Conditions: Glioblastoma Multiforme Anaplastic Astrocytoma Malignant Brain Tumor High Grade Glioma
Keywords: High Grade Glioma Cabozantinib GBM Children AA
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 4
Healthy volunteers: no

Brief summary:
This pilot will study the feasibility and exploratory efficacy of using Cabozantinib for recurrent or refractory central nervous system tumors for which there are no curative options. Patients will also be followed for safety, time to progression, event free survival and overall survival

Detailed description:

Arms:
arm 1: Cabozantininb will be taken daily at a dose of 40 mg/m2. Drug cycles will last 28 days and be continuous for up to 12 months of therapy on study.

Interventions: intervention 1: Cabozantinib
Intervention descriptions: intervention 1: Subjects will receive Cabozantinib

Protocol document:
Prot_SAP_000.pdf: 
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Pilot Study of Cabozantinib for Recurrent or Progressive Central 
Nervous System Tumors in Children 
 
IUSCC-0601 
 
Principal Investigator: 
Scott Coven, D.O., MPH 
Associate Professor of Neuro-Oncology 
Department of Pediatrics 
Division of Pediatric Hematology/Oncology 
Riley Hospital for Children at IU Health 
Indiana University School of Medicine 
705 Riley Hospital Dr.,Room 4340 
Indianapolis, IN  46202 
 
Co-Investigators: 
Alex Lion, DO 
Dan Runco, MD 
Michael Ferguson, MD 
Stephen Kralik, MD 
IND - 134168 
 
 


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Table of Contents: 
Table of Contents: ........................................................................................................................... 2 
1. 
Summary/Hypothesis ......................................................................................................... 5 
2. 
Background and Rationale ................................................................................................. 5 
3. 
Specific Aims ..................................................................................................................... 11 
4. 
Treatments ....................................................................................................................... 12 
4.1  Composition, Formulation, and Storage ........................................................................ 12 
Investigational Treatment .................................................................................................. 12 
Cabozantinib Tablets .......................................................................................................... 12 
4.2  Dose, Schedule and Route .............................................................................................. 13 
5. 
Inclusion/Exclusion Criteria .............................................................................................. 14 
6. 
Enrollment/ Study population .......................................................................................... 18 
7. 
Study Procedures ............................................................................................................. 19 
7.1  Dose Modifications ......................................................................................................... 21 
Warnings and Precautions and Guidelines for the Management of Adverse Events ..... 22 
Dose Modifications for Hematologic toxicity ................................................................... 23 
Dose Modifications for Non-Hematological toxicity ........................................................ 23 
Dose Modifications for Proteinuria .................................................................................. 23 
Dose Modifications for Hypertension .............................................................................. 23 
Dose Modifications for Liver Toxicity ............................................................................... 28 
Dose Modifications for Pancreatic Toxicity ...................................................................... 28 
Dose Modifications for Diarrhea ...................................................................................... 28 
Dose Modifications for Palmar Plantar Erythrodysthesia (PPE) ...................................... 29 
7.2  Supportive Care and Other Concomitant Therapy ......................................................... 29 
Concurrent Anticancer Therapy ........................................................................................ 29 
Investigational Agents ....................................................................................................... 29 
Supportive Care ................................................................................................................. 29 
Growth Factors .................................................................................................................. 30 
Concomitant Medications ................................................................................................. 30 
Wound Healing and Surgery ............................................................................................. 30 
Concurrent Anti-Hypertensive Therapy ........................................................................... 31 
Management of Hypothyroidism ..................................................................................... 31 


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Corrected QT Prolongation ............................................................................................... 32 
8. 
Safety ................................................................................................................................ 33 
8.1  Adverse Events ............................................................................................................... 33 
8.2  Serious Adverse Events ................................................................................................... 34 
8.3  Serious Adverse Event Reporting ................................................................................... 34 
8.4  Regulatory Reporting ...................................................................................................... 35 
9. 
Other Safety Considerations ............................................................................................ 36 
9.1  Laboratory Data .............................................................................................................. 36 
9.2  Pregnancy ....................................................................................................................... 36 
9.3  Medication Errors/Overdose .......................................................................................... 36 
9.4  Follow-Up of Adverse Events .......................................................................................... 36 
10. 
Data Forms and Submission Schedule ............................................................................. 36 
11. 
Data Safety Monitoring .................................................................................................... 37 
11.1  Data and Safety Monitoring Committee ...................................................................... 37 
11.2  IND Annual Reports ...................................................................................................... 38 
11.3  Study Auditing and Monitoring .................................................................................... 38 
11.4  Data Management/Oncore Reporting Requirements .................................................. 38 
11.5  Study Accrual Oversight ................................................................................................ 38 
11.6  Oncore Safety Reporting .............................................................................................. 38 
11.7  Protocol Deviation Reporting ....................................................................................... 39 
12.        Study Withdrawal/Discontinuation .................................................................................. 39 
13.        Evaluations ........................................................................................................................ 39 
14.        Statistical Considerations .................................................................................................. 41 
14.1  General Considerations ................................................................................................ 41 
14.2  Study Design ................................................................................................................. 41 
14.3  Analysis Population....................................................................................................... 41 
14.3.1  Enrolled Population ........................................................................................... 41 
14.3.2  Safety Population .............................................................................................. 42 
14.3.3  Efficacy Population ............................................................................................ 42 
14.4  Sample Size, Accrual and Study Duration ..................................................................... 42 
14.5  Safety Analysis .............................................................................................................. 42 
14.6  Efficacy Analysis ............................................................................................................ 43 


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14.7  Interim Analysis ............................................................................................................ 43 
15.      Privacy/Confidentiality Issues ............................................................................................. 43 
15.1  Ethical aspects .............................................................................................................. 44 
15.1.1  Local Regulations ............................................................................................... 44 
15.1.2  Informed Consent ............................................................................................. 44 
15.1.3  Institutional Review Board/Ethics Committee .................................................. 44 
15.1.4  Future Use of Patient Samples .......................................................................... 45 
16. 
Follow-up and Record Retention...................................................................................... 45 
17. 
Next Steps ......................................................................................................................... 45 
Appendix I: Performance Status Scales ......................................................................................... 48 
Appendix II: Blood Pressure norms: .............................................................................................. 49 
Blood pressure (BP) levels for GIRLS ...................................................................................... 50 
Appendix III: UNACCEPTABLE ENZYME INDUCING AND RECOMMENDED NON-ENZYME 
INDUCING ANTICONVULSANTS ..................................................................................................... 51 
Appendix IV: MEDICATIONS ASSOCIATED WITH PROLONGED QTC .............................................. 52 
Appendix V: CYP3A4 INDUCERS AND INHIBITORS......................................................................... 53 
Appendix VI: Cabozantinib Dosing Nomogram ............................................................................. 54 
Appendix VII: Summary of RANO Response Criteria 12 ................................................................ 55 
 
 
 


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1. 
Summary/Hypothesis 
 
 Children with high grade gliomas (HGG) including glioblastoma multiforme and 
anaplastic astrocytoma have expected overall survival rates of less than 35% at 3 years 
despite best available therapies.  Unfortunately, most patients succumb to their 
disease.  Additionally, most recurrent pediatric central nervous system tumors (CNS) 
are characterized by aggressive clinical behavior.  Children with refractory or recurrent 
CNS tumors are generally considered to have lower overall survival.  There is an urgent 
need for newer and innovative therapeutic options. 
 
 These include novel biologically driven treatments that have potential to extend and 
improve the survival of these patients. Cabozantinib is a novel tyrosine kinase inhibitor 
of VEGFR2, RET, and MET which shows promising response rates in adults with high 
grade gliomas. It is FDA approved for medullary thyroid cancer and has safety and 
toxicity data with recommended dosing for children. There is strong biological and 
clinical evidence that this treatment may improve outcomes. This pilot will study the 
feasibility and exploratory efficacy of using this agent for recurrent or refractory central 
nervous system tumors. Patients will also be followed for safety, time to progression, 
event free survival and overall survival. If successful, this study will support the 
development of an expanded multi-institutional efficacy trial in children with high grade 
glial tumors and other aggressive brain tumors.   
 
2. 
Background and Rationale 
 
Children with high grade gliomas including glioblastoma multiforme (GBM) and 
anaplastic astrocytoma (AA), have expected overall survival rates less than 35% despite 
our best available therapies. Numerous other histologic subtypes of pediatric central 
nervous system tumors have worse overall survival at recurrent. Additionally, most 
recurrent pediatric CNS tumors are characterized by aggressive clinical behavior. High 
grade gliomas are classified by the World Health Organization (WHO) as either grade III 
or IV meaning that they are highly malignant tumors with characteristic findings such as 
hypercellularity, nuclear atypia, and high mitotic activity with or without microvascular 
proliferation and pseudopalisading necrosis1.  High-grade gliomas include a variety of 
heterogenous tumors with differing histologies, but the most common histologies are 
anaplastic astrocytoma and glioblastoma multiforme.2  Although there truly is no one 
accepted standard of care and treatment algorithms can vary, most experts agree that a 
gross total resection (GTR) followed by focal irradiation to the tumor bed plus additional 


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chemotherapy is an appropriate treatment approach. 3  However, with such an approach, 
Progression Free Survival (PFS) in patients with GTR is 35% compared to 17% with 
subtotal resection of tumor.  Patients with recurrent disease approach mortality rates of 
100%.  Therefore, much work remains to be done to improve survival in these patients. 
Other histologic subtypes of aggressive childhood brain tumors follow a similar pattern to 
high grade gliomas. Children with medulloblastoma, ependymoma, atypical teratoid 
rhabdoid tumor and diffuse intrinsic pontine glioma often face challenges with overall 
survival both at diagnosis and at recurrence. Similar to high grade glioma, most of these 
tumors have no accepted standard of care at relapse/recurrence. Therefore, determining 
potential opportunities to improve outcomes for these children is pivotal. 
Cabozantinib (also known as XL184 and Cometriq) is an ATP-competitive inhibitor of c-
MET, VEGFR2, and RET and falls into the category of drugs called tyrosine kinase 
inhibitors.  This drug also inhibits KIT, AXL, and FLT-3, all of which have been implicated 
in tumor pathogenesis.4  Amplification of the c-MET gene is seen in glioblastomas and 
both c-MET and HGF are frequently overexpressed in glioma specimens and cell 
lines.5,6  Treatment with cabozantinib-inhibited MET and VEGFR2 phosphorylation in 
vitro and in tumor models in vivo led to significant reduction in cell invasion.  In mouse 
models, cabozantinib dramatically altered tumor pathology, resulting in decreased tumor 
and endothelial cell proliferation coupled with increased apoptosis and dose-dependent 
inhibition of tumor growth in breast, lung, and glioma tumor models.7  VEGF or vascular 
endothelial growth factor has been targeted as a potent inhibitor of angiogenesis.  
However, selective inhibition of this target has only yielded in modest short-lived 
response in high grade gliomas.  MET which is postulated to a mechanism of resistance 
to VEGF inhibition, activates downstream tumorigenic pathways such as PI3K and ERK 
pathways.  Therefore, therapies which target both VEGF and MET might be a promising 
approach against glioblastoma. 


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Evaluation of cabozantinib in pediatric brain tumor models has suggested potential 
clinical activity.  In an in vitro cell line from a pediatric Diffuse Intrinsic Pontine Glioma 
patient there was both synergy in the antiproliferative effect when combined with 
dasatinib and the inhibition of cell invasion in an inherently dasatinib-resistant cell line. 
The rate of c-MET amplification in pediatric GBM ranges from 0% to 44% 8-10 based on 
genome-wide copy number.  Additionally, there is evidence that targeting MET and 
VEGFR2 simultaneously suppresses metastasis, angiogenesis, and tumor growth.7 
2.2 Clinical Summary 
A promising Phase 2 study in adult patients with progressive glioblastoma in first or 
second relapse showed 38% radiologic response of >50% reduction in tumor size by 
imaging (ASCO abstract 2047 at ASCO 2009).  There was also evidence of decreased 
corticosteroid use and consistent reduction in edema at Day 28.11  Dosage on that study 
was 175 mg daily by mouth and 125 mg daily dosing is currently under investigation to 
allow for better tolerability.  This would translate to 140 mg and 100 mg Free base 
equivalent. 
A Pediatric Phase I safety, dosing, and tolerability trial has been completed by the 
Children’s Oncology Group (COG) in children with refractory solid tumors and presented 
at ASCO 2014.  Based on this study, the investigators recommended a Phase 2 dosing 
of 40 mg/m² daily which is equivalent to 72 mg adult dose.  Common toxicities noted with 
this drug included diarrhea, stomatitis, weight loss, anorexia, nausea, fatigue, oral pain, 
hair color changes, dysgeusia, hypertension, abdominal pain, and constipation.  Dose 
limiting toxicities (DLT) included lipase elevation, palmar-plantar erythrodysesthesia 


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syndrome (PPE), and mucositis.  Rare serious Adverse Events (AE) may include venous 
thromboembolism.  Response data from this trial has not been made available. 
Cabozantinib is currently FDA approved and commercially available for the treatment of 
medullary thyroid cancer and advanced renal cell carcinoma.  Cabozantinib is a good 
candidate for central nervous system (CNS) malignancies because there is evidence 
that it crosses the blood brain barrier.  Analysis of whole-brain lysates of non-tumor-
bearing mice indicated that cabozantinib attained 20% of peak plasma levels, 
demonstrating the ability of the drug to penetrate the blood-brain barrier (Investigational 
Brochure version 12).   
To date, there have been 17 clinical studies of cabozantinib for oncology indications 
including four Phase 1 studies, one Phase 1b/2 study, four Phase 2 studies, five Phase 
3 studies (a placebo-controlled study in subjects with MTC, two active-controlled studies 
in subjects with castration-resistant prostate cancer [CRPC], one ongoing open-label, 
active-controlled study in subjects with RCC, and one ongoing and enrolling double-
blinded placebo-controlled study in subjects with hepatocellular carcinoma [HCC]), one 
ongoing and enrolling Phase 4 study in MTC, one ongoing maintenance “roll-over” study, 
and one expanded access study. In addition, there are eleven clinical pharmacology 
studies; nine were conducted in healthy subjects alone, one study was conducted that 
included healthy subjects and subjects with renal impairment, and one study was 
conducted that included healthy subjects and subjects with hepatic impairment. In 
addition to these company-sponsored clinical studies, twenty-six investigator-sponsored 
trials (ISTs) and sixteen National Cancer Institute (NCI)-Cancer Therapy Evaluation 
Program (CTEP) trials have enrolled subjects in oncology indications.  (Investigator 
Brochure version 12). 
A tablet dose of 60 mg once daily (qd) was evaluated in two Phase 3 studies in prostate 
cancer, and two ongoing Phase 3 studies, one in RCC and one in HCC, are also 
evaluating this dose. Ongoing double-blind Study XL184-401 compares the efficacy and 
safety of cabozantinib 140 mg qd (capsule formulation) with cabozantinib 60 mg qd 
(tablet formulation). Common to all studies is the titration of the dose to individual patient 
tolerability. 
2.2.3 Clinical Safety Profile 
Across company-sponsored studies with single-agent cabozantinib, the most frequently 
observed AEs (≥ 20% of subjects), regardless of causality, are shown in Table 2-1. 
 
