 
diastolic blood pressure > 100 mmHg) despite antihypertensive medication.
2.1.2.8
New York Heart Association (NYHA) Grade II or greater congestive heart failure. 
2.1.2.9
History of myocardial infarction or unstable angina within 12 months prior to Day 1. 
2.1.2.10 History of stroke or transient ischemic attack. 
2.1.2.11 Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral 
arterial thrombosis) within 6 months prior to Day 1.
2.1.2.12 History of hemoptysis (≥ 1/2 teaspoon of bright red blood per episode) within 1 month prior to 
Day 1.


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2.1.2.13 Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic 
anticoagulation). (To be eligible, Prothrombin time/international normalized ratio (PT INR) should be < 
1.4 for patients not on warfarin.) 
2.1.2.14 Patients  receiving full dose anticoagulation therapy (e.g., warfarin or LMW heparin) and does 
not  meet both of the following criteria:
•
No active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor 
involving major vessels or known varices).
•
In-range INR (usually between 2 and 3) on a stable dose of oral anticoagulant or on a stable 
dose of low molecular weight heparin. 
2.1.2.15 Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to 
Day 1 of treatment or anticipation of need for major surgical procedure during the course of the study.
2.1.2.16 Core biopsy or other minor surgical procedure, excluding placement of a vascular access 
device, within 7 days prior to Day 1. 
2.1.2.17 History of abdominal fistula or gastrointestinal perforation within 6 months prior to Day 1. 
2.1.2.18 Serious, non-healing wound, active ulcer, or untreated bone fracture. 
2.1.2.19 Proteinuria as demonstrated by a UPC ratio ≥ 1.0 at screening, or Urine dipstick for proteinuria 
≥ 2+ (patients discovered to have ≥2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 
hour urine collection and must demonstrate ≤ 1g of protein in 24 hours to be eligible).
2.1.2.20 Known hypersensitivity to any component of bevacizumab.
2.1.2.21 Patients has current active hepatic or biliary disease (with exception of patients with Gilbert’s 
syndrome, asymptomatic gallstones, or stable chronic liver disease per investigator assessment)
2.2
SCREENING EVALUATION 
2.2.1
A complete medical history and review of concomitant medications, physical exam (height, 
weight, vital signs and BSA) and neurological examination (to include documentation of the 
patients Karnofsky Performance Status per Appendix 15.1), as well as neuro-imaging confirming 
tumor progression shall be performed on all patients.  The scan done prior to study entry 
documenting progression will be reviewed by the patient’s principal investigator.  The baseline 
scan should be obtained within 14 days before registration step 2, and should follow the 
instructions described in Appendix 15.4.
2.2.2
Pre-study laboratory tests shall include CBC, differential, platelets, PT/PTT and INR, serum 
creatinine, calculated creatinine clearance, bilirubin, SGOT, urine protein/ creatinine ratio (or 
urinalysis) and serum pregnancy test for women of childbearing potential. Pre-study laboratory 
tests must be obtained within 14 days before registration step 2. 
2.2.3
Documentation of tumor diagnosis. Following registration step 1, slides from the most recent 
pre-registration biopsy must be submitted for review.
Fifteen unstained paraffin slides, or a paraffin tissue block, will be obtained in all study patients from 
original surgery or definitive surgery or the surgery closest to initiation of this clinical trial and in those 
patients who will be undergoing resection at time of treatment failure. 


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In this study, paraffin embedded tissue or frozen tissue (or 15 unstained slides at a minimum) will be 
collected from all patients, for evaluation of expression of hypoxia-related and angiogenesis factors such 
as VEGF, VEGFR-2/KDR, CD31, CA9, HIF-2α and others, utilizing immunohistochemistry, RT-qPCR 
and gene expression studies. Tissue evaluation will be required for every case before study registration 
Step 2 (see Section 5.1):
2.3
REGISTRATION PROCEDURES 
2.3.1
Registration at NCI
Not applicable. As of Amendment C (Version Date 04/24/2017), participants will not be enrolled at the 
Clinical Center, NIH.
2.3.2
Participating Site Registration 
All patients must be registered through the NCI Coordinating Center’s Research Nurse. The 
Coordinating Center is open from 8:30am to 5:00pm EST Monday through Friday, excluding federal 
holidays.  An Eligibility Checklist and cover memo will be supplied by the Coordinating Center, NCI 
CCR and updates will be provided as needed. Subject eligibility (including source documents as 
described in section 6.1.1) and demographic information is required for registration. To initially register 
a subject, after the participant has signed consent, complete the top portion of the eligibility checklist 
form (step 1) and send via encrypted email to Coordinating Center’s Research Nurse,  240-760-6428, 
nci_bttc@mail.nih.gov.  Once eligibility is confirmed, complete the remainder of the eligibility checklist 
form and send via encrypted email.  If patient is not eligible, please notify the Coordinating Center, 240-
760-6428, nci_bttc@mail.nih.gov.  The Coordinating Center will review the registration form and 
forward it to the NCI Central Registration Office for processing. NCI Central Registration Office (CRO) 
will assign a unique patient/subject ID number for each subject that will be used to enter data into the 
C3D data base. Participating sites will receive a copy of the CRO’s confirmation of registration from the 
Research Nurse. Questions about eligibility should be directed to the Coordinating Center’s Research 
Nurse. 
Registration Step 1 
Registration step 1 must be completed:
•
After the patient has signed the informed consent. 
•
Before study related research tests and/or procedures are obtained.
•
Before tissue/slides are submitted for analysis and histologic diagnosis confirmation. 
Confirmation of histology by Central Review will not be known at this time point. At the time of 
registration step 1, the following information will be requested by the Research Nurse:
•
A faxed or emailed copy of a completed and signed, protocol specific, Step 1 Eligibility 
Checklist Form. 
•
One copy of a Pathology report from the patient’s most recent surgery or biopsy.
•
One copy of the signed and dated Informed Consent/Authorization. 
The Eligibility Checklist form should be prepared and signed prior to faxing or emailing to the Research 
Nurse.


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If the patient fails eligibility screening, do not proceed to Step 2 of the registration process. 
Subjects that do not meet screening criteria should be removed from the study following the procedure 
in section 3.6.3.2.
Registration Step 2
Registration step 2 must be completed:
•
After eligibility screening has been completed and the local investigator has determined that 
the patient meets eligibility requirements.
•
After centralized review and confirmation of histologic diagnosis.
•
Before initiation of study treatment of any modality.
Confirmation of histologic diagnosis at this time point must be known. Protocol treatment may not be 
initiated until Step 2 of the registration process has been completed by the Research Nurse.  At the time 
of registration step 2, the following information will be requested:
•
A faxed or emailed copy of a completed and signed, protocol specific, Step 2 eligibility 
checklist form
•
One copy of the Central Pathology Review results
The Eligibility Checklist form should be prepared and signed prior to faxing or emailing to the Research 
Nurse.
2.3.3
Initiation of Therapy
Treatment may not be initiated until the participating institution receives a faxed or emailed copy of the 
patient’s Registration Verification Letter from the NCI Registration Office. 
All Patients that are eligible to receive therapy must initiate treatment within 96 hours after the 
registration Step 2.  
2.3.4
Treatment Assignment
Cohorts
Number
Name
Description
1
First cohort
Patients with Recurrent Low-grade and Anaplastic 
Supratentorial, Infratentorial and Spinal Cord Ependymoma
Arms
Number
Name
Description
1
Experimental
Carboplatin will be given on day 1 of each cycle. 
Bevacizumab will be administered on days 1 and 15 of each 
cycle. The total duration of treatment will be 6 cycles. After 


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cycle 6, carboplatin should be discontinued, but bevacizumab 
may be continued at the discretion of the treating physician.
Stratifications
None.
Arm Assignment
Patients in cohort 1 will be directly assigned to arm 1.
2.4
BASELINE EVALUATION
2.4.1
Patients will complete a baseline MD Anderson Symptom Inventory-Brain Tumor Module 
(MDASI-BT or MDASI-SP) (Appendix 13.2 or 13.3) within 14 days (+ 3 working days) after 
enrollment on the clinical trial. The MDASI-BT or MDASI-SP will be completed only by the 
patient, unless changes in vision or weakness make this difficult. If this occurs, then the 
caregiver or research assistant may read the questions to the patient or assist with marking the 
severity number or score as described by the patient. A patient caregiver may complete the 
questionnaires as a patient-preference proxy if the patient’s deficits preclude self-report.
2.4.2
Prior to treatment start, a baseline MRI of the brain including diffusion, perfusion and 
spectroscopy should be obtained as specified in Appendix 13.4. This MRI should be performed 
within 14 days prior to registration step 2. In case of contra-indication to an MRI, a CT of the 
head with and without contrast should be performed. The same type of scan, i.e., MRI or CT 
must be used throughout the period of protocol treatment for tumor measurement. 
2.4.3
Prior to treatment start, a baseline creatinine clearance should be obtained from a 24-hour urine 
collection or calculated using the Cockcroft-Gault equation (see section 3.2). The maximum 
CrCl used should be 125 ml/min. The creatinine to be used for this baseline calculation should be 
obtained on the day of treatment or within 3 days prior. 
3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN
This is a phase II study to evaluate the efficacy of carboplatin and bevacizumab for the treatment of 
recurrent low grade or anaplastic ependymoma after failure of one line of chemotherapy. This trial is 
designed utilizing a Simon optimal two-stage design, as described in Section 8.  Patients must initiate 
study treatment within 96 hours after registration Step 2.  If the patient has undergone surgery, 
treatment should start no sooner than 28 days after surgery. All efforts should be made to obtain a post-
operative scan within 96 hours following surgery for evaluation of extent of surgery. A pre-treatment 
MRI must be obtained/repeated within 14 days prior to start of treatment, following the parameters 
established in Appendix 13.4. 


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Eligible patients will be treated as described below. One cycle will correspond to 4 weeks. A treatment 
window of +/- 3 days is acceptable for all treatments and procedures. Carboplatin will be given on day 1 
of each cycle. Bevacizumab will be administered on days 1 and 15 of each cycle. The total duration of 
treatment will be 6 cycles. After cycle 6, carboplatin should be discontinued, but bevacizumab may be 
continued at the discretion of the treating physician. Patients will be monitored for hematologic or 
serologic evidence of myelosuppression, hepatic injury, renal injury, and electrolyte disturbances and for 
clinical evidence of other toxicity as is described in sections 3.2.1, 3.2.2, 11.1 and 11.2. 
3.2
DRUG ADMINISTRATION
3.2.1
Carboplatin will be given on day 1 of each cycle. For cycle 1, the dose will be given at an 
AUC=5 mg/mL/min. If no toxicity higher than grade 1 is observed during cycle 1, the dose of 
carboplatin will be increased to AUC=6 mg/mL/min for cycle 2 and onwards.
The carboplatin dose should be calculated using the Calvert formula: Carboplatin dose (mg)  = target 
AUC x (CrCl + 25). 
The maximum CrCl used should be 125 ml/min. The creatinine to be used for calculation of AUC 
should be obtained on the day of treatment or within 3 days. 
The Cr Cl should be calculated using the Cockroft-Gault equation: 
Male: CrCl (ml/min) = (140-age) X (Actual weight in kg) / 72 x serum Creatinine (mg/dl). 
Female: CrCl (ml/min) = (140-age) X (Actual weight in kg) X 0.85 / 72 x serum Creatinine (mg/dL)
A measured CrCl from a 24 hour urine collection may also be used.
3.2.1.1
 Special considerations with the use of the Cockcroft-Gault (CG) in estimating GFR:
3.2.1.1.1 Adjustments for extremes of weight 
•
Actual weight is to be used unless patient has BMI> 25 
•
In patients with BMI > 25, using the adjusted body weight should be considered.
•
If using other weight, please justify rationale.
3.2.1.1.2 Serum creatinine details
•
IDMS creatinine is preferred; back-calculating to a non-IDMS creatinine will not be permitted.
•
Lower limits of reported serum creatinine: Recommendation is 0.7 mg/dL be the lower limit
If using lower serum creatinine value, please justify rationale.
3.2.1.1.3 Use of capping GFR (at 125) or Carboplatin dose or both.
3.2.1.2
Adjustments for first cycles compared with subsequent cycles.
At the discretion of the treating physician, deviations to the rules described for carboplatin dose 
Calculation may be proposed and discussed with the study PI.


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3.2.2
Bevacizumab will be administered at a dose of 10 mg/kg on days 1 and 15 of each cycle.
The total duration of treatment will be 6 cycles. After cycle 6, carboplatin should be discontinued, but 
bevacizumab may be continued at the discretion of the treating physician. Patients who have completed 
the maximum number of Carboplatin cycles will remain on-study and should be followed with MRI and 
correlative blood tests per protocol every 8 weeks (+/- 30 days), until withdrawal of consent or 
radiographic progression of disease. Patients who have completed the maximum number of Carboplatin 
cycles and are continuing on Bevacizumab should have CBC, pregnancy test (β-HCG), creatinine 
clearance, UPC or urinalysis at the discretion of the treating physician.  If carboplatin is discontinued 
prior to completion of 6 cycles due to toxicity, patients may continue with single-agent bevacizumab 
until disease progression, at the discretion of the treating physician.  
3.2.3
Dose Modifications 
Patients with stable or responding disease may be retreated at the same dose or at a reduced dose level, 
depending upon the adverse events observed in the current cycle and any adverse events present on the 
first day of the next cycle. If multiple toxicities are seen, the dose administered in a subsequent cycle 
should be based on the most severe toxicity experienced in the current cycle. Dose modifications or 
delays should be made based upon whether toxicities occur within a 4-week treatment cycle or at the 
expected start of the next treatment cycle. 
Patients who experience dose-limiting toxicity should have laboratory testing at least weekly until the 
toxicity has resolved.
There will be no dose modifications of the bevacizumab.  After the 1st year of treatment (the primary 
endpoint), treating physicians can decide to stop or modify the dose and or interval of bevacizumab as 
clinically indicated.  The protocol does not prescribe a schedule for this, but recognizes the common 
practice of tapering the dose/schedule to provide continued therapy once disease control is established 
but hopefully reducing the toxicity risk imposed by prolonged treatment at the full dose regimen.
3.2.3.1
Bevacizumab Dose Modification and Toxicity Management
There are no reductions in the bevacizumab dose. If adverse events occur that require holding 
bevacizumab, the dose will remain the same once treatment resumes.
Any toxicity associated or possibly associated with bevacizumab treatment should be managed 
according to standard medical practice. Discontinuation of bevacizumab will have no immediate 
therapeutic effect. Bevacizumab has a terminal half-life of 21 days; therefore, its discontinuation results 
in slow elimination over several weeks. There is no available antidote for bevacizumab. 
Subjects should be assessed clinically for toxicity prior to, during, and after each infusion. If 
unmanageable toxicity occurs because of bevacizumab at any time during the study, treatment with 
bevacizumab should be discontinued. 
Infusion Reaction: Infusion of bevacizumab should be interrupted for subjects who develop dyspnea or 
clinically significant hypotension. Subjects who experience a NCI CTCAE v 4.0 grade 3 or 4 allergic 
reaction / hypersensitivity, adult respiratory distress syndrome, or bronchospasm (regardless of grade) 
will be discontinued from bevacizumab treatment.
The infusion should be slowed to 50% or less or interrupted for subjects who experience any infusion-
associated symptoms not specified above. When the subject’s symptoms have completely resolved, the 


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infusion may be continued at no more than 50% of the rate prior to the reaction and increased in 50% 
increments every 30 minutes if well tolerated. Infusions may be restarted at the full rate during the next 
cycle. 
Adverse events requiring delays or permanent discontinuation of bevacizumab are listed in Table 1.  
Regardless of the reason for holding study drug treatment, the maximum allowable length of treatment 
interruption is 2 months.
If patients on treatment with bevacizumab require elective major surgery, it is recommended that 
bevacizumab be held for 4-8 weeks prior to the surgical procedure. Patients undergoing a major surgical 
procedure should not begin/restart bevacizumab until 4 weeks after that procedure (in the case of high 
risk procedures such as liver resection, thoracotomy, or neurosurgery, it is recommended that 
chemotherapy be restarted no earlier than 6 wk and bevacizumab no earlier than 8 wk after surgery). 


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Table 1: Bevacizumab Dose Management Due to Adverse Events
Event per CTCAEv4
Action to be Taken
Hypertension
No dose modifications for grade 1 or 2 events
Grade 3
If not controlled to 150/100 mmHg with medication, discontinue bevacizumab.
Grade 4 (including 
hypertensive encephalopathy)
Discontinue bevacizumab.
Hemorrhage
No dose modifications for grade 1 or 2 non-pulmonary and non-CNS events
  Grade 3  
  Non-pulmonary and
    non-CNS hemorrhage
Subjects who are also receiving full-dose anticoagulation will be discontinued from 
receiving bevacizumab.  
All other subjects will have bevacizumab held until all of the following criteria are 
met:
•
The bleeding has resolved and hemoglobin is stable.
•
There is no bleeding diathesis that would increase the risk of therapy.
•
There is no anatomic or pathologic condition that significantly 
increases the risk of hemorrhage recurrence.
Subjects who experience a repeat Grade 3 hemorrhagic event will be discontinued 
from receiving bevacizumab.
  Grade 4 
     non-pulmonary or 
    non-CNS hemorrhage
Discontinue bevacizumab.
   Grade 1pulmonary or CNS 
hemorrhage
Subjects who are also receiving full-dose anticoagulation will be discontinued from 
receiving bevacizumab.  
All other subjects will have bevacizumab held until all of the following criteria  are 
met:
•
The bleeding has resolved and hemoglobin is stable.
•
There is no bleeding diathesis that would increase the risk of therapy.
•
There is no anatomic or pathologic condition that significantly 
increases the risk of hemorrhage recurrence.
Grade 2, 3, or 4 pulmonary or 
CNS hemorrhage
Discontinue bevacizumab
Venous Thrombosis
No dose modifications for grade 1 or 2 events
Grade 3 or 4
Hold study drug treatment.  If the planned duration of full-dose anticoagulation is 
<2 weeks, bevacizumab should be held until the full-dose anticoagulation period is 
over.  If the planned duration of full-dose anticoagulation is >2 weeks, bevacizumab 
may be resumed during the period of full-dose anticoagulation if all of the 
following criteria are met:
•
The subject must have an in-range INR (usually between 2 and 3) if 
on warfarin; LMWH, warfarin, or other anticoagulant dosing must be 
stable prior to restarting bevacizumab treatment.
•
The subject must not have had a Grade 3 or 4 hemorrhagic event while 
on anticoagulation.
Arterial Thromboembolic event
(New onset, worsening, or unstable angina, myocardial infarction, transient ischemic attack, cerebrovascular 
accident, and any other arterial thromboembolic event)
 Any grade
Discontinue bevacizumab.
Proteinuria
No dose modifications for grade 1 or 2 events


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Grade 3
(UPC> 3.5, urine collection 
> 3.5 g/24 hr)  
Hold bevacizumab treatment until  Grade 2, as determined by either UPC ratio ≤ 3.5 
or 24 hr collection ≤ 3.5 g
Grade 4 (nephritic 
syndrome)
Discontinue bevacizumab
GI Perforation
Discontinue bevacizumab
Fistula 
Any grade (TE fistula)
Discontinue bevacizumab
Grade 4 fistula
Discontinue bevacizumab
Bowel Obstruction
Grade 1
Continue patient on study for partial obstruction NOT requiring medical intervention.
Grade 2
Hold bevacizumab for partial obstruction requiring medical intervention.  Patient may 
restart upon complete resolution.
Grade 3/4
Hold bevacizumab for complete obstruction.  If surgery is necessary, patient may 
restart bevacizumab after full recovery from surgery, and at investigator’s discretion.
Wound dehiscence Any 
grade (requiring medical or 
surgical therapy)
Discontinue bevacizumab
Reversible Posterior Leukoencephalopathy  
Any grade
(confirmed by MRI)
Discontinue bevacizumab.
Other Unspecified Bevacizumab-Related Adverse Events
Grade 3
Grade 4
Hold bevacizumab until recovery to ≤ Grade 1
Discontinue bevacizumab
3.2.3.2
Carboplatin Dose Modification and Toxicity Management
Recommendation for the management of carboplatin-related toxicities and required dose reductions for 
hematologic and non-hematologic toxicities are detailed below. Because dose levels may be important 
for achieving adequate brain penetration, all efforts will be taken to avoid dose reductions. Whenever 
required, the following dose levels will be utilized for dose reductions: 
Dose level 1
AUC 6 mg/mL/min
Dose level 0
AUC 5 mg/mL/min
Dose level -1
AUC 4 mg/mL/min
Dose level -2
AUC 3 mg/mL/min
Dose level -3
Discontinue treatment
(bevacizumab may be continued)
3.2.3.3
Hematologic Toxicity:
Dose Modifications Based on Weekly ANC and Platelet Counts:
ANC (/mcL) 
Platelets (/mcL)
% of Planned Carboplatin Dose
> 1000
and
> 75,000
100%
750-999
or 
50,000 to < 75,000
hold*
< 750
 or 
< 50,000
hold**
*Upon recovery to ANC > 1,000/mcL and platelets to > 100,000/mcL, the same dose level will be 
administered.