 
 
 
 
 


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Table 2-1:      Summary of Adverse Events Experienced by ≥ 20% of Subjects 
Treated with Single-Agent Cabozantinib, N = 2410 
   All AEs                                  Related AEs 
MedDRA Preferred Term 
Subjects 
with AE n 
(%) 
Subjects 
with 
≥ Grade 3 
AE 
Subjects 
with AE n 
(%) 
Subjects 
with 
≥ Grade 3 
AE 
Number of subjects with at least one 2404 (99.8) 1979 (82.1) 2324 (96.4) 1512 (62.7) 
Diarrhoea 
1471 (61.0) 251 (10.4) 1300 (53.9) 226 (9.4) 
Fatigue 
1458 (60.5) 369 (15.3) 1281 (53.2) 312 (12.9) 
Nausea 
1290 (53.5) 118 (4.9) 
1062 (44.1) 89 (3.7) 
Decreased appetite 
1283 (53.2) 136 (5.6) 
1080 (44.8) 104 (4.3) 
Vomiting 
861 (35.7) 95 (3.9) 
612 (25.4) 59 (2.4) 
Weight decreased 
860 (35.7) 97 (4.0) 
671 (27.8) 75 (3.1) 
Palmar-plantar erythrodysaesthesia 
835 (34.6) 186 (7.7) 
819 (34.0) 185 (7.7) 
Constipation 
779 (32.3) 31 (1.3) 
345 (14.3) 11 (0.5) 
Hypertension 
708 (29.4) 330 (13.7) 603 (25.0) 284 (11.8) 
Dysgeusia 
637 (26.4) 2 (0.1) 
605 (25.1) 2 (0.1) 
Dysphonia 
610 (25.3) 5 (0.2) 
520 (21.6) 4 (0.2) 
Asthenia 
557 (23.1) 165 (6.8) 
434 (18.0) 124 (5.1) 
Dyspnoea 
497 (20.6) 76 (3.2) 
187 (7.8) 
22 (0.9) 
AE, adverse event; MedDRA, Medical Dictionary for Regulatory Activities. 
Note: Reported AEs were coded using MedDRA version 17.0. At each level of summarization, a subject is 
counted only once if the subject reported one or more events. 
Note: This table summarizes pooled data in the clinical database for single-agent cabozantinib studies (XL184-
001, XL184-008, XL184-201, XL184-203, XL184-205, XL184-301 cabozantinib arm, XL184-306 cabozantinib 
arm, XL184-307 cabozantinib arm, XL184-308 cabozantinib arm, and XL184-401). 
As of 29 February 2016, the incidence of Grade 5 AEs from pooled single-agent studies 
was 10.5% (254 subjects). The Grade 5 AEs that occurred at ≥ 1% frequency were 
prostate cancer (2.9%) and general physical health deterioration (1.0%). Only one of 
these events (an event of general physical health deterioration on Study XL184-307) 
was assessed as related to study treatment, and per convention prostate cancer was the 
preferred term (PT) for disease progression of the cancer under study. Thirty-three (33) 
subjects had Grade 5 AEs that were assessed as related to study treatment. The only 
related Grade 5 AEs that occurred more than once were pulmonary embolism (n=4), 
death (unspecified; n=3), hemorrhage (n=2), respiratory failure (n=2), and sudden death 
(n=2). In the ongoing company-sponsored double-blind Study XL184-309 (N = 450) in 
subjects with advanced HCC, 58 Grade 5 AEs (regardless of causality) were reported as 
of 29 February 2016. 


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The most commonly reported SAEs (experienced by ≥ 1% of subjects), regardless of 
causality, are shown in Table 2-2. 
Table 2-2:      Summary of Serious Adverse Events Experienced by ≥ 1% of 
Subjects Treated with Single-Agent Cabozantinib Excluding 
Events of Disease Progression, N = 2410 
All SAEs                                          Related SAEs 
 
MedDRA Preferred Term 
Subjects with 
SAE 
n (%) 
Subjects with 
≥ Grade 3 SAE 
n (%) 
Subjects with 
SAE 
n (%) 
Subjects with 
≥ Grade 3 SAE 
n (%) 
Subjects reporting at least one SAE 
1332 (55.3) 
1221 (50.7) 
602 (25.0) 
516 (21.4) 
Pulmonary embolism 
120 (5.0) 
119 (4.9) 
85 (3.5) 
84 (3.5) 
Vomiting 
81 (3.4) 
48 (2.0) 
40 (1.7) 
27 (1.1) 
Nausea 
72 (3.0) 
44 (1.8) 
47 (2.0) 
31 (1.3) 
General physical health deterioration 
71 (2.9) 
65 (2.7) 
13 (0.5) 
9 (0.4) 
Dehydration 
69 (2.9) 
54 (2.2) 
41 (1.7) 
32 (1.3) 
Pneumonia 
69 (2.9) 
58 (2.4) 
5 (0.2) 
4 (0.2) 
Anaemia 
59 (2.4) 
49 (2.0) 
17 (0.7) 
13 (0.5) 
Abdominal pain 
53 (2.2) 
43 (1.8) 
13 (0.5) 
9 (0.4) 
Diarrhoea 
52 (2.2) 
36 (1.5) 
42 (1.7) 
31 (1.3) 
Deep vein thrombosis 
46 (1.9) 
36 (1.5) 
21 (0.9) 
16 (0.7) 
Fatigue 
43 (1.8) 
36 (1.5) 
27 (1.1) 
25 (1.0) 
Asthenia 
41 (1.7) 
30 (1.2) 
20 (0.8) 
13 (0.5) 
Back pain 
41 (1.7) 
36 (1.5) 
1 (0.0) 
1 (0.0) 
Dyspnoea 
39 (1.6) 
26 (1.1) 
7 (0.3) 
5 (0.2) 
Pyrexia 
36 (1.5) 
9 (0.4) 
5 (0.2) 
2 (0.1) 
Urinary tract infection 
35 (1.5) 
25 (1.0) 
4 (0.2) 
3 (0.1) 
Hyponatraemia 
31 (1.3) 
29 (1.2) 
15 (0.6) 
14 (0.6) 
Pleural effusion 
30 (1.2) 
22 (0.9) 
6 (0.2) 
5 (0.2) 
Renal failure acute 
30 (1.2) 
24 (1.0) 
7 (0.3) 
5 (0.2) 
Convulsiona 
29 (1.2) 
18 (0.7) 
5 (0.2) 
2 (0.1) 
Decreased appetite 
28 (1.2) 
20 (0.8) 
19 (0.8) 
14 (0.6) 
Bone pain 
27 (1.1) 
23 (1.0) 
0 
0 
Sepsis 
27 (1.1) 
27 (1.1) 
5 (0.2) 
5 (0.2) 
Metastatic pain 
26 (1.1) 
20 (0.8) 
1 (0.0) 
0 
Confusional state 
25 (1.0) 
17 (0.7) 
7 (0.3) 
5 (0.2) 
 
Constipation 
25 (1.0) 
9 (0.4) 
9 (0.4) 
4 (0.2) 
Spinal cord compression 
23 (1.0) 
22 (0.9) 
1 (0.0) 
1 (0.0) 


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MedDRA, Medical Dictionary for Regulatory Activities; SAE, serious adverse event. 
Note: Reported SAEs were coded using MedDRA version 17.0. At each level of summarization, a subject is counted 
only once if the subject reported one or more events. 
Note: This table summarizes pooled data from the safety database for single-agent cabozantinib studies (XL184-001, 
XL184-008, XL184-201, XL184-203, XL184-205, XL184-301 cabozantinib arm, XL184-306 cabozantinib arm 
XL184-307 cabozantinib arm, XL184 308 cabozantinib arm, and XL184-401). 
Note: Disease progression is expected for subjects with advanced cancer on cabozantinib clinical trials, and as such, 
events of progression of underlying cancer are not included. 
a   Twenty out of 29 of the observed convulsion events were reported in subjects with glioblastoma (GB) enrolled in 
Studies XL184-201 or XL184-205. For more information on safety observed in subjects with GB, see Section 
.4.3.1. 
 
 The primary aim of this proposed trial is to evaluate the safety and exploratory efficacy 
signal of this agent as a therapy in recurrent central nervous system tumors.  There is 
biological evidence that the targets of this drug are present and relevant in glioblastoma 
multiforme, anaplastic astrocytoma, and diffuse intrinsic pontine glioma, all of which are 
conditions with a dismal prognosis.  Subjects on study will have routine safety 
evaluations of complete blood counts, complete metabolic panel, and 12 lead ECGs.  All 
subjects will be followed closely for safety and tolerability. Therapy will be discontinued if 
there is evidence of tumor progression. 
3. 
Specific Aims 
 
Primary Safety Aim:  Assess the safety and tolerability of cabozantinib in refractory 
and/or recurrent central nervous system tumors who have previously received prior 
treatment, including radiation therapy. 
 
Primary Efficacy Aim:  Assess the disease control rate (CR, PR, or SD for at least 6 
months of cabozantinib in refractory and/or recurrent pediatric central nervous system 
tumors who have previously received prior treatment, including radiation therapy. 
 
 
Secondary Aims:   
1. Assess the 6 month progression free survival (PFS) in subjects with refractory or 
recurrent central nervous system tumors who have previously received prior 
treatment, including radiation therapy treated with cabozantinib 
2. Assess the utilization of corticosteroid use in subjects with recurrent or refractory 
central nervous system tumors treated with cabozantinib 


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3. Assess the objective response rate of target lesion in subjects with recurrent or 
refractory central nervous system tumors treated with cabozantinib 
4. Assess the overall survival (OS) rate at 6 months and 12 months in subjects with 
refractory or recurrent central nervous system tumors treated with cabozantinib 
5. Assess the 12 month PFS in subjects with refractory or recurrent central nervous 
system tumors treated with cabozantinib. 
4. 
Treatments 
4.1 Composition, Formulation, and Storage 
At study sites, all study medication will be stored as described in the pharmacy manual 
and inventoried in accordance with applicable state and federal regulations. 
Investigational Treatment  
 
Chemical Name:  
Chemical Name: N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N’-(4-
fluorophenyl)cyclopropane-1,1-dicarboxamide, (2S)-
hydroxybutanedioate 
 
Cabozantinib Tablets  
Exelixis internal number: XL184 
Cabozantinib tablets are supplied as film coated tablets containing cabozantinib malate 
equivalent to 20 mg and 60mg of cabozantinib and contain microcrystalline cellulose, 
lactose anhydrous, hydoxypropyl cellulose, croscarmellose sodium, colloidal silicon 
dioxide, magnesium stearate and Opadry® yellow. All tablet strengths are prepared from 
a common blend and are distinguished by shape. The 20 mg tablets are round and the 
60 mg tablets have an oval shape. The components of the tablets are listed in Table 4-1. 
 


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TABLE 4-1: 
CABOZANTINIB TABLET COMPONENTS AND COMPOSITION 
Ingredient  
Function 
% w/w 
Cabozantinib malate (25% drug load as cabozantinib) 
Active Ingredient 
31.7 
Microcrystalline Cellulose (Avicel PH-102) 
Filler 
38.9 
Lactose Anhydrous (60M) 
Filler 
19.4 
Hydroxypropyl Cellulose (EXF) 
Binder 
3.0 
Croscarmellose Sodium (Ac-Di-Sol) 
Disenegrant 
6.0 
Colloidal Silicon Dioxide, 
Glidant 
0.3 
Magnesium Stearate 
Lubricant 
0.75 
Opadry Yellow Film Coating which includes: 
- 
HPMC 2910/Hypromellose 6 cp  
- 
Titanium dioxide  
- 
Triacetin  
- 
Iron Oxide Yellow 
Film Coating 
4.00 
 
 
 
 
 
4.2 Dose, Schedule and Route 
Study medication will be taken daily at a dose of 40 mg/m2.  Drug cycles will last 28 
days and be continuous for up to 12 months of therapy on study.  
Cabozantinib will be held for subjects who experience toxicity until the toxicity has 
decreased to grade 1.  Cabozantinib will then be reduced by one dose level and not 
re-escalated in subsequent cycles.  Subjects who experience toxicity at dose level -1 
will be off study (See Section 7.0 for Dose Modification guidelines). 
 
 
Dose Level 
 
Dose (mg/m2/dose with max dose 60 mg/day) 
 
-1 
 
 
30 mg/m2 
 
 1 
 
 
40 mg/m2 
 
 
 
Actual dosing will be based on dosing nomogram in Appendix VI 
 
 


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Cabozantinib must be taken on an empty stomach.  Subjects must be instructed not to 
eat for at least 2 hours before and at least 1 hour after taking cabozantinib.  Subjects 
should be instructed to take their cabozantinib dose at approximately the same time 
every day.  If a subject misses a dose, the dose may be taken later only if it is within 12 
hours of when the missed dose should have been taken.  The missed dose should not 
be made up if it is within 12 hours of the next scheduled dose.   
Cabozantinib tablets should be swallowed whole with at least 8 ounces of water.  The 
tablets should not be crushed. Grapefruit, grapefruit juice, Seville oranges and their 
products should be avoided by subjects taking cabozantinib. 
5. 
Inclusion/Exclusion Criteria 
 
Inclusion Criteria 
 
1. Age:  Patients must be ≥2 years and ≤21 years of age 
2. Diagnosis:  Patients with relapsed or refractory central nervous system tumors.  
Patients must have had histologic verification of malignancy at original diagnosis 
or relapse.  Metastatic disease to the spine or primary tumors in the spine are 
eligible.  Patients may be in first, second, or third relapse.  Subjects with intrinsic 
brain stem gliomas may be eligible with or without histological confirmation.  
Please contact study chair prior to enrollment.  
3. Disease Status:  Patients must have measurable disease. Linear enhancement 
of leptomeningeal without measurable mass is excluded.   
4. Therapeutic Options:  Patient’s current disease state must be one for which there 
is no accepted standard therapy, no known curative therapy or therapy proven to 
prolong survival with an acceptable quality of life. For patients in whom surgery is 
feasible, maximal surgical resection must have occurred.  
5. Performance Level:  Karnofsky ≥ 50% for patients > 16 years of age and Lansky 
≥ 50 for patients ≤ 16 years of age (See Appendix I). Note: Neurologic deficits in 
patients must have been relatively stable for at least 7 days prior to study 
enrollment. Patients who are unable to walk because of paralysis, but who are in 
a wheelchair, will be considered ambulatory for the purpose of assessing the 
performance score. 
6. Subjects must have a reasonable life expectancy of at least 2 months. 
7. Prior Therapy 
a. Patients must have fully recovered from the acute toxic effects of all prior 
anti-cancer chemotherapy 


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i. Cytotoxic chemotherapy (including investigational agents) or 
biologic agents (eg. Cytokines or antibodies): At least 3 weeks 
after the last dose. 
ii. Nitrosoureas/mitomycin C: At least 6 weeks from the last dose.  
iii. XRT: At least 14 days after local palliative XRT (small port); At 
least 150 days must have elapsed if prior TBI, craniospinal XRT or 
if ≥ 50% radiation of pelvis; At least 42 days must have elapsed if 
other substantial BM radiation. e.g. Stem cell Infusion without TBI: 
No evidence of active graft vs. host disease and at least 56 days 
must have elapsed after transplant or stem cell infusion. 
8. Organ Function Requirements: 
a. Adequate bone marrow function defined as: absolute neutrophil count 
(ANC ≥1000/mm3) 
i. Platelet count ≥ 100,000/ mm3 (transfusion independent, defined 
as not receiving platelet transfusions for at least 7 days prior to 
enrollment) 
ii. Patients with bone marrow metastatic disease will not be eligible. 
b. Adequate renal function defined as:  
i. Creatinine clearance or radioisotope GFR ≥ 70mL/min/1.73 m² or 
a serum creatinine based on age/gender as follows: 
 
Age 
Maximum 
Serum
Male 
Female 
2 to < 6 years 
0.8 
0.8 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this table were derived 
from the Schwartz formula for estimating GFR (Schwartz et 
al. J. Peds, 106:522, 1985) utilizing child length and stature 
data published by the CDC. 
ii. Urine protein: ≤ 30 mg/dL in urinalysis or ≤ 1+ on dipstick, unless 
quantitative protein is < 1000 mg in a 24 hour urine sample.  
c. Adequate Liver Function Defined as:  
 


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i. Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of 
normal (ULN) for age  
ii. SGPT (ALT) ≤ 110 U/L. For the purpose of this study, the ULN for 
SGPT is 45 U/L.  
iii. Serum albumin ≥ 2.8 g/dL.  
d. Adequate coagulation status defined as: PT and INR ≤ 1.5x ULN  
e.  Adequate pancreatic function defined as: Serum amylase and lipase ≤ 
1.5 x ULN 
f. Adequate blood pressure control defined as: A blood pressure (BP) 
≤ the 95th percentile for age, height and gender (Appendix II) despite 
optimal antihypertensive treatment within 7 days of the first dose of 
the study treatment. Please note that 3 serial blood pressures should 
be obtained and averaged to determine baseline BP. 
g. Central nervous system function defined as: Patients with seizure 
disorder may be enrolled if receiving non-enzyme inducing 
anticonvulsants and well controlled. See Appendix III for a list of 
recommended non-enzyme inducing anticonvulsants. 
h.  Adequate cardiac function defined as:   
i. No history of congenital QTc syndrome, NYHA Class III or IV 
congestive heart failure (CHF) 
ii. No clinical significant cardiac arrhythmias, stroke or myocardial 
infarction within 6 months prior to enrollment 
iii. QTc  
≤ 480 msec. Note: One ECG must be performed for eligibility 
determination. If the QTc is > 480 msec, two additional ECGs 
must be performed and the average of the three ECGs will be 
used to determine eligibility. Patients with Grade 1 prolonged QTc 
(450-480 msec) at the time of study enrollment should have 
correctable causes of prolonged QTc addressed if possible (i.e. 
electrolytes, medications). See Appendix IV for a list of drugs that 
prolong QTc.  
9. Informed consent: All patients and/or their parents or legally authorized 
representatives must sign a written informed consent.  Assent, when appropriate 
will be obtained according to institutional guidelines. 
10. Archival tumor tissue slides must be sent or available, except for patients with 
intrinsic pontine glioma meeting the remainder of the inclusion criteria.  
 