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** Upon recovery to ANC > 1,000/mcL and platelets to > 100,000/mcL, one lower dose levels will be 
administered. If ANC < 750 but platelets >75,000, at the investigator’s discretion, prophylactic G-CSF 
may be used and the same dose may be administered.  
3.2.3.4
Non-hematologic Toxicity:
Dose Modifications Based on carboplatin-related Non-Hematologic Toxicities:
CTCAEv4 Grade
% of Planned  Carboplatin Dose
0-2∞
100%∞
3*
hold**
4
hold**
∞For symptomatic CTCAEv4 Grade 2 toxicity, the dose may be held until recovery to CTCAEv4 Grade 
0-1, then resume at one dose lower, at the investigator's discretion.
*Except nausea/vomiting (unless patients are on optimal antiemetic therapy)
**Hold until recovery to CTCAEv4 Grade 0-1 (or to within 1 grade of starting values for pre-existing 
laboratory abnormalities), and then resume at one dose level lower.  
*** Hold until recovery to CTCAEv4 Grade 0-1 (or to within 1 grade of starting values for pre-existing 
laboratory abnormalities), and then resume at two dose levels lower.
3.2.3.5
At the Start of the Next Treatment Cycle:
A new course of treatment may begin when the ANC is at least 1000/mm3 and the platelet count is at 
least 100,000/mm3 and any other treatment-related toxicities are less than or equal to grade 1.  If after a 
one-week delay all treatment related toxicities are less than or equal to grade 1, proceed with treatment 
at the dose level dictated by the modifications outlined above.  If treatment related toxicities have not 
resolved to less than or equal to grade 1 after a one-week delay, treatment will be held again, and the 
patient will be evaluated weekly.  If treatment will be held for 2 weeks for treatment related toxicities, 
reduce the Carboplatin dose by one dose level beyond that indicated by whether or not the patient had 
DLT in the prior cycle.  If re-treatment must be held for more than 2 weeks the investigator should be 
notified.  If a patient develops another DLT at the reduced dose or if they experience a life-threatening 
toxicity at any time, they will be removed from study. If the single delayed toxicity preventing the start 
of a new cycle is ANC persisting more than 2 weeks, the use of G-CSF for achieving treating parameters 
is permitted, at the discretion of the investigator, and the same carboplatin dose may be used for the 
following cycle if prophylactic G-CSF is utilized.  
For treatment or dose modification related questions, please contact the Lead PI, Mark Gilbert, 
MD 240-760-6023, mark.gilbert@nih.gov
3.3
QUESTIONNAIRES
The MDASI-BT or SP (Appendix 13.2 or 13.3) will be utilized for this portion of the study. Full 
instruments are provided in the appendix.  In addition, information regarding demographics and 
treatment history will be collected as part of the larger study and used in this analysis.
The MDASI-BT or SP consists of 23 symptoms rated on an 11-point scale (0 to 10) to indicate the 
presence and severity of the symptom, with 0 being “not present” and 10 being “as bad as you can 
imagine.” Each symptom is rated at its worst in the last 24 hours. Symptoms included on the instrument 
include those commonly associated with cancer therapies, those associated with increased intracranial 


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pressure, and those related to focal deficits.  The questionnaire also includes ratings of how much 
symptoms interfered with different aspects of a patient’s life in the last 24 hours. These interference 
items include: general activity, mood, work (includes both work outside the home and housework), 
relations with other people, walking, and enjoyment of life. The interference items are also measured on 
0 - 10 scales. The average time to complete these instruments is 5 minutes. The MDASI-BT or SP has 
been translated into 18 languages [18, 20].
3.4
STUDY CALENDAR
STUDIES TO BE 
OBTAINED
Pre-Study
(within 14 days 
of study 
registration 
Step 2)
Course 1-6
(+ 3 days)
Greater than 
Course 6
Discontinuation 
or Completion 
of Therapy
Consent 
X
History
X
X3
X8
Physical Exam (Ht, Wt, 
BSA, VS)
X
X3
X8
KPS Performance Status
X
X3
X8
Neurologic Exam
X
X3
X8
CBC, differential, platelets
X7
X7
X9
X
Serum Pregnancy Test (β-
HCG)1
X
X 9
X
PT, PTT, INR
X
Serum Creatinine, 
Calculated Creatinine 
Clearance, Urine protein/ 
creatinine ratio (or 
urinalysis)
X
X2
X9
X
SGOT (AST), Total 
Bilirubin
X
X2
X9
X
MRI Head and/or Spine 
(including diffusion, 
perfusion and 
spectroscopy)/ or CT
X
X3
X 6
MDASI Symptom 
Assessment
X
X3
X 8
Adverse Events Notation 
and relevant information
X5
X5
Off Treatment Follow-up 
Assessment
X4
Tissue to establish tumor 
diagnosis
(15 unstained slides at a 
minimum)
X
1  Serum pregnancy test (β-HCG) for women of childbearing potential.


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2  To be performed every 4 weeks prior to each cycle.  
3  To be performed every other cycle.  MDASI (BT or SP, depending on tumor location) to be completed 
+/- 1 week from date of MRI (every 8 weeks) as long as clinical therapy is being administered.
4  Patients who discontinue treatment due to progression will be followed for survival every 3 months.  
Patients who come off therapy for reasons other than progression should be followed until progression 
or institution of new anti-tumor therapy.
5  Patients will be evaluated for adverse events at the end of each cycle.  All relevant information 
regarding drug doses, concomitant medications, laboratory examinations and treatment related toxicities.
6  Patients who discontinued treatment for toxicity or maximum number of cycles was reached remain on 
study and should be followed with MRI every 8 weeks (+/- 30 days) until progression. 
7 To be performed every 2 weeks during treatment
8 To be performed every 8 weeks (+/- 30 days) at same time as MRI
9 At discretion of treating physician, as necessary for treatment management
3.5
ON STUDY EVALUATION
CBC, differential, and platelets will be performed every two weeks during treatment.  Creatinine, 
calculated creatinine clearance, bilirubin, SGOT, urine protein/ creatinine ratio (or urinalysis) will be 
performed every four weeks and prior to each cycle.
A brain MRI/CT will be done prior to every other cycle, following the parameters specified in Appendix 
13.4. 
All relevant information regarding drug doses, concomitant medications, and doses, measurable lesions 
with measurements, tumor response, laboratory examinations, and treatment-related toxicities shall be 
documented in the patient’s medical record and flow sheets.
A complete Neurologic exam (to include documentation of the patients Karnofsky Performance Status) 
will be performed prior to every other cycle. 
All patients will be followed for overall survival, when possible.
a) Patients who discontinue treatment due to progression will be followed for survival every 3 
months (+/- 30 days).  Each patient will be followed for survival for as long as the study is 
open “or” for a maximum of 5 years.
b) Patients who come off therapy for reasons other than progression should be followed until 
progression or institution of new anti-tumor therapy.  They should then be followed for 
survival.
Patients will be evaluated for adverse events at the end of each cycle. In addition, all serious adverse 
events will be reported to the NCI and the lead PI as directed in Section 7.3.
The patient will complete the MDASI-BT or MDASI-SP (Appendix 13.2 or 13.3) at the time of clinical 
evaluation with MRI as long as the clinical therapy is being administered, unless clinical deterioration 
makes self-report not possible before that time.  The time when patients are unable to complete the self 


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report questionnaires will be used as part of the study analysis.  The MDASI-BT or MDASI-SP will be 
completed only by the patient, unless changes in vision or weakness make this difficult. If this occurs, 
then the caregiver or research assistant may read the questions to the patient or assist with marking the 
severity number or score as described by the patient. A patient caregiver may complete the 
questionnaires as a patient-preference proxy if the patient’s deficits preclude self-report.
3.6
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
3.6.1
Criteria for Removal from Protocol Therapy
3.6.1.1
Progression of disease (as defined in Section 6.3.1)
Patients must be followed by the same type of brain scan, as was used for baseline tumor measurements, 
and will be removed from study if progression is documented after any cycle of treatment.  Patients with 
stable disease, partial or complete response will continue on therapy.
3.6.1.2
 Unacceptable toxicity (as defined by the investigator).
Note: A maximum of 6 cycles of carboplatin will be administered. If carboplatin is discontinued due to 
either toxicity or maximum number of treatment is reached, patients may continue to receive single-
agent bevacizumab until disease progression. Patients who discontinued treatment for toxicity or 
maximum number of cycles was reached remain on study and should be followed with MRI every 8 
weeks (+/- 30 days) and undergo study assessments as outlined in Section 3.4. 
3.6.1.3
The patient may withdraw from the study at any time for any reason.
3.6.1.4
Medical or psychiatric illness which in the investigator's judgment renders the patient 
incapable of further therapy.
3.6.1.5
Treatment delay due to toxicity greater than 60 days measured from the start of the preceding 
cycle.
All reasons for discontinuation of treatment must be documented.
3.6.2
Off Study Criteria
3.6.2.1
Participant requests to be withdrawn from study
3.6.2.2
Screen failure
3.6.2.3
Investigator discretion
3.6.2.4
Death
3.6.3
Off Protocol Therapy and Off-Study Procedure:
3.6.3.1
At NCI
N/A
3.6.3.2
For participating sites: 
The Participant Status Update Form will be supplied by the Research Nurse. This form must be 
completed for each patient taken off treatment as well as when the patient is taken off study. 
Participating sites will send a completed form with supporting source documentation to NCI RN via 
encrypted email at nci_bttc@mail.nih.gov . The source document should be redacted (“black out” any 
patient identifiers) and must confirm the date and reason why the patient is no longer on study.  For 


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questions, please contact the Coordinating Center.   The Participants Status Update Form will be 
forwarded to the CRO by the Coordinating Center.
4
CONCOMITANT MEDICATIONS/MEASURES
4.1
G-CSF ADMINISTRATION
Prophylactic use of G-CSF is not permitted prior or during cycle 1. After cycle 1, the prophylactic use of 
G-CSF will be left at the discretion of the treating physician.  Therapeutic use of G-CSF for the 
management of febrile neutropenia is permitted during any cycle, including cycle 1.  
4.2
SUPPORTIVE CARE
4.2.1
Corticosteroids should be used in the smallest dose to control symptoms of cerebral edema and 
mass effect, and discontinued if possible.
4.2.2
Febrile neutropenia may be managed according to the local institution's Infectious Disease 
guidelines.  Measures may include appropriate laboratory testing, including blood and urine 
cultures and the institution of broad-spectrum antibiotics.  If a source for the fever is not 
identified, or the fever resolves when the neutrophil count recovers, antibiotics may be 
discontinued and the patient observed. Use of G-CSF is permitted at the discretion of the treating 
physician.
4.2.3
Anti-emetics
The use of anti-emetics will be left to the investigators’ discretion and/or institutional guidelines. 
The following is an example of prophylactic anti-emetic therapy for carboplatin:  
Pre-treatment antiemetic therapy:
Ondansetron 20mg PO/Granisetron 1mg IV
Dexamethasone 12mg PO/IV
Aprepitant 125 mg PO
Post-treatment:
Dexamethasone 12mg PO daily on days 2&3
Aprepitant 80mg PO daily on days 2&3
PRN anti-emetic:
Metoclopromide 10mg PO/IV every 4 hours prn
(Chemotherapy can be given immediately after pre-treatment with oral ondansetron and/or oral 
dexamethasone; patients who fail ondansetron should receive granisetron 1 mg IV prior to 
chemotherapy; Patients who are unable to swallow should receive: Dexamethasone 12 mg IV, 
Ondansetron 24 mg ODT or granisetron 1 mg IV; patients receiving dexamethasone for hypersensitivity 
prophylaxis or for the brain tumor do not need additional oral dexamethasone).


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4.2.4
Other Concomitant Medications
Therapies considered necessary for the well-being of the patient may be given at the discretion of the 
investigator. Other concomitant medications should be avoided except for analgesics, chronic treatments 
for concomitant medical conditions, or agents required for life-threatening medical problems.  All 
concomitant medications must be recorded.
4.2.5
Other Anticancer or Experimental Therapies
No other anticancer therapy (including chemotherapy, radiation, hormonal treatment or immunotherapy) 
of any kind is permitted during the study period. No other drug under investigation may be used 
concomitantly with the study drug.
4.2.6
Surgery
If neurosurgical management is required for reasons not due to tumor progression, these procedures 
must be documented, including the indications for surgery, the surgical operative note and pathology 
report. Please refer to section  3.2.3for instruction on holding study drugs.
5
BIOSPECIMEN COLLECTION
5.1
PATHOLOGY REVIEW
Following step 1 registration, slides from the most recent pre-registration biopsy must be submitted for 
review.  The purpose of this review is to verify the histologic diagnosis before step 2 registration.
The materials are to be submitted after registration step 1 to Dr. Ken Aldape:
Ken Aldape, MD
Laboratory of Pathology
Center for Cancer Research
National Cancer Institute 
Building 10, Room 2S235
Bethesda, MD 20892-1500
Ph: 301-480-5010
kenneth.aldape@nih.gov
A Tissue Collection Shipping form Section 13.9 must be submitted to Dr. Aldape and the NCI Research 
Nurse each time specimen submissions are made.  If the patient’s slides have been reviewed on a 
previous CERN study and there has been no interim surgery or biopsy, the slides do not need to be re-
submitted. The site must submit a copy of the previous review results to the NCI Research Nurse, via 
encrypted email as documentation for the new study.
Pathology Materials Required for Review:
1. One to two representative H&E stained slides from a pre-registration biopsy demonstrating 
lesion.
2. A copy of the pathology report and the operative report.
3. The Tissue Collection Shipping form, (Section 13.9)


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4. The submitting institution is responsible for the costs of shipping and handling.
5.2
LABORATORY CORRELATES
5.2.1
Baseline tumor expression of hypoxia-related factors: 
In this study, paraffin embedded tissue or frozen tissue (or 15 unstained slides at a minimum) will be 
collected from all patients, for evaluation of expression of hypoxia-related and angiogenesis factors such 
as VEGF, VEGFR-2/KDR, CD31, CA9, HIF-2α and others, utilizing immunohistochemistry, RT-qPCR 
and gene expression studies. Tissue evaluation will be required for every case before study registration 
Step 2. Send pathology material by overnight mail directly to Dr. Ken Aldape. 
Ken Aldape, M.D.
Laboratory of Pathology
Center for Cancer Research
National Cancer Institute 
Building 10, Room 2S235
Bethesda, MD 20892-1500
Ph: 301-480-5010
             Kenneth.aldape@nih.gov
6
DATA COLLECTION AND EVALUATION
6.1
DATA COLLECTION
The PI will be responsible for overseeing entry of data into an in-house password protected electronic 
system (C3D) and ensuring data accuracy, consistency and timeliness. The principal investigator, 
associate investigators/research nurses and/or a contracted data manager will assist with the data 
management efforts.  All data obtained during the conduct of the protocol will be kept in secure network 
drives or in approved alternative sites that comply with NIH security standards. Primary and final 
analyzed data will have identifiers so that research data can be attributed to an individual human subject 
participant.
All Adverse Events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event. Patients will be 
followed for adverse events for 30 days after removal from study treatment or until off-study, whichever 
comes first. 
An abnormal laboratory value will be considered an AE if the laboratory abnormality is characterized by 
any of the following:
•
Results in discontinuation from the study
•
Is associated with clinical signs or symptoms 
•
Requires treatment or any other therapeutic intervention
•
Is associated with death or another serious adverse event, including hospitalization. 


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•
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.
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 as 
characterized in the bulleted list above are recorded on the Adverse Events Case Report Form.
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.
Data on this study will be entered into C3D within 2 weeks of completion of each cycle of treatment.  
Designated research staff from the registering institution will enter the data via remote electronic data 
entry. The protocol specific electronic forms are to be used by the participating sites.  All investigators 
will utilize these forms for Baseline, Treatment, Tumor Evaluation, Off Treatment, Survival, and Off-
study data.
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.
6.2
DATA SHARING PLANS
6.2.1
Human Data Sharing Plan
I will share human data generated in this research for future research as follows (check all that apply):
_x__ Coded, linked data in an NIH-funded or approved public repository.
_x__ Coded, linked data in another public repository.
_x__ Coded, linked data in BTRIS (automatic for activities in the Clinical Center)
__x_ Identified or coded, linked data with approved outside collaborators under appropriate agreements.
How and where will the data be shared? 
Data will be shared through:
_x__ An NIH-funded or approved public repository. Insert name or names:_ clinicaltrials.gov 
___ Another public repository. Insert name or names: 
_x__ BTRIS (automatic for activities in the Clinical Center)


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__x_ Approved outside collaborators under appropriate individual agreements.
__x_ Publication and/or public presentations.
When will the data be shared? 
_x__ Before publication.
_x__ At the time of publication or shortly thereafter.
6.3
RESPONSE CRITERIA
The primary efficacy endpoint for this study is PFS at one year.  Progression free survival will be 
calculated from patient registration.  However, objective response status should be measured and 
recorded. For this and all other time to event analyses that use registration date, if a patient is registered 
on the pre-operative portion of the study, the start date for calculation of time to event will be the date of 
first post-operative study drug administration.
RECIST criteria:  Criteria permitting uni-dimensional response measurement have been adopted and 
published by an international consensus committee, Response Evaluation Criteria In Solid Tumors 
Group (RECIST).  In order to ensure comparability of data from this trial with data from earlier trials, 
this trial will retain the traditional evaluation definition in Section 6.3.1.  However, RECIST criteria that 
can be collected will be used for secondary evaluation.  Concordance with the traditional approach will 
be summarized.
6.3.1
Definitions 
6.3.1.1
Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first 
treatment.
6.3.1.2
Evaluable for objective response: Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be 
considered evaluable for objective response. These patients will have their response classified according 
to the definitions stated below. However, all patients regardless of the presence or absence of 
measurable disease will be evaluated for the secondary endpoint of overall survival. (Note: Patients who 
exhibit objective disease progression prior to the end of cycle 1 will also be considered evaluable.)
6.3.1.3
Measurable Disease: Bidimensionally measurable lesions with clearly defined margins by CT 
or MRI scan.
6.3.1.4
Evaluable Disease: Unidimensionally measurable lesions, masses with margins not clearly 
defined. 
6.3.1.5
Non-Evaluable Disease: Not Applicable for response evaluation
6.3.1.6
Objective Status, To Be Recorded at Each Evaluation: If there are too many measurable lesions 
to measure at each evaluation, choose the largest two to be followed before a patient is entered on study.  
The remaining lesions will be considered evaluable for the purpose of objective status determination.  
Unless progression is observed, objective status can only be determined when ALL measurable and 
evaluable sites and lesions are assessed.
6.3.1.6.1 Complete Response (CR):  Complete disappearance of all measurable and evaluable disease.  
No new lesions.  No evidence of non-evaluable disease.  All measurable, evaluable and non-


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evaluable lesions and sites must be assessed using the same techniques as baseline.  Patients 
must not be on steroids.
6.3.1.6.2 Partial Response (PR):  Greater than or equal to 50% decrease under baseline in the sum of 
products of perpendicular diameters of all measurable lesions.  No progression of evaluable 
disease.  No new lesions.  All measurable and evaluable lesions and sites must be assessed using 
the same techniques as baseline. The steroid dose at the time of the scan evaluation should be 
no greater than the maximum dose used in the first 8 weeks from initiation of therapy.
6.3.1.6.3 Partial Response, Non-Measurable (PRNM): Not applicable.
6.3.1.6.4 Stable/No Response: Does not qualify for CR, PR, or progression.  All measurable and 
evaluable sites must be assessed using the same techniques as baseline.  The steroid dose at the 
time of the scan evaluation should be no greater than the maximum dose used in the first 8 
weeks from initiation of therapy.
6.3.1.6.5 Progression: 25% increase in the sum of products of all measurable lesions over smallest sum 
observed (over baseline if no decrease) using the same techniques as baseline, OR clear 
worsening of any evaluable disease, OR appearance of any new lesion/site, OR clear clinical 
worsening or failure to return for evaluation due to death or deteriorating condition (unless 
clearly unrelated to this cancer).
6.3.1.6.6 Unknown: Progression has not been documented and one or more measurable or evaluable sites 
have not been assessed.
6.3.2
Best Response: This will be calculated from the sequence of objective statuses.
For patients with all disease sites assessed at every evaluation period, the best response will be defined 
as the best objective status as measured according to Section 6.3.1.6.  If the response does not persist at 
the next regular scheduled MRI, the response will still be recorded based on the prior scan, but will be 
designated as a non-sustained response.  If the response is sustained, e. g., still present on the subsequent 
MRI, it will be recorded as a sustained response, lasting until the time of tumor progression.  Best 
response is unknown if the patient does not qualify for a best response or increasing disease and if all 
objective status determinations before progression are unknown.
6.3.3
Neurological Exam: Although not used for determining response, it is useful to evaluate 
improvement in the neurologic exam, (as compared to the baseline assessment), that should 
coincide with objective measurement of tumor size. 
+2
Definitely better
+1
Possibly better
  0
Unchanged
 -1
Possibly worse
 -2
Definitely worse
6.3.4
Performance Status: Patients will be graded according to Karnofsky Performance Status (see 
Appendix B).
6.3.5
Time to Treatment Failure: From date of registration step 2 to the date of first observation of 
progressive disease (as defined in Section 6.3.1.6.5), non-reversible neurologic progression or 
permanently increased steroid requirement (applies to stable disease only), death due to any 


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cause, or early discontinuation of treatment. If a patient is registered on the pre-operative portion 
of the study, the start date for calculation of time to event will be the date of first post-operative 
study drug administration.
6.3.6
Time to Death: From date of registration to date of death due to any cause.
6.4
TOXICITY CRITERIA
The following adverse event management guidelines are intended to ensure the safety of each patient 
while on the study.  The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting.  All 
appropriate treatment areas should have access to a copy of the CTCAE version 4.0.  A copy of the 
CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40). 
7
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN
7.1
DEFINITIONS
Please refer to definitions provided in Policy 801: Reporting Research Events found at 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements 
7.2
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING
7.2.1
Expedited Reporting
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 802 
Non-Compliance Human Subjects Research found at 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. 
7.2.1
IRB Requirements for PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events found at 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements.
7.3
NCI GUIDANCE FOR REPORTING EXPEDITED ADVERSE EVENTS FOR MULTI-CENTER TRIALS
Report events to the Reviewing IRB as per its policy. Please also notify the coordinating center PI and 
study coordinator of your submission at the time you make it. 
8
SAFETY REPORTING TO COORDINATING CENTER
8.1
DEFINITIONS
8.1.1
Adverse Event
Any untoward medical occurrence in a human subject, including any abnormal sign (for example, 
abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the 
subject’s participation in research, whether or not considered related to the subject’s participation in the 
research.


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8.1.2
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.
8.1.3
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.
8.1.4
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.
8.1.5
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.
8.1.6
Disability
A substantial disruption of a person’s ability to conduct normal life functions.
8.1.7
Life-threatening adverse drug experience
Any adverse event or suspected adverse reaction that places the patient or subject, in the view of the 
investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction that had it occurred in a more severe form, might have caused death.
8.1.8
Protocol Deviation (NIH Definition)
Any change, divergence, or departure from the IRB-approved research protocol.  


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8.1.9
Non-compliance (NIH Definition)
The failure to comply with applicable NIH Human Research Protections Program (HRPP) policies, IRB 
requirements, or regulatory requirements for the protection of human research subjects.
8.1.10 Unanticipated Problem
Any incident, experience, or outcome that:
•
 Is unexpected in terms of nature, severity, or frequency in relation to 
(a) the research risks that are described in the IRB-approved research protocol and informed 
consent document; Investigator’s Brochure or other study documents, and
(b) the characteristics of the subject population being studied; AND
•
Is related or possibly related to participation in the research; AND
•
Suggests that the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized.
8.2
ASSESSING CAUSALITY
Investigators are required to assess whether there is a reasonable possibility that the study agent/s caused 
or contributed to an adverse event.  The following general guidance may be used.
Yes:
If the temporal relationship of the clinical event to the study agent/s administration makes 
a causal relationship possible, and other drugs, therapeutic interventions or underlying conditions 
do not provide a sufficient explanation for the observed event.
No:
If the temporal relationship of the clinical event to the study agent/s administration makes 
a causal relationship unlikely, or other drugs, therapeutic interventions or underlying conditions 
provide a sufficient explanation for the observed event.
8.2.1
Reporting Pregnancy
Pregnancy, although not itself a serious adverse event, should also be reported on a serious adverse 
event form and be followed up to determine outcome, including spontaneous or voluntary termination, 
details of birth, and the presence or absence of any birth defects or congenital abnormalities.
The site PI must report to the lead PI within 5 working days from the time the research team becomes 
aware of event.
8.3
DATA AND SAFETY MONITORING PLAN
8.3.1
Principal Investigator/Research Team 
The clinical research team will have a teleconference on a regular basis when patients are being actively 
treated on the trial to discuss each patient. Decisions about dose level enrollment and dose escalation if 
applicable will be made based on the toxicity data from prior patients. 
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Adverse events will be reported as required above. Any safety concerns, new 
information that might affect either the ethical and or scientific conduct of the trial, or protocol 
deviations will be immediately reported to the NIH Intramural IRB. 


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The principal investigator will review adverse event and response data on each patient to ensure safety 
and data accuracy. The principal investigator will personally conduct or supervise the investigation and 
provide appropriate delegation of responsibilities to other members of the research staff. 
8.3.2
NCI Coordinating Center Monitoring Plan
As the CCR is the coordinating center for this multi-site study, the CCR will maintain a monitoring 
program. The CCR’s program allows for confirmation of: study data, specifically data that could affect 
the interpretation of primary study endpoints; adherence to the protocol, regulations, and SOPs; and 
human subjects protection. This is done through independent verification of study data with source 
documentation focusing on:
•
Informed consent process
•
Eligibility confirmation
•
Drug administration and accountability
•
Adverse events monitoring
•
Response assessment.
This trial will be monitored by personnel employed by an NCI contractor. Monitors are qualified by 
training and experience to monitor the progress of clinical trials. Personnel monitoring this study will 
not be affiliated in any way with the trial conduct.
8.3.3
Safety Monitoring Committee
This protocol will require oversight from the Safety Monitoring Committee (SMC).  Initial review will 
occur as soon as possible after the annual NIH Intramural IRB continuing review date.   Subsequently, 
each protocol will be reviewed as close to annually as the quarterly meeting schedule permits or more 
frequently as may be required by the SMC.   For initial and subsequent reviews, protocols will not be 
reviewed if there is no accrual within the review period. Written outcome letters will be generated in 
response to the monitoring activities and submitted to the Principal investigator and Clinical Director or 
Deputy Clinical Director, CCR, NCI.
9
STATISTICAL CONSIDERATIONS 
This is a phase II study to evaluate the efficacy of carboplatin and bevacizumab for the treatment of 
recurrent low grade or anaplastic ependymoma. 
The primary endpoint of this study is PFS rate at one year.  A review of the MSKCC experience (N=12) 
has shown that the median PFS in this population is approximately 5 months after start of second line of 
chemotherapy, and the 1y- PFS was approximately 30% (Omuro et al, personal data). This was 
confirmed by analysis of the CERN database, which found a median PFS of 6 months (N=14) in patients 
at second recurrence (Armstrong et al, personal communication). 
In this trial, we will utilize a Simon optimal two-stage design in which a 30% one-year progression-free 
rate is considered not promising, a 50% one-year recurrence free rate is considered promising, and the 
probabilities of a type I error (falsely accepting a non-promising therapy) and type II error (falsely 
rejecting a promising therapy) are set at 0.1 and 0.1, respectively.   In the first stage of this design, 22 
patients will be accrued.  If at least 8 patients are progression-free at one year among these 22 patients, 


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then an additional 24 patients will be accrued to the second stage.  At the end of the trial, if 18 or more 
patients are progression-free at one year, the regimen will be declared worthy of further study.  This 
design yields at least a 0.90 probability of a positive result if the true progression-free rate is at least 50% 
and yields a 0.90 probability of a negative result if the true recurrence free rate is 30%.    At the interim 
time-point some patients will have been followed for less than 1 year.  We will implement the following 
strategy to deal with this situation: We will calculate the predictive probability of observing at least 8 
progression free patients by the end of 1 year.  This predictive probability will be calculated based on a 
discrete time survival model (Albert and Chib, 2001).  If the predictive probability is greater than 60% 
we will continue to enroll patients and evaluate the 1st stage data once it is mature.  If it is less than 60% 
we will suspend accrual and wait for the first stage data to mature.  A schematic of these rules is 
presented below:
We do not expect patients to drop out of the trial once they initiate therapy.  If patients do dropout we 
will use appropriate methods to account for this fact.  Options will include: 1) treating these patients as 
failures; 2) Using a time to response model and treating the dropped out patients as censored 
observations. 3) A sensitivity analysis for patient withdrawals. In this approach, we will jointly model 
time to response and time to dropout to account for the possibility that dropouts are informative in the 
sense that patients with longer survival time may be more/less likely to drop out the study. We will 
compare the results of this approach to option 2, which treats dropout as independent censored events.
Enroll 1
st stage patients
> 8 with PFS at 1 year?
Continue with Simon Design
Use Predictive Probability
yes
no
Predictive Prob > 60%
yes
no
Enroll 2
nd stage Patients.
Allow 1
st stage patients to mature.  
Once 1
st stage data is mature assess 
1
st stage data using Simon stopping 
rules.
Suspend accrual.  Allow 1
st stage 
data to mature.  Once 1
st stage data is 
mature assess using Simon stopping 
rules


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9.1.1
Secondary objectives (not including patient-reported outcomes)
Secondary objectives include overall survival, response rates and toxicity profile. Kaplan Meier 
methodology will be utilized for calculation of overall survival estimates. The crude incidence rates of 
treatment responses (PR + CR) and toxicities will be calculated, and reported along with 95% 
confidence intervals. 
9.1.2
Patient-reported outcomes  
Received MDASI-BT or SP forms will be checked versus the timing schedule and considered as valid if 
they fall within ten days 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 greater (on a 0-10 scale) will also be 
reported.  We will construct individual patient profiles for each of the selected symptoms to describe the 
individual patients’ patterns of change over time. We will calculate the mean core symptom severity, 
mean severity of the MDASI-BT or SP and mean symptom interference at the time of clinical 
evaluation. Estimates of differences in the mean symptom severity and mean symptom interference 
between responders and non-responders will be estimated in the intent to treat population.  All patients 
with at least one valid questionnaire will be included in the analyses.  Questionnaires completed at study 
registration will be considered baseline.  All questionnaire data received after randomization will be 
used in the primary analyses.
Differences of at least 2 points will be classified as the minimum clinically meaningful change in the 
symptom severity and symptom interference measures. For example, an increase of 2 points or more 
would mean a moderate improvement, whereas a decrease of 2 points or more would be interpreted as 
moderate worsening. For individual symptoms, a rise in a symptom score means deterioration, whereas 
a reduced score means improvement of the specific symptom.
9.1.3
Exploratory objectives will include
•
Evaluation of PFS, overall survival, response rates and toxicities according to anatomical 
location (supratentorial, posterior fossa and spinal cord).  Evaluate treatment effects of this 
combination on advanced MRI of the brain. Perfusion and diffusion-based MRI parameters 
including but not restricted to blood volume, mean and median ADC and structural volumes will 
be analyzed. Results will be summarized, and mean and median values at different time points 
will be tabulated. Changes in such parameters will be checked for statistical significance and 
correlated with the disease status. 
•
Evaluation of plasma levels of angiogenesis-related factors. Percent changes in levels of each 
protein will be correlated with responses to treatment.  Additionally, means and medians of all 
patients together will be calculated and tabulated for each time point, with depiction of standard 
deviations. A Wilcoxon test will be used to determine p value of changes in mean values of 
YKL-40 and HES1, with a p value of less than 0.05 considered statistically significant.
10 COLLABORATIVE AGREEMENTS 


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This study was transferred from MDACC to NCI, under the executed Data Transfer Agreement (12472-
16).
10.1 MULTI-INSTITUTIONAL GUIDELINES
10.1.1 IRB Approvals 
The PI will provide the NIH Intramural IRB and Central Registration Office with a copy of the 
participating institution’s approved yearly continuing review.  Registration will be halted at any 
participating institution in which a current continuing approval is not on file at the NIH Intramural IRB.
10.2 PROTOCOL THERAPY ADMINISTRATION AT A NON-PARTICIPATING SITE 
We expect the majority of patients to be treated at a participating site. However, this study allows 
protocol therapy to be administered at a venue other than the participating site.  An example of this 
venue would be the patient’s community/local oncologist’s facility.  This is particularly applicable to 
patients whose residence is at a significant distance away from the participating institution.  The 
community or local oncologist must strictly follow instructions and requirements as mandated by the 
protocol.  
10.2.1 Participating Site Responsibilities
10.2.1.1 The local oncologist must be given instructions by the registering Investigator on the proper 
conduct of the study.  This will include (but is not limited to);  
▪
The treatment plan.
▪
Study agent dosing or dose modification as applicable, Carboplatin dose calculation is 
per Calvert Formula, calculations must be verified by the registering Investigator or 
his/her designee.
▪
Required laboratory work up and submission of lab results to the site.
▪
Documentation of visits which may include AE reporting and the patient’s general status. 
10.2.1.2 Protocol oversight at the community/local oncologists level will be the responsibility of the 
registering Investigator.  This scope of responsibility includes:
▪
Protocol Orientation/Education:  Educating the local physician about the protocol specifics, AE, 
and source document submission requirements.
▪
Source Documentation:  Collecting and retaining of all of the patients source documentation from 
the local physician.
▪
AEs and SAEs:  Monitoring and tracking of all of the patients adverse events, and reporting all 
SAEs as required by the protocol.
▪
Patient Assessments:  Patients must return to the registering Institution for protocol assessments 
that are used to make decisions on patient’s retention on the trial. 
▪
Monitoring and Auditing:  because the Site PI is responsible for all of the above, the NCI monitors 
will not travel to the local Physicians facilities to audit the local physician’s records. These records 
must be present at the participating site, then flagged and made available to the monitors by the site 
Investigator’s designee’s.


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10.2.1.3 Protocol compliance with study requirements is a necessity for all patients participating in this 
study.  If the community/local oncologist is unable to provide the care as mandated by the protocol, 
and/or is unable to comply with the required documentation, the patient must agree to return to the 
registering investigator’s institution to continue on with the study.  The patient’s protocol participation 
may also be reconsidered.
10.2.2 Responsibilities of Local Physicians
The local physician will receive a copy of this protocol to reference for guidance on drug administration 
It is the responsibility of the local physician to administer drug per protocol and to collect laboratory and 
research data. The local physician should complete and return the Local Physician Agreement found in 
Appendix 15.6 to affirm these delegated responsibilities.
10.2.2.1 Reliance Agreement
A reliance agreement (Appendix 13.5) as well as a letter of agreement between the registering 
Investigator and the community/local oncologist (Appendix 15.6) must be signed.
10.2.2.2 Drug Accountability
Carboplatin and Bevacizumab are commercially available and will be provided by treating physicians. 
Progress notes should include the date, drug, dose, route, and start time and end time of the 
administration. Please document all concomitant medications to include the date, drug, dose, route, and 
time given. Documentation should be sent via facsimile report to the participating site. within three 
business days of drug administration.
10.2.2.3 Laboratory Testing
Documentation of required values should be sent via facsimile report to the participating site.within 
three business days of drug administration:
10.2.2.4 Adverse Event Reporting
See Section 7, Safety Reporting Requirements/Monitoring Plan for further guidance on adverse events.
11 HUMAN SUBJECTS PROTECTIONS
11.1 RATIONALE FOR SUBJECT SELECTION
This study was designed to include women and minorities, but was not designed to measure differences 
of intervention effects.  Males and females will be recruited with no preference tosex.  No exclusion to 
this study will be based on race.  Minorities will actively be recruited to participate.
11.2 PARTICIPATION OF CHILDREN
As there are no data on the combination of Carboplatin and Bevacizumab in children, they are not 
included in this protocol. 
11.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT (CERN SITES)
Each institution will follow their own procedure for re-consenting subjects unable to re-consent and will 
notify the Coordinating Center at time of continuing review of these occurrences.