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Exclusion Criteria 
 
1. Pregnancy or Breast-Feeding:  Pregnant or breast-feeding women will not be 
entered on this study due to risks of fetal and teratogentic adverse events as 
seen in animal/human studies.  Pregnancy tests must be obtained in girls who 
are post-menarchal. Males or females of reproductive potential may not 
participate unless they have agreed to use two methods of birth control- a 
medically accepted barrier method of contraceptive method (e.g., male or female 
condom) and a second effective method of birth control- during protocol therapy 
and for at least 4 months after the last dose of cabozantinib. Abstinence is an 
acceptable method of birth control. 
2. Concomitant Medications: 
a. 
Corticosteroids: Patients receiving corticosteroids who have not been on 
a stable or decreasing dose of corticosteroid for at least 7 days prior to 
enrollment are not eligible. 
b. 
Investigational drugs:  Patients who are currently receiving another 
investigational drug are not eligible. 
c. 
Anti-cancer agents:  patients who are currently receiving other anti-cancer 
agents are not eligible. 
d. 
CYP3A4 active agents:  Patients must not be receiving any of the 
following potent CYP3A4 inducers or inhibitors: erythromycin, 
clarithromycin, ketoconazole, azithromycin, itraconazole, grapefruit juice 
or St. John’s wort. A list of other known CYP3A4 inducers and inhibitors 
that should be discontinued prior to initiation of protocol therapy and 
should be avoided during study therapy if reasonable alternatives exist is 
included in Appendix V.  
e. 
Patients who are receiving systemic therapeutic treatment anticoagulation 
are not eligible. Patients receiving prophylactic systemic anticoagulation 
will be allowed with heparin or LMWH as long as eligibility PT/INR 
requirements are met.  Concomitant anticoagulation with oral 
anticoagulations (e.g. warfarin, direct thrombin and Factor Xa inhibitors) 
or platelet inhibitors (eg. Clopidogrel) are not allowed.   
f. 
Enzyme-inducing anticonvulsants: Patients must not have received 
enzyme–inducing anticonvulsants within 14 days prior to enrollment (See 
Appendix III for a list of unacceptable enzyme inducing anticonvulsants).  
g. 
QTc Agents: Patients who are receiving drugs that prolong QTc are not 
eligible (See Appendix IV for a list of agents).  
3. Patients must be able to swallow intact tablets. Patients who cannot swallow 
intact tablets are not eligible. 


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4. Patients with active bleeding are not eligible. Specifically, no clinically significant 
GI bleeding, GI perforation, intra-abdominal abscess or fistula for 6 months prior 
to enrollment, no hemoptysis or other signs of pulmonary hemorrhage for 3 
months prior to enrollment.  
5. Patients with evidence of an acute intracranial or intratumoral hemorrhage on CT 
or MRI are not eligible (patients with evidence of resolving hemorrhage will be 
eligible).  
6. Major surgery within 28 days of enrollment. Complete wound healing from major 
or minor surgery must have occurred prior to enrollment. Minor surgery (including 
uncomplicated tooth extractions) within 7 days of enrollment. Subjects with 
clinically relevant ongoing complications from prior surgery are not eligible. 
7. Concurrent uncontrolled hypertension defined as sustained blood pressure> 95th 
percentile for age, height and gender (systolic or diastolic) despite optimal 
antihypertensive treatment within 7 days of the first dose of study treatment. 
8. Patients with any medical or surgical conditions that would interfere with 
gastrointestinal absorption of this oral agent are not eligible. 
9. Infection: Patients who have an uncontrolled infection are not eligible. 
10. Patients who have received a prior solid organ transplantation are not eligible. 
11. Patients who in the opinion of the investigator may not be able to comply with the 
safety monitoring requirements of the study are not eligible. 
12. Subjects who have received cabozantinib or have an allergy to cabozantinib are 
excluded.  Subjects who have previously received tyrosine kinase inhibitors are 
allowed. 
13. Subjects who have not received radiation therapy as part of their prior treatment 
are excluded.  
6. 
Enrollment/ Study population 
 
Eleven patients between the ages of 2 years and 21 years with a diagnosis of recurrent 
or refractory central nervous system tumor.  
All patients will be enrolled through the Neuro-Oncology Program at Riley Hospital for 
Children at IU Health.  This is an open label trial and there will be no randomization. 
Justification for Institutional Enrollment:  Between 2014 to date (5/2016), 15 patients 
with newly diagnosed high grade glioma were evaluated in the Neuro-oncology clinic at 
Riley Hospital for Children.  As of 5/2016, 14 of 15 have recurred, relapsed, or died as a 
consequence of their disease.  Based on this we expect to be able to enroll 11 subjects 
on this study as proposed within the 5 year period of enrollment.   


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7. 
Study Procedures 
 
Pre-study evaluations: The investigational nature and objectives of the trial, the 
procedures and treatments involved and their attendant risks and discomforts and 
potential alternative therapies will be carefully explained to the patient and or the 
patient’s parent(s) or guardian if the patient is a child, and a signed informed consent 
and assent will be obtained according to institutional and federal guidelines.   
Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial 
must only be done after obtaining written informed consent.  Documentation of the 
informed consent for screening will be maintained in the subject’s research chart.  
Studies or procedures that were performed for clinical indications (not exclusively to 
determine eligibility) may be used for baseline values even if the studies were done 
before informed consent was obtained.  
Within 14 days of starting study drug, pre-study evaluations include: History and physical 
exam, laboratory studies, performance status, pregnancy test (for females of child 
bearing age), 12-lead ECG and MRI of brain +/- spinal cord. 
Criteria for Starting Subsequent cycles: A cycle may be repeated every 28 days(+/- 3 
days) if the subject does not have evidence of progressive disease and has again met 
laboratory parameters as defined in the eligibility criteria, with the exception of ANC, 
which must be ≥1000/mm3to start each cycle. 
 
History and physical exam, laboratory studies, performance status, study drug and 
corticosteroid drug diaries will be collected every 15 days (+/- 72 hours) after initiation of 
drug for cycles 1-3.   
History and physical exam, laboratory studies, performance status, study drug and 
corticosteroid drug diaries will be collected every 28 days (+/- 72 hours) for cycles 4-12.  
MRI’s will be performed every 3 months (+/- 1 week).  
12-lead ECG will be performed at pre-study, End of Cycle 1, End of Cycle 3 and End of 
Cycle 6, unless additional ECGs are required per protocol guidance (dose modification 
or concomitant medication usage) 
 


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^ Studies may be obtained within +/- 72 hours unless otherwise specified within the table 
1. All studies to determine eligibility must be performed within 2 weeks prior to enrollment.  Consent 
must be obtained prior to enrollment but does not expire at 2 weeks. 
2. Baseline BP should be obtained by collecting 3 serial BP measurements at least 5 minutes apart and 
then averaging the second and third BP measurements. 
3. CMP should include: sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, 
glucose, albumin, total protein, SGOT (AST), SGPT (ALT), total bilirubin, alkaline phosphatase 
4. For females of childbearing age 
5. If the subject starts a medication with substantial evidence that the drug prolongs the QT interval, then 
ECG monitoring must be performed at the end of each cycle while on the medication  
6. For subjects with Complete or Partial response confirmatory MRI per RANO criteria will be performed 
within 6 weeks. For scheduling purpose, obtain within +/- 1 week of required observation 
Study Schedule:STUDIES 
TO BE OBTAINED 
Pre-
Study
1 
Cycle 1 
^ 
Cycle 2, 3 
^ 
Cycle 4-12     
^ 
Completion 
of Study 
Informed Consent obtained 
X 
 
 
 
 
History (including Con Meds) 
X 
Day 28 
Days 15, 
28 
Day 28 
X 
Physical exam with vital signs 
and pulse ox 
X 
Days 15 
and 28  
Days 15, 
28 
Day 28 
X 
Height, weight, BSA 
X 
Day 28 
Days 15, 
28 
Day 28 
X 
Blood pressure2 
X 
Days 15 
and 28 
Days 15, 
28 
Day 28 
X 
Performance Status 
X 
Day 28 
Days 15, 
28 
Day 28 
X 
Subject Diaries (Study drug 
and steroid use) 
X 
Day 15 
& 28 
Day 15 & 
28) 
Day 28 
X 
CBC, differential, platelets 
X 
Days 15 
and 28 
Days 15, 
28 
Day 28 
X 
CMP3 with Ca, Mg, Phos, 
lipase, amylase 
X 
Days 15 
and 28 
Days 15, 
28 
Day 28 
X 
PT, PTT, INR 
X 
Day 28 
Day 28 
Day 28 
X 
Urinalysis 
X 
Day 28 
Day 28 
Day 28 
X 
Urine protein/creatinine 
X 
Day 28 
Day 28 
Day 28 
X 
Pregnancy test4 
X5 
 
Day 28 
Cycle 2  
Day 28 
Cycles 4, 6, 8, 
10, 12 
X 
Thyroid stimulating hormone 
X 
Day 28 
Day 28 
Cycle 3 
Day 28  
Cycles 6, 9, 
12 
X 
12- lead ECG5 
X 
Day 28 
Day 28 
Cycle 3 
Day 28  
Cycles 6 
 
MRI of brain +/- spinal cord if 
clinically indicated6 
X 
 
Day 28 
Cycle 3 
Day 28 
Cycles 6 and 
9 
X 
Assess for adverse events 
 
x 
x 
x 
x 


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7.1 Dose Modifications  
Dose Modifications of Cabozantinib for Treatment-Related AEs 
CTCAE v.5.0 Grade 
Recommended Guidelines for Managementa 
Grade 1 AEs 
Add supportive care as indicated. Continue 
cabozantinib treatment at the current dose level if 
AE is manageable and tolerable. 
Grade 2 AEs which are tolerable 
and are easily managed 
 
Grade 2 AEs which are 
intolerable and cannot be 
adequately managed  
Continue cabozantinib treatment at the current dose 
level with supportive care. 
 
At the discretion of the investigator, cabozantinib 
should be dose reduced or interrupted. 
Note: It is recommended that dose holds be as brief 
as possible.  
Grade 3 AEs (except clinically 
non-relevant laboratory 
abnormalities) 
Cabozantinib should be interrupted unless the 
toxicity can be easily managed with a dose reduction 
and optimal medical care.  
Note: It is recommended that dose holds be as brief 
as possible. 
Grade 4 AEs (except clinically 
non-relevant laboratory 
abnormalities) 
Subjects should have cabozantinib interrupted 
immediately.  
Discontinue cabozantinib unless the following 
criteria are met:  
• 
Subject is deriving clear clinical benefit as 
determined by the investigator and agreed by 
the Sponsor 
• 
Toxicity can be managed with a dose 
reduction following recovery to Grade 1 (or 
baseline) and optimal medical care  
AE, adverse event. 
Note: The dose delay and modification criteria for specific medical conditions are provided 
below. 
a Study treatment dose adjustment is only needed if the toxicity was deemed related to 
cabozantinib treatment or had an unclear relationship to cabozantinib treatment. 
 
 


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Warnings and Precautions and Guidelines for the Management of Adverse Events 
The most frequent adverse events experienced by ≥ 20% of subjects treated with 
cabozantinib were diarrhea, fatigue, nausea, decreased appetite, vomiting, weight 
decreased, PPES, constipation, hypertension, dysgeusia, dysphonia, and asthenia. 
Adverse events associated with laboratory abnormalities experienced by ≥ 5% of 
subjects treated with cabozantinib include anemia, AST increased, ALT increased, 
hypothyroidism, hypokalemia, hypomagnesemia, thrombocytopenia, hypocalcemia, 
hypophosphatemia, lipase increased, lactate dehydrogenase (LDH) increased, 
neutropenia, ALP increased, hyponatremia, and leukopenia. Mild to moderate QTc 
interval prolongation (10-15ms) has also been observed with a QT interval calculated by 
the Fridericia formula (QTcF) not exceeding 500 ms. 
Subjects may also experience medically important but less frequent adverse events 
including arterial and venous thrombotic AEs (eg, DVT, pulmonary embolism [PE], 
transient ischemic attack [TIA], and myocardial infarction [MI]), severe hemorrhagic 
events, proteinuria, wound healing complications, GI perforation, abscesses including 
intra-abdominal and pelvic abscess, GI and non-GI fistulae formation, osteonecrosis, 
and reverse posterior leukoencephalopathy syndrome (RPLS). 
Cabozantinib treatment should be permanently discontinued for the following adverse 
events: visceral perforation or fistula formation, severe hemorrhage, serious arterial 
thromboembolic events, nephrotic syndrome, malignant hypertension, hypertensive 
emergency, persistent uncontrolled hypertension despite optimal medical management, 
osteonecrosis of the jaw (ONJ), and RPLS. 
Guidelines for the management of AEs (ie, dose interruptions and dose reductions) are 
presented in the next sections. Each dose reduction of cabozantinib should be to one 
dose level lower that the current dose. Dose reductions of more than one dose level are 
acceptable per Investigator judgment. All AEs should also be managed with supportive 
care at the earliest signs of toxicity.   Adverse reactions are presumed to be attributable 
to study drug. Adverse events classified as “not related” are defined as AEs that are, 
without question, not associated with the study treatment and definitely attributable to 
another cause. 
The predicted effective plasma half-life of cabozantinib is 55 hours. Thus, when initiating 
therapy with cabozantinib, it will take most subjects 2 to 3 weeks to reach steady state. If 
AEs attributable to cabozantinib occur within the initial 3-week period of dosing, early 
intervention with dose modifications may be justified for AEs that, if worsened, could 
potentially be dangerous or debilitating, because without a dose adjustment, systemic 
exposure of cabozantinib might be expected to increase after the onset of the AE.   
Events that generally have an early onset include hypocalcemia, hypokalemia, 
thrombocytopenia, hypertension, PPES, abdominal pain, mucosal inflammation, 
constipation, diarrhea and vomiting. In addition, earlier onset for events of dehydration 
was observed in subjects with CRPC when compared with subjects with other tumor 
types. 