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11.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS
11.4.1 Potential Risks/ Discomforts
Carboplatin and Bevacizumab may each cause low blood cell counts (red blood cells, 
platelets, and/or white blood cells): A low red blood cell count (anemia) may cause 
difficulty breathing and/or fatigue. A low platelet count increases the risk of bleeding 
(such as nosebleeds, bruising, stroke, and/or digestive system bleeding). 
A low white blood cell count increases the risk of infection (such as pneumonia and/or 
severe blood infection). Infections may occur anywhere and become life-threatening. 
Symptoms of infection may include fever, pain, redness, and difficulty breathing. 
Using the study drugs together may cause side effects that are not seen when each is 
given alone.  The study drug combination may also increase the frequency and/or severity 
of the side effects listed above.
Blood draws may cause pain, bleeding, and/or bruising.  Fainting and/or development of 
an infection with redness and irritation of the vein at the site where blood is drawn may 
occur.  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. This study may involve 
unpredictable risks to the participants.
Taking part in this study can result in risks to an unborn or breastfeeding baby, and 
participants should not become pregnant, breastfeed a baby, or father a child while on this 
study.  Participants must use birth control during the study if sexually active and for 1 
month after the last dose of study drug(s).  Medically acceptable birth control types 
include approved hormonal birth control (such as birth control pills, Depo-Provera, or 
Lupron Depot), barrier methods (such as a condom or diaphragm) with spermicide, or 
intrauterine device (IUD).  Talk to the study doctor about acceptable methods of birth 
control.
11.4.2 Potential Benefits
The study drugs may help to control the disease.  Future patients may benefit from what 
is learned.  There may be no benefits for participants in this study.
11.5 RISKS/BENEFITS ANALYSIS
This study is for patients who have relapsed from standard therapies for ependymoma.  Currently, no 
standard therapy at recurrence has been established, and the impact of chemotherapy at recurrence has 
been limited. Participants may obtain better response with the combination of carboplatin and 
bevacizumab. 
11.6 CONSENT AND ASSENT PROCESS AND DOCUMENTATION
The investigational nature and objectives of this trial, the procedures and treatments involved and their 
attendant risks and discomforts, and the potential benefits will be carefully explained to the patient or 
the patient’s advocate.  This process will include a general description of the disease process, as well as 
a description of the patient’s expected clinical course. Alternative therapies will be carefully explained, 


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and outlined in the consent document. The patient will be asked to read the consent at his/her 
convenience and will be encouraged to ask questions.  
Enrollment for treatment on this study will only occur if the patient meets all eligibility criteria, is 
judged by the investigator to potentially benefit from the therapy, is able and willing to provide full 
consent, and has signed the consent document.  
The treatment consent must be signed in person prior to protocol treatment.
11.6.1 For reconsent only (NCI)
Not applicable. As of Amendment C (Version Date 04/24/2017), participants will not be enrolled at the 
Clinical Center, NIH.   
12 REGULATORY AND OPERATIONAL CONSIDERATIONS 
12.1 QUALITY ASSURANCE AND QUALITY CONTROL
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management plan will 
be developed to describe a site’s quality management.
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the site(s) for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial 
is conducted and data are generated and biological specimens are collected, documented (recorded), and 
reported in compliance with the protocol, International Council for Harmonisation Good Clinical 
Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), 
Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory 
authorities.
12.2 CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial.  The study leadership 
in conjunction with the NCI has established policies and procedures for all study group members to 
disclose all conflicts of interest and will establish a mechanism for the management of all reported 
dualities of interest.
12.3 CONFIDENTIALITY AND PRIVACY
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s). This confidentiality is extended to cover testing of biological samples and 
genetic tests in addition to the clinical information relating to participants. Therefore, the study protocol, 
documentation, data, and all other information generated will be held in strict confidence. No 


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information concerning the study or the data will be released to any unauthorized third party without 
prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional 
Review Board (IRB), and/or regulatory agencies may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) 
and pharmacy records for the participants in this study. The clinical study site will permit access to such 
records.
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements.
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at the NCI CCR. This will not include the participant’s contact or 
identifying information. Rather, individual participants and their research data will be identified by a 
unique study identification number. The study data entry and study management systems used by 
clinical sites and by NCI CCR research staff will be secured and password protected. At the end of the 
study, all study databases will be archived at the NCI CCR
To further protect the privacy of study participants, a Certificate of Confidentiality has been issued by 
the National Institutes of Health (NIH).  This certificate protects identifiable research information from 
forced disclosure. It allows the investigator and others who have access to research records to refuse to 
disclose identifying information on research participation in any civil, criminal, administrative, 
legislative, or other proceeding, whether at the federal, state, or local level. By protecting researchers 
and institutions from being compelled to disclose information that would identify research participants, 
Certificates of Confidentiality help achieve the research objectives and promote participation in studies 
by helping assure confidentiality and privacy to participants.
13 PHARMACEUTICAL INFORMATION
13.1 RATIONALE FOR IND EXEMPTION
This investigation of Bevacizumab and Carboplatin, both marketed drugs are exempt from the IND 
requirements because all the criteria for an exemption in § 312.2(b) are met:
•
The drug products are lawfully marketed in the United States. 
•
The investigation is not intended to be reported to FDA as a well-controlled study in support of a 
new indication and there is no intent to use it to support any other significant change in the 
labeling of the drug. 
•
In the case of a prescription drug, the investigation is not intended to support a significant change 
in the advertising for the drug.
•
The investigation does not involve a route of administration, dose, patient population, or other 
factor that significantly increases the risk (or decreases the acceptability of the risk) associated 
with the use of the drug product (21 CFR 312.2(b)(1)(iii)). 
•
The investigation is conducted in compliance with the requirements for review by an IRB (21 
CFR part 56) and with the requirements for informed consent (21 CFR part 50). 


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The investigation is conducted in compliance with the requirements of § 312.7 (i.e., the 
investigation is not intended to promote or commercialize the drug product).
13.2 DRUG NAME: BEVACIZUMAB
13.2.1 Appearance:   Bevacizumab is a clear to slightly opalescent, colorless to pale brown, sterile 
liquid concentrate for solution for intravenous (IV) infusion.
13.2.2 How supplied: Bevacizumab may be supplied 20-cc (400-mg) glass vials containing 16 ml 
bevacizumab, at 25 mg/ml).
13.2.3 Formulation:   Vials contain bevacizumab with phosphate, trehalose, polysorbate 20, and sterile 
water for injection (swfi), usp. Vials contain no preservative and are suitable for single use only.
13.2.4 Storage and Stability: Upon receipt of the study drug, vials are to be refrigerated at 2C– 8C  
(36F–46F) and should remain refrigerated until just prior to use.  DO NOT FREEZE.  DO 
NOT SHAKE. Vials should be protected from light.
Opened vials must be used within 8 hours.  VIALS ARE FOR SINGLE USE ONLY.  Vials used for 
1 subject may not be used for any other subject.  Once a study drug has been added to a bag of sterile 
saline, the solution must be administered within 8 hours.
13.2.5 Mechanism of Action: Bevacizumab is a recombinant, humanized monoclonal antibody which 
binds to, and neutralizes, VEGF, preventing its association with endothelial receptors, Flt-1 and 
KDR. VEGF binding initiates angiogenesis (endothelial proliferation and the formation of new 
blood vessels). The inhibition of microvascular growth is believed to retard the growth of all 
tissues.
13.2.6 Human Toxicity:  
Likely (occurring in more than 10% of patients)
Cardiovascular: Hypertension (23% to 67%; grades 3/4: 5% to 18%), thromboembolic event (≤21%; 
grades 3/4: 15%; venous thrombus/embolus: 8%; grades 3/4: 5% to 7%; arterial thrombosis 6%; grades 
3/4: 3%), hypotension (7% to 15%) 
Central nervous system: Pain (31% to 62%), headache (24% to 37%; grades 3/4: 2% to 4%), dizziness 
(19% to 26%), fatigue (≤45%; grades 3/4: 4% to 19%), sensory neuropathy (grades 3/4: 1% to 17%; in 
combination with paclitaxel: 24%)
Dermatologic: Alopecia (6% to 32%), dry skin (7% to 20%), exfoliative dermatitis (3% to 19%), skin 
discoloration (2% to 16%)
Endocrine & metabolic: Hypokalemia (12% to 16%)
Gastrointestinal: Abdominal pain (50% to 61%; grades 3/4: 8%), vomiting (47% to 52%; grades 3/4: 6% 
to 11%), anorexia (35% to 43%), constipation (29% to 40%), diarrhea (grades 3/4: 1% to 34%), 
stomatitis (25% to 32%), gastrointestinal hemorrhage (19% to 24%), dyspepsia (17% to 24%), taste 
disorder (14% to 21%), flatulence (11% to 19%), weight loss (9% to 20%), nausea (grades 3/4: 4% to 
12%) 
Hematologic: Hemorrhage (≤40%; grades 3/4: 1% to 5%), leukopenia (grades 3/4: 37%), neutropenia 
(grade 4: 6% to 27%) 


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Neuromuscular & skeletal: Weakness (57% to 74%), myalgia (8% to 19%), back pain (≤12%) 
Ocular: Tearing increased (6% to 18%)
Renal: Proteinuria (4% to 36%; grades 3/4: ≤7%; median onset: 5.6 months; median time to resolution: 
6.1 months) 
Respiratory: Upper respiratory infection (40% to 47%), epistaxis (16% to 35%), dyspnea (25% to 26%), 
rhinitis
Miscellaneous: Infection (≤55%; serious: 9% to 14%; pneumonia, catheter, or wound infections)
Common (occurring in 1 – 10% of Patients)
Cardiovascular: DVT (6% to 9%; grades 3/4: 9%), syncope (grades 3/4: 3%), intra-abdominal venous 
thrombosis (grades 3/4: 3%), cardio-/cerebrovascular arterial thrombotic event (2% to 4%), CHF (with 
prior anthracycline therapy: 4%; grades 3/4: 2%), left ventricular dysfunction (grades 3/4: 1%) 
Central nervous system: Confusion (1% to 6%), abnormal gait (1% to 5%); CNS hemorrhage (1% to 
5%; grades 3/4: 1%), reversible posterior leukoencephalopathy syndrome ([RPLS] ≤1%)
Dermatologic: Nail disorder (2% to 8%), skin ulcer (≤6%), rash desquamation (grades 3/4: 3%), wound 
dehiscence (1% to 6%), acne (≤1%) 
Endocrine & metabolic: Dehydration (grades 3/4: 3% to 10%), hyponatremia (grades 3/4: 4%) 
Gastrointestinal: Xerostomia (4% to 7%), colitis (1% to 6%), ileus (grades 3/4: 4% to 5%), gingival 
bleeding (2% to 4%), fistula (1%), gastrointestinal perforation (≤4%), gastroesophageal reflux (≤2%), 
gingivitis (≤2%), mouth ulceration (≤2%), tooth abscess (≤2%), intra-abdominal abscess (1%), gastritis 
(≤1%), gingival pain (≤1%)
Genitourinary: Polyuria/urgency (3% to 6%), vaginal hemorrhage (4%)
Hematologic: Neutropenic fever/infection (5%; grades 3 and/or 4: 4% to 5%), thrombocytopenia (5%)
Hepatic: Bilirubinemia (1% to 6%)
Neuromuscular & skeletal: Bone pain (grades 3/4: 4%), neuropathy (other than sensory: grades 3/4: 1% 
to 5%)
Ocular: Blurred vision (≤2%)
Otic: Tinnitus (≤2%), deafness (≤1%)
Respiratory: Voice alteration (5% to 9%), pneumonitis/pulmonary infiltrates (grades 3/4: 5%), 
hemoptysis (nonsquamous histology 2%), pulmonary embolism (≤1%)
Miscellaneous: Infusion reactions (<3%)
Rare but Serious (occurring in fewer than 1% of patients)
Anaphylaxis, anastomotic ulceration, angina, cerebral infarction; fistula (biliary, bladder, 
bronchopleural, duodenal, endophthalmitis, enterocutaneous, esophageal, eye inflammation, 
gastrointestinal, rectal, renal, tracheoesophageal [TE] and vaginal); hemorrhagic stroke, hypersensitivity, 
hypertensive crises, hypertensive encephalopathy, intestinal necrosis, intestinal obstruction, mesenteric 
venous occlusion, microangiopathic hemolytic anemia (when used in combination with sunitinib), MI, 
nasal septum perforation, nephrotic syndrome, pancytopenia, polyserositis, pulmonary hemorrhage, 


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pulmonary hypertension, renal failure, renal thrombotic microangiopathy, sepsis, subarachnoid 
hemorrhage, toxic anterior segment syndrome (TASS), transient ischemic attack, ureteral stricture 
wound healing complications.   
13.2.7 Clinical Pharmacokinetic Properties: 
Distribution: Vd: 46 mL/kg
Half-life elimination: ~20 days (range: 11-50 days)
Excretion: Clearance: 2.75-5 mL/kg/day
13.2.8 Administration: 
Bevacizumab will be diluted in a total volume of 100mL of 0.9% Sodium Chloride Injection, USP or as 
per institutional guidelines.  Administration will be as a continuous IV infusion.  Anaphylaxis 
precautions should be observed during study drug administration.   It is not necessary to correct dosing 
based on ideal weight.  Dose administration will follow institutional guidelines. 
If a subject experiences an infusion–associated adverse event, he or she may be premedicated for the 
next study drug infusion; however, the infusion time may not be decreased for the subsequent infusion.  
If the next infusion is well tolerated with premedication, the subsequent infusion time may then be 
decreased by 3010 minutes as long as the subject continues to be premedicated.  If a subject 
experiences an infusion-associated adverse event with the 60-minute infusion, it is recommended that all 
subsequent doses be given over 9015 minutes.  Similarly, if a subject experiences an 
infusion-associated adverse event with the 30-minute infusion, all subsequent doses should be given 
over 6010 minutes.
13.2.9 Supplier: 
Bevacizumab and Carboplatin are commercially available agents.  Both agents will be dispensed by the 
participating site’s pharmacy and will be charged to the patient’s medical insurance carrier. 
13.3 DRUG NAME:   CARBOPLATIN
13.3.1 Appearance:  Carboplatin is available as a sterile lyophilized powder.
13.3.2 How supplied: Carboplatin is commercially supplied as a sterile lyophilized powder in single-
dose vials containing 50 mg, 150 mg, or 450 mg of the drug, in equal parts by weight with 
mannitol.
13.3.3 Formulation: Immediately prior to use, each vial of carboplatin should be reconstituted with 
either sterile water for injection, D5W, or sodium chloride injection, in sufficient volume to 
produce a carboplatin concentration of 10 mg/ml.
13.3.4 Storage and Stability:  Carboplatin in unopened vials is stable for as long as three years when 
stored at temperatures of 15-30 C and when protected from light.
13.3.5 Mechanism of Action:  Carboplatin is an alkylating agent which covalently binds to DNA; 
possible cross-linking and interference with the function of DNA.
13.3.6 Human Toxicity:  The following side effects have been reported with carboplatin:
Likely (occurring in more than 10% of patients)
Central nervous system: Pain (23%)


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Endocrine & metabolic: Hyponatremia (29% to 47%), hypomagnesemia (29% to 43%), hypocalcemia 
(22% to 31%), hypokalemia (20% to 28%)
Gastrointestinal: Vomiting (65% to 81%), abdominal pain (17%), nausea (10% to 15%)
Hematologic: Myelosuppression (dose related and dose limiting; nadir at ~21 days; recovery by ~28 
days), leukopenia (85%; grades 3/4: 15% to 26%), anemia (71% to 90%; grades 3/4: 21%), neutropenia 
(67%; grades 3/4: 16% to 21%), thrombocytopenia (62%; grades 3/4: 25% to 35%)
Hepatic: Alkaline phosphatase increased (24% to 37%), AST increased (15% t19%)
Neuromuscular & skeletal: Weakness (11%)
Renal: Creatinine clearance decreased (27%), BUN increased (14% to 22%)
Common (occurring in 1-10% of patients)
Central nervous system: Neurotoxicity (5%)
Dermatologic: Alopecia (2% to 3%)
Gastrointestinal: Constipation (5%), diarrhea (6%), stomatitis/mucositis (1%), taste dysgeusia (1%)
Hematologic: Hemorrhagic complications (5%)
Hepatic: Bilirubin increased (5%)
Local: Pain at injection site
Neuromuscular & skeletal: Peripheral neuropathy (4% to 6%; up to 10% in older and/or previously-
treated patients)
Ocular: Visual disturbance (1%)
Otic: Ototoxicity (1%)
Renal: Creatinine increased (6% to 10%)
Miscellaneous: Infection (5%), hypersensitivity (2%)
Rare but serious (occurring in fewer than 1% of patients)
Anaphylaxis, anorexia, bronchospasm, cardiac failure, cerebrovascular accident, embolism, erythema, 
fever, hemolytic uremic syndrome (HUS), hyper-/hypotension, malaise, necrosis (associated with 
extravasation), nephrotoxicity, neurotoxicity, pruritus, rash, secondary malignancies, urticaria, loss of 
vision. 
Clinical Pharmacokinetic Properties:
Distribution: Vd: 16 L/kg; into liver, kidney, skin, and tumor tissue
Protein binding: 0%; platinum is 30% irreversibly bound
Metabolism: Minimally hepatic to aquated and hydroxylated compound
Half-life elimination: Terminal: 22-40 hours; Clcr >60 mL/minute: 2.5-5.9 hours
Excretion: Urine (~60% to 90%) within 24 hours


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13.3.7 Administration:   Immediately prior to use, each vial of carboplatin should be reconstituted with 
either sterile water for injection, D5W, or sodium chloride injection, in sufficient volume to 
produce a carboplatin concentration of 10 mg/ml, or as per institutional guidelines. IV infusion 
over 30 minutes: Do not use aluminum products in the mixing or administration of carboplatin 
because aluminum may react with it and cause potential loss of potency. 
13.3.8 Supplier:  Bevacizumab and Carboplatin are commercially available agents.  Both agents will be 
dispensed by the participating site’s pharmacy and will be charged to the patient’s medical 
insurance carrier. 


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14 REFERENCES
1.
Friedman, H.S., et al., Treatment of children with progressive or recurrent brain tumors with 
carboplatin or iproplatin: a Pediatric Oncology Group randomized phase II study. J Clin Oncol, 
1992. 10(2): p. 249-56.
2.
Gaynon, P.S., et al., Carboplatin in childhood brain tumors. A Children's Cancer Study Group 
Phase II trial. Cancer, 1990. 66(12): p. 2465-9.
3.
Ruda, R., M. Gilbert, and R. Soffietti, Ependymomas of the adult: molecular biology and 
treatment. Curr Opin Neurol, 2008. 21(6): p. 754-61.
4.
Brandes, A.A., et al., A multicenter retrospective study of chemotherapy for recurrent 
intracranial ependymal tumors in adults by the Gruppo Italiano Cooperativo di Neuro-
Oncologia. Cancer, 2005. 104(1): p. 143-8.
5.
Preusser, M., et al., Vascularization and expression of hypoxia-related tissue factors in 
intracranial ependymoma and their impact on patient survival. Acta Neuropathol, 2005. 109(2): 
p. 211-6.
6.
Korshunov, A., A. Golanov, and V. Timirgaz, Immunohistochemical markers for prognosis of 
ependymal neoplasms. J Neurooncol, 2002. 58(3): p. 255-70.
7.
Chan, A.S., et al., Expression of vascular endothelial growth factor and its receptors in the 
anaplastic progression of astrocytoma, oligodendroglioma, and ependymoma. Am J Surg Pathol, 
1998. 22(7): p. 816-26.
8.
Green, R.M., et al., Bevacizumab for recurrent ependymoma. Neurology, 2009. 73(20): p. 1677-
80.
9.
Stark-Vance, V., Bevacizumab and CPT-11 in the treatment of relapsed malignant glioma. 
Neuro-Oncology (Meeting Abstracts), 2005. 7(3): p. 369.
10.
Vredenburgh, J.J., et al., Phase II trial of bevacizumab and ironotecan in recurrent malignant 
gliomas. Clin Cancer Res, 2007. 13(4): p. 1253-1259.
11.
Cloughesy, T., et al., A phase II randomised, non comparative clinical trial of the effect of 
bevacizumab alone or in combination with irinotecan on 6-month progression free survival in 
recurrent, treatment refractory glioblastoma J Clin Oncol (Meeting Abstracts), 2008. 26(15S): p. 
91s.
12.
Nghiemphu, P.L., et al., Safety of anticoagulation use and bevacizumab in patients with glioma. 
Neuro Oncol, 2008. 10(3): p. 355-60.
13.
Merchant, T.E. and M. Fouladi, Ependymoma: new therapeutic approaches including radiation 
and chemotherapy. J Neurooncol, 2005. 75(3): p. 287-99.
14.
Maksoud, Y.A., Y.S. Hahn, and H.H. Engelhard, Intracranial ependymoma. Neurosurg Focus, 
2002. 13(3): p. e4.
15.
Moynihan, T.J., Ependymal tumors. Curr Treat Options Oncol, 2003. 4(6): p. 517-23.


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Version Date: 07/22/2025
49
16.
Carmichael, J., et al., Phase II study of gemcitabine in patients with advanced pancreatic cancer. 
Br J Cancer, 1996. 73(1): p. 101-5.
17.
Terri S. Armstrong, et al., Reliability and validity of the M. D. Anderson Symptom Inventory–
Spine Tumor Module. Journal of Neurosurgery: Spine, 2010. 12(4): p. 421-430.
18.
Armstrong, T.S., et al., Validation of the M. D. Anderson Symptom Inventory Brain Tumor 
Module (MDASI-BT). J Neurooncol, 2006. In press.
19.
Sathornsumetee, S., et al., Tumor Angiogenic and Hypoxic Profiles Predict Radiographic 
Response and Survival in Malignant Astrocytoma Patients Treated With Bevacizumab and 
Irinotecan. J Clin Oncol, 2008. 26(2): p. 271-278.
20.
Armstrong, C., Mollman, J., Corn, B.W., Alavi, J., Grossman, M., Effects of radiation therapy on 
adult brain behavior:  evidence for a rebound phenomenon in a Phase I trial. Neurology, 1993. 
43(1961-1965).
21.
Patlak, C.S., R.G. Blasberg, and J.D. Fenstermacher, Graphical evaluation of blood-to-brain 
transfer constants from multiple-time uptake data. J Cereb Blood Flow Metab, 1983. 3(1): p. 1-7.
22.
Dennie, J., et al., NMR imaging of changes in vascular morphology due to tumor angiogenesis. 
Magn Reson Med, 1998. 40(6): p. 793-9.


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15 APPENDICES
15.1 KARNOFSKY PERFORMANCE STATUS AND NEUROLOGICAL FUNCTION
Patient's performance status and Neurologic Functions will be graded according to the following scales:
Karnofsky Performance Status
KPS 100
Normal; no complaints; no evidence of disease
KPS   90
Able to carry on normal activity; minor signs or symptoms of disease
KPS   80
Normal activity with effort; some sign or symptoms of disease
KPS   70
Cares for self; unable to carry on normal activity or do active work
KPS   60
Requires occasional assistance, but is able to care for most personal needs
KPS   50
Requires considerable assistance and frequent medical care
KPS   40
Disabled; requires special care and assistance
KPS   30
Severely disabled; hospitalization is indicated, although death no imminent
KPS   20
Very sick; hospitalization necessary; active support treatment is necessary
KPS   10
Moribund; fatal processes progressing rapidly
KPS     0
Dead
Neurologic Function
+2
Definitely Better
+1
Possibly Better
 0
Unchanged
-1
Possibly Worse
-2
Definitely Worse
 B
Baseline


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15.2 MD ANDERSON SYMPTOM INVENTORY FOR BRAIN TUMORS (MDASI-BT)


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15.3 MD ANDERSON SYMPTOM INVENTORY FOR SPINE TUMORS (MDASI-SP)


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15.4 MRI ACQUISITION PROTOCOL (OPTIONAL PROCEDURE)
Acquisition protocol
•
Auto-align scout
                          (2 min)
•
Pre-contrast T1                                            (2 min)
•
High resolution T2 Volume                         (5 min)
•
FLAIR                                                         (3 min)
•
BOLD/ASL (optional)                                (14 min)
•
Pre-contrast variable flip angle T1 maps     (1 min)
•
Permeability (T1 dynamic)
                          (6 min)
•
Post-contrast variable flip angle T1 maps    (1 min)
•
Diffusion Tensor Imaging
                      (7 min)
•
Perfusion (T2/T2*)                                      (3 min)
•
3D Post-contrast                                          (5 min)
•
Post-contrast T1                                           (2 min)          
•
MR Spectroscopy   (optional)                      (8 min)        
Our proposed acquisition protocol is described in the box, and consists of approximately 65 minutes of 
imaging time (typically 90 to 120 minutes of time that the subject is in the magnet, counting setup and 
scan delays). Each of these datasets will be analyzed using tools that are published and well known in 
the neuroradiologic community. A brief outline of our analysis techniques follows:
Dynamic Contrast Enhanced – Magnetic Resonance Imaging (DCE-MRI)
DCE-MRI will be used to monitor the effects on tumor vasculature through parameters reflecting both 
tumor perfusion and permeability. This sequence uses a bolus injection of 0.1 mmol/kg of Gd-DTPA. 
Data will be analyzed using the standard Tofts/Kermode model with the typical approach of Patlak et al 
[21]. 
T2-weighted contrast-enhanced MRI or perfusion weighted imaging (PWI)
A second dose of Gd-DTPA (typically 0.1-0.2 mmol/kg) is administered for first-pass T2/T2-weighted 
imaging. We use a combination gradient-echo/spin echo approach to allow estimation of tumor vascular 
size based on the equations in the box. As shown in our earlier work [22], this can be used to estimate 
average vessel diameter, which we believe may change with effective anti-angiogenic therapy. This 
approach also provides estimates of cerebral blood volume (CBV), cerebral blood flow (CBF), mean 
transit time (MTT), and perfusion efficiency (1/MTT).
Diffusion Tensor Imaging (DTI)
We will measure the full water self-diffusion tensor before and after treatment in this patient population. 
The tensor fractional anisotropy (FA) will be calculated and can be used to define white matter tract 
directions and tumor invasion. Apparent diffusion coefficient (ADC) maps will also be calculated. 
Simultaneous Blood Oxygenation Level Dependent (BOLD) and Arterial Spin Labeling (ASL) Imaging 
(Optional)
Combined BOLD/ASL imaging is a non-contrast approach to simultaneously measuring cerebral blood 
flow (ASL) and cerebral metabolic rate of oxygen consumption (BOLD) (Wong EC, NMR Biomed, 


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1997, 10:237). Our standard approach for this is to use a pulsed ASL sequence followed by a single-
shot, gradient echo (GE) echo planar imaging acquisition. Two echoes are acquired, short echo (TE = 11 
ms) for ASL (CBF maps) and longer echo (TE = 40 ms) for BOLD. Patients are administered room air 
and 100% oxygen at varying time points throughout the scan. The gas paradigm is as follows: baseline 
room air (8 min) – 100% O2 (4 min) – washout room air (2 min) at a constant ~35 L/min flow rate. 
Blood oxygen levels are continuously monitored throughout the scan with a pulse oximeter. 
MRS (Magnetic resonance spectroscopy) - Optional Procedure
Chemical shift imaging (CSI) is performed to obtain spatial distribution of metabolites (NAA, choline, 
creatine, lactate, myoinositol, mobile lipids) in tumors and normal brain tissue. An adiabatic LASER 
sequence (Andronesi et al., 2009) with improved localization and excitation profile is used. Typical 
parameters include TR = 1.5 s, TE = 45 ms, weighted phase encoding, TA = 5 min, and a final voxel 
size of 5x5x15 mm3.  Optimization of shimming and water suppression is performed prior of CSI which 
needs 3 min, making the total time 8 min.  Metabolite maps are calculated using LCModel fitting 
software (Provencher et al., 1993). 


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15.5 RELIANCE AGREEMENT
Agreement between
Institution Name
and
THE NATIONAL INSTITUTES OF HEALTH
To Rely on an NIH IRB
Pursuant to 45 C.F.R. 46.114, the National Institutes of Health (NIH) and Institution Name are entering 
into this agreement for NIH to conduct Institutional Review Board (IRB) review of the research protocol 
or activities identified below, which are jointly conducted by NIH and Institution B.
Name of Institution Providing IRB Review (Institution A): National Institutes of Health
Federal Wide Assurance (FWA) # 00005897, expiration date 08/28/2018
IRB Number: IRB00000001
Name of Institution Relying on the Designated IRB (Institution B): Institution Name
FWA #__________, expiration date __________
Institution B will rely on the designated NIH IRB for review and continuing oversight of its human 
subjects research described below.  This agreement is limited to the following specific protocol(s) or 
research activity:
Name of Research Project/Activity:  Phase II trial of Carboplatin and Bevacizumab for the 
Treatment of Recurrent Low-grade and Anaplastic Supratentorial, Infratentorial and Spinal 
Cord Ependymoma in Adults: A Multi- Center Trial
Protocol Number(s):
Name of Principal Investigator (NIH):
Mark Gilbert, MD 
Name of Investigator(s) (Institution B):       PI Name
Name of NIH Principal Investigator’s Institute or Center: National Cancer Institute
 
The review performed by the NIH IRB will meet the human subject protection requirements of Institution 
B’s OHRP-approved FWA.  The protocol(s) reviewed by the NIH IRB must include a description of the 


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research to be conducted by Institution B.  The NIH IRB will follow written procedures for reporting its 
findings and actions to appropriate officials at Institution B.   Relevant minutes of IRB meetings will be 
made available to Institution B upon request.  Institution B remains responsible for ensuring compliance 
with the IRB’s determinations and with the terms of its OHRP-approved FWA and for providing local 
context.  
Both Institutions will maintain current copies of the IRB approved protocol.  NIH will conduct its 
portion of this joint research in accord with the terms and conditions of its OHRP-approved FWA.  
Institution B will conduct its portion of this joint research in accord with the terms and conditions of its 
OHRP-approved FWA.  This Agreement will be kept on file at both Institutions and will be available to 
OHRP upon request.
The NIH IRB retains responsibility for compliance with regulatory requirements under 45 C.F.R. Part 
46 and 21 C.F.R. 56 (as applicable) related to the administration and operation of the IRB.  These 
include, for example, following written procedures and maintaining records in accord with 45 C.F.R. 
parts 46.103 and 115, respectively.  Institution B agrees that the NIH IRB may suspend or terminate 
approval of research that is not conducted in accordance with the NIH IRB’s requirements or that is 
associated with unexpected serious harm to subjects pursuant to 45 C.F.R. 46.113.  The NIH IRB will 
notify Institution B of any non-compliance, or suspensions, or terminations of this research in a timely 
manner. 
Institution B will ensure that before implementing a change to an NIH IRB-approved protocol its 
investigator will obtain NIH IRB approval for the change (unless the change is designed to eliminate an 
apparent immediate hazard to subjects), pursuant to 45 C.F.R. 46.103.  Institution B retains 
responsibility, pursuant to 45 C.F.R. Part 46, including subsections103 and 113, to promptly report to 
the NIH IRB, appropriate institutional officials, and the HHS or NIH agency head any unanticipated 
risks to subjects or others, and any serious or continuing noncompliance with 45 C.F.R. Part 46 or the 
IRB’s requirements or determinations.  The NIH IRB may also make these reports, but doing so does 
not relieve Institution B of the obligation to report to institutional officials and HHS or NIH officials. 
This Agreement is effective on the date that the last official signs and may be terminated by either party 
at any time.  If the Agreement is terminated prior to the completion of the research, Institution B will 
need to obtain alternative IRB review.


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Signatory Officials:
X_____________________________
Institution Name
Name: ________________________
Title:
________________________
Address: _______________________
______________________________
______________________________
Phone:  ________________________
Fax:
 ________________________
E-mail: ________________________
Date: __________________________
X_____________________________
National Institutes of Health
Charlotte Holden, JD
Deputy Director, Office of Human Subjects
Research, National Institutes of Health
10 Center Drive, Room 2C146
Bethesda, Maryland 20892, MSC 1154
Phone: 301-402-3444 
Fax:
301-402-3443
E-mail:  HoldenC@od.nih.gov 
Date: __________________________


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15.6 LOCAL PHYSICIAN AGREEMENT  
I am a licensed physician in the state of ___________________.  I am credentialed in the facility 
__________________________________________(list name and address of facility) where I practice 
medicine to prescribe chemotherapeutic agents.
I agree to administer the therapy as written in the protocol and follow other protocol guidance.
I understand that my role in the study is limited to standard medical care practices such as: prescribing 
and administering therapy, performing physical exams, obtaining blood work as outlined in the protocol, 
obtaining research specimens as outlined in the protocol, and sending all documentation of drug 
administration and other related medical record documents to the (Enrolling Site Name) in a timely 
manner.
I agree to maintain the privacy and confidentiality of all information received or developed in 
connection with this protocol.  
Protocol Title:
Phase II trial of Carboplatin and Bevacizumab for the Treatment of Recurrent Low-grade and 
Anaplastic Supratentorial, Infratentorial and Spinal Cord Ependymoma in Adults: A Multi- 
Center Trial
_______________________________________           
___________________     
Signature of Physician
Date
_________________________________________
Name of Physician (printed or typed)


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15.7 LOCAL PHYSICIAN INFORMATION
Physician Name 
Facility Name
Facility Address
Facility Contact 
Number
Alissa Thomas, MD
University of Vermont 
Medical Center
111 Colchester Ave, 
Burlington, VT  05401
802-847-8400


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15.8 CCR PROBLEM REPORT FORM 
NCI Protocol #: 
Protocol Title: 
Report version: (select one)
____Initial Report 
____Revised Report
____Follow-up 
Site Principal Investigator:
 
Date of problem:    
Location of problem: (e.g.,  patient’s home, doctor’s 
office )
Who identified the problem? (provide role (not name of person): nurse, investigator, monitor, etc…)
Brief Description of Subject (if 
applicable) 
(Do NOT include personal identifiers) 
Sex:  ___ Male  ___ Female Age:  
 ___ Not applicable (more than subject one is involved)
Diagnosis under study:  
Name the problem: (select all that apply)  
[  ] Adverse drug reaction  
[  ] Abnormal lab value  
[  ] Death  
[  ] Cardiac Arrest/ code 
[  ] Anaphylaxis 
[  ] Sepsis/Infection  
[  ] Blood product reaction
[  ] Unanticipated surgery/procedure  
[  ] Change in status (e.g. increased level of care required)   
[  ] Allergy (non-medication) 
[  ] Fall 
[  ] Injury/Accident (not fall) 
[  ] Specimen collection issue  
[  ] Informed consent issue  
[  ] Ineligible for enrollment  
[  ] Breach of PII 
[  ] Tests/procedures not performed on schedule 
[  ]  Other, brief  1-2 word description: _________________________
Detailed Description of the problem: (Include any relevant treatment, outcomes or pertinent history):
*Is this problem unexpected? (see the definition of unexpected in the protocol))  __YES __NO  Please 
explain:


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 *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 NIH 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:  


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15.9 TISSUE COLLECTION SHIPPING FORM
A Tissue Collection Shipping Form (below) listing pathology materials being submitted for Tissue 
Evaluation completed by the local pathologist must be included in the pathology submission. These 
forms must include the protocol number, patient case number, and the patient’s initials.
Tissue evaluation is highly recommended for every case. Send pathology material by overnight mail 
directly to Dr. Ken Aldape:
Ken Aldape, MD
Laboratory of Pathology
Center for Cancer Research
National Cancer Institute 
Building 10, Room 2S235
Bethesda, MD 20892-1500
Ph: 301-480-5010
kenneth.aldape@nih.gov
•
Include on the form the name, telephone number, and fax number of the person to notify with the 
results of the tissue evaluation.
•
Shipments must be made Monday through Thursday.
•
Notify Dr. Aldape by email on or before the day of submission: (1) that a case is being submitted 
for review; (2) the name of the contact person; (3) when to expect the sample; and (4) the 
overnight shipping carrier and tracking number.
•
Dr. Aldape will email the appropriate contact person from the submitting institution with the 
results and will fax a copy of the completed form to the institution.
When Dr. Aldape has completed testing of the tumor tissue, the remaining tissue will be sent back to the 
submitting institution.
Submission of frozen tissue is strongly encouraged in order to maximize the information gained from 
this trial. When available, frozen tissue should be sent in dry ice to Dr. Aldape at the above address. 
Upon receipt, the specimen is labeled with the protocol number and the patient’s case number only. 
The specimens will be stored for an indefinite period of time. If at any time the patient withdraws 
consent to store and use the specimens, the material will be returned to the institution that submitted it.


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Tissue Collection Shipping Form
**PLEASE USE ONE FORM PER PATIENT**
CC 16C0009 (Prior CERN09-02): Phase II trial of Carboplatin and Bevacizumab for the 
Treatment of Recurrent Low-grade and Anaplastic Supratentorial, Infratentorial and Spinal 
Cord Ependymoma in Adults: A Multi- Center Trial
DATE SHIPPED:   
SITE NAME:  
INVESTIGATOR’S NAME:   
PATIENT’S INITIALS:  
PATIENT’S ID NUMBER:  
Tissue sample:
Collection Date:  
Number of paraffin blocks:  
Number of unstained slides (15 slides preferred if block is not available):  
Please remember all samples for a patient must be shipped within 28 days of collection and to label 
samples as instructed in the protocol. 
Name of person completing this form:  
Telephone number:  
Signature:  
Date:  
SHIP TO:
Ken Aldape, M.D. 
Laboratory of Pathology
Center for Cancer Research
National Cancer Institute 
Building 10, Room 2S235
Bethesda, MD 20892-1500
Ph: 301-480-5010
**Note: Prior to shipping the samples, please contact Dr. Aldape by email on or before the day of to 
ensure appropriate tracking and receipt of the sample. Shipment must be made Mondays through 
Thursdays by overnight shipment to ensure timely arrival of samples during working days.