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Dose Modifications for Hematologic toxicity 
If a patient experiences dose-limiting Grade 4 neutropenia or thrombocytopenia, the 
treatment will be withheld. Counts should be checked every 3 - 4 days for 
thrombocytopenia and every other day for neutropenia during this time. If the toxicity 
resolves to meet eligibility parameters within 14 days of drug interruption, the patient 
may resume treatment at the next lower dose level. Doses reduced for toxicity will not be 
re-escalated, even if there is minimal or no toxicity with the reduced dose.  
 
If dose-limiting toxicity does not resolve to meet eligibility or baseline parameters within 
14 days of drug interruption, the patient must be removed from protocol therapy.  
 
One dose reduction will be allowed for toxicity.  If a patient does not tolerate reduced 
dose, they must be removed from protocol therapy. 
 
Dose Modifications for Non-Hematological toxicity 
If a patient experiences non-hematological dose-limiting toxicity as defined above, the 
treatment will be withheld. If the toxicity resolves to meet eligibility or baseline 
parameters within 14 days of drug discontinuation, the patient may resume treatment at 
the next lower dose level. Doses reduced for toxicity will not be re-escalated, even if 
there is minimal or no toxicity with the reduced dose.  
 
The exception to this is Grade 3 weight loss as it is unlikely that the patient would return 
to baseline within 14 days. Patients who experience Grade 3 weight loss may resume 
study medication after a 14 day interruption with a dose-reduction if the patient is 
deriving benefit from therapy, and the treating physician feels it is in the best interest of 
the patient. If the weight loss does not recover within 6 weeks the patient must be 
removed from protocol therapy.  
 
Dose Modifications for Proteinuria  
Cabozantinib should be permanently discontinued in subjects who develop nephrotic 
syndrome (proteinuria > 3.5 grams per day in combination with hypoalbuminemia and 
peripheral edema [hyperlipidemia and thrombotic disease may also be present]) or any 
other relevant renal disease. 
 
 


24 
 
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Management of Treatment-emergent Proteinuria 
Severity of Proteinuria 
(UPCR) 
Management of Proteinuria 
≤ 1 mg/mg 
(≤ 113.1 mg/mmol) 
• 
No change in cabozantinib treatment or monitoring 
> 1 and < 3.5 mg/mg 
(> 113.1 and < 395.9 
mg/mmol) 
• 
Consider confirming with a 24-hour protein assessment within 7 days 
• 
No change in cabozantinib treatment required if UPCR ≤ 2 mg/mg or 
urine protein ≤ 2 g/24 hours on 24-hour urine collection. 
• 
Dose reduce or interrupt cabozantinib treatment if UPCR > 2 mg/mg 
on repeat UPCR testing or urine protein > 2 g/24 hours on 24-hour 
urine collection. Continue cabozantinib on a reduced dose if UPCR 
decreases to < 2 mg/mg. Consider holding cabozantinib treatment if 
UPCR remains > 2 mg/mg despite a dose reduction until UPCR 
decreases to < 2 mg/mg. Restart cabozantinib treatment at a reduced 
dose after a dose hold unless otherwise approved by sponsor. 
• 
Repeat UPCR within 7 days and once per week. If UPCR < 1 mg/mg 
on 2 consecutive readings, UPCR monitoring can revert to protocol-
specific times. (Second reading is confirmatory and can be done 
within 1 week of first reading.) If UPCR remains > 1 mg/mg and < 2 
mg/mg for 1 month or is determined to be stable (< 20% change) for 
1 month, check urine protein/creatinine per protocol or as clinically 
indicated. 
≥ 3.5 mg/mg 
(≥ 395.9 mg/mmol) 
• 
Hold cabozantinib treatment pending repeat UPCR within 7 days 
and/or 24-hour urine protein.  
• 
If ≥ 3.5 mg/mg on repeat UPCR, continue to hold cabozantinib 
treatment and check UPCR every 7 days. If UPCR decreases to < 2 
mg/mg, restart cabozantinib treatment at a reduced dose and 
monitoring of urine protein/creatinine should continue weekly until 
the UPCR decreases to < 1 mg/mg. If UPCR remains > 1 mg/mg and 
< 2 mg/mg for 1 month or is determined to be stable (< 20% change) 
for 1 month, check urine protein/creatinine per protocol or as 
clinically indicated. 
Nephrotic syndrome 
• 
Discontinue all study treatment 
UPCR, urine protein/creatinine ratio. 
 
 
 
 
 
 


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Dose Modifications for Hypertension  
• Baseline blood pressure (BP) is defined as the blood pressure obtained at the 
examination used for study enrollment. This baseline BP should be obtained as 
follows:  
1. Obtain 3 serial blood pressures from the same extremity with the 
patient in the same position at rest with an appropriately sized cuff that 
are separated by at least 5 minutes. Avoid using the lower extremity if 
possible.  
2. Average the systolic blood pressure from the 2nd and 3rd 
measurements.  
3. Average the diastolic blood pressure from the 2nd and 3rd 
measurements.  
4. The baseline BP is the average of the systolic over the average of the 
diastolic measurements.  
 
• Elevation in either the systolic or diastolic blood pressure should be considered 
when following the algorithm below.  
• The upper limit of normal (ULN) is defined as a BP equal to the 95th percentile 
for age, height, and gender. See Appendix II.  
• The NCI CTCAE 5.0 will be utilized to determine the grade of hypertension for 
reporting purposes.  
• Elevated BP measurements should be repeated on the same day to confirm the 
elevation. If confirmed, patients with elevated BP should have BP measurements 
performed at least twice weekly until BP is ≤ ULN.  
• The algorithm12 below will be used to manage cabozantinib-related 
hypertension.  
• Hypertension should be managed with appropriate anti-hypertensive agent(s) 
as clinically indicated. It is strongly recommended that nephrology or cardiology 
be consulted in the evaluation and management of hypertension. 
 


26 
 
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Arm 1 of algorithm:  
• If blood pressure (BP) ≤ 95% for age, height, and gender, continue cabozantinib at the 
same dose.  
 
Arm 2 of algorithm:  
• If BP ≤ 10 mm Hg above the ULN for age, height, and gender, continue cabozantinib at 
the same dose and recheck the BP within 72 hours. o If the BP is ≤ ULN on recheck, 
continue cabozantinib at the same dose.  
o If the BP remains above the ULN on recheck, then start antihypertensive therapy and 
follow Arm 3 of the algorithm from the point that anti-hypertensive therapy is started.  
 
Arm 3 of algorithm:  
• If BP is 11 to 25 mm Hg above the 95% for age, height, and gender on ≥ 2 of 3 
measurements or > 35 mmHg above baseline on ≥ 2 of 3 measurements, start anti-
hypertensive therapy, continue cabozantinib at the same dose, and monitor BP at least 
twice weekly.  


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• 
If the BP returns to ≤ ULN within 14 days, continue cabozantinib at the 
same dose and continue anti-hypertensive therapy.  
• 
If the BP remains elevated ≤ 25 mm Hg above the 95% or > 35 mm 
Hg above baseline for more than 14 days after the institution of 
anti-hypertensive therapy, hold cabozantinib, monitor BP at least 
every 3 days, and follow Arm 4 of the algorithm from the point that 
cabozantinib is held. The antihypertensive therapy should be 
continued until the BP is less than the ULN.  
o If the BP returns to ≤ ULN within 14 days of holding cabozantinib, 
restart cabozantinib at a reduced dose  
o If the BP remains > ULN for more than 14 days after holding 
cabozantinib, patient is off protocol therapy. 
• 
If the BP increases to > 25 mm Hg above the ULN despite anti-
hypertensive therapy, hold cabozantinib, but continue the anti-
hypertensive agent(s). Monitor the BP as clinically indicated and follow 
Arm 4 of the algorithm from the point that cabozantinib is held. 
o If the BP is ≤ ULN within 14 days of holding cabozantinib, 
cabozantinib may be restarted at a reduced dose  
o If the BP is > ULN for > 14 days after holding cabozantinib, the 
patient is off protocol therapy.  
 
Arm 4 of algorithm:  
• If BP is > 25 mm Hg above the 95% for age, height, and gender, hold cabozantinib, 
monitor BP and administer anti-hypertensive therapy as clinically indicated. 
• 
If the BP returns to ≤ ULN within 14 days of holding cabozantinib, 
cabozantinib may be restarted at a reduced dose  
• 
If the BP is > ULN for >14 days after holding cabozantinib, the patient is 
off protocol therapy. 
 
Arm 5 of algorithm:  
• If the participant develops Grade 4 hypertension, discontinue cabozantinib, monitor BP 
and administer anti-hypertensive therapy as clinically indicated. The patient is off 
protocol therapy.  
 
 


28 
 
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Dose Modifications for Liver Toxicity  
Dose reductions of study treatment should be considered in any subject who develops 
drug-related Grade 2 elevated ALT, AST, or bilirubin lasting longer than 1 week. A 
subject who develops Grade ≥ 3 elevated ALT, AST, or bilirubin should have study 
treatment held and restarted at a reduced dose (see Appendix VI) after ALT, AST, and 
bilirubin levels resolve to at least Grade ≤ 1 or baseline. In subjects with recurrence of 
drug-related Grade ≥ 3 elevated ALT, AST, or bilirubin at the lowest dose level, study 
treatment should be discontinued. In subjects who develop ALT/AST elevations > 3  
ULN in combination with a bilirubin elevation > 2  ULN without reasonable other 
explanation, drug-induced liver injury should be suspected and cabozantinib treatment 
interrupted. 
 
Dose Modifications for Pancreatic Toxicity  
Cabozantinib should be held if patient experiences Grade 3 asymptomatic amylase or 
lipase elevation. Elevated laboratory parameters should be checked at least twice 
weekly until ≤ Grade 1.  
If lab values do not resolve to ≤ 1 Grade within 7 days of interruption or if toxicity recurs 
with re-challenge at reduced dose, then this will be considered dose-limiting. 
Cabozantinib will then be discontinued.  
 
Dose Modifications for Diarrhea  
If dose-limiting Grade 3 (> 3 days) or Grade 4 therapy-associated diarrhea is 
experienced by a patient despite maximal use of anti-diarrheal medications, the dose of 
cabozantinib should be reduced. Loperamide should be used at the first sign of 
significant diarrhea. 
Subjects should be instructed to notify their physician immediately at the first signs of 
poorly formed or loose stool or an increased frequency of bowel movements. 
Administration of antidiarrheal/antimotility agents is recommended at the first sign of 
diarrhea as initial management. Some subjects may require concomitant treatment with 
more than one antidiarrheal agent. When therapy with antidiarrheal agents does not 
control the diarrhea to tolerable levels, study treatment should be temporarily interrupted 
or dose reduced per table at beginning of section 7.1. 
In addition, general supportive measures should be implemented including hydration, 
correction of fluid and electrolyte abnormalities, small frequent meals, and stopping 
lactose-containing products, high fat meals, and alcohol.  
 
 
 


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Dose Modifications for Palmar Plantar Erythrodysthesia (PPE)  
CTCAE v.5.0 Grade  
Action To Be Taken  
Grade 1 
Study treatment may be continued at the current dose if PPES is clinically 
insignificant and tolerable. Otherwise, study treatment should be reduced 
to the next lower dose level.a Start urea 20% cream twice daily AND 
clobetasol 0.05% cream once daily. Reassess at least weekly; if PPES 
worsens at any time or does not improve after 2 weeks, proceed to the 
intervention guidelines for Grade 2. 
Grade 2  
Study treatment may be continued if PPES is tolerated. Study treatment 
should be dose reduced or interrupted if PPES is intolerable. Continue 
urea 20% cream twice daily AND clobetasol 0.05% cream once daily and 
add analgesics (eg, NSAIDs/gamma-aminobutyric acid agonists) for pain 
control if needed. Reassess at least weekly; if PPES worsens or affects 
self-care, proceed to the intervention guidelines for Grade 3. 
Grade 3 
Interrupt study treatment until severity decreases to Grade 1 or 0. 
Continue treatment of skin reaction with clobetasol 0.05% cream twice 
daily AND analgesics. Resume study drug at a reduced dose if PPES 
recovers to Grade ≤ 1. Discontinue subject from study treatment if PPES 
does not improve within 6 weeks. 
CTCAE, Common Terminology Criteria for Adverse Events; NSAID, non-steroidal anti-inflammatory drug; 
PPES, palmar plantar erythrodysesthesia syndrome. 
a Permitted dose levels are defined by individual protocols. 
 
7.2 Supportive Care and Other Concomitant Therapy 
 
Concurrent Anticancer Therapy 
Concurrent cancer therapy, including chemotherapy, radiation therapy, immunotherapy, 
or biologic therapy may NOT be administered to subjects receiving study drug. If these 
treatments are administered the subject will be removed from protocol therapy. 
 
Investigational Agents 
No other investigational agents may be given while the subject is on study. 
 
Supportive Care 
Appropriate antibiotics, blood products, anti-emetics, fluids, electrolytes and general 
supportive care are to be used as necessary. See Appendix III and V for drugs that should 
not be used concomitantly due to potential interactions with cabozantinib. 
 


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Diarrhea is a common side effect of cabozantinib. Loperamide should be used at the first 
sign of significant diarrhea.  
 
Palmar-plantar erythrodysesthesia syndrome (PPE; also known as hand-foot syndrome) is 
a common side effect of cabozantinib. Careful attention should be paid to skin exams and 
supportive care instituted early if any swelling or erythematous skin changes or symptoms 
of pain or burning/tingling are noted. Subjects should be instructed to apply moisturizing 
creams, avoid any trauma, harsh chemicals and limit hot water exposure. Topical steroid 
creams may be used and consider early dermatology referral. 
 
Growth Factors 
Growth factors that support platelet or white cell number or function can only be 
administered for culture proven bacteremia or invasive fungal infection. The Study Chair 
should be notified before growth factors are initiated. 
 
Concomitant Medications 
Medications that are strong inhibitors or inducers of CYP3A4 should be avoided  
The use of enzyme inducing anticonvulsants is not permitted.  
Medications that prolong the QT interval and have a known or possible risk of Torsades 
de Pointes should be avoided if possible, but are not explicitly excluded see appendix IV. 
If the subject starts a medication with substantial evidence that the drug prolongs the QT 
interval, then ECG monitoring must be end of each cycle while on the medication 
 
Wound Healing and Surgery 
VEGFR inhibitors can cause wound healing complications and wound dehiscence which 
may occur even long after a wound has been considered healed. Therefore, surgical and 
traumatic wounds must have completely healed before starting cabozantinib treatment 
and be monitored for wound dehiscence or wound infection while the subject is being 
treated with cabozantinib. Subjects should not have elective surgical procedures while 
on therapy. If possible, cabozantinib treatment should be stopped for at least 28 days 
prior to major surgery. For subjects who require emergent or urgent procedures, therapy 
may not be restarted until 28 days after major procedures and 7 days after minor 
procedures such as line replacement (3 days for external lines [e.g. Hickman or 
Broviac]). 
 


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Thromboembolic Events 
Thromboembolic complications are frequent in cancer patients due to procoagulant 
changes induced by the malignancy or anticancer therapy including inhibitors of VEGF 
pathways. Deep vein thrombosis and PE have been observed in clinical studies with 
cabozantinib; including fatal events (please refer to the Investigator’s Brochure). The risk 
of hemorrhage in cabozantinib-treated subjects with brain metastases has not been 
thoroughly analyzed. The incidence of CNS hemorrhage events in a study of subjects 
with GBM was higher than observed in general population of subjects with cancer 
treated with cabozantinib.  Based on this observation, any subjects on this study will be 
taken off study if DVT occurs and anticoagulation is required to reduce the risk of 
hemorrhage of subjects on study.  Subjects who require anticoagulation for any reason 
will be considered off-study. 
 
 Subjects with DVT who may require anticoagulant therapy will be taken off study.   
Arterial thrombotic events (eg, transient ischemic attack, myocardial infarction) have 
been observed in studies with cabozantinib. Subjects should be evaluated for preexisting 
risk factors for arterial thrombotic events such as diabetes mellitus, hyperlipidemia, 
hypertension, coronary artery disease, history of tobacco use, and cardiac or 
thromboembolic events that occurred before initiation of study treatment. Cabozantinib 
treatment should be discontinued in subjects who develop an acute myocardial 
infarction, cerebral infarction or any other clinically relevant arterial thromboembolic 
complication. 
 
Concurrent Anti-Hypertensive Therapy 
The algorithm above (See Section 7.1) will be used to grade and manage cabozantinib 
related hypertension. Should initiation of anti-hypertensive therapy be required, single 
agent therapy (commonly including the calcium channel blockers amlodipine or 
nifedipine, which are permissible without discussion with the study chair) should be 
started and the blood pressure should be monitored at least twice weekly until BP is 
within the 95th percentile for age, height, and gender. 
 
Management of Hypothyroidism 
Subjects with Grade 2 hypothyroidism adequately managed with thyroid hormone 
replacement may continue on protocol therapy. Subjects with Grade 3 or greater 
hypothyroidism will be considered to have had a dose-limiting toxicity. These subjects 
should be managed according to guidelines for non-hematologic toxicity and should also 
be evaluated by an endocrinologist for further management. Subjects who enter the 
study on thyroid replacement should have their medication adjusted to maintain TSH in 
the normal range. 
 


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Corrected QT Prolongation 
If at any time on study there is an increase in QTcF to an absolute value > 500 ms or an 
increase of > 60 ms above baseline, two additional ECGs must be performed with 
intervals not less than 3 min apart within 30 min after the initial ECG. 
If the average QTcF from the three ECGs is > 500 ms or increased by > 60 ms above 
baseline, the following actions must be taken: 
• Withhold study treatment 
• Immediately notify the Sponsor 
• Hospitalize symptomatic subjects (eg, with palpitations, dizziness, syncope, 
orthostatic hypotension, a significant ventricular arrhythmia on ECG) for a 
thorough cardiology evaluation and management 
• Consider cardiology consultation for asymptomatic subjects for evaluation and 
management 
• Check electrolytes, especially magnesium, potassium and calcium; correct 
abnormalities as clinically indicated 
• Check concomitant medications for any medication that may have contributed 
to QT prolongation, and if possible, discontinue these medications 
(http://www.qtdrugs.org) 
• Repeat ECG triplicates hourly until the average QTcF is ≤ 500 msec, or 
otherwise determined by consultation with a cardiologist or appropriate expert. 
Subjects with QTc prolongation and symptoms must be monitored closely until the QTc 
elevation and symptoms have resolved. Study treatment may be restarted at a reduced 
dose level if all of the following conditions are met: 
• Symptoms are determined to be unrelated to the QT interval prolongation 
The QTcF value > 500 ms or increase of > 60 ms above baseline is not 
confirmed according to protocol procedures 
• Study treatment has been interrupted through a minimum of 1 week following 
the return of the QTcF to ≤ 500 msec or return to ≤ 60 ms above baseline. 
• QT prolongation can be unequivocally associated with an event other than 
cabozantinib administration and is treatable/has been resolved 
• Sponsor has reviewed all available information and has agreed to the 
continuation of study treatment 
Following re-initiation of study treatment, ECGs must be repeated weekly for 2 weeks, 
then every 2 weeks for 1 month, then according to the protocol-defined time points. 
 
 


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All study treatment must be permanently discontinued if either of the following applies: 
• Cardiac evaluation confirms that symptoms are the consequence of QT interval 
prolongation 
• Recurrence of QTcF prolongation (confirmed by central ECG lab) after 
reinitiation of study treatment at a reduced dose 
8. 
Safety 
8.1 Adverse Events  
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
who has been enrolled in a clinical study and who may have been given an 
investigational product, regardless of whether or not the event is assessed as related to 
the study treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of an investigational product, regardless of whether or not the event is 
assessed as related to the investigational product. Pre-existing medical conditions that 
worsen during a study should be recorded as AEs. Abnormal laboratory values, ECG 
findings, or vital signs are to be recorded as AEs if they meet the criteria described in 
Section 7.0.  All Adverse Events will be graded using CTCAE v5.0.  per section 9.1 of 
this protocol.   
All untoward events that occur after informed consent through 30 after the decision to 
discontinue study treatment (or the date the subject is deemed to be a screen failure) 
are to be recorded by the investigational site. This requirement includes AEs from 
unscheduled as well as scheduled visits. 
Assessment of the relationship of the AE to the study treatment by the investigator is 
based on the following two definitions: 
• 
Not Related: A not-related AE is defined as an AE that is not associated with the 
study treatment and is attributable to another cause or there is no evidence to 
support a causal relationship; 
• 
Related: A related AE is defined as an AE where a causal relationship between 
the event and the study treatment is a reasonable possibility. A reasonable 
causal relationship is meant to convey that there are facts (eg, evidence such as 
dechallenge/rechallenge) or other clinical arguments to suggest a causal 
relationship between the AE and study treatment. 
 


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8.2 Serious Adverse Events  
The SAE definition and reporting requirements are in accordance with the International 
Conference of Harmonisation (ICH) Guideline for Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting, Topic E2A. 
An SAE is defined as any untoward medical occurrence that at any dose:  
• 
Result in death 
• 
Is immediately life-threatening (ie, in the opinion of the investigator, the AE 
places the subject at immediate risk of death; it does not include a reaction that, 
had it occurred in a more severe form, might have caused death) 
• 
Requires inpatient hospitalization or results in prolongation of an existing 
hospitalization 
• 
Results in persistent or significant disability or incapacity: 
o Note: The term “disability” refers to events that result in a substantial 
disruption of a subject’s ability to conduct normal life function. 
• 
Is a congenital anomaly or birth defect 
• 
Is an important medical event (IME) 
o Note: The term “important medical event” refers to an event that, based 
upon appropriate medical judgment, may not be immediately life-
threatening or result in death or hospitalization, but may jeopardize the 
subject or require intervention to prevent one of the other serious 
outcomes listed under the definition of SAE. Examples of IMEs include 
intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias, or convulsions that do not result in 
hospitalization; or development of product dependency or product abuse. 
8.3 Serious Adverse Event Reporting 
As soon as an investigator becomes aware of an AE that meets the definition of 
‘serious,’ this should be documented to the extent that information is available. 
Investigator shall notify Exelixis within twenty-four (24) hours of making such discovery 
by submitting a completed SAE report form and any other pertinent SAE information as 
indicated on the SAE reporting form. 
For multicenter studies the Investigator must notify the IND/CTA Sponsor by submitting 
a completed SAE report form and any other pertinent SAE information as indicated on 
the SAE reporting form within 24 hours to allow the IND/CTA Sponsor to submit the SAE 
report form to Exelixis no later than 2 business days. 
This report must be submitted by Institution to Exelixis at e-mail: 
drugsafety@exelixis.com or fax 650-837-7392, even if it is not felt to be drug related. 
Pregnancy (for a subject or for the partner of a subject), although not itself an SAE, 
should also be reported on a pregnancy form and be followed up to determine outcome, 


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including spontaneous or voluntary termination, details of birth, and the presence or 
absence of any birth defects or congenital abnormalities 
SAEs that must be recorded on an SAE Reporting form include the following: 
• 
all SAEs that occur after informed consent and through 30 days after the decision 
to discontinue study treatment (or the date the subject is deemed to be a screen 
failure) 
• 
any SAEs assessed as related to study treatment or study procedures, even if 
the SAE occurs more than 30 days after the decision to discontinue study 
treatment 
Although most hospitalizations necessitate reporting of an SAE, some hospitalizations 
do not require SAE reporting, as follows:  
• 
elective or previously scheduled surgeries or procedures for pre-existing 
conditions that have not worsened after initiation of treatment (eg, a previously 
scheduled ventral hernia repair) 
• 
pre-specified study hospitalizations for observation  
• 
events that result in hospital stays of fewer than 24 hours and that do not require 
admission (eg, an emergency room visit for hematuria that results in a diagnosis 
of cystitis and discharge to home on oral antibiotics).  
SAEs must, however, be reported for any surgical or procedural complication resulting in 
prolongation of the hospitalization. 
Adverse event terms recorded on the CRFs will be mapped to preferred terms using the 
Medical Dictionary for Regulatory Activities (MedDRA). Seriousness, severity grade and 
relationship to study treatment will be assessed by the investigator. Severity grade will 
be defined by the National Cancer Institute (NCI) CTCAE v5.0. Listings of AEs will be 
provided.  
8.4 Regulatory Reporting 
The Investigator will assess the expectedness of each related SAE. The current 
cabozantinib Reference Safety Information (Investigator Brochure) will be used as the 
reference document for assessing the expectedness of the event with regard to 
cabozantinib. All serious unexpected adverse drug reactions (unexpected related SAEs) 
must be reported to all appropriate regulatory authorities and Ethics Committees by the 
investigator as required by 21 CFR 312.32 or by Directive 2011/20/EC: 
• 
These reports are to be filed utilizing the Form FDA 3500A (MedWatch Form) or 
a CIOMS-1 form. 
• 
The final MedWatch Form or CIOMS-1 form must be submitted by the study site 
to Exelixis within one to two business days of submission to the FDA or 
applicable regulatory agency (including confirmation of date that the report was 
submitted) to allow Exelixis time to cross-report to Exelixis’ IND. E-mail: 
drugsafety@exelixis.com; Fax 650-837-7392. 


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• 
Exelixis reserves the right to upgrade the Investigator assessment of an SAE 
based on Sponsor reporting responsibilities. 
9. 
Other Safety Considerations 
9.1 Laboratory Data 
All laboratory data required by this protocol and any other clinical investigations should 
be reviewed. Any abnormal value that leads to a change in subject management 
(eg, dose reduction or delay or requirement for additional medication or monitoring) or 
that is considered to be of clinical significance by the investigator should be reported as 
an AE or SAE as appropriate. 
9.2 Pregnancy 
If a subject becomes pregnant during the study, she will be taken off study treatment and 
will be followed through the end of her pregnancy. The investigator must inform the 
Sponsor of the pregnancy. Forms for reporting pregnancies will be provided to the study 
sites upon request. The outcome of a pregnancy (for a subject or for the partner of a 
subject) and the medical condition of any resultant offspring must be reported to Exelixis 
or designee. Any birth defect or congenital anomaly must be reported as an SAE, and 
any other untoward events occurring during the pregnancy must be reported as AEs or 
SAEs, as appropriate. 
9.3 Medication Errors/Overdose 
Any study drug administration error or overdose that results in an AE, even if it does not 
meet the definition of serious, requires reporting within 24 hours to Exelixis or designee. 
9.4 Follow-Up of Adverse Events 
Any related SAEs or any AEs assessed as related that led to treatment discontinuation, 
including clinically significant abnormal laboratory values that meet these criteria, 
ongoing 30 days after the decision to discontinue study treatment must be followed until 
either resolution of the event or determination by the investigator that the event has 
become stable or irreversible. This follow-up guidance also applies to related SAEs that 
occur > 30 days after the decision to discontinue study treatment. The status of all 
other continuing AEs will be documented as of 30 days after the decision to discontinue 
study treatment. 
10. Data Forms and Submission Schedule 
 


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Study data will be collected and stored in OnCore®, developed by Forte Research 
Systems, Inc. (www.forteresearch.com).OnCore® Enterprise Research is a 
comprehensive, web-based, Clinical Trial Management System (CTMS) which utilizes 
an Oracle database.  It has been licensed by Indiana University (IU) to support the 
operations and data capture of clinical research trials. The system has been installed 
and configured within a HIPAA-aligned, Information Technology (IT), operations center 
supported by IU’s IT organization, University Information Technology Services (UITS). 
OnCore® provides users secure access with unique IDs/passwords and restricts access 
by assigned roles, from any location, to record, manage, and report on data associated 
with the operation and conduct of clinical trials. The system is comprised of three 
specific applications—Clinical Research Management (CRM), Biospecimen 
Management (BSM), and Unified Registries Management (URM). Indiana University 
leverages OnCore® to support clinical research operations specifically as it relates to the 
following functions/processes: electronic Scientific Review Committee (SRC), regulatory 
management, protocol and subject life cycle management, coverage analysis, study 
financials management, subject registration and visit management, subject safety 
monitoring, protocol deviation monitoring, study auditing and monitoring, electronic data 
management, correlative study sample management, specimen banking and 
management, registries management, effort tracking, and reporting. 
11.  Data Safety Monitoring 
 
This study will be conducted in accordance with the IU Simon Cancer Center Institutional 
DSMP for High Risk Trials.    
Investigators will conduct continuous review of data and subject safety. Weekly review 
meetings for high risk trials are required and will include the principal investigator, clinical 
research specialist and/or research nurse (other members per principal investigator’s 
discretion). Weekly meeting summaries should include review of data and subject safety 
by including for each dose level: the number of subjects, significant toxicities as 
described in the protocol, dose adjustments and responses observed. Study teams 
should maintain meeting minutes and attendance for submission to the DSMC upon 
request.    
Data and Safety Monitoring Committee  
The IUSCC Data and Safety Monitoring Committee (DSMC) is responsible for oversight 
of subject safety, regulatory compliance, and data integrity for this trial.  The DSMC will 
review this study semi-annually to review overall trial progress, toxicity, compliance, data 
integrity, and accrual per the Institutional DSMP.    
Furthermore, the DSMC conducts an administrative review of serious adverse events 
(SAEs), deviations, reportable events, and any other outstanding business. Major issues 
may require further DSMC review or action.    


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For any increase in frequency of grade 3 or above adverse events (above the rate 
reported in the Investigator Brochure or package insert), the principal investigator will 
notify the DSMC Chair immediately.  The notification will include the incidence of study 
adverse events, grades, and attributions, as well as investigator statements regarding 
comparison with risks per the IB/ package insert.     
At any time during the conduct of the trial, if it is the opinion of the investigators that the 
risks (or benefits) to the subject warrant early closure of the study, the DSMC Chair and 
Compliance Officer must be notified within 1 business day via email, and the IRB must 
be notified within 5 business days. Alternatively, the DSMC may initiate suspension or 
early closure of the study based on its review.  
IND Annual Reports  
For trials with an IND held locally by the IU principal investigator or university, the IND 
Annual Report will be prepared and submitted to the Compliance Team.  This report will 
be reviewed by the DSMC at the time of FDA submission.  
Study Auditing and Monitoring   
All trials conducted at the IUSCC are subject to auditing and/or monitoring per the 
Institutional DSMP. Reports will be reviewed by the full DSMC at the time of study 
review.   
Data Management/ Oncore Reporting Requirements  
The DSMC reviews data and study progress directly from Oncore; therefore, timely data 
entry and status updates are vital.  Study data must be entered within Oncore promptly, 
no later than one week from study visit occurrence.  Subject status in Oncore will be 
updated in real time, as this may affect overall trial enrollment status.  Global SAEs and 
deviations will be reviewed on a monthly basis by the DSMC Chair directly from Oncore.    
Study Accrual Oversight   
Accrual data will be entered into the IU Simon Cancer Center OnCore system. The 
Protocol Progress Committee (PPC) reviews study accrual twice per year, while the PPC 
coordinator reviews accrual quarterly.   
Oncore Safety Reporting  
In addition to protocol- and regulatory-required safety reporting, all serious adverse 
events (SAEs) will be captured in the Oncore system within 1 business day of 
notification.  Initial SAE reporting will include as much detail as available, with follow-up 
to provide complete information.  Attributions will be assessed to study drugs, 
procedures, study disease, and other alternate etiology.     
 