ICF_001.pdf: 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
INSTITUTE: 
National Cancer Institute 
STUDY NUMBER: 
16-C-0009 
PRINCIPAL INVESTIGATOR: 
Mark Gilbert, M.D. 
STUDY TITLE:  
Phase II Trial of Carboplatin and Bevacizumab for the Treatment of Recurrent 
Low-grade and Anaplastic Supratentorial, Infratentorial and Spinal Cord Ependymoma 
in Adults: A Multi-Center Trial 
 
Continuing Review Approved by the IRB on 08/07/17 
Amendment Approved by the IRB on 04/07/16 (B) 
 
Date posted to web: 08/22/17 
Standard 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
 
 
 
INTRODUCTION 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
First, we want you to know that: 
Taking part in NIH research is entirely voluntary.  
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  However, 
to receive care at the NIH, you must be taking part in a study or be under evaluation for 
study participation. 
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future. 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your NIH doctors or research team before you agree 
to the study. 
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional.   
Why is this study being done?  
This is an investigational study.  Carboplatin is designed to interfere with the growth of cancer 
cells by stopping cell division, which may cause the cells to die. Carboplatin is FDA approved 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 16-C-0009 
CONTINUATION: page 2 of 13 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
and commercially available for the treatment of advanced ovarian cancer.  Bevacizumab is 
designed to prevent or slow down the growth of cancer cells by blocking the growth of blood 
vessels. Bevacizumab is FDA approved and commercially available for the treatment of 
glioblastoma multiforme (a type of brain tumor).   The use of these drugs in combination in 
ependymoma is investigational.  At this time, this combination is only being used in research. 
The goal of this clinical research study is to learn if the combination of bevacizumab and 
carboplatin can help to control recurrent ependymoma.  The safety of this drug combination will 
also be studied. 
Why are you being asked to take part in this study? 
You are being asked to take part in this study because you have a brain or spinal cord tumor 
called an ependymoma that is recurrent (has returned after treatment). Clinical trials include only 
patients who choose to take part. Your participation in this study is entirely voluntary. 
How many people will take part in this study?  
Up to 46 participants will take part in this multicenter study.  Up to 13 participants will be 
enrolled at NCI. 
Description of Research Study 
What will happen if I take part in this research study?   
Before you begin the study 
You will have screening tests to help the doctor decide if you are eligible to take part in this 
study. If some of these tests have been performed within the past 14 days, they may not need to 
be repeated. These tests include medical history, physical exam, routine blood and urine tests, 
CT scan or MRI of your brain, CT scan or x-ray of your chest, an EKG and you will also 
complete a questionnaire about your quality of life. Tumor tissue left over from a previous 
procedure (such as disease diagnosis slides or tumor tissue leftover from a previous biopsy) will 
be collected to confirm your diagnosis and to test for biomarkers. 
During the study 
If you are found to be eligible to take part in this study you will receive carboplatin by vein over 
30 minutes on Day 1 of each 28-day cycle.  You will receive bevacizumab by vein over 90 
minutes on Days 1 and 15 of each cycle. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 16-C-0009 
CONTINUATION: page 3 of 13 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Study Visits 
Every week: 
• Blood (about 1-2 teaspoons) will be drawn for routine tests. 
Every 4 weeks: 
• Urine will be collected to check your kidney function. 
• You will be asked about any drugs you may be taking and if you have had any side 
effects. 
Every 8 weeks: 
• Your medical history will be recorded. 
• 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 complete the quality of life questionnaire.   
• You will have an MRI scan or CT scan of the head and/or spine to check the status of the 
disease. 
At any time during the study, extra tests may be performed if the doctor thinks they are needed 
for your safety.  The study doctor will tell you more about any extra tests. 
How long will I be in this study? 
You will receive up to 6 cycles of the study drug combination.  You will be taken off study early 
if the disease gets worse or you experience intolerable side effects.    
If the disease has not gotten worse after 6 cycles of receiving the study drug combination, you 
will be able to continue receiving bevacizumab alone for as long as the doctor thinks it is in your 
best interest.  You will continue to follow the same study visit schedule detailed above.   
When you are finished taking the drugs 
After you stopped taking the study drugs, the study staff will call you every 3 months to check 
how you are doing.  Each phone call will take about 5 minutes. 
Birth Control 
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. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 16-C-0009 
CONTINUATION: page 4 of 13 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Birth Control Specifications:  If you are able to become pregnant or father a child, you must use 
acceptable birth control while on study and for 1 month after the last dose of study drug(s).  
Medically acceptable birth control types include approved hormonal birth control (such as birth 
control pills, Depo-Provera, or Lupron Depot), barrier methods (such as a condom or diaphragm) 
with spermicide, or intrauterine device (IUD).  Talk to the study doctor about acceptable 
methods of birth control. 
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. 
Alternative Approaches or Treatments 
What other choices do I have if I do not take part in this study?  
Instead of being in this study, you have these options: 
• You may choose to receive other treatments for recurrent ependymoma (such as 
chemotherapy [such as temozolomide], radiation therapy, or a combination of both) 
• Taking part in another study, if available. 
• Getting comfort care, also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not treat 
the cancer directly.  Instead, it tries to improve how you feel.  Comfort care tries to keep 
you as active and comfortable as possible. 
Please talk to your doctor about these and other options. 
Risks or Discomforts of Participation 
What side effects or risks can I expect from being in this study?  
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.  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 cause death. 
Tell the study staff about any side effects that you may have, even if you do not think they are 
related to the study drugs. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 16-C-0009 
CONTINUATION: page 5 of 13 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Carboplatin and bevacizumab each may cause low blood cell counts (red blood cells, platelets, 
and/or white blood cells): 
• A low red blood cell count (anemia) may cause difficulty breathing and/or fatigue. You 
may need a blood transfusion. 
• A low platelet count increases your risk of bleeding (such as nosebleeds, bruising, stroke, 
and/or digestive system bleeding). You may need a platelet transfusion. 
• A low white blood cell count increases your risk of infection (such as pneumonia and/or 
severe blood infection). Infections may occur anywhere and become life-threatening. 
Symptoms of infection may include fever, pain, redness, and difficulty breathing. 
Carboplatin Side Effects 
Likely (occurring in more than 20% of patients) 
• abnormal salts, minerals, 
and/or acids in the blood 
(possible weakness, 
swelling, fatigue, low blood 
pressure, organ failure, heart 
problems, changes in mental 
status, and/or seizure) 
• vomiting 
• low blood counts 
(red, white, platelets) 
• pain 
• abnormal liver tests 
(possible liver damage) 
• abnormal kidney test 
(possible kidney damage 
 
Less Likely (occurring in 3-20% of patients) 
• nerve damage (possible 
numbness, pain, and/or loss 
of motor function) 
• hair loss (partial or total) 
• abdominal pain  
• nausea 
• constipation 
• diarrhea 
• abnormal taste 
• mouth blisters/sores 
(possible difficulty 
swallowing) 
• weakness 
• abnormal liver tests 
(possible yellowing of 
the skin and/or eyes) 
• allergic reaction 
• infection  
 
Rare but serious (occurring in fewer than 3% of patients) 
• high blood pressure 
• low blood pressure (possible 
dizziness/fainting) 
• heart failure 
• stroke 
• dehydration 
• multiple blood clots 
(possible organ 
dysfunction and/or 
failure) 
• reduced blood supply 
to the arms and legs 
• visual problems 
• difficulty breathing due 
to narrowing of the 
airways  
• tissue death at the 
injection site caused by 
drug leakage 
• life-threatening allergic 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 16-C-0009 
CONTINUATION: page 6 of 13 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
• blood vessel blockage  
• anemia due to destruction of 
red blood cells 
• blindness 
• hearing loss 
reaction (such as 
difficulty breathing, low 
blood pressure, and/or 
organ failure) 
Carboplatin may cause you to develop another type of cancer (such as skin cancer and lung 
cancer). 
Bevacizumab Side Effects 
Likely (occurring in more than 20% of patients) 
• high blood pressure 
 
• blood clots in a vein 
(possible pain, swelling, 
and/or redness)  
• pain 
• nerve damage (loss of 
sensory function) 
• headache 
• dizziness 
• fatigue 
• hair loss (partial or total) 
• abdominal pain 
• loss of appetite 
• constipation 
• diarrhea 
• mouth blisters/sores 
(possible difficulty 
swallowing) 
• digestive system 
bleeding 
• upset stomach 
• vomiting 
• abnormal taste 
• failure of the ovaries to 
produce hormones, 
which may be permanent 
(possible stopped 
menstrual cycle) 
• bleeding  
• nosebleed 
• low white blood cell 
counts 
• difficulty breathing 
• weakness 
• abnormal kidney test 
(possible kidney damage) 
 
Less Likely (occurring in 3-20% of patients) 
• blood clots in an artery 
(possible organ damage 
such as stroke and/or 
heart attack) 
• low blood pressure 
(possible 
dizziness/fainting)  
• heart failure 
• fainting 
• bleeding in the brain 
and/or spinal cord 
• stroke 
• shedding and scaling of 
the skin (possible fatal 
loss of bodily fluids) 
• change of skin color 
• low blood levels of 
sodium (possible 
headache, confusion, 
seizures, and/or coma)  
• dehydration 
• gas 
• dry mouth  
• hole in the intestines 
• inflammation or paralysis 
of the intestines  
• weight loss 
• nausea  
• uterine and/or vaginal 
bleeding  
• low platelet cell counts 
• pain (back/muscle) 
• voice changes 
• runny nose 
• lung inflammation 
(possible difficulty 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 16-C-0009 
CONTINUATION: page 7 of 13 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
• difficulty walking 
• dry skin 
• skin sores 
• opening of a wound 
(possibly leaking 
contents into the 
abdomen)  
• bleeding gums  
breathing) 
• infusion reaction 
(possible chills and/or 
hives) 
 
 
Rare but serious (occurring in fewer than 3% of patients) 
• severe heart problems 
• heart attack 
• chest pain due to heart 
trouble 
• severe increase in blood 
pressure (possible stroke) 
• brain injury that may be 
reversible (possible 
headache, confusion, 
seizures, and/or vision 
loss)  
• decreased brain function 
due to high blood 
pressure 
• decreased blood flow to 
part of the bowel 
(possibly causing death 
of tissue) 
• bleeding around the brain 
• temporary stroke 
symptoms 
• intestinal blockage 
• stomach and/or small 
intestine ulcer 
• vein blockage in the 
abdomen 
• hole in the gall bladder 
(possible abdominal 
pain, gall stones, nausea, 
and/or infection) 
• hole in the bladder  
• destruction of red blood 
cells  
• low red blood cell counts 
• bone destruction 
(including destruction of 
the jaw bone) 
• inflammation inside the 
eye 
• blurry vision  
• increased pressure in the 
eye (possible pain and/or 
blurry vision) 
• detached retina (possible 
partial blindness) 
• deafness  
• kidney failure 
• decreased kidney 
function (possible kidney 
failure) 
• coughing up blood 
• increased blood pressure 
in the lungs (possible 
difficulty breathing 
and/or heart failure) 
• blockage in the lung 
(possible pain, shortness 
of breath, and/or failure 
to breathe)  
• abnormal hole inside the 
nose 
• life-threatening allergic 
reaction (such as 
difficulty breathing, low 
blood pressure, and/or 
organ failure) 
• wound healing problems 
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 16-C-0009 
CONTINUATION: page 8 of 13 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Bevacizumab may rarely cause an abnormal opening that develops between one area of the body 
and another (for example, an abnormal connection and opening in one or more places between 
the trachea [breathing tube] and esophagus, which may interfere with swallowing, digestion, 
and/or choking).  This may result in death.  
Rarely (in about 1-2% of patients), bevacizumab may cause bleeding in the brain in patients who 
have received bevacizumab for the treatment of primary brain tumors. You will be monitored for 
this complication and removed from the study if this were to occur. 
If you are taking Coumadin (warfarin) or other blood-thinning drugs, you may be at higher risk 
of blood clots and/or bleeding. 
Using the study drugs together may cause side effects that are not seen when each is given 
alone. The study drug combination may also increase the frequency and/or severity of the side 
effects listed above. 
Other Risks 
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. 
This study may involve unpredictable risks to the participants. 
Potential Benefits of Participation 
What possible benefits can I expect from taking part in this study? 
The aim of this study is to determine a safe dose and to see if this experimental treatment will 
cause your tumors to shrink.   We do not know if you will receive personal medical benefit from 
taking part in this study.  These potential benefits could include shrinking of your tumor or 
lessening of your symptoms, such as pain, that are caused by the cancer.  Because there is not 
much information about the drug’s effect on your cancer, we do not know if you will benefit 
from taking part in this study, although the knowledge gained from this study may help others in 
the future who have cancer.   


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 16-C-0009 
CONTINUATION: page 9 of 13 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Research Subject’s Rights 
What are the costs of taking part in this study?  
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 
• 
You will receive study treatment at no charge to you. This may include 
surgery, medicines, laboratory testing, x-rays or scans done at the 
Clinical Center, National Institutes of Health (NIH), or arranged for you 
by the research team to be done outside the Clinical Center, NIH if the 
study related treatment is not available at the NIH.  
• 
There are limited funds available to cover the cost of some tests and 
procedures performed outside the Clinical Center, NIH.  You may have 
to pay for these costs if they are not covered by your insurance company. 
• 
Medicines that are not part of the study treatment will not be provided or 
paid for by the Clinical Center, NIH. 
• 
Once you have completed taking part in the study, medical care will no 
longer be provided by the Clinical Center, NIH.  
• 
You will not be paid for taking part in this study. 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage.    You 
can print a copy of the “Clinical Trials and Insurance Coverage” information from this Web site. 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy. 
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. 
• National Cancer Institute Institutional Review Board 
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.  


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 16-C-0009 
CONTINUATION: page 10 of 13 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Can I stop taking part in this study? 
Yes. You can decide to stop at any time.  If you decide to stop for any reason, it is important to 
let your study doctor know as soon as possible so you can stop safely. If the carboplatin and 
bevacizumab are stopped, you can decide whether or not to let your study doctor continue to 
provide medical information to the organization running the study.   
Your doctor may decide to stop your therapy for the following reasons: 
• if your disease comes back during treatment 
• if you become pregnant while on study therapy 
• if you have side effects from the treatment that your doctor thinks are too severe 
In this case, you will be informed of the reason therapy is being stopped. 
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. 
Conflict of Interest 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a Protocol Review Guide.  You may ask your research 
team for a copy of the Protocol Review Guide or for more information.  Members of the research 
team who do not work for NIH are expected to follow these guidelines but they do not need to 
report their personal finances to the NIH. 
 
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest.  
Use of Specimens and Data for Future Research 
To advance science, it is helpful for researchers to share information they get from studying 
human samples.  They do this by putting it into one or more scientific databases, where it is 
stored along with information from other studies. A researcher who wants to study the 
information must apply to the database and be approved.  Researchers use specimens and data 
stored in scientific databases to advance science and learn about health and disease.   


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 16-C-0009 
CONTINUATION: page 11 of 13 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
We plan to keep some of your specimens and data that we collect and use them for future 
research and share them with other researchers. We will not contact you to ask about each of 
these future uses.  These specimens and data will be stripped of identifiers such as name, address 
or account number, so that it may be used for future research on any topic and shared broadly for 
research purposes.  Your specimens and data will be used for research purposes only and will not 
benefit you.  It is also possible that the stored specimens and data may never be used.  Results of 
research done on your specimens and data will not be available to you or your doctor.  It might 
help people who have cancer and other diseases in the future.   
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers. 
Optional Procedures for the Study 
If you agree, blood (about 1 teaspoon) will be drawn for biomarker testing before you begin 
receiving the study drugs and then every 8 weeks while you are on study. Biomarkers are 
chemical "markers" in the blood that may be related to your reaction to the study drug. 
There are no benefits to you for taking part in the optional procedures.  You may stop taking part 
at any time.  The optional procedure will be performed at no cost to you. 
You do not have to agree to take part in the optional procedures in order to receive treatment on 
this study. 
Optional Procedure Risks 
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. 
Circle your choice of “yes” or “no” for each of the following optional procedures: 
Do you agree to have extra blood drawn for biomarker testing? 
YES 
 
NO 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER: 16-C-0009 
CONTINUATION: page 12 of 13 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
OTHER PERTINENT INFORMATION 
1. 
Confidentiality.  When results of an NIH research study are reported in medical journals 
or at scientific meetings, the people who take part are not named and identified.  In most cases, 
the NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance. 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations. 
2. 
Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-
term medical care for any injury resulting from your participation in research here.  In general, 
no long-term medical care or financial compensation for research-related injuries will be 
provided by the National Institutes of Health, the Clinical Center, or the Federal Government.  
However, you have the right to pursue legal remedy if you believe that your injury justifies such 
action. 
3. 
Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research studies at 
the National Institutes of Health.  Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines. 
4. 
Problems or Questions.  If you have any problems or questions about this study, or 
about your rights as a research participant, or about any research-related injury, contact the 
Principal Investigator, Mark Gilbert, M.D., Building 82, Room 235A, Telephone:  240-760-
6023. You may also call the Clinical Center Patient Representative at 301-496-2626. If you have 
any questions about the use of your specimens or data for future research studies, you may also 
contact the Office of the Clinical Director, Telephone:  240-760-6070. 
5. 
Consent Document.  Please keep a copy of this document in case you want to read it 
again. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER: 16-C-0009 
CONTINUATION: page 13 of 13 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby consent to 
take part in this study. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby give 
permission for my child to take part in this 
study.   
(Attach NIH 2514-2, Minor’s Assent, if 
applicable.) 
 
  
  
 
 
 
Signature of Adult Patient/ 
Legal Representative 
Date 
Signature of Parent(s)/ Guardian Date 
 
 
Print Name 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to 
participate in the study. 
 
  
  
 
Signature of Parent(s)/Guardian 
Date 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM AUGUST 07, 2017 THROUGH AUGUST 06, 2018.  
 
 
 
 
 
 
 
 
Signature of Investigator 
Date 
Signature of Witness 
Date 
 
 
Print Name 
 
 
Print Name 
 

ICF_003.pdf: 
Standard Model Consent 
Phase II trial of carboplatin and bevacizumab for the treatment of recurrent low-grade 
and anaplastic supratentorial, infratentorial and spinal cord ependymoma in adults 
Subtitle: Phase II Ependymoma 
Study 16C0009 
Version - Amendment D, May 7, 2019 
IRB approval - June 18, 2019 


Amendment D 
May 07, 2019 
Page 1 of 11 
Informed Consent 
INFORMED CONSENT/AUTHORIZATION FOR PARTICIPATION IN RESEARCH 
Phase II trial of carboplatin and bevacizumab for the treatment of recurrent low-grade and 
anaplastic supratentorial, infratentorial and spinal cord ependymoma in adults 
Subtitle: Phase II 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 
and authorization 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 called 
an ependymoma that is recurrent (has returned after treatment). 
PURPOSE OF STUDY 
The goal of this clinical research study is to learn if the combination of bevacizumab and 
carboplatin can help to control recurrent ependymoma.  The safety of this drug combination will 
also be studied. 
DESCRIPTION OF STUDY 
Study Drugs 
Carboplatin is designed to interfere with the growth of cancer cells by stopping cell division, 
which may cause the cells to die. 
Bevacizumab is designed to prevent or slow down the growth of cancer cells by blocking the 
growth of blood vessels. 
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 
some of these tests have been performed within the past 14 days, they may not need to be repeated.  
The following tests and procedures will be performed: 
•
Your complete medical history will be recorded, including any drugs you may have taken
and/or be taking.
•
You will have a complete physical exam, including measurement of your height, weight,
and vital signs (heart rate, temperature, breathing rate, and blood pressure).