Protocol Deviation Reporting   
Protocol deviations will be entered into OnCore within 5 days of discovery and reviewed 
by the DSMC Chair on a monthly basis. Findings will be reported to the full DSMC at the 


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time of study review.  For serious or repetitive protocol deviations, additional action may 
be required by the DSMC. 
12.   Study Withdrawal/Discontinuation 
 
Reasons for a patient to not complete the study: 
a) Death 
b) Disease progression 
c) Lost to follow-up 
d) Entry into another therapeutic study 
e) Patient request to withdraw from clinical trial 
f) Manufacturing limitations on drug supplies 
g) Adverse events requiring removal from study 
h) Pregnancy 
i) Breastfeeding 
j) Non-compliance that in the opinion of the investigator does not allow for ongoing 
participation 
k) Physician determines that it is not in the patient’s best interest  
l) Subject develops DVT and requires anticoagulation therapy 
13. Evaluations 
Response criteria are assessed based on the product of the longest diameter and its 
longest perpendicular diameter.  Development of new disease or progression in any 
established lesions is considered progressive disease, regardless of response in other 
lesions. Response criteria are based on the Glioblastoma and Response Assessment in 
Neuro-Ocology (RANO) Criteria. 12 
Response criteria will be assessed by an independent radiologist Dr. Stephen Kralik. 
Complete response (CR):  Complete response requires all of the following: complete 
disappearance of all enhancing measurable and non-measurable disease sustained for 
at least 4 weeks; no new lesions; stable or improved non-enhancing (T2/FLAIR) lesions; 
and patient must be off corticosteroids or on physiologic replacement doses only, and 
stable or improved clinically. In the absence of a confirming scan 4 weeks later, this 
response will be considered only stable disease.  
Partial response (PR):  Partial response requires all of the following: ≥ 50% decrease, 
compared with baseline, in the sum of products of perpendicular diameters of all 
measurable enhancing lesions sustained for at least 4 weeks; no progression of non-
measurable disease; no new lesions; stable or improved non-enhancing (T2/FLAIR) 
lesions on same or lower dose of corticosteroids compared with baseline scan; and 
patient must be on a corticosteroid dose not greater than the dose at time of baseline 


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scan and is stable or improved clinically. In the absence of a confirming scan 4 weeks 
later, this response will be considered only stable disease.  
Stable disease (SD): Stable disease occurs if the patient does not qualify for complete 
response, partial response, or progression (see next section) and requires the following: 
stable non-enhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids 
compared with baseline scan and clinically stable status. In the event that the 
corticosteroid dose was increased for new symptoms and signs without confirmation of 
disease progression on neuroimaging, and subsequent follow-up imaging shows that 
this increase in corticosteroids was required because of disease progression, the last 
scan considered to show stable disease will be the scan obtained when the 
corticosteroid dose was equivalent to the baseline dose. 
 
Progressive Disease (PD):  
Progression is defined by any of the following: ≥ 25% increase in sum of the products of 
perpendicular diameters of enhancing lesions (compared with baseline if no decrease) 
on stable or increasing doses of corticosteroids; a significant increase in T2/FLAIR non-
enhancing lesions on stable or increasing doses of corticosteroids compared with 
baseline scan or best response after initiation of therapy, not due to comorbid events; 
the appearance of any new lesions; clear progression of non-measurable lesions; or 
definite clinical deterioration not attributable to other causes apart from the tumor, or to 
decrease in corticosteroid dose. Failure to return for evaluation as a result of death or 
deteriorating condition should also be considered as progression. 
Increase in corticosteroid dose alone, in the absence of clinical deterioration related to 
tumor, will not be used as a determinant of progression. Patients with stable imaging 
studies whose corticosteroid dose was increased for reasons other than clinical 
deterioration related to tumor do not qualify for stable disease or progression. They 
should be observed closely. If their corticosteroid dose can be reduced back to baseline, 
they will be considered as having stable disease; if further clinical deterioration related to 
tumor becomes apparent, they will be considered to have progression. The date of 
progression should be the first time point at which corticosteroid increase was 
necessary. 
The definition of clinical deterioration is left to the discretion of the treating physician, but 
it is recommended that a decline in the KPS from 100 or 90 to 70 or less, a decline in 
KPS of at least 20 from 80 or less, or a decline in KPS from any baseline to 50 or less, 
for at least 7 days, be considered neurologic deterioration unless attributable to 
comorbid events or changes in corticosteroid dose. Similarly, a decline in the Eastern 
Cooperative Oncology Group and WHO performance scores from 0 or 1 to 2 or 2 to 3 
would be considered neurologic deterioration. 
Patients with non-measurable enhancing disease whose lesions have significantly 
increased in size and become measurable (minimal bidirectional diameter of ≥ 10 mm 
and visible on at least two axial slices that are preferably, at most, 5 mm apart with 0-
mm skip) will also be considered to have experienced progression. The transition from a 


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non-measurable lesion to a measurable lesion resulting in progression can theoretically 
occur with relatively small increases in tumor size (eg, a 9 × 9 mm lesion [non-
measurable] increasing to a 10 × 11 mm lesion [measurable]). Ideally, the change 
should be significant (> 5 mm increase in maximal diameter or ≥ 25% increase in sum of 
the products of perpendicular diameters of enhancing lesions). In general, if there is 
doubt about whether the lesion has progressed, continued treatment and close follow-up 
evaluation will help clarify whether there is true progression. 
If there is uncertainty regarding whether there is progression, the patient may continue 
on treatment and remain under close observation (eg, evaluated at 4-week intervals). If 
subsequent evaluations suggest that the patient is in fact experiencing progression, then 
the date of progression should be the time point at which this issue was first raised. 
(Appendix VII) 
 14 Statistical Considerations 
 
14.1 General Considerations 
 
Parameter estimates and relevant summary statistics will be reported for both efficacy 
and safety outcomes. Continuous variables will be summarized by means, medians, 
minima, maxima and standard deviations. Categorical variables will be summarized by 
frequencies and percentages. Missing data will not be imputed. Additional exploratory 
analysis will be conducted when appropriate. Changes from the analysis plan will not 
require an amendment to the protocol unless it changes a significant feature in the 
protocol. The statistical analysis methods are outline below. 
 
14.2 Study Design 
 
This is a single arm pilot study. No randomization or blinding is involved. 
 
14.3 Analysis Population 
 
14.3.1  Enrolled Population 
 
The enrolled population comprises all patients who meet the eligibility 
criteria and are registered onto the study. 


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14.3.2   Safety Population 
 
The safety population comprises all patients who have received at least 
one dose of the study medication. This set will be used for safety analysis. 
14.3.3   Efficacy Population 
 
The efficacy population comprises all patients who have received at least 
one dose of the study medication, have been evaluated for the primary 
endpoint, and have no significant protocol violations. This population will 
be used for efficacy analysis. 
 
14.4 Sample Size, Accrual and Study Duration 
 
Our sample size is based on several considerations.  For binary events, such as 
observing specific AEs or see at least one patient with clinical benefit (or primary 
efficacy objective), the following table shows the probability of seeing at least one event 
with a sample of size 10.  
 
True Probability 
0.05 
0.10 
0.15 
0.20 
0.25 
0.30 
Chance of observing ≥1 
Event 
0.40 
0.65 
0.80 
0.89 
0.94 
0.97 
 
Thus, we will be able to see events that have a true probability of 0.15 or higher with 80% 
probability.  Accrual should take approximately 2 years and the entire length of the study 
approximately 3.5 years to allow up for start-up, at least 1 year follow-up per patient, and 
analysis and closure. 
 
 
14.5 Safety Analysis 
 
The safety set will be used for all safety analysis. All safety data will be listed. For the 
treatment-emergent AEs, namely AEs started or worsened during the on-treatment 
period, the incidence will be summarized by system organ class and/or preferred term, 
severity based on CTCAE 5.0 grades, type of adverse event and the relation to the 


43 
 
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study drug. Deaths reportable as SAEs and non-fatal serious adverse events will be 
listed by patient and tabulated by type of adverse event. 
 
14.6 Efficacy Analysis 
 
The efficacy set will be used for all the efficacy analysis.  For the primary efficacy aim of 
the disease control rate (CR, PR, or SD for at least 6 months), an estimate will be 
determined along with the corresponding exact 95% binomial confidence interval.  A 
similar analysis will be done for the secondary objective of objective response rate (CR, 
PR). 
 
For PFS and OS, the median and their corresponding two-sided 95% confidence 
intervals will be calculated using the Kaplan-Meier method.  Estimates and 95% 
confidence intervals will also be provided for 6 and 12 months. 
 
A listing of the patients who used corticosteroid will be provided. 
 
14.7 Interim Analysis 
 
No interim analysis will be performed. 
 
15 Privacy/Confidentiality Issues 
 
An informed consent shall be used prior to initiating any treatments.   The informed 
consent shall be approved by the Indiana University Institutional Review Board prior to 
the initiation of any treatments. 
 
Study data will be entered into a password protected database.  All institutional policies 
regarding protected health information will be followed. 


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15.1 Ethical aspects 
15.1.1 Local Regulations 
The study must fully adhere to the principles outlined in “Guideline for Good Clinical 
Practice” (GCP) ICH E6 Tripartite Guideline (January 1997). The investigator will ensure 
that the conduct of the study complies with the basic principles of GCP as outlined in the 
current version of 21 Code of Federal Regulations, subpart D, Part 312, “Responsibilities 
of Sponsors and Investigators” Part 50, “Protection of Human Subjects” and Part 56, 
“Institutional Review Boards.” 
15.1.2 Informed Consent 
It is the responsibility of the investigator, or a person designated by the investigator, to 
obtain written informed consent from each subject participating in this study after 
adequate explanation of the aims, methods, anticipated benefits, and potential hazards 
of the study. In the case where the subject is unable to read, an impartial witness should 
be present during the entire informed consent discussion. After the subject has orally 
consented to participation in the trial, the witness’s signature on the form will attest that 
the information in the consent form was accurately explained and understood. 
The CRF for this study contains a section for documenting informed subject consent, 
and this must be completed appropriately. If new safety information results in significant 
changes in the risk/benefit assessment, the consent form should be reviewed and 
updated as necessary. All subjects (including those already being treated) should be 
informed of the new information, should be given a copy of the revised form, and should 
give their consent to continue in the study. 
15.1.3 Institutional Review Board/Ethics Committee  
This study is being conducted under a United States Investigational New Drug 
application or other Clinical Trial Application, as appropriate. This protocol (and any 
modifications) and appropriate consent procedures must be reviewed and approved by 
an IRB/EC. This board must operate in accordance with current local, regional, and 
federal regulations. The investigator will send a letter or certificate of IRB/EC approval to 
Exelixis (or designee) before subject enrollment and whenever subsequent modifications 
to the protocol are made. 


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15.1.4 Future Use of Patient Samples 
No samples for anything other than safety testing will be collected during this study.  
  
16 Follow-up and Record Retention 
 
The study will last for 60 months.  Records will be stored in password protected 
databases. Any paper records will be stored in locked file cabinets only accessible to 
study staff.   Records will be maintained for a minimum of 7 years after completion of 
study at which time they will be destroyed. 
 
17 Next Steps 
 
Phase 2 efficacy trial of cabozantinib in brain tumors has been proposed to the CNS 
Committee of the COG (Children’s Oncology Group) Consortium who requested 
additional pilot response data before considering to support a larger Consortia-wide 
efficacy trial. Exelilxis (pharmaceutical company) has expressed that the company is 
highly motivated to develop the drug in the pediatric solid tumor and brain tumor 
population to support a pediatric indication for this drug and would be supportive of an 
efficacy trial should the data warrant.  Depending on the result of this pilot, the current 
most feasible plan is to pursue NIH and/or foundation grant to support a regional or 
national (through COG) multi-site clinical trial in this population.  Patients have the option 
of COG phase 1 safety trials with limited availability, outside single institutional trials, or 
limited institution Pediatric Brain Tumor Consortium (PBTC) trials for which there is 
limited availability and not available in Indiana and require significant travel commitment.  
The goal is to have an institutionally available option for clinical trial enrollment at Riley 
Hospital for Children.  


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REFERENCES 
 
1. 
Louis DN, Ohgaki H, Wiestler OD, et al. The 2007 WHO classification of tumours 
of the central nervous system. Acta Neuropathol. 2007; 114(2):97-109. 
2. 
Broniscer A, Gajjar A. Supratentorial high-grade astrocytoma and diffuse 
brainstem glioma: two challenges for the pediatric oncologist. The oncologist. 
2004; 9(2):197-206. 
3. 
Fangusaro J. Pediatric high-grade gliomas and diffuse intrinsic pontine gliomas. 
Journal of child neurology. 2009; 24(11):1409-1417. 
4. 
Castellone MD, Carlomagno F, Salvatore G, Santoro M. Receptor tyrosine 
kinase inhibitors in thyroid cancer. Best practice & research. Clinical 
endocrinology & metabolism. 2008; 22(6):1023-1038. 
5. 
Comprehensive genomic characterization defines human glioblastoma genes 
and core pathways. Nature. 2008; 455(7216):1061-1068. 
6. 
Koochekpour S, Jeffers M, Rulong S, et al. Met and hepatocyte growth 
factor/scatter factor expression in human gliomas. Cancer research. 1997; 
57(23):5391-5398. 
7. 
Yakes FM, Chen J, Tan J, et al. Cabozantinib (XL184), a novel MET and 
VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and 
tumor growth. Molecular cancer therapeutics. 2011; 10(12):2298-2308. 
8. 
Antonelli M, Massimino M, Morra I, et al. Expression of pERK and pAKT in 
pediatric high grade astrocytomas: correlation with YKL40 and prognostic 
significance. Neuropathology : official journal of the Japanese Society of 
Neuropathology. 2012; 32(2):133-138. 
9. 
Giunti L, Pantaleo M, Sardi I, et al. Genome-wide copy number analysis in 
pediatric glioblastoma multiforme. American journal of cancer research. 2014; 
4(3):293-303. 
10. 
Paugh BS, Broniscer A, Qu C, et al. Genome-wide analyses identify recurrent 
amplifications of receptor tyrosine kinases and cell-cycle regulatory genes in 
diffuse intrinsic pontine glioma. J Clin Oncol. 2011; 29(30):3999-4006. 
11. 
Beal K, Abrey LE, Gutin PH. Antiangiogenic agents in the treatment of recurrent 
or newly diagnosed glioblastoma: analysis of single-agent and combined 
modality approaches. Radiat Oncol. 2011; 6:2. 
12.      Chuk, M., MD. (2014, June). Children's Oncology Group protocol ADVL 1211 
titled "A Phase 1 study of XL184 (CAbozantinib) in Children and adolescents with 
recurrent or refractory solid tumors including CNS tumors. Presented at 
American Society of Clinical Oncology, Chicago. 


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13. 
 Wen PY, Macdonald DR, Reardon DA et al: Updated response assessment 
criteria for high-grade gliomas: response assessment in neuro-oncology working 
group. J Clin Oncol 2010, 28:1963–1972. 
 
 
 


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Appendix I: Performance Status Scales 
 
 
 
 
 
 
 


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Appendix II: Blood Pressure norms: 
Blood pressure (BP) levels for BOYS 
 
Systolic Blood Pressure, mm Hg 
Diastolic Blood Pressure, mm 
Age 
BP 
Percentile of Height 
Percentile of Height 
(years) 
Percentile 5th 
10th 
25th 
50th 
75th 
90th 95th 5th 
10t
25t
50t
75t
90t
95t
1 
95th 
98 
99 
101 
103 
104 
106 106 54 
54 
55 
56 
57 
58 
58 
2 
95th 
101 
102 
104 
106 
108 
109 110 59 
59 
60 
61 
62 
63 
63 
3 
95th 
104 
105 
107 
109 
110 
112 113 63 
63 
64 
65 
66 
67 
67 
4 
95th 
106 
107 
109 
111 
112 
114 115 66 
67 
68 
69 
70 
71 
71 
5 
95th 
108 
109 
110 
112 
114 
115 116 69 
70 
71 
72 
73 
74 
74 
6 
95th 
109 
110 
112 
114 
115 
117 117 72 
72 
73 
74 
75 
76 
76 
7 
95th 
110 
111 
113 
115 
117 
118 119 74 
74 
75 
76 
77 
78 
78 
8 
95th 
111 
112 
114 
116 
118 
119 120 75 
76 
77 
78 
79 
79 
80 
9 
95th 
113 
114 
116 
118 
119 
121 121 76 
77 
78 
79 
80 
81 
81 
10 
95th 
115 
116 
117 
119 
121 
122 123 77 
78 
79 
80 
81 
81 
82 
11 
95th 
117 
118 
119 
121 
123 
124 125 78 
78 
79 
80 
81 
82 
82 
12 
95th 
119 
120 
122 
123 
125 
127 127 78 
79 
80 
81 
82 
82 
83 
13 
95th 
121 
122 
124 
126 
128 
129 130 79 
79 
80 
81 
82 
83 
83 
14 
95th 
124 
125 
127 
128 
130 
132 132 80 
80 
81 
82 
83 
84 
84 
15 
95th 
126 
127 
129 
131 
133 
134 135 81 
81 
82 
83 
84 
85 
85 
16 
95th 
129 
130 
132 
134 
135 
137 137 82 
83 
83 
84 
85 
86 
87 
≥17 
95th 
131 
132 
134 
136 
138 
139 140 84 
85 
86 
87 
87 
88 
89 
Instructions for using this BP Chart: 
1. Measure the patient’s blood pressure using an appropriate size cuff. 
2. Select appropriate chart for a female or male patient. 
3. Using the “age” row and “height” column determine if the BP is within the ULN. 
 
 
This table was taken from “The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and 
Adolescents” PEDIATRICS Vol. 114 No. 2 August 2004, pp. 555-576. 
 
 
 
 
 


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Blood pressure (BP) levels for GIRLS 
 
Systolic Blood Pressure, mm Hg 
Diastolic Blood Pressure, mm Hg 
 
 
Age 
BP 
Percentile of Height 
Percentile of Height 
(years) Percentile 5th 10th 25th 50th 75th 90th 95th 
5th 
10t
25th 50th 
75th 
90th 
95th 
1 
95th 
100 101 102 104 105 106 107 
56 
57 
57 
58 
59 
59 
60 
2 
95th 
102 103 104 105 107 108 109 
61 
62 
62 
63 
64 
65 
65 
3 
95th 
104 104 105 107 108 109 110 
65 
66 
66 
67 
68 
68 
69 
4 
95th 
105 106 107 108 110 111 112 
68 
68 
69 
70 
71 
71 
72 
5 
95th 
107 107 108 110 111 112 113 
70 
71 
71 
72 
73 
73 
74 
6 
95th 
108 109 110 111 113 114 115 
72 
72 
73 
74 
74 
75 
76 
7 
95th 
110 111 112 113 115 116 116 
73 
74 
74 
75 
76 
76 
77 
8 
95th 
112 112 114 115 116 118 118 
75 
75 
75 
76 
77 
78 
78 
9 
95th 
114 114 115 117 118 119 120 
76 
76 
76 
77 
78 
79 
79 
10 
95th 
116 116 117 119 120 121 122 
77 
77 
77 
78 
79 
80 
80 
11 
95th 
118 118 119 121 122 123 124 
78 
78 
78 
79 
80 
81 
81 
12 
95th 
119 120 121 123 124 125 126 
79 
79 
79 
80 
81 
82 
82 
13 
95th 
121 122 123 124 126 127 128 
80 
80 
80 
81 
82 
83 
83 
14 
95th 
123 123 125 126 127 129 129 
81 
81 
81 
82 
83 
84 
84 
15 
95th 
124 125 126 127 129 130 131 
82 
82 
82 
83 
84 
85 
85 
16 
95th 
125 126 127 128 130 131 132 
82 
82 
83 
84 
85 
85 
86 
≥17 
95th 
125 126 127 129 130 131 132 
82 
83 
83 
84 
85 
85 
86 
Instructions for using this BP Chart: 
1. 
Measure the patient’s blood pressure using an appropriate size cuff. 
2. 
Select appropriate chart for a female or male patient. 
3. 
Using the “age” row and “height” column determine if the BP is within the ULN. 
 
This table was taken from “The Fourth Report on the Diagnosis, Evaluation, and Treatment of High 
Blood Pressure in Children and Adolescents” PEDIATRICS Vol. 114 No. 2 August 2004, pp. 555-576. 
 


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Appendix III: UNACCEPTABLE ENZYME INDUCING AND 
RECOMMENDED NON-ENZYME INDUCING 
ANTICONVULSANTS 
Recommended Non-enzyme inducing 
anticonvulsants
Generic Name 
Trade Name 
Gabapentin 
Neurontin 
Lamotrigine 
Lamictal 
Levetiracetam 
Keppra 
Tigabine 
Gabitril 
Topiramate 
Topamax 
Valproic Acid 
Depakote, Depakene 
Zonisamide 
Zonegran 
Unacceptable Enzyme inducing anticonvulsants 
Generic Name 
Trade Name 
Carbamazepine 
Tegretol 
Felbamate 
Felbatol 
Phenobarbital 
Phenobarbital 
Phenytoin 
Dilantin 
Primidone 
Mysoline 
Oxcarbazepine 
Trileptal 


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Appendix IV: MEDICATIONS ASSOCIATED WITH 
PROLONGED QTC 
Medications that prolong QTc 
Generic name 
Brand name 
Generic name 
Brand name 
Amiodarone 
Cordarone® 
Haloperidol 
Haldol® 
Arsenic trioxide 
Trisenox® 
Ibutilide 
Corvert® 
Astemizole 
Hismanal® 
Mesoridazine 
Serentil® 
Azithromycin 
Zithromax® 
Methadone 
Dolophine® 
Bepridil 
Vascor® 
Moxifloxacin 
Avelox® 
Chloroquine 
Aralen® 
Pentamidine 
Pentam® 
Chlorpromazine 
Thorazine® 
Pimozide 
Orap® 
Clarithromycin 
Biaxin® 
Probucol 
Lorelco® 
Disopyramide 
Norpace® 
Procainamide 
Procan® 
Dofetilide 
Tikosyn® 
Quinidine 
Quinaglute® 
Domperidone 
Motilium® 
Sotalol 
Betapace® 
Droperidol 
Inapsine® 
Sparfloxacin 
Zagam® 
Erythromycin 
Erythrocin® 
Terfenadine 
Seldane® 
Flecainide 
Tambocor® 
Thioridazine 
Mellaril® 
Halofantrine 
Halfan® 
Vandetanib 
Caprelsa® 
Medications that may prolong QTc 
Generic name 
Trade name 
Generic name 
Trade name 
Alfuzosin 
Uroxatral® 
Moexipril/HCTZ 
Uniretic® 
Amantadine 
Symmetrel® 
Nicardipine 
Cardene® 
Atazanavir 
Reyataz® 
Nilotinib 
Tasigna® 
Chloral hydrate 
Noctec® 
Octreotide 
Sandostatin® 
Clozapine 
Clozaril® 
Ofloxacin 
Floxin® 
Dolasetron 
Anzemet® 
Ondansetron 
Zofran® 
Dronedarone 
Multaq® 
Oxytocin 
Pitocin® 
Eribulin 
Halaven® 
Paliperidone 
Invega® 
Escitalopram 
Cipralex® 
Quetiapine 
Seroquel® 
Escitalopram 
Lexapro® 
Ranolazine 
Ranexa® 
Famotidine 
Pepcid® 
Risperidone 
Risperdal® 
Felbamate 
Felbatrol® 
Roxithromycin 
Rulide® 
Fingolimod 
Gilenya® 
Sertindole 
Serdolect® 
Foscarnet 
Foscavir® 
Sertindole 
Serlect® 
Fosphenytoin 
Cerebyx® 
Sunitinib 
Sutent® 
Gemifloxacin 
Factive® 
Tacrolimus 
Prograf® 
Granisetron 
Kytril® 
Tamoxifen 
Nolvadex® 
Iloperidone 
Fanapt® 
Telithromycin 
Ketek® 
Indapamide 
Lozol® 
Tizanidine 
Zanaflex® 
Isradipine 
Dynacirc® 
Vardenafil 
Levitra® 
Lapatinib 
Tykerb® 
Venlafaxine 
Effexor® 
Levofloxacin 
Levaquin® 
Voriconazole 
VFend® 
Lithium 
Lithobid® 
Ziprasidone 
Geodon® 


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Appendix V: CYP3A4 INDUCERS AND INHIBITORS 
Strong 
Inhibitors 
Moderate 
Inhibitors 
Weak 
Inhibitors 
Other 
Inhibitors 
Inducers 
Clarithromycin 
Indinavir Itraconazole 
Ketoconazole 
Nefazodone 
Nelfinavir 
Posaconazole 
Ritonavir Saquinavir 
Telithromycin 
Aprepitant 
Diltiazem 
Erythromycin 
Fluconazole 
Grapefruit 
Grapefruit juice 
Verapamil 
Cimetidine 
Amiodarone 
Bocepravir 
Chloramphenicol 
Ciprofloxacin 
Delaviridine 
Fluvoxamine 
Imatinib 
Mifepristone 
Norfloxacin 
Norfluoxetine 
(fluoxetine) 
Star fruit 
Telaprevir 
Voriconazole 
Barbiturates 
Carbamazepine 
Efavirenz 
Glucocorticoids
* Modanfinil 
Nevirapine 
Oxcarbazepine 
Phenobarbital 
Phenytoin 
Pioglitazone 
Rifabutin 
Rifampin 
St. John’s wort 
 
 
 


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Appendix VI: Cabozantinib Dosing Nomogram 
 
40 mg/m2,  
Level 1 
Dose/Schedule 
Weekly 
Dose 
Weekly Dose/Schedule for 
Reduced Dose For Toxicity  
30 mg/m2 
0.33 – 0.39 
20 mg M, W, H, Sat, Sun 
100 mg 
60 mg = 20 mg M, W, F 
0.40 – 0.45 
20 mg M, T, W, F, Sat, Sun 
120 mg 
80 mg = 20 mg M, W, F, Sun 
0.46 – 0.55 
20 mg Daily 
140 mg 
100 mg = 20 mg M, W, H, Sat, 
Sun 
0.56 – 0.64 
40 mg M, W, F, Sun 
160 mg 
120 mg = 20 mg M, T, W, F, Sat, 
Sun 
0.65 – 0.78 
40 mg M, W, H, Sat, Sun 
200 mg 
140 mg = 20 mg Daily 
0.79 – 0.90 
40 mg M, T, W, F, Sat, Sun 
240 mg 
160 mg = 40 mg M, W, F, Sun 
0.91 – 1.09 
40 mg Daily 
280 mg 
200 mg = 40 mg M, W, H, Sat, 
Sun 
1.10 – 1.17 
60 mg M, W, H, Sat, Sun 
300 mg 
200 mg = 40 mg M, W, H, Sat, 
Sun 
1.18 – 1.36 
60 mg M, T, W, F, Sat, Sun 
360 mg 
240 mg = 40 mg M, T, W, F, Sat, 
Sun 
≥ 1.37  
60 mg Daily 
 
420 mg 
300 mg = 60 mg M, W, H, Sat, 
Sun 
 
 
 
 
 


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Appendix VII: Summary of RANO Response Criteria13  
Criterion 
Complete 
Response 
Partial 
Response 
Stable Disease 
Progressive 
Disease 
T1 enhancing disease 
None 
≥ 50% ↓ 
< 50% ↓ but < 25% ↑ 
≥ 25% ↑* 
T2/FLAIR 
Stable or ↓ 
Stable or ↓ 
Stable or ↓ 
↑* 
New lesion 
None 
None 
None 
Present* 
Corticosteroids 
None 
Stable or ↓ 
Stable or ↓ 
NA† 
Clinical status 
Stable or ↑ 
Stable or ↑ 
Stable or ↑ 
↓* 
Requirement for 
response 
All 
All 
All 
Any* 
* Progression occurs when this criterion is present. 
† Increase in corticosteroids alone will not be taken into account in determining 
progression in the persistent clinical deterioration. 
 

ICF_001.pdf: 
IU Consent Version Date: March 5, 2021 
1 
 
INDIANA UNIVERSITY INFORMED CONSENT STATEMENT FOR 
Pilot Study of Cabozantinib for Recurrent or Progressive Central Nervous System 
Tumors in Children 
 
You/your child are invited to participate in a research study of the use of Cabozantinb for treatment of children 
with a central nervous system tumor. If you are the parent or guardian of a child under 18 years old, you will be 
asked  to read and sign this document to give permission for your child to participate. Your child may also be 
asked to sign an assent form agreeing to participate in the study. You/your child were selected as a possible 
subject because you/your child have a refractory or recurrent central nervous system tumor. Please read this form 
and ask any questions you may have before agreeing to be in  the study. 
 
The study is being conducted by Dr. Scott Coven, Department of Pediatrics – Hematology/Oncology. It is funded 
by Indiana University; the drug Cabozantinib is provided by the manufacturer, Exelixis. 
 
STUDY PURPOSE 
 
The purpose of this study is to find out if the drug, Cabozantinib, is safe and tolerable in pediatric patients with 
refractory and/or recurrent central nervous system tumors who have previously received prior treatment. We are 
also looking to see if the drug has an effect on the rate at which the tumor grows at 6 months. 
 
NUMBER OF PEOPLE TAKING PART IN THE STUDY 
 
If you agree to participate, you will be one of 11 subjects who will be participating in this research. Participation 
in the study can last for up to one year. 
 
PROCEDURES FOR THE STUDY 
 
If you agree to be in the study, you will do the following things: 
 
Before starting the study… 
Prior to enrolling on this clinical trial, your study doctor will make sure you are eligible to receive this treatment. 
The following tests will be done: 
 
• 
Urine Pregnancy Test for females of child-bearing potential (this test must be negative, not pregnant) 
If your child is 14 and older, pregnancy results will be provided to your child only. If your child is 13 
or younger and has a positive pregnancy test, you and your child will be informed of the results, as 
well as applicable state agencies. 
• 
Physical Exam and Medical History 
• 
Laboratory tests including blood tests and urine tests to monitor your health during treatment  
• 
MRI (Magnetic Resonance Imaging) scan - These are scans that will be performed to evaluate the 
tumor prior to starting your treatment 
• 
ECG – to monitor the electrical activity of your heart 
 
If these tests show that you are eligible to participate in the clinical trial, you will begin the study treatment. If you 
do not meet the eligibility criteria, you will not be able to participate in this clinical trial. 
 
During Study Treatment: 
 
The start of receiving Cabozantinib will be within 14 days of study enrollment. Cabozantinib should be taken on an 
empty stomach (fasting is required 2 hours before and 1 hour after each Cabozantinib dose). 


IU Consent Version Date: March 5, 2021 
2 
 
Cabozantinib should NOT be re-taken if vomiting occurs after taking a scheduled dose. Dosing may continue the 
next day as scheduled. You will take Cabozantinib once a day. 
 