   
Amendment D 
May 07, 2019 
Page 2 of 11 
• You will be asked how well you are able to perform the normal activities of daily living 
(performance status). 
• You will have a neurological exam (tests to check the functioning of your nervous system, 
including tests of your balance and reflexes).  You will also be asked how well you are able 
to perform tasks like remembering, communicating, and following simple instructions.  
This should take about 20 minutes to complete. 
• Blood (about 2-3 tablespoons) will be drawn for routine tests.  This routine blood draw will 
also include a pregnancy test if you are able to become pregnant.  To take part in this study, 
you must not be pregnant. 
• Blood (about 1 teaspoon) will be drawn to check your blood's ability to clot. 
• Urine will be collected to check your kidney function. 
• You will have a magnetic resonance imaging (MRI) scan or computed tomography (CT) 
scan of the head and/or spine to check the status of the disease.   
• You will complete a questionnaire about your quality of life.  The questionnaire should take 
about 5 minutes to complete. 
• Tumor tissue left over from a previous procedure (such as disease diagnosis slides or tumor 
tissue leftover from a previous biopsy) will be collected to confirm your diagnosis and to 
test for biomarkers. 
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, you will receive carboplatin by vein over 
30 minutes on Day 1 of each 28-day cycle.  You will receive bevacizumab by vein over 90 minutes 
on Days 1 and 15 of each cycle. 
Study Visits 
Every 2 weeks: 
• Blood (about 1 - 2 teaspoons) will be drawn for routine tests 
Every 4 weeks: 
• Urine will be collected to check your kidney function. 
• You will be asked about any drugs you may be taking and if you have had any side effects. 
Every 8 weeks: 
• Your medical history will be recorded. 
• 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 complete the quality of life questionnaire.   
• You will have an MRI scan or CT scan of the head and/or spine to check the status of the 
disease. 
At any time during the study, extra tests may be performed if the doctor thinks they are needed for 
your safety.  The study doctor will tell you more about any extra tests.  


   
Amendment D 
May 07, 2019 
Page 3 of 11 
Length of Study 
You will receive up to 6 cycles of the study drug combination.  You will be taken off study early if 
the disease gets worse or you experience intolerable side effects.    
If the disease has not gotten worse after 6 cycles of receiving the study drug combination, you will 
be able to continue receiving bevacizumab alone for as long as the doctor thinks it is in your best 
interest.  You will continue to follow the same study visit schedule detailed above.   
Long-Term Follow-up 
If you go off study because the disease got worse or you experienced intolerable side effects, the 
study staff will call you every 3 months from then on to check your health.  Each phone call should 
take about 5 minutes.  
This is an investigational study.   Carboplatin is FDA approved and commercially available for the 
treatment of advanced ovarian cancer.  Bevacizumab is FDA approved and commercially available 
for the treatment of glioblastoma (a type of brain tumor).   The use of these drugs in combination in 
ependymoma is investigational.  
You and/or your insurance provider will be responsible for the costs of carboplatin and 
bevacizumab.  
Up to 46 patients will take part in this 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.  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 cause death. 
Tell the study staff about any side effects you may have, even if you do not think they are related to 
the study drugs. 
Carboplatin and bevacizumab may each cause low blood cell counts (red blood cells, platelets, 
and/or white blood cells):  
• A low red blood cell count (anemia) may cause difficulty breathing and/or fatigue. You 
may need a blood transfusion.  
• A low platelet count increases your risk of bleeding (such as nosebleeds, bruising, stroke, 
and/or digestive system bleeding). You may need a platelet transfusion.  
• A low white blood cell count increases your risk of infection (such as pneumonia and/or 
severe blood infection). Infections may occur anywhere and become life-threatening. 
Symptoms of infection may include fever, pain, redness, and difficulty breathing.  
Carboplatin Side Effects 
Common (occurring in more than 20% of patients) 
• abnormal salts, minerals, 
and/or acids in the blood 
• vomiting 
• low blood counts (red, 
white, platelets) 
abnormal liver tests 
(possible liver damage) 


   
Amendment D 
May 07, 2019 
Page 1 of 11 
Informed Consent 
INFORMED CONSENT/AUTHORIZATION FOR PARTICIPATION IN RESEARCH  
Phase II trial of carboplatin and bevacizumab for the treatment of recurrent low-grade and 
anaplastic supratentorial, infratentorial and spinal cord ependymoma in adults 
 
Subtitle: Phase II 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 
and authorization 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 called 
an ependymoma that is recurrent (has returned after treatment). 
PURPOSE OF STUDY 
The goal of this clinical research study is to learn if the combination of bevacizumab and 
carboplatin can help to control recurrent ependymoma.  The safety of this drug combination will 
also be studied. 
DESCRIPTION OF STUDY 
Study Drugs 
Carboplatin is designed to interfere with the growth of cancer cells by stopping cell division, 
which may cause the cells to die. 
Bevacizumab is designed to prevent or slow down the growth of cancer cells by blocking the 
growth of blood vessels. 
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 
some of these tests have been performed within the past 14 days, they may not need to be repeated.  
The following tests and procedures will be performed: 
• Your complete medical history will be recorded, including any drugs you may have taken 
and/or be taking. 
• You will have a complete physical exam, including measurement of your height, weight, 
and vital signs (heart rate, temperature, breathing rate, and blood pressure). 


   
Amendment D 
May 07, 2019 
Page 2 of 11 
• You will be asked how well you are able to perform the normal activities of daily living 
(performance status). 
• You will have a neurological exam (tests to check the functioning of your nervous system, 
including tests of your balance and reflexes).  You will also be asked how well you are able 
to perform tasks like remembering, communicating, and following simple instructions.  
This should take about 20 minutes to complete. 
• Blood (about 2-3 tablespoons) will be drawn for routine tests.  This routine blood draw will 
also include a pregnancy test if you are able to become pregnant.  To take part in this study, 
you must not be pregnant. 
• Blood (about 1 teaspoon) will be drawn to check your blood's ability to clot. 
• Urine will be collected to check your kidney function. 
• You will have a magnetic resonance imaging (MRI) scan or computed tomography (CT) 
scan of the head and/or spine to check the status of the disease.   
• You will complete a questionnaire about your quality of life.  The questionnaire should take 
about 5 minutes to complete. 
• Tumor tissue left over from a previous procedure (such as disease diagnosis slides or tumor 
tissue leftover from a previous biopsy) will be collected to confirm your diagnosis and to 
test for biomarkers. 
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, you will receive carboplatin by vein over 
30 minutes on Day 1 of each 28-day cycle.  You will receive bevacizumab by vein over 90 minutes 
on Days 1 and 15 of each cycle. 
Study Visits 
Every 2 weeks: 
• Blood (about 1 - 2 teaspoons) will be drawn for routine tests 
Every 4 weeks: 
• Urine will be collected to check your kidney function. 
• You will be asked about any drugs you may be taking and if you have had any side effects. 
Every 8 weeks: 
• Your medical history will be recorded. 
• 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 complete the quality of life questionnaire.   
• You will have an MRI scan or CT scan of the head and/or spine to check the status of the 
disease. 
At any time during the study, extra tests may be performed if the doctor thinks they are needed for 
your safety.  The study doctor will tell you more about any extra tests.  


   
Amendment D 
May 07, 2019 
Page 3 of 11 
Length of Study 
You will receive up to 6 cycles of the study drug combination.  You will be taken off study early if 
the disease gets worse or you experience intolerable side effects.    
If the disease has not gotten worse after 6 cycles of receiving the study drug combination, you will 
be able to continue receiving bevacizumab alone for as long as the doctor thinks it is in your best 
interest.  You will continue to follow the same study visit schedule detailed above.   
Long-Term Follow-up 
If you go off study because the disease got worse or you experienced intolerable side effects, the 
study staff will call you every 3 months from then on to check your health.  Each phone call should 
take about 5 minutes.  
This is an investigational study.   Carboplatin is FDA approved and commercially available for the 
treatment of advanced ovarian cancer.  Bevacizumab is FDA approved and commercially available 
for the treatment of glioblastoma (a type of brain tumor).   The use of these drugs in combination in 
ependymoma is investigational.  
You and/or your insurance provider will be responsible for the costs of carboplatin and 
bevacizumab.  
Up to 46 patients will take part in this 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.  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 cause death. 
Tell the study staff about any side effects you may have, even if you do not think they are related to 
the study drugs. 
Carboplatin and bevacizumab may each cause low blood cell counts (red blood cells, platelets, 
and/or white blood cells):  
• A low red blood cell count (anemia) may cause difficulty breathing and/or fatigue. You 
may need a blood transfusion.  
• A low platelet count increases your risk of bleeding (such as nosebleeds, bruising, stroke, 
and/or digestive system bleeding). You may need a platelet transfusion.  
• A low white blood cell count increases your risk of infection (such as pneumonia and/or 
severe blood infection). Infections may occur anywhere and become life-threatening. 
Symptoms of infection may include fever, pain, redness, and difficulty breathing.  
Carboplatin Side Effects 
Common (occurring in more than 20% of patients) 
• abnormal salts, minerals, 
and/or acids in the blood 
• vomiting 
• low blood counts (red, 
white, platelets) 
abnormal liver tests 
(possible liver damage) 


   
Amendment D 
May 07, 2019 
Page 1 of 11 
Informed Consent 
INFORMED CONSENT/AUTHORIZATION FOR PARTICIPATION IN RESEARCH  
Phase II trial of carboplatin and bevacizumab for the treatment of recurrent low-grade and 
anaplastic supratentorial, infratentorial and spinal cord ependymoma in adults 
 
Subtitle: Phase II 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 
and authorization 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 called 
an ependymoma that is recurrent (has returned after treatment). 
PURPOSE OF STUDY 
The goal of this clinical research study is to learn if the combination of bevacizumab and 
carboplatin can help to control recurrent ependymoma.  The safety of this drug combination will 
also be studied. 
DESCRIPTION OF STUDY 
Study Drugs 
Carboplatin is designed to interfere with the growth of cancer cells by stopping cell division, 
which may cause the cells to die. 
Bevacizumab is designed to prevent or slow down the growth of cancer cells by blocking the 
growth of blood vessels. 
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 
some of these tests have been performed within the past 14 days, they may not need to be repeated.  
The following tests and procedures will be performed: 
• Your complete medical history will be recorded, including any drugs you may have taken 
and/or be taking. 
• You will have a complete physical exam, including measurement of your height, weight, 
and vital signs (heart rate, temperature, breathing rate, and blood pressure). 


   
Amendment D 
May 07, 2019 
Page 3 of 11 
Length of Study 
You will receive up to 6 cycles of the study drug combination.  You will be taken off study early if 
the disease gets worse or you experience intolerable side effects.    
If the disease has not gotten worse after 6 cycles of receiving the study drug combination, you will 
be able to continue receiving bevacizumab alone for as long as the doctor thinks it is in your best 
interest.  You will continue to follow the same study visit schedule detailed above.   
Long-Term Follow-up 
If you go off study because the disease got worse or you experienced intolerable side effects, the 
study staff will call you every 3 months from then on to check your health.  Each phone call should 
take about 5 minutes.  
This is an investigational study.   Carboplatin is FDA approved and commercially available for the 
treatment of advanced ovarian cancer.  Bevacizumab is FDA approved and commercially available 
for the treatment of glioblastoma (a type of brain tumor).   The use of these drugs in combination in 
ependymoma is investigational.  
You and/or your insurance provider will be responsible for the costs of carboplatin and 
bevacizumab.  
Up to 46 patients will take part in this 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.  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 cause death. 
Tell the study staff about any side effects you may have, even if you do not think they are related to 
the study drugs. 
Carboplatin and bevacizumab may each cause low blood cell counts (red blood cells, platelets, 
and/or white blood cells):  
• A low red blood cell count (anemia) may cause difficulty breathing and/or fatigue. You 
may need a blood transfusion.  
• A low platelet count increases your risk of bleeding (such as nosebleeds, bruising, stroke, 
and/or digestive system bleeding). You may need a platelet transfusion.  
• A low white blood cell count increases your risk of infection (such as pneumonia and/or 
severe blood infection). Infections may occur anywhere and become life-threatening. 
Symptoms of infection may include fever, pain, redness, and difficulty breathing.  
Carboplatin Side Effects 
Common (occurring in more than 20% of patients) 
• abnormal salts, minerals, 
and/or acids in the blood 
• vomiting 
• low blood counts (red, 
white, platelets) 
abnormal liver tests 
(possible liver damage) 


   
Amendment D 
May 07, 2019 
Page 4 of 11 
(possible weakness, 
swelling, fatigue, low blood 
pressure, organ failure, 
heart problems, changes in 
mental status, and/or 
seizure) 
• pain 
abnormal kidney test 
(possible kidney damage 
Occasional (occurring in 3-20% of patients) 
• nerve damage (possible 
numbness, pain, and/or loss 
of motor function) 
• hair loss (partial or total) 
• abdominal pain  
• nausea 
• constipation 
• diarrhea 
• abnormal taste 
• mouth blisters/sores 
(possible difficulty 
swallowing) 
• weakness 
• abnormal liver tests 
(possible yellowing of 
the skin and/or eyes) 
• allergic reaction 
• infection  
Rare but serious (occurring in fewer than 3% of patients)  
• high blood pressure 
• low blood pressure 
(possible dizziness/fainting) 
• heart failure 
• stroke 
• dehydration 
• blood vessel blockage  
• anemia due to destruction 
of red blood cells 
• multiple blood clots 
(possible organ 
dysfunction and/or 
failure) 
• reduced blood supply 
to the arms and legs 
• visual problems 
• blindness 
• hearing loss 
• difficulty breathing due 
to narrowing of the 
airways  
• tissue death at the 
injection site caused by 
drug leakage 
• life-threatening allergic 
reaction (such as 
difficulty breathing, 
low blood pressure, 
and/or organ failure) 
Carboplatin may rarely cause you to develop another type of cancer. 
Bevacizumab Side Effects  
Common (occurring in more than 20% of patients) 
• high blood pressure 
 
• blood clots in a vein 
(possible pain, swelling, 
and/or redness)  
• pain 
• nerve damage (loss of 
sensory function) 
• headache 
• dizziness 
• fatigue 
• hair loss (partial or total) 
• abdominal pain 
• loss of appetite 
• constipation 
• diarrhea 
• mouth blisters/sores 
(possible difficulty 
swallowing) 
• digestive system 
bleeding 
• upset stomach 
• vomiting 
• abnormal taste 
• failure of the ovaries to 
produce hormones, 
which may be permanent 
(possible stopped 
menstrual cycle) 
• bleeding  
• nosebleed 
• low white blood cell 
counts 
• difficulty breathing 
• weakness 


   
Amendment D 
May 07, 2019 
Page 5 of 11 
• abnormal kidney test 
(possible kidney 
damage) 
Occasional (occurring in 3-20% of patients) 
• blood clots in an artery 
(possible organ damage such 
as stroke and/or heart attack) 
• low blood pressure (possible 
dizziness/fainting)  
• heart failure 
• fainting 
• bleeding in the brain and/or 
spinal cord 
• stroke 
• difficulty walking 
• dry skin 
• skin sores 
• opening of a wound 
• shedding and scaling of 
the skin (possible fatal 
loss of bodily fluids) 
• change of skin color 
• low blood levels of 
sodium (possible 
headache, confusion, 
seizures, and/or coma)  
• dehydration 
• gas 
• dry mouth  
• hole in the intestines 
(possibly leaking 
contents into the 
abdomen)  
• bleeding gums  
• inflammation or 
paralysis of the 
intestines  
• weight loss 
• nausea  
• uterine and/or vaginal 
bleeding  
• low platelet cell counts 
• pain (back/muscle) 
• voice changes 
• runny nose 
• lung inflammation 
(possible difficulty 
breathing) 
• infusion reaction 
(possible chills and/or 
hives) 
Rare but serious (occurring in fewer than 3% of patients)  
• severe heart problems 
• heart attack 
• chest pain due to heart 
trouble 
• severe increase in blood 
pressure (possible stroke) 
• brain injury that may be 
reversible (possible 
headache, confusion, 
seizures, and/or vision loss)  
• decreased brain function due 
to high blood pressure 
• decreased blood flow to part 
of the bowel (possibly 
causing death of tissue) 
• bleeding around the brain 
• temporary stroke symptoms 
• intestinal blockage 
• stomach and/or small 
intestine ulcer 
• vein blockage in the 
abdomen 
• hole in the gall bladder 
(possible abdominal 
pain, gall stones, nausea, 
and/or infection) 
• hole in the bladder  
• destruction of red blood 
cells  
• low red blood cell 
counts  
• bone destruction 
(including destruction of 
the jaw bone) 
• inflammation inside the 
eye 
• blurry vision  
• deafness  
• kidney failure 
• decreased kidney 
function (possible 
kidney failure) 
• coughing up blood 
• increased blood pressure 
in the lungs (possible 
difficulty breathing 
and/or heart failure) 
• blockage in the lung 
(possible pain, shortness 
of breath, and/or failure 
to breathe)  
• abnormal hole inside the 
nose 
• life-threatening allergic 
reaction (such as 
difficulty breathing, low 
blood pressure, and/or 
organ failure) 


   
Amendment D 
May 07, 2019 
Page 6 of 11 
• increased pressure in the 
eye (possible pain and/or 
blurry vision) 
• detached retina (possible 
partial blindness) 
• wound healing problems 
Bevacizumab may rarely cause an abnormal opening that develops between one area of the body 
and another (for example, an abnormal connection and opening in one or more places between the 
trachea [breathing tube] and esophagus, which may interfere with swallowing, digestion, and/or 
choking).  This may result in death.  
Rarely (in about 1-2% of patients), bevacizumab may cause bleeding in the brain in patients who 
have received bevacizumab for the treatment of primary brain tumors. You will be monitored for 
this complication and removed from the study if this were to occur. 
If you are taking Coumadin (warfarin) or other blood-thinning drugs, you may be at higher risk of 
blood clots and/or bleeding. 
Using the study drugs together may cause side effects that are not seen when each is given alone.  
The study drug combination may also increase the frequency and/or severity of the side effects 
listed above. 
Other Risks 
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. 
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:  If you are able to become pregnant or father a child, you must use 
acceptable birth control while on study and for 1 month after the last dose of study drug(s).  
Medically acceptable birth control types include approved hormonal birth control (such as birth 
control pills, Depo-Provera, or Lupron Depot), barrier methods (such as a condom or diaphragm) 
with spermicide, or intrauterine device (IUD).  Talk to the study doctor about acceptable methods 
of birth control. 
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. 


   
Amendment D 
May 07, 2019 
Page 4 of 11 
(possible weakness, 
swelling, fatigue, low blood 
pressure, organ failure, 
heart problems, changes in 
mental status, and/or 
seizure) 
• pain 
abnormal kidney test 
(possible kidney damage 
Occasional (occurring in 3-20% of patients) 
• nerve damage (possible 
numbness, pain, and/or loss 
of motor function) 
• hair loss (partial or total) 
• abdominal pain  
• nausea 
• constipation 
• diarrhea 
• abnormal taste 
• mouth blisters/sores 
(possible difficulty 
swallowing) 
• weakness 
• abnormal liver tests 
(possible yellowing of 
the skin and/or eyes) 
• allergic reaction 
• infection  
Rare but serious (occurring in fewer than 3% of patients)  
• high blood pressure 
• low blood pressure 
(possible dizziness/fainting) 
• heart failure 
• stroke 
• dehydration 
• blood vessel blockage  
• anemia due to destruction 
of red blood cells 
• multiple blood clots 
(possible organ 
dysfunction and/or 
failure) 
• reduced blood supply 
to the arms and legs 
• visual problems 
• blindness 
• hearing loss 
• difficulty breathing due 
to narrowing of the 
airways  
• tissue death at the 
injection site caused by 
drug leakage 
• life-threatening allergic 
reaction (such as 
difficulty breathing, 
low blood pressure, 
and/or organ failure) 
Carboplatin may rarely cause you to develop another type of cancer. 
Bevacizumab Side Effects  
Common (occurring in more than 20% of patients) 
• high blood pressure 
 
• blood clots in a vein 
(possible pain, swelling, 
and/or redness)  
• pain 
• nerve damage (loss of 
sensory function) 
• headache 
• dizziness 
• fatigue 
• hair loss (partial or total) 
• abdominal pain 
• loss of appetite 
• constipation 
• diarrhea 
• mouth blisters/sores 
(possible difficulty 
swallowing) 
• digestive system 
bleeding 
• upset stomach 
• vomiting 
• abnormal taste 
• failure of the ovaries to 
produce hormones, 
which may be permanent 
(possible stopped 
menstrual cycle) 
• bleeding  
• nosebleed 
• low white blood cell 
counts 
• difficulty breathing 
• weakness 


   
Amendment D 
May 07, 2019 
Page 5 of 11 
• abnormal kidney test 
(possible kidney 
damage) 
Occasional (occurring in 3-20% of patients) 
• blood clots in an artery 
(possible organ damage such 
as stroke and/or heart attack) 
• low blood pressure (possible 
dizziness/fainting)  
• heart failure 
• fainting 
• bleeding in the brain and/or 
spinal cord 
• stroke 
• difficulty walking 
• dry skin 
• skin sores 
• opening of a wound 
• shedding and scaling of 
the skin (possible fatal 
loss of bodily fluids) 
• change of skin color 
• low blood levels of 
sodium (possible 
headache, confusion, 
seizures, and/or coma)  
• dehydration 
• gas 
• dry mouth  
• hole in the intestines 
(possibly leaking 
contents into the 
abdomen)  
• bleeding gums  
• inflammation or 
paralysis of the 
intestines  
• weight loss 
• nausea  
• uterine and/or vaginal 
bleeding  
• low platelet cell counts 
• pain (back/muscle) 
• voice changes 
• runny nose 
• lung inflammation 
(possible difficulty 
breathing) 
• infusion reaction 
(possible chills and/or 
hives) 
Rare but serious (occurring in fewer than 3% of patients)  
• severe heart problems 
• heart attack 
• chest pain due to heart 
trouble 
• severe increase in blood 
pressure (possible stroke) 
• brain injury that may be 
reversible (possible 
headache, confusion, 
seizures, and/or vision loss)  
• decreased brain function due 
to high blood pressure 
• decreased blood flow to part 
of the bowel (possibly 
causing death of tissue) 
• bleeding around the brain 
• temporary stroke symptoms 
• intestinal blockage 
• stomach and/or small 
intestine ulcer 
• vein blockage in the 
abdomen 
• hole in the gall bladder 
(possible abdominal 
pain, gall stones, nausea, 
and/or infection) 
• hole in the bladder  
• destruction of red blood 
cells  
• low red blood cell 
counts  
• bone destruction 
(including destruction of 
the jaw bone) 
• inflammation inside the 
eye 
• blurry vision  
• deafness  
• kidney failure 
• decreased kidney 
function (possible 
kidney failure) 
• coughing up blood 
• increased blood pressure 
in the lungs (possible 
difficulty breathing 
and/or heart failure) 
• blockage in the lung 
(possible pain, shortness 
of breath, and/or failure 
to breathe)  
• abnormal hole inside the 
nose 
• life-threatening allergic 
reaction (such as 
difficulty breathing, low 
blood pressure, and/or 
organ failure) 


   
Amendment D 
May 07, 2019 
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Informed Consent 
INFORMED CONSENT/AUTHORIZATION FOR PARTICIPATION IN RESEARCH  
Phase II trial of carboplatin and bevacizumab for the treatment of recurrent low-grade and 
anaplastic supratentorial, infratentorial and spinal cord ependymoma in adults 
 
Subtitle: Phase II 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 
and authorization 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 called 
an ependymoma that is recurrent (has returned after treatment). 
PURPOSE OF STUDY 
The goal of this clinical research study is to learn if the combination of bevacizumab and 
carboplatin can help to control recurrent ependymoma.  The safety of this drug combination will 
also be studied. 
DESCRIPTION OF STUDY 
Study Drugs 
Carboplatin is designed to interfere with the growth of cancer cells by stopping cell division, 
which may cause the cells to die. 
Bevacizumab is designed to prevent or slow down the growth of cancer cells by blocking the 
growth of blood vessels. 
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 
some of these tests have been performed within the past 14 days, they may not need to be repeated.  
The following tests and procedures will be performed: 
• Your complete medical history will be recorded, including any drugs you may have taken 
and/or be taking. 
• You will have a complete physical exam, including measurement of your height, weight, 
and vital signs (heart rate, temperature, breathing rate, and blood pressure). 


   
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• You will be asked how well you are able to perform the normal activities of daily living 
(performance status). 
• You will have a neurological exam (tests to check the functioning of your nervous system, 
including tests of your balance and reflexes).  You will also be asked how well you are able 
to perform tasks like remembering, communicating, and following simple instructions.  
This should take about 20 minutes to complete. 
• Blood (about 2-3 tablespoons) will be drawn for routine tests.  This routine blood draw will 
also include a pregnancy test if you are able to become pregnant.  To take part in this study, 
you must not be pregnant. 
• Blood (about 1 teaspoon) will be drawn to check your blood's ability to clot. 
• Urine will be collected to check your kidney function. 
• You will have a magnetic resonance imaging (MRI) scan or computed tomography (CT) 
scan of the head and/or spine to check the status of the disease.   
• You will complete a questionnaire about your quality of life.  The questionnaire should take 
about 5 minutes to complete. 
• Tumor tissue left over from a previous procedure (such as disease diagnosis slides or tumor 
tissue leftover from a previous biopsy) will be collected to confirm your diagnosis and to 
test for biomarkers. 
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, you will receive carboplatin by vein over 
30 minutes on Day 1 of each 28-day cycle.  You will receive bevacizumab by vein over 90 minutes 
on Days 1 and 15 of each cycle. 
Study Visits 
Every 2 weeks: 
• Blood (about 1 - 2 teaspoons) will be drawn for routine tests 
Every 4 weeks: 
• Urine will be collected to check your kidney function. 
• You will be asked about any drugs you may be taking and if you have had any side effects. 
Every 8 weeks: 
• Your medical history will be recorded. 
• 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 complete the quality of life questionnaire.   
• You will have an MRI scan or CT scan of the head and/or spine to check the status of the 
disease. 
At any time during the study, extra tests may be performed if the doctor thinks they are needed for 
your safety.  The study doctor will tell you more about any extra tests.  


   
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Length of Study 
You will receive up to 6 cycles of the study drug combination.  You will be taken off study early if 
the disease gets worse or you experience intolerable side effects.    
If the disease has not gotten worse after 6 cycles of receiving the study drug combination, you will 
be able to continue receiving bevacizumab alone for as long as the doctor thinks it is in your best 
interest.  You will continue to follow the same study visit schedule detailed above.   
Long-Term Follow-up 
If you go off study because the disease got worse or you experienced intolerable side effects, the 
study staff will call you every 3 months from then on to check your health.  Each phone call should 
take about 5 minutes.  
This is an investigational study.   Carboplatin is FDA approved and commercially available for the 
treatment of advanced ovarian cancer.  Bevacizumab is FDA approved and commercially available 
for the treatment of glioblastoma (a type of brain tumor).   The use of these drugs in combination in 
ependymoma is investigational.  
You and/or your insurance provider will be responsible for the costs of carboplatin and 
bevacizumab.  
Up to 46 patients will take part in this 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.  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 cause death. 
Tell the study staff about any side effects you may have, even if you do not think they are related to 
the study drugs. 
Carboplatin and bevacizumab may each cause low blood cell counts (red blood cells, platelets, 
and/or white blood cells):  
• A low red blood cell count (anemia) may cause difficulty breathing and/or fatigue. You 
may need a blood transfusion.  
• A low platelet count increases your risk of bleeding (such as nosebleeds, bruising, stroke, 
and/or digestive system bleeding). You may need a platelet transfusion.  
• A low white blood cell count increases your risk of infection (such as pneumonia and/or 
severe blood infection). Infections may occur anywhere and become life-threatening. 
Symptoms of infection may include fever, pain, redness, and difficulty breathing.  
Carboplatin Side Effects 
Common (occurring in more than 20% of patients) 
• abnormal salts, minerals, 
and/or acids in the blood 
• vomiting 
• low blood counts (red, 
white, platelets) 
abnormal liver tests 
(possible liver damage) 


   
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(possible weakness, 
swelling, fatigue, low blood 
pressure, organ failure, 
heart problems, changes in 
mental status, and/or 
seizure) 
• pain 
abnormal kidney test 
(possible kidney damage 
Occasional (occurring in 3-20% of patients) 
• nerve damage (possible 
numbness, pain, and/or loss 
of motor function) 
• hair loss (partial or total) 
• abdominal pain  
• nausea 
• constipation 
• diarrhea 
• abnormal taste 
• mouth blisters/sores 
(possible difficulty 
swallowing) 
• weakness 
• abnormal liver tests 
(possible yellowing of 
the skin and/or eyes) 
• allergic reaction 
• infection  
Rare but serious (occurring in fewer than 3% of patients)  
• high blood pressure 
• low blood pressure 
(possible dizziness/fainting) 
• heart failure 
• stroke 
• dehydration 
• blood vessel blockage  
• anemia due to destruction 
of red blood cells 
• multiple blood clots 
(possible organ 
dysfunction and/or 
failure) 
• reduced blood supply 
to the arms and legs 
• visual problems 
• blindness 
• hearing loss 
• difficulty breathing due 
to narrowing of the 
airways  
• tissue death at the 
injection site caused by 
drug leakage 
• life-threatening allergic 
reaction (such as 
difficulty breathing, 
low blood pressure, 
and/or organ failure) 
Carboplatin may rarely cause you to develop another type of cancer. 
Bevacizumab Side Effects  
Common (occurring in more than 20% of patients) 
• high blood pressure 
 
• blood clots in a vein 
(possible pain, swelling, 
and/or redness)  
• pain 
• nerve damage (loss of 
sensory function) 
• headache 
• dizziness 
• fatigue 
• hair loss (partial or total) 
• abdominal pain 
• loss of appetite 
• constipation 
• diarrhea 
• mouth blisters/sores 
(possible difficulty 
swallowing) 
• digestive system 
bleeding 
• upset stomach 
• vomiting 
• abnormal taste 
• failure of the ovaries to 
produce hormones, 
which may be permanent 
(possible stopped 
menstrual cycle) 
• bleeding  
• nosebleed 
• low white blood cell 
counts 
• difficulty breathing 
• weakness 


   
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• abnormal kidney test 
(possible kidney 
damage) 
Occasional (occurring in 3-20% of patients) 
• blood clots in an artery 
(possible organ damage such 
as stroke and/or heart attack) 
• low blood pressure (possible 
dizziness/fainting)  
• heart failure 
• fainting 
• bleeding in the brain and/or 
spinal cord 
• stroke 
• difficulty walking 
• dry skin 
• skin sores 
• opening of a wound 
• shedding and scaling of 
the skin (possible fatal 
loss of bodily fluids) 
• change of skin color 
• low blood levels of 
sodium (possible 
headache, confusion, 
seizures, and/or coma)  
• dehydration 
• gas 
• dry mouth  
• hole in the intestines 
(possibly leaking 
contents into the 
abdomen)  
• bleeding gums  
• inflammation or 
paralysis of the 
intestines  
• weight loss 
• nausea  
• uterine and/or vaginal 
bleeding  
• low platelet cell counts 
• pain (back/muscle) 
• voice changes 
• runny nose 
• lung inflammation 
(possible difficulty 
breathing) 
• infusion reaction 
(possible chills and/or 
hives) 
Rare but serious (occurring in fewer than 3% of patients)  
• severe heart problems 
• heart attack 
• chest pain due to heart 
trouble 
• severe increase in blood 
pressure (possible stroke) 
• brain injury that may be 
reversible (possible 
headache, confusion, 
seizures, and/or vision loss)  
• decreased brain function due 
to high blood pressure 
• decreased blood flow to part 
of the bowel (possibly 
causing death of tissue) 
• bleeding around the brain 
• temporary stroke symptoms 
• intestinal blockage 
• stomach and/or small 
intestine ulcer 
• vein blockage in the 
abdomen 
• hole in the gall bladder 
(possible abdominal 
pain, gall stones, nausea, 
and/or infection) 
• hole in the bladder  
• destruction of red blood 
cells  
• low red blood cell 
counts  
• bone destruction 
(including destruction of 
the jaw bone) 
• inflammation inside the 
eye 
• blurry vision  
• deafness  
• kidney failure 
• decreased kidney 
function (possible 
kidney failure) 
• coughing up blood 
• increased blood pressure 
in the lungs (possible 
difficulty breathing 
and/or heart failure) 
• blockage in the lung 
(possible pain, shortness 
of breath, and/or failure 
to breathe)  
• abnormal hole inside the 
nose 
• life-threatening allergic 
reaction (such as 
difficulty breathing, low 
blood pressure, and/or 
organ failure) 


   
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• increased pressure in the 
eye (possible pain and/or 
blurry vision) 
• detached retina (possible 
partial blindness) 
• wound healing problems 
Bevacizumab may rarely cause an abnormal opening that develops between one area of the body 
and another (for example, an abnormal connection and opening in one or more places between the 
trachea [breathing tube] and esophagus, which may interfere with swallowing, digestion, and/or 
choking).  This may result in death.  
Rarely (in about 1-2% of patients), bevacizumab may cause bleeding in the brain in patients who 
have received bevacizumab for the treatment of primary brain tumors. You will be monitored for 
this complication and removed from the study if this were to occur. 
If you are taking Coumadin (warfarin) or other blood-thinning drugs, you may be at higher risk of 
blood clots and/or bleeding. 
Using the study drugs together may cause side effects that are not seen when each is given alone.  
The study drug combination may also increase the frequency and/or severity of the side effects 
listed above. 
Other Risks 
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. 
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:  If you are able to become pregnant or father a child, you must use 
acceptable birth control while on study and for 1 month after the last dose of study drug(s).  
Medically acceptable birth control types include approved hormonal birth control (such as birth 
control pills, Depo-Provera, or Lupron Depot), barrier methods (such as a condom or diaphragm) 
with spermicide, or intrauterine device (IUD).  Talk to the study doctor about acceptable methods 
of birth control. 
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. 


   
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• increased pressure in the 
eye (possible pain and/or 
blurry vision) 
• detached retina (possible 
partial blindness) 
• wound healing problems 
Bevacizumab may rarely cause an abnormal opening that develops between one area of the body 
and another (for example, an abnormal connection and opening in one or more places between the 
trachea [breathing tube] and esophagus, which may interfere with swallowing, digestion, and/or 
choking).  This may result in death.  
Rarely (in about 1-2% of patients), bevacizumab may cause bleeding in the brain in patients who 
have received bevacizumab for the treatment of primary brain tumors. You will be monitored for 
this complication and removed from the study if this were to occur. 
If you are taking Coumadin (warfarin) or other blood-thinning drugs, you may be at higher risk of 
blood clots and/or bleeding. 
Using the study drugs together may cause side effects that are not seen when each is given alone.  
The study drug combination may also increase the frequency and/or severity of the side effects 
listed above. 
Other Risks 
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. 
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:  If you are able to become pregnant or father a child, you must use 
acceptable birth control while on study and for 1 month after the last dose of study drug(s).  
Medically acceptable birth control types include approved hormonal birth control (such as birth 
control pills, Depo-Provera, or Lupron Depot), barrier methods (such as a condom or diaphragm) 
with spermicide, or intrauterine device (IUD).  Talk to the study doctor about acceptable methods 
of birth control. 
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. 


   
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POTENTIAL BENEFITS 
The study drugs may help to control the disease.  Future patients may benefit from what is learned.    
There may be no benefits for you in this study. 
ALTERNATIVE PROCEDURES OR TREATMENTS 
You may choose not to take part in this study.  You may choose to receive other treatments for 
recurrent ependymoma (such as chemotherapy [such as temozolomide], 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. 
 
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 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 
National Cancer Institute, 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. 
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. 
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 


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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.
•
Insert local IRB name
•
National Institute of Health Institutional Review Board
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.  
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 NIH 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. 
CERTIFICATE OF CONFIDENTIALITY 
To help us protect your privacy, we have obtained a Certificate of Confidentiality. The researchers 
can use this Certificate to legally refuse to disclose information that may identify you in any 
federal, state, or local civil, criminal, administrative, legislative, or other proceedings, for example, 
if there is a court subpoena. The researchers will use the Certificate to resist any demands for 
information that would identify you, except as explained below. 
You should also know that there are several circumstances in which the Certificate does not 
provide coverage. These include when information:  
•
will be used for auditing or program evaluation internally by the NIH; or
•
must be disclosed to meet the legal requirements of the federal Food and Drug
Administration (FDA).
•
is necessary for your medical treatment and you have consented to this disclosure;
•
is for other research.


   
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In addition, identifiable, sensitive information protected by this Certificate cannot be admissible as 
evidence or used for any purpose in any action, suit, or proceeding without your consent.  
You should understand that a Certificate of Confidentiality does not prevent you or a member of 
your family from voluntarily releasing information about yourself or your involvement in this 
research. If an insurer, employer, or other person obtains your written consent to receive research 
information, then the researchers will not use the Certificate to withhold that information. 
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. 
 
 
USE OF SPECIMENS AND DATA FOR FUTURE RESEARCH 
To advance science, it is helpful for researchers to share information they get from studying human 
samples.  They do this by putting it into one or more scientific databases, where it is stored along 
with information from other studies. A researcher who wants to study the information must apply 
to the database and be approved.  Researchers use specimens and data stored in scientific databases 
to advance science and learn about health and disease.   
We plan to keep some of your specimens and data that we collect and use them for future research 
and share them with other researchers. We will not contact you to ask about each of these future 
uses.  These specimens and data will be stripped of identifiers such as name, address or account 
number, so that they may be used for future research on any topic and shared broadly for research 
purposes. Your specimens and data will be used for research purposes only and will not benefit 
you.  It is also possible that the stored specimens and data may never be used.  Results of research 
done on your specimens and data will not be available to you or your doctor.  It might help people 
who have cancer and other diseases in the future.   
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers. 
 
 
 
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. 
 


   
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April 24, 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