While participating in this trial, you will be followed at this center to monitor the safety of this treatment and to 
evaluate if the tumor is responding well. Once the treatment begins, you will have follow-up visits as outlined below: 
 
Study Schedule: 
 
STUDIES TO BE OBTAINED 
Pre- 
Study1 
Cycle 1 
Cycle 2, 3 
Cycle 4-12 
Completion 
of Study 
History 
X 
Day 28 
Days 15, 28 
Day 28 
X 
Physical exam with vital signs 
and pulse ox 
X 
Days 15 
and 28 
Days 15, 28 
Day 28 
X 
Height, weight, BSA 
X 
Day 28 
Days 15, 28 
Day 28 
X 
Blood pressure2 
X 
Days 15 
and 28 
Days 15, 28 
Day 28 
X 
Performance Status 
X 
Day 28 
Days 15, 28 
Day 28 
X 
Subject Diaries (Study drug and 
steroid use) 
X 
Day 15 
& 28 
Day 15 & 
28) 
Day 28 
X 
CBC, differential, platelets 
X 
Days 15 
and 28 
Days 15, 28 
Day 28 
X 
CMP3 with Ca, Mg, Phos, lipase, 
amylase 
X 
Days 15 
and 28 
Days 15, 28 
Day 28 
X 
PT, PTT, INR 
X 
Day 28 
Day 28 
Day 28 
X 
Urinalysis 
X 
Day 28 
Day 28 
Day 28 
X 
Urine protein/creatinine 
X 
Day 28 
Day 28 
Day 28 
X 
Pregnancy test4 
X5 
Day 28 
Cycle 2 
Day 28 Cycles 
4, 6, 8, 10, 12 
X 
Thyroid stimulating hormone 
X 
Day 28 
Day 28 
Cycle 3 
Day 28 Cycles 
6, 9, 12 
X 
12- lead ECG5 
X 
Day 28 
Day 28 
Cycle 3 
Day 28 Cycles 
6 
MRI of brain +/- spinal cord if 
clinically indicated6 
X 
Day 28 
Cycle 3 
Day 28 Cycles 
6 and 9 
X 
1. All studies to determine eligibility must be performed within 2 weeks prior to enrollment. Consent must be obtained prior 
to enrollment but does not expire at 2 weeks. 
2. Baseline BP should be obtained by collecting 3 serial BP measurements at least 5 minutes apart and then averaging the 
second and third BP measurements. 
3. CMP should include: sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, glucose, albumin, total  
protein, SGOT (AST), SGPT (ALT), total bilirubin, alkaline phosphatase 
4. For females of childbearing age 
5. If the subject starts a medication with substantial evidence that the drug prolongs the QT interval, then ECG monitoring must 
performed at the end of each cycle while on the medication 
6. For subjects with Complete or Partial response confirmatory MRI per RANO criteria will be performed within 6 weeks 
 
 
MRI Scans will be performed to evaluate how well your tumor is responding to this treatment. These scans will be 
performed during treatment and prior to cycle 4, Cycle 7, prior to cycle 10 and after cycle 
12. If you remain on study beyond 12 cycles of treatment, you will have an MRI scan done to evaluate your disease 
every 6 cycles, annually thereafter, and/or one final scan done when you stop participating in this study. 
 
 
Additional exams, blood draws, etc. may be required if clinically indicated for standard of care. 


IU Consent Version Date: March 5, 2021 
3 
 
WHAT RISKS OR DISCOMFORTS ARE INVOLVED? 
 
You may have side effects while on the study. Everyone taking part in the study will be watched carefully for any 
side effects. However, doctors don’t know all the side effects that may happen. 
Side effects may be mild or very serious. Your study doctor may give you medicines to help lessen side effects. 
Many side effects go away soon after you stop taking the Cabozantinib. In some cases, side effects can be serious, 
long-lasting, or may never go away. There also is a risk of death. We will tell you if we learn any new 
information that may affect your health, welfare, or decision to stay in this study. 
 
You should talk to your study doctor about any side effects that you have while taking part in the study. 
Risks and side effects related to Cabozantinib include those which are: 
Very Common 
• Abdominal pain 
• Alteration of thyroid function tests 
• Blisters, rash, or pain in hands or feet 
• Changes in blood tests used to monitor the liver, which may indicate liver damage 
• Change in voice 
• Changes to the way things taste 
• Constipation 
• Diarrhea# 
• Fatigue 
• Hair color changes or hair loss 
• High blood pressure 
• Inflammation of mucus membranes 
• Loss of appetite 
• Mouth and/or throat sores or swelling 
• Nausea 
• Rash 
• Vomiting 
• Weakness 
• Weight loss 
 
Cabozantinib can cause diarrhea or other digestive problems. Not all subjects will have bad diarrhea or other 
digestive problems. Using the supportive care drug loperamide (also known as Imodium) may help prevent 
diarrhea. Loperamide should be used at the first sign of diarrhea. 
Common 
• 
Abnormal thickening of the outer layer of the skin 
• 
Change in the feeling of touch 
• 
Cough 
• 
Bleeding, including bleeding from stomach or intestines which may look like coffee grounds or black 
sticky bowel movements and bleeding within the brain 
• 
Blood clot in a large vein, usually in the leg 
• 
Blood clot that travels from a vein to the lung 
• 
Confusion and disorientation 
• 
Decreased amounts of red blood cells (anemia), which may cause feelings of tiredness or shortness of 
breath 
• 
Decreased amounts of calcium or sodium in the blood 


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• 
Decreased or increased amounts of potassium in the blood 
• 
Decreased amounts of magnesium or phosphorus in the blood 
• 
Decreased level of albumin in the blood 
• 
Decreased platelet counts, which increases the risk of bleeding or makes bleeding more difficult 
to stop 
• 
Decreased white blood cell counts, which may increase chances of infection 
• 
Dermatitis acneiform, a type of acne 
• 
Dehydration 
• 
Difficulty swallowing 
• 
Dizziness 
• 
Dry mouth 
• 
Dry skin 
• 
Fever 
• 
Fungal infections including mouth, lung, and other locations 
• 
Hemorrhoids and bleeding hemorrhoids 
• 
Headache 
• 
Increased amounts of pancreas enzymes in the blood, which may indicate damage to the pancreas 
• 
Increased levels of bilirubin in the blood, which may indicate complications with the liver 
• 
Increased levels of creatinine in the blood, which may indicate complications with the kidneys 
• 
Mouth or throat pain 
• 
Muscle spasm 
• 
Muscle weakness 
• 
Pain in a joint or muscle 
• 
Pain in extremities 
• 
Protein in the urine, which may indicate kidney damage 
• 
Shortness of breath 
• 
Stomach acid coming up from the stomach into the esophagus 
• 
Swelling of the limb(s) 
• 
Ulcer 
• 
Upset stomach or indigestion 
Uncommon: 
• 
Abnormal electrical activity in the heart that could cause a potentially serious change in heart rhythm 
• 
Abnormal opening between two organs or from an organ to the outside of the body 
• 
Abscesses (infected cavities filled with pus) 
• 
Blood clot in an artery 
• 
Chest discomfort originating from the heart 
• 
Clouding of the lens in the eye that affects vision 
• 
Damage to skeletal muscle tissue 
• 
Decreased brain function or decreased alertness and ability to think 
• 
Decrease in all blood counts (red blood cells, white blood cells and platelets) 
• 
Destruction of bone tissue, in particular, bone in the jaw 
• 
Feelings of unease or fear 
• 
Gallstones 
• 
Heart attack 
• 
Heart failure 


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• 
Holes in the stomach or intestines 
• 
Infections 
• 
Inflammation of the intestine, appendix, gall bladder or thin tissue lining the inner wall of the abdomen 
and most of the abdominal organs 
• 
Reduced kidney function 
• 
Loss of consciousness, fainting episode 
• 
Pneumonia and inflammation of the lungs 
• 
Rapid heart rhythm 
• 
Re-opening of wounds after surgery 
• 
Respiratory failure 
• 
Seizure 
• 
Stroke / mini-stroke 
• 
Tear or inflammation in skin that lines the anus 
• 
Uncoordinated movements 
 
Rare but Medically important 
• 
Air in the chest between lungs and chest wall 
• 
Allergic reaction 
• 
Anemia caused by destruction of red blood cells 
• 
Blocked intestines 
• 
Brain dysfunction caused by brain swelling 
• 
Cancer of the mouth or skin 
• 
Damage to the outermost surface of the eye 
• 
Inflammation and blockage of channels that carry bile from the liver 
• 
Severe swelling of the mouth, lips, tongue, eyes and throat, or difficulty swallowing or breathing 
• 
Temporary paralysis of the intestines 
• 
Throat swelling 
• 
Very high blood pressure that comes on suddenly and quickly and which can lead to serious injury to the 
heart and brain 
 
If you have a drop in the red blood cell count, the cells that carry oxygen around the body, you may feel tired. If 
your red blood cell count drops very low, you may need a blood transfusion. 
 
If you have a decrease in the white blood cell count, the cells that fight infection, you may be more likely to get an 
infection, including a serious infection that spreads through the bloodstream (sepsis). If this happens, you will 
have to come to the hospital to be treated with antibiotics. If your white blood cell count is very low and you get 
a fever, you may have to come to the hospital to get treated with antibiotics. 
 
If you have a low platelet count, particles in the blood that help with clotting, you may have easy bruising or 
bleeding. If the count is very low and there is bleeding, you might need platelet transfusions to help stop the 
bleeding. 
 
Cabozantinib may have an effect on the growth plates of bones of children who are still growing. In a study, a 
small number of children who received cabozantinib developed growth plate thickening. However, all children 
with this thickening still experienced bone growth; it is unclear if treatment with cabozantinib has an effect on bone 
length. 
Reproductive risks: 
Because the drug in this study can possibly cause abnormalities in an unborn baby and infants, you should not 
become pregnant or father a baby or breastfeed while you are on this study. Also, because Cabozantinib remains 
in your body for weeks to months, you should continue to use adequate contraceptive measures and avoid 
nursing a baby for at least 6 months after your last dose of Cabozantinib, although the optimal or the maximal 
time required for drug clearance cannot be precisely predicted. Let your doctor know immediately if you become 


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pregnant or find out that you are going to be the father of a child. We can provide counseling about preventing 
pregnancy for either male or female study participants. In addition, the effect of the study drug on the ability to 
have children in the future is uncertain. The study drug may make it more difficult or impossible to have children 
in the future. 
 
MRI Risks: 
This may cause some discomfort if you are uncomfortable in tight spaces. During this procedure, it is necessary 
for you to lie still for long periods of time. There are some loud noises you will hear from the machine, and ear 
plugs are available for you to use while in the MRI machine. Although this procedure may be uncomfortable, this 
is not painful. 
 
Risks of blood drawing or placing an intravenous catheter for blood drawing: 
Risks associated with drawing blood are slight, but some risks include: pain, excessive bleeding, fainting or 
feeling lightheaded, bruising, infection (a slight risk any time the skin is broken), and multiple punctures to locate 
veins. 
 
There is a possible risk of loss of confidentiality, but standard measures are in place to protect your medical and 
research information. 
 
For more information about risks and side effects, ask your study doctor. 
 
BENEFITS OF TAKING PART IN THE STUDY 
 
You may not directly benefit from participation in this study, however, a possible benefit may be that the tumor 
stops growing or becomes smaller. It is hoped that the information gained from this study will benefit future subjects 
with central nervous system tumors. 
 
 
ALTERNATIVES TO TAKING PART IN THE STUDY 
 
Instead of being in the study, alternative strategies will be offered at the discretion of your primary oncology 
team. 
 
CONFIDENTIALITY 
 
Efforts will be made to keep your personal information confidential. We cannot guarantee absolute 
confidentiality. Your personal information may be disclosed if required by law. Your identity will be held in 
confidence in reports in which the study may be published 
 
Organizations that may inspect and/or copy your research records for quality assurance and data analysis include 
groups such as the study investigator and his/her research associates, the Indiana University Institutional Review 
Board or its designees, Indiana Clinical Research Center (ICRC), IU Clinical Trials Data Safety Monitoring 
Committee and (as allowed by law) state or federal agencies, specifically the Office for Human Research 
Protections (OHRP) and the Food and Drug Administration (FDA), the National Cancer Institute (NCI) etc., who 
may need to access your medical and/or research records. 
 
A description of this clinical trial will be available on ClinicalTrials.gov, as required by U.S. law. This website 
will not include information that can identify you. At most, the website will include a summary of the results. You 
can search this website at any time. 
 
COSTS 
 
Taking part in this study may lead to added costs to you or your insurance company. You or your insurance 


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company will be responsible for the following costs 
• 
MRIs 
• 
Laboratory testing 
• 
ECG 
• 
Physical Exams 
You will not be responsible for these study-specific costs: 
• 
The drug: Cabozantinib 
 
PAYMENT 
 
You will not receive payment for taking part in this study. 
 
WILL MY INFORMATION BE USED FOR RESEARCH IN THE FUTURE? 
 
Information or specimens for this study may be used for future research studies or shared with other researchers 
for future research. If this happens, information which could identify you will be removed before any information 
or specimens are shared. Since identifying information will be removed, we will not ask for your additional 
consent. Specimens will not be used for whole genome sequencing. 
 
COMPENSATION FOR INJURY 
 
In the event of physical injury resulting from your participation in this research, necessary medical treatment will 
be provided to you and billed as part of your medical expenses. Costs not covered by your health care insurer will 
be your responsibility. Also, it is your responsibility to determine the extent of your health care coverage. There 
is no program in place for other monetary compensation for such injuries. However, you are not giving up any 
legal rights or benefits to which you are otherwise entitled. 
 
CONTACTS FOR QUESTIONS OR PROBLEMS 
 
For questions about the study or a research-related injury, contact the researcher, Dr. Scott Coven at 317-944- 
2143 during normal business hours. If you cannot reach the researcher during regular business hours (i.e., 8 a.m. 
to 5 p.m.), please call the IU Human Subjects Office at 317-278-3458 or 800-696-2949. After business hours, 
please call the Pediatric Hematologist/Oncologist on call at (317) 944-5000. 
 
In the event of an emergency, you may contact the Pediatric Hematologist/Oncologist on call at (317)944-5000. 
 
If you are unable to reach the investigator at the above number, in an emergency you may contact the Indiana 
University Hospital Pharmacy at 317-944-0362. 
 
For questions about your rights as a research participant, to discuss problems, complaints, or concerns about a 
research study, or to obtain information or offer input, contact the IU Human Subjects Office at 317-278-3458 or 
800-696-2949. 
 
VOLUNTARY NATURE OF THIS STUDY 
 
Taking part in this study is voluntary. You may choose not to take part or may leave the study at any time. 
Leaving the study will not result in any penalty or loss of benefits to which you are entitled. Your decision 
whether or not to participate in this study will not affect your current or future relations with Dr. Scott Coven or 
any other Pediatric Hematologist/Oncologist at IU Health. 


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Your participation may be terminated by the investigator without regard to your consent in the following 
circumstances: 
A. 
If you fail to follow the investigator's instructions including not completing the procedures required by the 
study and/or are unable or unwilling to come for the required doctor visits including any required follow-up 
visits 
B. 
If you experience a serious and unexpected side effect that may require evaluation. 
C. 
If your disease gets worse while on this treatment. 
D. 
If your tumor is not responding to Cabozantinib 
E. 
If you experience side effects that are considered to outweigh benefits of your participation. 
F. 
If the investigator feels it is in the best interest of your health and welfare. 
G. 
If the sponsor no longer provides the drug. 
H.  If you begin another treatment for your central nervous system tumor.


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SUBJECT’S CONSENT 
 
In consideration of all of the above, I give my consent to participate in this research study. 
 
I will be given a copy of this informed consent document to keep for my records. I agree to take part in this 
study. 
 
Subject’s Printed Name:  
 
 
 
Subject’s Signature: 
Date:  
 
 
(must be dated by the subject) 
 
Printed Name of Person Obtaining Consent:  
 
 
 
 
 
 
 
 
Signature of Person Obtaining Consent: 
Date:  
 
 
 
 
Printed Name of Parent:  
 
 
 
Signature of Parent: 
Date:  
 
 
 
Printed Name of Person Obtaining Consent:  
 
  
Signature of Person Obtaining Consent: 
Date: