Clinical trial NCT03352427
Conditions: Glioma High Grade Glioma Pontine Tumors
Sponsor: University of Michigan Rogel Cancer Center
Start date: 2017-12-06; Completion date: 2019-05-15
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This trial will evaluate the activity of dasatinib in combination with everolimus for children with gliomas harboring PDGFR alterations, including newly diagnosed high-grade glioma (HGG) or diffuse intrinsic pontine glioma (DIPG) after radiation (stratum A); and recurrent/progressive glioma (grade II-IV, including DIPG) (stratum B).

Detailed description:

Arms: arm 1: Dasatinib = 60 mg/m2 orally twice daily

Everolimus = starting dose of 3.0 mg/m2, with titration of dosing after first cycle to keep everolimus trough level of 5-15 ug/ml

Both agents will be taken daily for 28 day cycles. Cycles will be repeated every 28 days and patients may receive up to 24 cycles.
Interventions: intervention 1: Dasatinib intervention 2: Everolimus
Intervention descriptions: intervention 1: 60 mg/m2 orally twice daily intervention 2: 3.0 mg/m2, with titration of dosing after first cycle to keep trough level of 5-15 ug/ml

Protocol documents:
Prot_SAP_000.pdf: 
PI: Carl Koschmann, MD 
Protocol Version: 19-Feb-2019 
1 
UMCC 2017.042 
A Phase 2 Study of Dasatinib in Combination with Everolimus for 
Children with Gliomas Harboring PDGFR/Alterations 
Principal Investigator/Study Chair: 
Carl Koschmann, MD 
Assistant Professor of Pediatrics, University of Michigan 
Clinicaltrials.gov Identifier: 03352427 
Co-Investigators: 
Patricia Robertson, MD  
Hemant Parmar, MD  
Bernard Marini, PharmD 
Marcia Leonard, NP 
Denise Leung, MD MS 
Yoshie Umemura, MD 
Madhava Aryul, PhD 
Lili Zhao, PhD 
NCT03352427


 
PI: Carl Koschmann, MD 
Protocol Version: 19-Feb-2019 
 
2 
 
 
TABLE OF CONTENTS 
 
1.0 Protocol Summary 
4 
1.1 Study Schema 
5 
 
2.0 Objectives and Scientific Aims 
5 
2.1 Primary Objectives 
5 
2.2 Secondary Objectives 
5 
 
3.0 Background and Rationale 
6 
3.1 Precision Medicine for Pediatric Brain Tumors 
6 
3.2 PDGFR and Alterations in Pediatric Gliomas 
6 
3.3 Targeting PDGFR and with TKIs and Overcoming 
Efflux Proteins 
7 
3.4 Dasatinib 
7 
3.5 Everolimus 
8 
3.6 Novel imaging biomarkers for therapy response 
9 
3.7 Prospective analysis of CSF cell-free tumor DNA as a 
marker for therapy response 
9 
3.8 Proposed Study 
9 
 
4.0 Eligibility Requirements 
10 
4.1 Patient 
10 
4.2 Disease 
11 
4.3 Prior Therapies 
11 
4.4 Consent 
12 
4.5 Tumor Testing  
12 
4.6 Exclusion Criteria 
12 
 
5.0 Treatment/Intervention Plan 
13 
5.1 Therapy 
13 
5.2 Supportive Care 
14 
5.3 Therapy Modifications for Toxicity 
14 
5.3.1 Definition of Dose Limiting Toxicity (DLT) 
14 
5.3.2 Dasatinib 
16 
5.3.3 Everolimus 
17 
5.3.4 Dose reductions for specific agents 
18 
 
6.0 Biology and Imaging Correlates 
18 
6.1 Mandatory Biology Testing 
18 
6.2 Optional Biology Testing 
19 
6.3 Mandatory Imaging Correlates 
19 
 
7.0 Evaluations To Be Obtained 
20 
7.1 Pre-Treatment Evaluation 
20 
7.2 On-Study Evaluation 
21 
7.3 Follow-up Evaluation  
22 


 
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8.0 Therapeutic Agents 
23 
8.1 Use of Commercial Medications 
23 
8.2 Toxicities/Side Effects 
23 
8.2.1 Dasatinib 
23 
8.2.2 Everolimus 
24 
 
9.0 Criteria for Therapeutic Response/Outcome Assessment 
25 
9.1 Methodology to determine tumor measurement 
25 
9.2 Response criteria for target lesions 
26 
9.3 Overall response 
26 
 
10.0 Criteria for Removal From Study 
27 
10.1 Criteria for removal from study therapy 
27 
10.2 Off study criteria 
27 
 
11.0 Biostatistics 
27 
11.1 Estimated patient enrollment and study duration 
27 
11.2 End points 
28 
11.2.1 Primary End Points 
28 
11.2.2 Secondary End Points 
29 
 
12.0 Data Management 
30 
 
13.0 Protection of Human Subjects and Data Safety Monitoring Plan 
30 
 
14.0 Privacy and Confidentiality 
30 
 
15.0 Informed Consent Procedures 
30 
 
16.0 Adverse Events (AEs) 
31 
16.1 AE Definition 
31 
16.2 SAE Definition 
31 
16.3 Expectedness 
31 
16.4 Attribution 
32 
16.5 Reporting 
32 
 
References 
33 
 
Appendix A Data Safety Monitoring Plan 
36 
Appendix B CYP3A4 Inhibitors  
37 


 
PI: Carl Koschmann, MD 
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1.0 Protocol Summary 
 
Outcomes for children with brain tumors have lagged and brain tumors have become the leading 
cause of cancer-related mortality in younger patients.1 Because the blood brain barrier (BBB) 
restricts access to the central nervous system (CNS) to all but 5% of chemical compounds screened 
for drug development, utilization of targeted therapies in CNS tumors remains challenging.2 
Furthermore, traditional early-phase studies in pediatric neuro-oncology have not been designed 
to select patients based on individual tumor biology. Incorporating a precision medicine approach 
that both takes into account individual tumor biology and optimizes BBB drug penetration is a 
promising approach to improve outcomes for this devastating group of tumors. 
 
This phase 2 trial will evaluate the activity of dasatinib in combination with everolimus for children 
with gliomas harboring PDGFR or alterations, including newly diagnosed high-grade glioma 
or DIPG after radiation (stratum A) and recurrent/progressive glioma (grade II-IV, 
including DIPG) (stratum B). This approach involves incorporating a precision medicine 
approach (dasatinib targeting PDGFR/) with BBB optimization (everolimus inhibition of Bcrp1 
and P-gp and 
further RTK/PI3K pathway targeting). Eligibility will be determined by 
documentation of PDGFR or pathway alterations through tumor DNA and RNA sequencing. We 
will provide CLIA- certified molecular profiling of tumors through the University of Michigan 
PEDS-MIONCOSEQ study (HUM00056496). We will also accept CLIA-certified profiling 
(DNA/RNA sequencing) from private sequencing facilities. 
The primary objective of this study is to test and estimate the efficacy of the proposed regimen. 
The planned starting dose for dasatinib is the dose currently undergoing phase 2 trial in children 
with refractory solid tumors (AALL1131, NCT02883049), 60 mg/m2 orally twice daily. No dose 
escalation is planned. The planned starting dose for everolimus is 2/3 the current FDA-approved 
starting dose for children with sub-ependymal giant cell astrocytoma (SEGA) (3.0 mg/m2), with 
titration of dosing after first cycle to keep everolimus trough level of 5-15 ug/ml. Both agents will 
be taken daily for 28 day cycles. Cycles will be repeated every 28 days and patients may receive 
up to 24 cycles. Disease evaluation by MRI will be performed every two cycles. Drug levels of 
both agents will be monitored after first month; and serum level of everolimus will be monitored 
monthly throughout therapy to adjust dosing to trough concentration to 5-15 ng/ml. High b-
value diffusion weighted imaging (DWI) will be performed at the time of clinical MRIs to evaluate 
its utility as an imaging biomarker for therapy response. 
Cerebrospinal fluid (CSF) and plasma dasatinib pharmacokinetics will be performed by the 
University of Michigan to determine whether blood-CSF permeability of dasatinib is impacted by 


 
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dual therapy with everolimus.  Prior to first cycle, dasatinib will be taken as mono-therapy for 1 
week followed by CSF collection in order to establish mono-therapy dasatinib CSF level.  After 
cycle 2, CSF will be collected to establish dual-therapy dasatinib level (while on everolimus).  
Additionally, CSF collected at these time points will be used to explore CSF cell-free tumor DNA 
burden as a possible predictor of treatment response.  CSF collection prior to subsequent odd-
numbered cycles for above analysis will be optional. Up to 32 subjects will be enrolled on this 
trial.  
 
1.1  Study Schema 
 
Dasatinib
therapy 
alone
(7 days before  
cycle 1)
-6
 
day
1
visit,
CSF  collection
(mandatory),
labs
28 
Dasatinib and 
everolimus 
oral daily
(days 1-28 all 
subsequent cycles)
Cycle 1
28
Cycle 2
visit,
labs,
echo, EKG
visit,
labs
visit
MRI Brain (+/- spine),
CSF collection 
(mandatory),
labs,
echo, EKG
visit,
labs
Prior to 
cycle 4 and 
Evencycle #s
Prior to 
cycle 5 and 
odd cycle #s
visit,
MRI Brain (+/- spine),
CSF collection 
(optional),
labs,
echo, EKG
14 
Enrollment 
visit
MRI Brain 
(+/- spine),
labs
echo, EKG
 
 
2.0 Objectives and Scientific Aims 
 
2.1 Primary Objective 
2.1.1 STRATUM A: To determine the 1 year and 2 year progression-free and overall 
survival rates in patients receiving dasatinib in combination with everolimus as an adjuvant 
therapy following surgery and radiation therapy for children with newly diagnosed high- 
grade glioma or DIPG harboring PDGFR or alterations. 
2.1.2 STRATUM B: To determine the overall response rate after 2 cycles of dasatinib in 
combination with everolimus in children with refractory or recurrent glioma (grade II-IV, 
including DIPG) with PDGFR or alterations. 
2.2 Exploratory Objectives 
2.2.1 To define and describe the toxicities of dasatinib and everolimus administered as 
dual therapy. 
2.2.2 To prospectively evaluate high b-value diffusion weighted imaging (DWI) as an 
imaging biomarker for dasatinib and everolimus activity. 
2.2.3 To prospectively evaluate CSF a n d  p l a s m a  cell-free tumor DNA (ct-DNA) 
as a marker of disease activity in refractory glioma with PDGFR/alterations. 
2.2.4 To prospectively evaluate CSF dasatinib level as (1) a marker of blood-CSF 
permeability of dasatinib and (2) a predictor of treatment response.


 
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3.0 Background and Rationale 
 
Although outcomes for children and young adults with cancer have steadily improved over the 
past half-century, outcomes for children with brain tumors have lagged and brain tumors have 
become the leading cause of cancer-related mortality in younger patients.1 This is in large part 
due to the difficulty of employing many of the effective oncology treatments in this patient 
population.1,3,4 Because the blood brain barrier (BBB) restricts access to the central nervous 
system (CNS) to all but 5% of chemical compounds screened for drug development, utilization of 
targeted therapies in CNS tumors remains challenging.2 Furthermore, traditional early-phase 
studies in pediatric neuro-oncology have not been designed to select patients based on individual 
tumor biology. New therapies for malignant glioma are urgently needed. Incorporating a precision 
medicine approach that both takes into account individual tumor biology and optimizes BBB drug 
penetration is a promising approach to improve outcomes for this devastating group of tumors. 
This trial will evaluate the activity of dasatinib in combination with everolimus for children with 
malignant gliomas harboring PDGFR or alterations, including newly diagnosed high-grade (grade 
III-IV) glioma after radiation (stratum A) and recurrent/progressive grade II-IV glioma (stratum 
B). 
 
3.1  Precision Medicine for Pediatric Brain Tumors 
 
By histology, adult and pediatric brain tumors are identical; but at the molecular level, they are 
dissimilar tumors.3,5 Recurrent mutations and gene expression profiles of pediatric brain tumors 
are clearly distinct from their adult counterparts.3,6,7 In fact, molecular characterization of pediatric 
brain tumors has documented key differences among subgroups of the same tumor, as separated 
by age and location.3,5,8 Treatment responses may differ as well, with younger children responding 
to chemotherapy better than older children for certain brain tumors.9 Effective therapies for 
children and young adults with higher risk or refractory brain tumors are in urgent need, ideally 
based on the unique biology of each tumor. 
 
In contrast to analyses of adult tumors, recent surveys of pediatric tumors have shown that most 
develop from relatively few mutational events, many of which may be targetable with personalized 
clinically available agents.3,10 With the increasing use of tumor molecular profiling at many tertiary 
pediatric hospitals, multiple studies have demonstrated the feasibility 
of incorporating 
personalized genomic characterization into the management of higher-risk, refractory, or rare 
pediatric tumors.11-13 Precision medicine is therefore an exciting potential therapeutic area for 
younger patients with brain tumors. 
 
3.2  PDGFR and Alterations in Pediatric Gliomas 
 
Recent work has documented the mutation, amplification and up-regulation of PDGFRA in a 
significant subset (15-39%) of pediatric patients with high-grade glioma (HGG).7,14 In 
collaboration with Chris Jones (Institute for Cancer Research, London, UK), we recently analyzed 
an integrated genomic dataset from pediatric HGG patients (n=290) using multiple pediatric 
datasets and sequencing platforms. We found activating PDGFR alterations in 41 (14.1%) 
patients.  In multivariate analysis, PDGFRA mutation was correlated with worse prognosis (P = 


 
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0.026), and by Kaplan-Meier analysis, non-brainstem HGG with PDGFRA amplification carried 
a worse prognosis than non-brainstem HGG without PDGFRA amplification (P = 0.021), thus 
demonstrating its potential role as a significant tumor driver in pediatric HGG.15  
 
Additionally, our group recently performed an observational consecutive case-series involving 
children and young adults with brain tumors designated by their treating neuro-oncologist to be 
high risk (>25% chance for treatment failure) (mean age 9.7 years, range age 0-39, with only 3 
patients over 21). Participants underwent integrative clinical exome (tumor and germline DNA) 
and transcriptome (tumor RNA) sequencing using clinically integrated sequencing that was 
performed according to previous published CLIA-certified methodology.11,17 Of the 50 enrolled 
patients, eighteen patients (36%) had relapsed or refractory tumors (of which we sequenced the 
original tumor in 12 cases), and 13 patients (26%) had metastatic tumors. Sequencing revealed 
potentially actionable genomic alterations (as defined by our group in Mody et al, JAMA, 2015) 
Sequencing revealed a potentially actionable germline or tumor alterations in 25 (63%) tumors, of 
which 21 (53%) resulted in an impact on treatment or change of diagnosis. Seventeen of 20 
patients (85%) with glial tumors were found to have a potentially actionable result, which resulted 
in change of therapy in 14 (70%) patients. Six (15%) patients who underwent therapy changes 
had potential clinical benefit (partial response or stable disease greater than 6 months on therapy). 
Interestingly, 9 of 20 (45%) of glial tumors harbored genomic alteration (activating mutation or 
amplification) in the growth factor receptors PDGFR or FGFR or their ligands (PDGF, FGF). All 
six alterations were associated with corresponding outlier increased expression on RNA 
sequencing (Koschmann et al, Under Review). 
 
3.3  Targeting PDGFR and with TKIs and Overcoming Efflux Proteins 
 
There are multiple orally bioavailable tyrosine kinase inhibitors (TKIs) with published safety data 
in pediatric cancers. While many of these were originally developed for targeting receptor tyrosine 
kinases in human cancers, their kinase inhibition is not specific, and many display nanomolar 
efficacy against PDGFRA or .18 Some TKIs display activity active against HGG in vitro and in 
vivo in orthotopic animal models, and target many of the growth factor receptor pathways active 
in human glioma, including PDGFRA, PDGFRB, FGFR1/3, c-Kit, and VEGFR.15,19-21 Many 
TKIs display favorable characteristics for BBB penetration (small size, high lipophilicity), but are 
substrates for the active efflux proteins P-glycoprotein (P-gp) and breast cancer resistance protein 
(BCRP), which significantly limits their brain penetration.20 Importantly, recent work has shown 
that TKI delivery to brain tumor parenchyma may be further improved by strategies to inhibit 
P-gp and Bcrp1.20,22,23 Recent pre-clinical strategies have included co-administration of TKIs 
with agents that inhibit these proteins, including mammalian target of rapamycin (mTOR) 
inhibitors.24 
 
Given that efflux mechanisms appear to be the main limitation to CNS penetration of dasatinib, 
the concomitant use of a P-gp inhibiting pharmacologic agent (everolimus) may be beneficial.  We 
recently reviewed this topic and described our early clinical experience with this model (Marini et 
al).25 A common theme in the evaluation of targeted agents in neuro-oncology is the impediment 
of BBB penetration due to the presence of efflux pumps. These energy-dependent transporters are 
expressed on the apical surface of the cells that line the vasculature and actively efflux compounds 
that are able to cross the membrane via passive diffusion or other methods, thus limiting CNS 
accumulation of promising targeted therapies.26 The most commonly found ABC efflux 


 
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transporters, P-gp (also known as ABCB1 or MDR1) and BRCP (also known as ABCG2), are 
responsible for the efflux of a wide variety of traditional chemotherapy agents (e.g., 
anthracyclinces, taxanes, methotrexate).27 While small molecule inhibitors that have been 
developed in the last 15 years allow for targeted therapy based on molecular abnormalities, the 
vast majority of these molecules are also substrates for P-gp and BCRP efflux pumps. Animal 
models with a variety of targeted therapies have demonstrated that inhibition of the efflux pumps 
can result in increased concentrations of the targeted therapy into the brain.20,24,28-31  
The concept of efflux pump inhibition to enhance CNS concentrations of the desired targeted 
agents has been shown to be effective pre-clinically, as well as in several patient cases.20,24,29-32 
Elacridor, a dual P-gp and BCRP inhibitor, was developed as such a pharmacokinetic modulator; 
however, this agent is not FDA approved or currently available clinically. There are few known, 
FDA-approved agents that inhibit both P-gp and BCRP, yet have minimal adverse pharmacologic 
effects. Everolimus, an orally bioavailable mTOR inhibitor, inhibits both P-gp and BCRP. In a 
preclinical study, everolimus was added to vandetanib, an oral multikinase inhibitor and P-gp and 
BCRP substrate with minimal CNS penetration but demonstrated in vitro activity in preclinical 
non-small cell lung cancer and brain tumor cells.24 Concomitant administration of everolimus 
resulted in a 3–4-fold increase in the murine brain to plasma concentration ratio of vandetanib. 
Based on these findings, as well as identified targetable RET mutation, a group of investigators 
reported treating a patient with non-small cell lung cancer with brain metastases using concomitant 
everolimus and vandetanib on a study protocol (ClinicalTrials.gov #NCT01582191), ultimately 
achieving both a systemic and intracranial response by PET/CT and MRI, respectively.32 Similarly, 
in pre-clinical models, by modulating P-gp and BCRP with the epidermal growth factor (EGFR) 
inhibitors erlotinib and canertinib, brain accumulation of pazopanib, a multikinase inhibitor 
approved for renal cell carcinoma and soft-tissue sarcoma, was increased 2–2.5-fold.20  
Importantly, recent work has shown that dasatinib delivery to brain tumor parenchyma is primarily 
restricted by P-gp, and inihibition of P-gp can improve penetration.  We therefore propose the use 
of dasatinib with the mTOR (and P-gp) inhibitor everolimus for the treatment of PDGF- and - 
altered pediatric brain tumors.33 
 
3.4  Dasatinib 
 
Dasatinib (SPRYCEL™, Bristol Myers Squib) is an orally bioavailable, ATP competitive small- 
molecular multi-targeted tyrosine kinase inhibitor.34 Dasatinib is currently FDA approved for the 
treatment  of patients  with  Philadelphia chromosome positive acute lymphoblastic leukemia. 
Dasatinib is active against the growth factor receptors BCR/ABL, Src, C-kit, and PDGFR-A/B. 
Dasatinib is a promising agent for pediatric HGG with PDGF pathway alterations. Dasatinib is an 
orally bioavailable tyrosine kinase inhibitor with ~60 fold greater inhibition of PDGFR signaling 
than earlier generation TKIs, such as imatinib.36 Our group previously performed paired molecular 
profiling (germline / tumor / primary cell culture) and targeting of infant thalamic HGG cells 
(UMPED05) with amplification and outlier increased expression of PDGFRA.15 Dasatinib 
inhibited proliferation most effectively. While it was originally developed for targeting the BCR- 
ABL gene fusion, it exhibits nanomolar range activity against PDGFRA in leukemia.18 In the 
previous pediatric Phase I trial using dasatinib in patients with leukemia and solid tumors, it was 
found to be well tolerated.37 Dasatinib displays moderately favorable characteristics for blood- 
brain barrier penetration and has demonstrated efficacy in adult patients with CNS metastases of 
CML,38 where CSF concentrations (3 nMol/L and 20 nMol/L) were near the IC50 we obtained for 


 
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UMPED05 (50 nMol/L) and previously published tumor cell cultures (4 nMol/L).36 
 
3.5  Everolimus 
Everolimus (AFFINITOR™, ZORTRESS™, Novartis) is an mTOR pathway inhibitor which is 
FDA approved for the treatment of advanced renal cell carcinoma, pancreatic neuroendocrine 
tumor, and subependymal giant cell astrocytoma (SEGA), including pediatric SEGA.39,40 
Everolimus has undergone phase 1 testing in pediatric solid tumor patients and the recommended 
phase 2 dose was 5 mg/m2 daily.41 Many children with tuberous sclerosis, who harbor a germline 
deficit related to the mTOR pathway, develop SEGA. In a phase 3 trial in children with 
SEGA, efficacy of everolimus was demonstrated in 75% of patients and no patients experienced 
disease progression during treatment.42 The efficacy of everolimus is currently being studied in 
a variety of tumors including pediatric brain tumors. Rare dose-limiting toxicities have included 
mucositis, infection and non-infectious pneumonitis. The starting dose for everolimus in the phase 
3 trial of everolimus was 4.5 mg/m2 daily, which resulted in excellent efficacy and minimal 
toxicity.42 
Everolimus displays active Bcrp1 and P-gp inhibition, which has been shown to improve brain 
parenchymal penetration of TKIs.24 Additionally, mTOR is downstream of the RTK/PI3K/AKT 
signaling pathway, which is active in pediatric gliomas with growth factor receptor activation, thus 
providing an additional benefit to its use in the treatment of these tumors.7,24 
3.6  Novel imaging biomarkers for therapy response: 
 
Conventional gadolinium (Gd) contrast-enhanced T1-weighted (T1W) and T2W or fluid- 
attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) may inadequately 
represent the extent of actively proliferating human high-grade glioma.43,44 Differentiating 
hypercellular components of high-grade glioma from vascular components, edema, and normal 
tissue is a challenge using FLAIR and conventional diffusion-weighted imaging (DWI) when 
standard b-values (1000 s/mm2 or lower) are used for diffusion measurement.43 Increasing b- 
values in the diffusion sequence beyond the conventional b-values has been shown to distinctly 
reveal high cellularity tumor volume (HCV).43 We propose to study the utility of adding increased 
b-value (3000 s/mm2) DWI to surveillance in the measurement of response to therapy. Both of 
these imaging correlates can be performed at tertiary clinical radiology centers. These imaging 
biomarkers will be explored as secondary objectives, and will be examined separately from 
primary imaging endpoints. 
 
3.7  Prospective analysis of CSF and plasma cell-free tumor DNA as a marker for therapy response: 
 
Due to their location in midline or deep structures, pediatric brain tumors would greatly benefit 
from non-invasive methods for tumor diagnosis and treatment surveillance. Recently, digital 
polymerase chain reaction–based technologies have been developed to evaluate the ability of cell- 
free tumor DNA to detect various cancer types.45 Cell-free DNA shed by cancer cells has been 
shown to provide tumor specific genomic information. Dr. Bettwegowda (Johns Hopkins), co- 
investigator for this study, has shown that cerebrospinal fluid tumor DNA (CSF-tDNA) can be 


 
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used as a patient-specific genomic biomarker in three-fourths of primary adult brain and spinal 
cord tumors.46 
 
We propose to prospectively evaluate CSF and plasma tDNA as a marker of disease activity 
in patients undergoing therapy. We will measure and compare CSF and plasma samples 
prior to cycle 1 and 3 (mandatory) and with surveillance MRIs thereafter (optional). Dr. 
Koschmann will work with Dr. Bettwegowda (Johns Hopkins) to use PCR-based ultra-deep 
sequencing platform to perform focused ultra-deep sequencing of confirmed tumor DNA 
alterations to assess the ability to use this assay to provide minimal residual disease estimates 
and to predict treatment response and recurrence (no clinical treatment decisions will be made 
based on these correlate tests). Dr. Koschmann (University of Michigan) will use genomic 
information from sequenced tumors to develop a non-invasive pediatric glioma CSF sequencing 
panel for validation on CSF samples. 
 
3.8  Proposed Study 
 
This trial will evaluate the activity of dasatinib in combination with everolimus for children with 
gliomas harboring PDGFR or alterations, including newly diagnosed high-grade (grade III- 
IV) glioma after radiation (stratum A) and recurrent/progressive grade II-IV glioma (stratum B). 
 
Participants must have a genomic (DNA and/or RNA) alteration (mutation, fusion, and/or 
amplification) involving PDGF-A, PDGF-B, PDGFR-A, PDGFR-B, as identified by tumor 
sequencing. Patients who undergo sequencing at the University of Michigan to determine 
eligibility will first enroll in the U of Michigan Mi-ONCOSEQ study (HUM00056496). MI-
ONCOSEQ includes clinically integrated exome (tumor and germline DNA) and transcriptome 
(tumor RNA) sequencing (CLIA certified), as previously described.11,17,47 
Off-site (non U of 
Michigan academic or private) CLIA-certified tumor DNA/RNA sequencing can also be used to 
determine eligibility. 
 
Patients will receive oral dasatinib and everolimus daily. The planned starting dose for dasatinib 
is 60 mg/m2 twice daily as oral pill (as oral suspension if the patient is unable to swallow pills). 
The maximum dose of dasatinib is 100 mg twice daily if < 18 years old, and 140mg once daily if 
> 18 years old. No dose escalation is planned. The planned starting dose for everolimus (oral 
pill or /Affinitor disperz tablet) is 3.0 mg/m2 once daily, with titration of dosing to keep everolimus 
trough level of 5-15 ng/ml. The maximum dose of everolimus is 10mg once daily. Both agents will 
be taken daily for 28 days. This is considered 1 cycle. CSF and plasma dasatinib pharmacokinetics 
will be performed by the University of Michigan to determine whether blood-CSF permeability of 
dasatinib is impacted by dual therapy with everolimus. Prior to first cycle only, dasatinib will be 
taken as mono-therapy for 1 week followed by CSF collection in order to establish mono-therapy 
dasatinib CSF level. Cycles will be repeated every 28 days and patients may receive up to 24 cycles. 
Up to 32 participants will be enrolled on this trial. 
 
4.0 Eligibility Requirements 
 
Eligibility requirements 4.2 (disease status) and 4.4 (consent) must be met prior to tumor testing. 
All other eligibility requirements must be met prior to the start of treatment. 


 
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4.1  Patient 
 
4.1.1 Age at enrollment: Greater than 1 year and less than 50 years 
 
4.1.2 BSA (body surface area):  BSA greater than 0.3 m2 
 
4.1.3 Functional status: Karnofsky > 50% for patients > 16 years of age and Lansky > 50% for 
patients < 16 years of age. Neurologic deficits in patients with CNS tumors must have been 
relatively stable for a minimum of 7 days. Patients who are unable to walk because of paralysis, 
but who are able to sit in a wheelchair, will be considered ambulatory for the purpose of assessing 
the performance score. 
 
4.1.4 Organ function: 
 
4.1.4.1 Adequate bone marrow function including 
• 
ANC > 750 
• 
Platelet count > 100,000/uL without platelet transfusion within the past 7 days 
 
4.1.4.2 Adequate liver function defined as Bilirubin < 1.5 x upper limit of normal and ALT < 2.5 
x upper limit of normal. 
 
4.1.4.3 Adequate renal and metabolic function defined as: 
a. Creatinine clearance or radioisotope glomerular filtration rate (GFR) >70 
mL/min/1.73 m2, or 
b. A serum creatinine based on age/gender as follows: 
 
Age 
Maximum Serum 
Creatinine (mg/dL) 
Male 
Female 
1 to < 2 years 
0.6 
0.6 
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 utilizing child length and 
stature data published by the CDC. 
 
c. Urine protein:creatinine  (UPC)  ratio  of  <1;  or  a  urinalysis  that  is negative  for 
protein; or 24-hour urine protein level < 1000 mg/dL 
 
4.1.5 Patients with known seizure disorder must have seizures adequately controlled with non- 
enzyme inducing antiepileptic medications 
 
4.1.6 No increase in steroid dose within the past 7 days. 


 
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4.2  Disease 
 
4.2.1 STRATUM  A:  histological  confirmation  of  a  newly  diagnosed  high-grade  glioma 
or DIPG 
 
4.2.2 STRATUM  B:  histological  confirmation  (at  diagnosis  or  relapse)  of  a  recurrent  or 
progressive grade II-IV glioma (including DIPG) 
 
4.2.3 ALL STRATA: 
 
4.2.3.1 Location: Primary brain or spine tumor are eligible, including tumors with metastases, 
multiple lesions 
 
4.3  Prior therapies 
 
4.3.1 Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, 
immunotherapy, or radiotherapy. 
4.3.2 Myelosuppressive chemotherapy: Must not have received within 3 weeks (6 weeks if prior 
nitrosourea). 
 
4.3.3 Hematopoietic growth factors: At least 7 days since the completion of therapy with a 
growth factor, 14 days for long- acting (e.g. PEG-filgrastim) 
 
4.3.4 Biologic (anti-neoplastic agent): At least 7 days or 3 half-lives (whichever is longer) since 
the completion of therapy with a biologic agent. 
 
4.3.5 Radiation therapy: 
 
 Strata A: ≥ 2 weeks and </= to 12 weeks must have elapsed from radiation. 
 Strata B: ≥ 2 weeks must have elapsed from focal radiation. 
 
4.3.6 Surgery: > 3 weeks from major surgery.  If recent craniotomy, adequate wound healing 
must be determined by neurosurgical team. 
 
4.3.7 Autologous Stem Cell Transplant or Rescue: No evidence of active graft vs. host disease 
and ≥ 4 weeks must have elapsed. 
 
4.4  Consent 
 
All patients and/or a legal guardian must sign institutionally approved written informed consent 
and assent documents. 
 
4.5  Tumor Testing 
PDGF or alteration: Participants must have a genomic (DNA and/or RNA) alteration (mutation, 
fusion, and/or amplification) involving PDGF-A, PDGF-B, PDGFR-A, PDGFR-B, or, as 


 
PI: Carl Koschmann, MD 
Protocol Version: 19-Feb-2019 
 
13 
 
identified by tumor (FFPE or fresh, diagnosis or relapse tissue, but relapse tissue preferred) 
sequencing. Sequencing will be performed through the University of Michigan MI-ONCOSEQ 
study (CLIA-certified), or other (non-U of Michigan) CLIA-certified tumor DNA or RNA 
sequencing. For MI-ONCOSEQ, at least 1 mm cubed of tumor tissue or >1 core biopsy of tumor 
tissue is required, fresh or FFPE]. 
 
4.6  Exclusion criteria 
 
4.6.1 Reproductive Exclusions: Patients who are breastfeeding, pregnant or refuse to use an 
effective form of birth control are excluded. Abstinence is considered an effective form of birth 
control. 
 
4.6.2 Infection: Patients with uncontrolled infection are excluded. 
 
4.6.3 Other medications: 
4.6.3.1 Patients receiving other anti-neoplastic agents are excluded. 
4.6.3.2 Patients requiring strong CYP3A4 or PGP inhibitors are excluded (Appendix B). 
4.6.3.3 Patients requiring anticoagulation or with uncontrolled bleeding are excluded. 
4.6.3.4 Patients on steroids for symptom management must be on a stable dose for 7 days 
prior to start of treatment. 
 
4.6.4 Allogeneic stem cell transplant: Patients within 1 year of allogeneic stem cell transplant, 
patients with active GVHD or requiring immunosuppression are excluded. 
 
4.6.5 Previous hypersensitivity to rapamycin or rapamycin derivatives. 
 
5.0 Treatment/Intervention Plan 
 
Participants will be evaluated for toxicity using CTCAE v4. Stopping rules for toxicity and 
response are included below. Patients will receive oral dasatinib and everolimus daily. The 
maximum dose of dasatinib is 100 mg twice daily if < 18 years old, and 140mg once daily if > 18 
years old. No dose escalation is planned. The planned starting dose for everolimus (oral pill or 
/Affinitor disperz tablet) is 3.0 mg/m2 once daily, with titration of dosing to keep everolimus trough 
level of 5-15 ng/ml. The maximum dose of everolimus is 10mg once daily. Doses of both agents 
may be rounded to the nearest tablet size within 20% of calculated dose. Both agents will be 
taken daily for 28 days. This is considered 1 cycle. Cycles will be repeated every 28 days and 
patients may receive up to 24 cycles. Up to 32 participants will be enrolled on this trial. 
 
CSF and plasma dasatinib pharmacokinetics will be performed by the University of Michigan to 
determine whether blood-CSF permeability of dasatinib is impacted by dual therapy with 
everolimus. Prior to first cycle, dasatinib will be taken as mono-therapy for 1 week followed by 
CSF collection in order to establish mono-therapy dasatinib CSF level. After cycle 2, CSF will be 
collected to establish dual-therapy dasatinib level (while on everolimus). Additionally, CSF 
collected at these time points will be used to assess CSF cell-free tumor DNA burden as a possible 
predictor of treatment response. CSF collection at subsequent prior to subsequent odd-numbered 
cycles for CSF cell-free tumor DNA analysis will be optional. 
 


 
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Protocol Version: 19-Feb-2019 
 
14 
 
5.1  Therapy 
 
5.1.1 Dasatinib will be administered orally at a dose of 60 mg/m2 orally, twice daily days 1-28 
each cycle continuously. The maximum dose of dasatinib is 100 mg twice daily if < 18 years old, 
and 140mg once daily if > 18 years old. Ideally, capsules should be swallowed whole with a 
glass of water. However, if patient is unable to swallow capsules, a suspension form may 
be prepared for administration. Medication should be taken at least one hour before and two 
hours after large meals. 
 
5.1.2 Everolimus will be administered orally at a dose of 3.0 mg/m2 daily days 1-28 each cycle 
continuously. The maximum dose of everolimus is 10mg once daily. Ideally, tablets should be 
swallowed whole with a glass of water. If patients are unable to swallow tablets, a suspension 
form may be prepared for administration (same dose). The medication should be taken at the 
same time every day and either consistently with food or 
consistently without food. 
5.1.3 Each cycle will be repeated every 28 days and when the following criteria are met: 
5.1.3.1 Absolute neutrophil count must be greater than 750/uL 
5.1.3.2 Platelet count must be greater than 75,000/uL 
5.1.3.3 Bilirubin < 1.5 x upper limit of normal and ALT must be <2.5 x upper limit of 
normal 
 
5.2  Supportive care 
 
5.2.1 Neutropenic precautions: Patients and/or parents or guardians should receive education 
about the risk of infection and neutropenia. Patients should receive laboratory evaluation for 
neutropenia at the time of fever or expected infection. Empiric IV antibiotic therapy will be given 
for patients found to have fever and neutropenia according to institutional guidelines. 
 
5.2.2 Infection prophylaxis: Patients should receive appropriate prophylaxis for pneumocystis 
(PCP) pneumonia starting during first cycle and continuing until a minimum of three months after 
completion of chemotherapy. 
 
5.2.3 Transfusion of blood products: Blood products should be transfused for bleeding or 
symptomatic anemia. In asymptomatic patients, transfusion should be used to maintain platelet 
count above 30,000 and hemoglobin above 7 g/dl. Patients cannot be transfused within 7 days of 
study start (Section 4.1.4.1). Platelet could must be > 75,000 to start a new cycle (Section 5.1.3.1). 
 
5.2.4 Antiemetic management: Appropriate anti-emetics may be used prior to chemotherapy. 
Steroids are discouraged for antiemetic management. 
 
5.2.5 Cytokine support: Patients should not receive routine cytokine support. In the setting of 
neutropenia and documented life- threatening infection, cytokine support and/or granulocyte 
infusion should be considered. 
 
5.2.6 Electrolyte and fluid support: Diarrhea, dehydration and electrolyte abnormalities are 
known potential side-effects of dasatinib. Additional oral or intravenous fluid, sodium, calcium, 
magnesium, phosphorus or potassium should be given to maintain euvolemia and electrolyte levels 


 
PI: Carl Koschmann, MD 
Protocol Version: 19-Feb-2019 
 
15 
 
within normal range for patients who develop diarrhea to prevent dehydration or symptomatic 
electrolyte abnormalities. Imodium may be used to manage symptomatic diarrhea. 
 
5.3  Therapy Modifications for Toxicity 
 
All dose modifications should be based on the worst preceding toxicity. The severity of adverse 
events will be graded utilizing the National Cancer Institute (NCI) CTCAE, version 4. 
 
5.3.1 Definition of Dose Limiting Toxicity (DLT) 
 
DLT will be defined as any of the following events that are at least possibly, probably, or definitely 
attributable to dasatinib or everolimus. See below for the potential dasatinib and everolimus 
specific side effects. Dose-limiting hematological and non-hematological toxicities are defined 
differently. 
 
5.3.1.1 Hematological Dose-Limiting Toxicity 
 Grade 4 thrombocytopenia (platelet count < 25,000/mm3) or Grade 4 neutropenia 
 Any hematologic toxicity requiring  dose  reduction  or  treatment interruption for >14 
days 
 ≥ Grade 2 arterial thromboembolic events (visceral arterial ischemia, peripheral ischemia, 
or ischemia cerebrovascular) 
 Grade 3 or 4 venous thromboembolic event 
 Any thrombotic event (other than central venous line [CVL] associated thrombosis) 
requiring systemic anticoagulation 
 
5.3.1.2 Non-Hematological Dose-Limiting Toxicity 
 Any Grade 4 non-hematologic toxicity, with the exception of alopecia 
 Any Grade 3 non-hematological toxicity, with the specific exclusion of the following: 
Grade 3 nausea and vomiting of < 3 days duration; Grade 3 fever or infection, Grade 3 
hypophosphatemia, hypokalemia, hypocalcemia or hypomagnesemia responsive to oral 
supplementation within 7 days of start of supplement 
 Grade 2 allergic reactions that necessitate discontinuation of protocol therapy will not be 
considered a dose-limiting toxicity 
 Any Grade 2 non-hematological toxicity that persists for ≥ 7 days and is considered 
sufficiently medically significant or sufficiently intolerable by patients that it requires 
treatment interruption may also be considered a DLT following discussion with the Study 
chair and an appropriate pharmaceutical medical monitor. 
 Hypertension will be graded according to the NCI CTCAE; however, dose limiting 
hypertension will be considered as the following: 
o Grade 4 hypertension 
o A blood pressure >25 mmHg above the 95th percentile for age, height, and gender 
confirmed  by repeated measurement on the same day 
o In patients already on anti-hypertensive therapy due to previous hypertension, 
any blood pressure 1-25 mmHg above the 95th percentile for age, height, and 
gender for > 14 days 
 


 
PI: Carl Koschmann, MD 
Protocol Version: 19-Feb-2019 
 
16 
 
5.3.1.3 Dose Modifications for Hematologic Toxicity 
 
All dose modifications should be based on the worst preceding toxicity. For step-wise dose 
reductions, see section 5.3.4 for the dosing nomogram. For all patients: 
 If Grade 4 neutropenia occurs, dasatinib should be held, and CBC should be checked at 
least twice a week (every 3 to 4 days) until ANC ≥ 750/µL. Subsequent doses of dasatinib 
should be given at a reduced dose, when ANC ≥ 750/µL 
 If Grade 4 thrombocytopenia occurs, dasatinib should be held. CBCs should be checked at 
least twice a week (every 3 to 4 days) until platelet count ≥ 75,000/µL without need for 
platelet transfusion in the preceding 7 days. Subsequent doses of dasatinib should be given 
at a reduced dose, when platelets count ≥ 75,000/µL without need for platelet transfusion 
in the preceding 7 days. 
 For patients who have a dose limiting hematological toxicity that does not resolve to the 
parameters defined above within 14 days of holding dasatinib: if re-challenge is to be 
considered the Study Chair must be contacted and provide approval prior to re-challenge. 
 
5.3.1.4 Dose Modifications for Non-Hematological Toxicity 
 
For any non-hematologic dose limiting special toxicity attributed to dasatinib or everolimus, the 
respective agent should be held. If the non-hematologic DLT returns to baseline within 14 days of 
holding dasatinib, subsequent doses of reduced agent should be given at a reduced dose. If toxicity 
does not resolve to meet continued treatment parameters within 14 days of drug discontinuation, 
and if re-challenge is to be considered, the Study Chair must be contacted to discuss. If DLT recurs 
in a patient who has resumed treatment after the maximum allowed dose reductions,  the patient 
must be removed from protocol therapy, unless the patient has been approved for a further dose 
reduction following discussion with the Study Chair. 
 
5.3.2 Dasatinib 
 
5.3.2.1 Special Toxicities Potentially Related to Dasatinib: 
 
5.3.2.1.1 Pleural effusion 
 
Effusions are a documented side effect of dasatinib. If symptomatic grade 2 pleural effusions 
develop for > 1 week or grade 3, dose should be held and then restarted at reduced dose when 
symptoms resolve. 
 
5.3.2.1.2 Diarrhea 
 
Diarrhea is a common side effect of dasatinib. If diarrhea is not adequately controlled to less than 
grade 3 with supportive care including hydration and loperamide, then dose may be held until 
symptoms resolve and restarted at the reduced dose 
 
5.3.2.1.3 Electrolyte Abnormalities 
 
Serum K+, Ca++, Mg++, phosphate levels should be monitored given the risk of prolonged QTc 
with dasatinib. If serum Ca++ is abnormal, ionized calcium should be obtained and interventions 
based on ionized calcium only. Dasatinib should be held and an EKG obtained for ≥ Grade 2 


 
PI: Carl Koschmann, MD 
Protocol Version: 19-Feb-2019 
 
17 
 
hypokalemia or hyperkalemia; and ≥ Grade 3 Ca++, Mg++, phosphate abnormalities. Dasatinib may 
be resumed at a reduced dose when K+ abnormality is ≤ Grade 1 or within institutional limits, and 
other abnormalities (Ca++, Mg++, phosphate) are ≤ Grade 2. 
 
5.3.2.1.4 QT Prolongation: 
 
If QTc elevation is seen, the following adjustments should be made: 
 QTc interval < 500 msec: No specific therapy needed. Continue dasatinib at the same dose. 
Serum electrolytes should be monitored and repleted if low. 
 QTc interval ≥ 500 msec: Hold dasatinib, review concomitant medications, and replete 
serum electrolytes as needed. The EKG should be repeated within 7 days and if the QTc 
interval is < 500 msec then resume dasatinib at a reduced dose. If the QTc interval remains 
≥ 500 msec, continue obtain EKG in 7 days. 
 
5.3.2.1.5 Other toxicity 
 
For any grade 3 toxicity determined to be clinically significant and at least possibly related to 
dasatinib treatment, drug should be held until toxicity resolves to <grade 3, and dose reduction 
should be made as described below, with the specific exception of nausea, vomiting or electrolyte 
imbalances which are corrected by supplementation. 
 
5.3.3 Everolimus 
 
5.3.3.1 Special Toxicities Potentially Related to Everolimus 
 
5.3.3.1.1 Mucositis 
 
Mucositis and oral ulceration is a common/known side effect of everolimus. If grade 3 mucositis 
occurs on therapy, everolimus should be held and then restarted at the reduced dose (see chart 
below). 
5.3.3.1.2 Thrombosis 
 
If thrombosis occurs, the following adjustments to everolimus should be made: 
 
Dose Modifications & Evaluations 
Grade 2 
Continue everolimus at the current dose and monitor as 
clinically indicated. 
Grade 3 (CVL associated 
only) 
1. Hold everolimus 
2. Treat thrombosis  according  to  institutional 
standards; would consider removal of the CVL. 
3. Resume everolimus when all symptoms have 
resolved. If anticoagulation is required, use 
with caution. 


 
PI: Carl Koschmann, MD 
Protocol Version: 19-Feb-2019 
 
18 
 
All non-CVL associated 
Grade 3 AND 
Discontinue everolimus permanently and remove from 
protocol therapy 
 
 
5.3.4 Dose reductions for specific agents if dose reduction warranted after dose held. 
 
Starting 
dose 
1st dose 
reduction 
2nd dose 
reduction 
Dasatinib 
60 mg/m2/ 
dose BID 
60 mg/m2/ 
dose daily 
30 mg/m2/ 
dose daily 
Everolimus 
3 mg/m2/ dose 
daily 
2 mg/m2/dose 
daily 
1 mg/m2/ dose 
daily 
 
Additionally, there will be stopping rules for toxicity to avoid excessive toxicity.  If more than one 
patient develops clinically relevant grade 3 or greater toxicity possibly or probably attributed to 
study treatment, then subsequent patients should start at the first dose reduction level of that 
agent.  If an additional patient on the same treatment regimen develops clinically relevant grade 3 
or 4 toxicity possibly or probably attributed to study treatment, then the study will be placed on 
hold for further patient enrollment until further review. 
 
6.0 Biology and Imaging Correlates 
 
6.1  Mandatory biology testing 
Participants must have a genomic (DNA and/or RNA) alteration (mutation, fusion, and/or 
amplification) involving PDGF-A, PDGF-B, PDGFR-A, PDGFR-B, or, as identified by tumor 
(FFPE or fresh, diagnosis or relapse tissue, but relapse tissue preferred) sequencing. Sequencing 
will be performed through the University of Michigan MI- ONCOSEQ study (CLIA-certified, 
HUM00056496), or other (non-U of Michigan) CLIA-certified tumor DNA or RNA sequencing. 
For MI-ONCOSEQ, at least 1 mm cubed of tumor tissue or >1 core biopsy of tumor tissue is 
required, fresh or FFPE]. 
 
CSF and plasma dasatinib pharmacokinetics will be performed by the University of Michigan to 
determine whether blood-CSF permeability of dasatinib is impacted by dual therapy with 
everolimus. 
 
6.1.1 Tumor sequencing (mandatory): To confirm eligibility, participants must have a genomic 
alteration (mutation, fusion, or amplification involving PDGF-A, PDGF-B, PDGFR-A, PDGFR- 
B. Participants will undergo tumor (FFPE or fresh, diagnosis or relapse tissue, but relapse tissue 
preferred) sequencing to determine eligibility. CLIA certified DNA or RNA sequencing that 
identifies an alteration in PDGF-A, PDGF-B, PDGFR-A, PDGFR- B, will be accepted. Over-
expression (RNA) alone is not sufficient, and must be accompanied by DNA alteration or 
DNA/RNA fusion. 
 
Patients will be offered enrollment/ tumor/germline sequencing through the U of Michigan Mi- 
Oncoseq protocol. Enrollment on Mi-Oncoseq will be performed through separate IRB approved 
consent form and enrollment process. Mi-Oncoseq enrollment is not necessary for enrollment on 


 
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Protocol Version: 19-Feb-2019 
 
19 
 
this trial, and alternate CLIA-certified sequencing will be accepted to confirm eligibility. Mi- 
Oncoseq clinically integrated sequencing will be performed according to previous published 
methodology.11,17,47 
 
6.1.2 Dasatinib CSF/plasma pharmacokinetics (mandatory): CSF and plasma dasatinib 
pharmacokinetics will be performed by the University of Michigan to determine whether 
blood- CSF permeability of dasatinib is impacted by dual therapy with everolimus. Prior to 
first cycle, dasatinib will be taken as mono-therapy for 1 week followed by CSF collection in 
order to establish mono-therapy dasatinib CSF level. After cycle 2, CSF will be collected to 
establish dual-therapy dasatinib level (while on everolimus). 
 
6.1.3 CSF and plasma cell-free tumor DNA analysis: CSF collected at above time points 
(prior to first and third cycle) will be used to assess CSF cell-free tumor DNA to explore 
tumor DNA burden as a possible predictor of treatment response. 
 
6.1.4 Everolimus serum level of everolimus: Everolimus serum level will be monitored 
monthly throughout therapy at clinical lab to adjust dosing to trough concentration to 5-15 
ng/ml. 
 
6.2  Optional Biology Testing 
 
Additional optional correlate assays include CSF and plasma collection for CSF tDNA 
analysis at subsequent odd-numbered cycles. 
 
6.3  Mandatory Imaging Correlates 
 
Disease evaluation by MRI will be performed every two cycles. High b-value diffusion 
weighted imaging (DWI) will be performed at the time of clinical MRIs to evaluate their 
utility as imaging biomarkers for therapy response. 
 
Correlative Objective 
(Name of Correlate & Lead PI and Site) 
Imaging Technique 
Organ(s) Scanned and Timing of Scans 
M/O 
MRI brain 
Magnetic Resonance Imaging 
Brain  (+/-  Spine);  Baseline  and  with 
interval scans (every second cycle) 
M 
Hypercellularity by High b-Value Diffusion-Weighted 
Imaging as an Imaging Biomarker for Dasatinib Therapy 
Response (Hemant Parmar, M.D./Yue Cao, PhD; University 
of Michigan) 
Diffusion-Weighted Imaging 
Brain; Baseline and with interval scans 
(every second cycle) 
M 
 
Diffusion-Weighted Imaging: In addition to conventional clinical post-Gd T1WI and 
FLAIR- MRI, DWI in 3 orthogonal directions with b values of 0, 1000, and 3000 s/mm2 
will be acquired in all patients. DWI will be acquired with the following imaging protocol. 
 
2D multiple b-value diffusion weighted images 
 
Sequence type 
Ep2d (*ep_b0) 
TE (ms) 
Min(98) 
3D or 2D 
2D 
TR (ms) 
8200 


 
PI: Carl Koschmann, MD 
Protocol Version: 19-Feb-2019 
 
20 
 
FOV (mm) 
270x270x144 
Diffusion 
Gradient 
Bipolar* 
Voxel Size (mm) 
1.4x1.4x4.8 
3 
orthogonal 
diffusion 
directions 
yes 
Slice 
thickness 
and gap 
4mm and 20% 
b-value 
(s/mm2) 
0, 1000, 2000 and 
3000 
Orientation 
Axial 
Average 
1, 2, 3 and 4 for 4 
b-values 
# of slices 
Whole brain 
Parallel    imaging 
factor 
4** 
*: to reduce eddy current; 
**: to reduce geometric distortion 
***: We will test if we can replace this sequence by the RESOLVE sequence to further improve geometric 
accuracy.  We assessed the geometric distortion using the current protocol and reported in reference 3. 
Additional  questions  and  guidance  on  DWI  acquisition  should  be  addressed  to  Yue  Cao,  PhD 
(yuecao@med.umich.edu). 
 
7.0 Evaluations to Be Obtained 
 
7.1  Pre-Treatment Evaluation 
 
MRI must be obtained within 28 days prior to starting therapy. If patient undergoes surgery, MRIs 
are required pre-surgery, and within 72 hours post-surgery. Timing of other evaluations is 
indicated below. Any child who receives two cycles of therapy and undergoes MRI prior to third 
cycle will be considered evaluable.  


 
PI: Carl Koschmann, MD 
Protocol Version: 19-Feb-2019 
21 
 
 
 
 
7.2  On-Study Evaluation 
 
 
T1 Window for assessment is Day 1 +/- 3 days for any assessment with the exception of disease 
evaluations. 
T2 Should be performed, if possible, at the time the patient comes off protocol therapy regardless 
of the reason, unless the test or procedure has been performed within the past 2 weeks. 
-14 to 0
-7 to 0
Day -6
Day 1
Day 14
Performance status
X
X
X
X
X
Concomitant Medicines
X
X
X
X
X
Everolimus serum level
X
X
Cell free tumor DNA- 
CSF/blood tDNA
(mandatory)
Cell free tumor DNA- 
CSF/blood tDNA
(optional)
History, Physical Exam, 
VitalsT3 
Height, weight, BSAT 4
During Cycle 1
Pre-Study
Prior to 
Cycle 1
Prior to 
Every 
CycleT1 
Prior to 
Every Other 
Subsequent 
Cycle T1
Prior to 3rd 
CycleT1
Adverse Event 
Collection
CBC, differential, 
platelets
X
X
X
X
Electrolytes, including 
K, Ca, Phos and Mg, 
ALT and bilirubin
Disease evaluation (MRI 
brain including high b- 
value DWI)T7 
X
XT8 
XT8 
FFPE or fresh tissue for 
sequencing
X
X
EKG, including QTcT 10
X
Serum pregnancy testT9 
X
Dasatinib therapy alone
X
Studies to be Obtained
XT 11
Dasatinib plasma level
X
Dasatinib CSF 
pharmacokineticsT12
X
X
X
X
X
X
X
X
X
X
End of 
therapyT2 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
XT 5,T 6


 
PI: Carl Koschmann, MD 
Protocol Version: 19-Feb-2019 
22 
 
 
T3 Blood pressures will be measured with an appropriate sized cuff at rest. Blood pressure 
measurement will be repeated within the same day if the blood pressure (BP) is elevated (> the 
95th percentile for age, height, and gender). If both BP measurements are > 95th percentile for 
age, height, and gender, follow the guidelines for elevated BP with dasatinib. 
T4 Evaluations obtained for screening will ONLY be repeated at Cycle 1 Day 1 if they are older 
than 7 days. 
T5 If patients have Grade 4 neutropenia, then CBCs should be checked every 3 to 4 days until 
recovery to Grade ≤3. 
T6 If patients have Grade 3 or 4 thrombocytopenia, then CBCs should be checked twice a week 
until recovery to Grade ≤2. 
T7 Obtain spine MRI with brain MRI if there is spinal disease involvement at enrollment. MRI must 
be obtained within 90 days prior to starting therapy. If patient undergoes surgery, MRIs are required 
pre-surgery, and within 72 hours post-surgery. 
T8 Disease evaluation should be performed on Day 1 of the current cycle -7 days ( Day 21-28 of the 
previous cycle) prior to Cycles 3 and every other cycle thereafter. If the institutional investigator 
determines that the patient has progressed based on clinical or laboratory evidence, the 
investigator can remove the patient from protocol therapy, he/she may opt not to confirm this 
finding radiographically; however, an end of study disease assessment should be completed. 
T9 Females of childbearing potential require a negative serum pregnancy test prior to starting 
treatment. Patients of childbearing potential must use an acceptable method of birth control. 
Abstinence is an acceptable method of birth control. 
T10 More frequent EKG monitoring is required for Grade 2 potassium and Grade 3 calcium 
(confirmed by ionized calcium), magnesium and phosphorous abnormalities. See section on 
electrolyte abnormalities with dasatinib 
T11 Dasatinib therapy will be administered alone 7 days prior to Cycle 1. 
T12 Dasatinib CSF pharmacokinetics will be required prior to the first cycle and after cycle 2. CSF 
analysis at subsequent odd numbered cycles will be optional. 
 
 
7.3  Follow-up  Evaluation 
 
Survival endpoints will be estimated including time to progression as well as progression-free and 
overall survival rates at the 6 month, 1 year and 2 year time point (+/- 2 months) from start of study 
treatment. Follow-up will be accomplished by standard of care visits and MRI if at U of M, or a 
phone call to the patient at above time points if patient is primarily receiving care elsewhere. 
Patients will be contact at one and 2 year interval to confirm MRI and visit is scheduled (if receiving 
care elsewhere).


 
PI: Carl Koschmann, MD 
Protocol Version: 19-Feb-2019 
23 
 
 
 
8.0 Therapeutic Agents 
 
8.1  Use of Commercial Medications 
The products used in this study are the commercially available US-Licensed product without 
modification to the approved packaging.  
 
8.2  Toxicities/Side Effects 
The following are known/expected side effects of agents used on this study 
 
8.2.1 Dasatinib 
Frequency defined below: 
 Cardiovascular: Facial edema, peripheral edema (~10%); Cardiac conduction disturbance 
(7%), ischemic heart disease (4%), cardiac disease (≤4%; includes cardiac failure, 
cardiomyopathy, diastolic dysfunction, ejection fraction decreased, left ventricular 
dysfunction, ventricular failure), edema (≤4%; generalized), pericardial effusion (≤4%; 
grades 3/4: ≤1%), prolonged Q-T interval on ECG (≤1%), cardiac arrhythmia, chest pain, 
flushing, hypertension, palpitations, tachycardia 
 Central nervous system: Headache (12% to 33%), fatigue (8% to 26%), pain (11%); Chills, 
depression, dizziness, drowsiness, insomnia, myasthenia, neuropathy, peripheral 
neuropathy (all < 10%) 
 Dermatologic: Skin rash (11% to 21%; includes drug eruption, erythema, erythema 
multiforme, erythematous rash, erythrosis, exfoliative rash, follicular rash, heat rash, 
macular rash, maculopapular rash, milia, papular rash, pruritic rash, pustular rash, skin 
exfoliation, skin irritation, urticaria vesiculosa, vesicular rash), pruritus (12%); Acne 
vulgaris, alopecia, dermatitis, eczema, hyperhidrosis, urticaria, xeroderma (all < 10%) 
 Endocrine & metabolic: Fluid retention (19% to 48%; grades 3/4: 1% to 8%; cardiac- 
related: 9%); Hyperuricemia, weight gain, weight loss (all < 10%) 
 Gastrointestinal: Diarrhea (17% to 31%), nausea (8% to 24%), vomiting (5% to 16%), 
abdominal pain (7% to 12%); Constipation (10%), gastrointestinal hemorrhage (2% to 
9%; grades 3/4: 1% to 7%), abdominal distention, change in appetite, colitis (including 
neutropenic colitis), dysgeusia, dyspepsia, enterocolitis, gastritis, mucositis, stomatitis 
(all less <10%); Increased serum bilirubin (grades 3/4: ≤6%), increased serum ALT 
(grades 3/4: ≤5%), increased serum AST (grades 3/4: ≤4%), ascites (≤1%) 
 Hematologic & oncologic: Thrombocytopenia (grades 3/4: 22% to 85%), neutropenia 
(grades 3/4: 29% to 79%), anemia (grades 3/4: 13% to 74%), hemorrhage (8% to 26%; 
grades 3/4: 1% to 9%), febrile neutropenia (4% to 12%; grades 3/4: 4% to 12%); 
Intracranial hemorrhage (≤3%; grades 3/4: ≤3%), bruise (<10%) 
 Infection: Infection (9% to 14%; includes bacterial, fungal, viral); Herpes virus infection, 
sepsis (<10%) 
 Local: Localized edema (3% to 22%; grades 3/4: ≤1%; superficial) 
 Neuromuscular & skeletal: Musculoskeletal pain (<22%), myalgia (7% to 13%), arthralgia 
(≤13%); Muscle spasm (5%), stiffness, weakness (<10%) 
 Renal: Increased serum creatinine (grades 3/4: ≤8%) 


 
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Protocol Version: 19-Feb-2019 
24 
 
 
 
 Respiratory: Pleural effusion (5% to 28%; grades 3/4: ≤7%), dyspnea (3% to 24%); 
Pulmonary hypertension (≤5%; grades 3/4: ≤1%), pulmonary edema (≤4%; grades 3/4: 
≤3%); cough, pneumonia (bacterial, viral, or fungal), pneumonitis, pulmonary infiltrates, 
upper respiratory tract infection (all < 10%) 
 Miscellaneous: Fever (6% to 18%) 
8.2.2 Everolimus 
Common: 
• 
Cardiovascular: Hypertension (kidney transplant recipients, 30% ; advanced renal 
cancer, 4%; subependymal giant cell astrocytoma, 4%), Peripheral edema (kidney 
transplant recipients, 45% ; advanced renal cancer, 25%; subependymal giant cell 
astrocytoma, 4% ) 
• 
Dermatologic: Infection of skin AND/OR subcutaneous tissue (18% ), Rash (advanced 
renal cancer, 29%; subependymal giant cell astrocytoma, 18%; advanced pancreatic 
neuroendocrine tumor, 59% ) 
• 
Endocrine metabolic: Decreased phosphate level (37% to 40% ), Dyslipidemia (15%), 
Hyperlipidemia (21% ), Increased glucose level, All grades (advanced pancreatic 
neuroendocrine tumor, 75%; advanced renal cell cancer, 57%; subependymal giant cell 
astrocytoma, 25% ), Serum cholesterol raised (advanced renal cancer, 77%; 
subependymal giant cell astrocytoma, 68% ; advanced pancreatic neuroendocrine 
tumor, 66% ), Serum triglycerides raised (advanced renal cell cancer, 73%; 
subependymal giant cell astrocytoma, 43% ; advanced pancreatic neuroendocrine 
tumor, 39% ) 
• 
Gastrointestinal: Constipation (kidney transplant recipients, 38% ; subependymal giant 
cell astrocytoma, 11% ), Diarrhea (kidney transplant recipients, 19% ; advanced renal 
cancer, 30%; subependymal giant cell astrocytoma, 25%; advanced pancreatic 
neuroendocrine tumor, 50% ), Loss of appetite (25% to 30% ), Nausea (26% to 29%), 
Oropharyngeal mucositis, Stomatitis (kidney transplant recipients, 8% ; advanced renal 
cancer, 44%; advanced pancreatic neuroendocrine tumor, 70%; subependymal giant 
cell astrocytoma, 86% ), Ulcer of mouth, Vomiting (advanced renal cancer, 20%; 
subependymal giant cell astrocytoma, 21%; advanced pancreatic neuroendocrine 
tumor, 29% ; kidney transplant recipients, 15% ) 
• 
Hematologic: Anemia (kidney transplant recipients, 26% ; renal cell cancer, 50% or 
higher ), Decreased hemoglobin, All grades (advanced renal cancer, 92%; 
subependymal giant cell astrocytoma, 39% ; advanced pancreatic neuroendocrine 
tumor, 86% ), Decreased lymphocyte count, All grades (45% to 51% ), Decreased 
platelet count, All grades (21% to 45% ) 
• 
Hepatic: ALT/SGPT level raised (advanced renal cell cancer, 21%; subependymal 
giant cell astrocytoma, 46%; advanced pancreatic neuroendocrine tumor, 48% ), 
AST/SGOT level raised (advanced renal cancer, 25%; advanced pancreatic 
neuroendocrine tumor, 56%; subependymal giant cell astrocytoma, 89% ) 
• 
Immunologic: Surgical wound finding (35% ) 
• 
Neurologic: Asthenia (33% ) 
• 
Otic: Otitis media (36% ) 


 
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• 
Renal: Serum creatinine raised (advanced renal cancer, 50%; advanced pancreatic 
neuroendocrine tumor, 19%; subependymal giant cell astrocytoma, 11% ; kidney 
transplant recipients, 18% ), Urinary tract infectious disease (advanced pancreatic 
neuroendocrine tumor, 16% ; kidney transplant recipients, 22% ) 
• 
Respiratory: Cough (advanced renal cancer, 30%; advanced pancreatic neuroendocrine 
tumor, 25%; subependymal giant cell astrocytoma, 21% ; kidney transplant recipients, 
7% ), Dyspnea (20% to 24% ), Sinusitis (39% ), Upper respiratory infection (kidney 
transplant recipients, 16% ; subependymal giant cell astrocytoma, 82% ) 
• 
Other: Fatigue (advanced pancreatic neuroendocrine tumor, 45% advanced renal 
cancer, 31%; subependymal giant cell astrocytoma, 7% kidney transplant recipients, 
9% ), Fever (advanced renal cancer, 20%; advanced pancreatic neuroendocrine tumor, 
31%; subependymal giant cell astrocytoma, 32% ; kidney transplant recipients, 19% ) 
 
Serious: 
• 
Hematologic: Decreased hemoglobin, Grade 4 (advanced renal cancer, 1% ; advanced 
pancreatic neuroendocrine tumor, 15% ), Decreased lymphocyte count, Grade 4 
(advanced renal cancer, 2% ; advanced pancreatic neuroendocrine tumor, 16% ), 
Hemorrhage (3% ), Leukopenia (kidney transplant recipients, 3% ; subependymal giant 
cell astrocytoma, 54% ; advanced pancreatic neuroendocrine tumor, 43% ), 
Thrombosis, Thrombotic microangiopathy, Thrombotic thrombocytopenic purpura 
• 
Immunologic: Infectious disease (advanced renal cancer, 37% ; kidney transplant 
recipients, 62% ) 
• 
Neurologic: Seizure (29% ) 
• 
Renal: Hemolytic uremic syndrome, Renal failure (3% ), Thrombosis of renal artery 
(1% to less than 10% ) 
• 
Respiratory: Non-infectious pneumonia (14% to 17% ), Pleural effusion (7% ), 
Pneumonia, Pulmonary embolism 
 
 
9.0 Criteria for Therapeutic Response/Outcome Assessment 
 
Although this is not a cooperative group study, for the purpose of uniformity and in order to 
compare results of this study to other contemporary studies, response assessment will be performed 
according to Children’s Oncology Group guidelines.48 Response will be assessed using MRI and 
two-dimensional measurement of target lesions. 
 
9.1  Methodology to Determine Tumor Measurement 
 
Tumor response criteria are determined by changes in size using all 3 dimensional measurements: 
width (W), transverse (T), and length (L) measurements. Thus for all tumors these 3 measurements 
need to be recorded, using either T1 or T2 weighted images (which ever gives the best estimate of 
tumor size). The following section describes the methodology. 
 
1. Longest diameter of target lesion(s) should be selected in the axial plane only for CT. 
For MRI imaging, the longest diameter can be measured from the axial plane or the 


 
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26 
 
 
 
plane in which the tumor is best seen or measured, provided the same plane is used in 
follow up. 
2. The longest measurement of the tumor (or width, W) should be determined. 
3. The 2 perpendicular measurements should be determined (transverse (T) measurement- 
perpendicular to the width in the selected plane, and the length (L) – tumor extent in 
the plane perpendicular to the selected plane) 
4. The cystic or necrotic components of a tumor are not considered in tumor 
measurements. Therefore, only the solid component of cystic/necrotic tumors should 
be measured. If cysts/necrosis compose the majority of the lesion, the lesion may not 
be “measurable”. Options: 
a. if the cyst/necrosis is eccentric, the W, T and L of the solid portion should be 
measured, the cyst/necrosis excluded from measurement 
b. if the cyst/necrosis is central but represents a small portion of the tumor (<25%), 
disregard and measure the whole lesion 
c. if the cyst/necrosis is central but represents a large portion of the tumor, identify a 
solid aspect of the mass that can be reproducibly measured 
5. Leptomeningeal tumor spread is usually not a target lesion, and usually cannot be 
measured accurately. Presence and location of leptomeningeal tumor spread should be 
noted, change in extent/thickness assessed on follow up studies. 
 
9.2  Response Criteria for Target Lesions 
 
Comparison of maximal 2-dimentional measurements, TxW (product of the longest diameter 
[width (W)] and its longest perpendicular diameter [transverse (T)] will be used for Response 
Criteria for Target Lesions. A maximum of five target lesions will be included in the response 
criteria. 
 
• 
Complete Response (CR): The disappearance of all abnormal signal. This includes 
return to normal size of the brainstem for brainstem lesions. 
• 
Partial Response (PR): ≥50% decrease in size of tumor in comparison to baseline 
measurements. 
• 
Minor Response (MR): ≥25% decrease in size of tumor in comparison to baseline 
measurements. 
• 
Stable Disease (SD):  No more than 25% increase or decrease in the size of tumor in 
comparison to baseline. 
• 
Progressive Disease (PD): > 25% increase in the size of the tumor or appearance of 
new lesions. 
 
9.3  Overall Response 
 
The overall response assessment takes into account response in both target and non-target lesions, 
and the appearance of new lesions, where applicable, according to the criteria described in the 
table below (11.2.1). The overall response assessment is shown in the last column, and depends 
on the assessments of target, nontarget, and new lesions in the preceding columns. 


 
PI: Carl Koschmann, MD 
Protocol Version: 19-Feb-2019 
 
27 
 
 
10.0 Criteria for Removal from Study 
 
10.1  Criteria for Removal from Study Therapy 
 
• 
Patient/parent preference 
• 
Non-compliance with treatment or required observations Physician decision that study 
is not in patient’s best interest 
• 
Uncontrolled allergic reaction to protocol therapy 
• 
Progressive disease 
• 
Completion of all planned therapy (24 cycles)  
10.2  Off Study Criteria 
• 
Death 
• 
Loss to follow-up (documented in patient shadow chart if unable to reach patient after 
three attempts to contact)  
• 
Two-years from start of study treatment +/- 2 months 
 
11.0  Biostatistics 
 
11.1  Estimated Patient Enrollment and Study Duration 
 
11.1.1 Estimated Study Duration 
 
This study will require 32 patients to complete. The treatment period is expected to last from 8 
weeks to up to 96 weeks depending on response and tolerability. The University of Michigan sees 
on average 10 new high-grade glioma patients and 10 refractory/relapsed glioma (grade II- 
IV) patients annually. Based on our experience, ~1/3 of these patients will harbor relevant DNA 
alterations to be eligible for this study. Based on these estimates, this study will require 
approximately 5 years of accrual, with an additional 2 years for completion of study activity and 
analysis. Any subject who receives two cycles of therapy and undergoes MRI prior to third cycle 
will be considered evaluable. 
11.1.2 Early Stopping Rules 
 
  At the end of the first stage, we stop the trial if Pr(OR>3/data)<0.115. 
 
Additionally, there will be stopping rules for toxicity to avoid excessive toxicity.  If more than one 
patient develops clinically relevant grade 3 or greater toxicity possibly, probably, or definitely 
attributed to study treatment, then subsequent patients should start at the first dose reduction level 
of that agent.  If an additional patient on the same treatment regimen develops clinically relevant 
grade 3 or 4 toxicity possibly, probably, or definitely attributed to study treatment, then the study 
will be placed on hold for further patient enrollment until further review. 
 
 
 


 
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11.2  End Points 
 
11.2.1 Primary End Point: 
 
The primary objective of this study is to test and estimate the efficacy of dasatinib and everolimus. 
The endpoint in stratum A is progression-free survival (PFS) rate and the endpoint in stratum B 
is the overall response rate (partial response or better) at two cycles after treatment (RR2). Stratum 
A includes HGG and DIPG patients at diagnosis. Using the standard of care, the estimated median 
PFS is 12 and 8 months for HGG and DIPG, respectively, based previous clinical trials. Thus, we 
set 50% as the uninteresting PFS rate for both diagnosis groups. That is, the PFS rate in DIPG is 
50% at 8 months (PFS8) and the same rate in HGG at 12 months (PFS12).49-51 For both diagnosis 
groups, we are targeting an improvement of 25% with the combination of dasatinib and 
everolimus as adjuvant therapy. In Stratum B, the RR at 2 cycles (RR2) in pediatric patients with 
refractory or relapsed high-grade is glioma is approximately 10% to recently explored therapies,
 
52,53 and the combination is expected to increase the rate to 25%.  It is important to note that the 
odds ratio (OR) comparing the combination to the standard of care is 3 in both stratums (i.e., the 
treatment effect is the same). Therefore, OR of 1 is the uninteresting treatment effect, while OR 
of 3 is the expected treatment effect. 
 
The proposed model is a Bayesian two-stage design. The statistical model in stratum A is 
𝑙𝑜𝑔𝑖𝑡(𝑝𝐴) = 𝛼𝐴+  𝛽,  and 𝑙𝑜𝑔𝑖𝑡(𝑝𝐵) = 𝛼𝐵+  𝛽 in stratum B, where the intercepts are log odds 
of success (RR2, PFS8 or PFS12) in the historical control. That is, 𝛼𝐴= log (0.5/(1 −0.5), 𝛼𝐵=
log (0.1/(1 −0.1) and 𝛽 is log OR (the combination therapy vs standard of care) in both stratum 
A and B, and 𝑝𝐴 and 𝑝𝐵 are PFS rate (PFS8 for DIPG  or PFS12 for HGG) and RR2 respectively. 
At the first stage, it’s likely that some patients are free of progression and have not reached the 
observation window (the window is 8 months for DIPG and 12 months for HGG).  To incorporate 
the partial information for these patients into the statistical modelling, we assign a weight, 𝑤𝑖 (0 
< 𝑤𝑖 < 1), to each of these patients based upon how long he/she has been followed divided by the 
observation window. For patients who progressed or have completed the observation window, the 
weight is fixed to be one. All patients in stratum B have weights equal to one. 
 
In the proposed design, decisions are made based on the posterior distribution of β. At the end of 
the first stage, we stop the trial if Pr(OR>3/data)<0.115. At the end of the trial, we reject the null 
hypothesis and declare the new drug is worth of further investigation if Pr(OR>1/data)>0.95. We 
ran simulation studies to compare the proposed design to Simon’s design, with regarding to 
frequentist operating characteristics, including type I error, power, probability of early stopping 
(PET) and expected sample size under the null (E(n)). Simon’s design cannot incorporate the 
partial follow-up information, therefore, the interim decision is made until all enrolled patients 
experience the event or complete the observation window. In the simulation studies, we simulated 
patients to arrive via a Poisson process such that an average of 5 patients was enrolled per year in 
each stratum (the arrival rate is the same for DIPG and HGG patients). For RR2, an indicator of 
success for each patient was drawn from a Bernoulli distribution with the RR2 specified in the 


 
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29 
 
null an alternative hypothesis.  For PFS8 and PFS12, survival times were simulated from 
exponential distributions with rate parameters corresponding to PFS8=50% and PFS12=50% or 
PFS8=75% and PFS12=75%. The first stage was at the enrollment of (n1+1)th patient. Simulation 
results based on 5,000 simulated trials were summarized in Table 2.  This table shows that the 
proposed Bayesian design dramatically reduced sample size compared to Simon’s MiniMax 
design,54 given similar type I error and power. More importantly, the proposed design allows 
continuous patient enrollment without recruitment pause. 
 
Table 1: Simon’s MiniMax Design:54 
Stratum 
Response 
rates 
(H0 vs H1) 
 
n1 
 
Decision to stop 
at stage I 
 
n 
 
Reject H0 
at final stage 
 
A 
 
50% vs 75% 
 
14 
 
# response ≤ 7 
 
23 
 
# response ≥ 16 
 
B 
 
10% vs 25% 
 
22 
 
# response ≤ 2 
 
40 
 
# response ≥  8 
 
 
Table 2: Trial operating characteristics  
Design 
Stratum  
Max 
Sample size 
n1 
Type I 
error 
 
Power 
PET 
under H0 
E(n) 
under H0 
 
Simon 
 
A 
 
23 
 
14 
 
0.05 
 
0.80 
 
0.60 
 
18 
 
Simon 
 
B 
 
40 
 
22 
 
0.05 
 
0.80 
 
0.62 
 
29 
 
 
 
 
 
 
 
 
 
Bayesian 
 
A & B 
 
32 
 
16 
 
0.05 
 
0.82 
 
0.50 
 
24 
 
For the primary endpoint: We will obtain a posterior distribution for the overall OR using 
combined data from two stratums as described in the above trial design. Specifically, we will 
calculate the posterior mean for the OR, along with a 95% credible set. Furthermore, we will 
summarize the results within each stratum. For stratum A, the median survival and survival 
probability will be estimated from the Kaplan-Meier method for DIPG and HGG separately.  For 
stratum B, the RR2 will be calculated with a 95% confidence interval. 
 
11.2.2 Exploratory End Points: 
 
11.2.2.1 
The toxicity profile will be described, both overall and by grade. Toxicity rates 
will be tabulated by type and category. Toxicity endpoints will be descriptive and include 
grading of patient toxicity according to the National Cancer  Institute common  terminology 
criteria for adverse events (CTCAE version 4.0). This combination therapy will be considered 
intolerable if toxicity attributed to study treatment warrants closure as detailed in section 11.1.2 
above. 
 
11.2.2.2 
Exploratory correlative imaging (high-B value DWI-MRI), genomic studies 
(circulating tumor DNA), and CSF pharmacokinetics will be reported descriptively. 


 
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30 
 
 
For DWI endpoint:  DWI will be measured at baseline, 2 and 4 cycles. We will correlate the 
change of DWI from baseline to the change in tumor size measured by MRI. Specifically, a 
linear mixed effect model with a random effect will be used to evaluate the association while 
considering the correlation between data measured within the same subject. 
 
For CSF endpoint: CSF and blood will be measured at baseline and 2 cycles. Pearson 
correlation coefficient will be calculated to assess the association between the change in CSF 
and blood, and change in tumor size. 
 
 
12.0 Data Management 
 
Data for patients enrolled on study will be maintained locally in password- protected electronic 
files or locked file cabinet for the duration of the study, to include reports of patient eligibility 
criteria and biology testing results, treatment including modifications, all toxicity of therapy, 
disease evaluations and survival. All files will be maintained by authorized study team members 
at the University of Michigan.  
 
13.0 Protection of Human Subjects and Data Safety Monitoring Plan 
 
This trial will be monitored in accordance with the NCI approved University of Michigan 
Comprehensive Cancer Center Data and Safety Monitoring Plan (Appendix A). 
 
The study team will meet quarterly or more frequently depending on the activity of the protocol. 
The discussion will include matters related to the safety of study participants (SAE/UaP reporting), 
validity and integrity of the data, enrollment rate relative to expectations, characteristics of 
participants, retention of participants, adherence to the protocol (potential or real protocol 
deviations) and data completeness. At these regular meetings, the protocol specific Data and Safety 
Monitoring Report form will be completed and signed by the Principal Investigator or by one of 
the co-investigators. 
 
Data and Safety Monitoring Reports will be submitted to the University of Michigan 
Comprehensive Cancer Center Data and Safety Monitoring Committee on a quarterly basis for 
independent review. 
 
14.0 Privacy and Confidentiality 
 
Data provided will be treated in strictest confidence. Each subject enrolled will, from that point 
forward, be identified by a unique identifier (study number). This study number will also be used 
for any research specimens collected and shipped to analysts outside of the study sites. All records 
generated will be stored in a locked office area, only accessible to study personnel. Clinical 
information will be accessed, according to HIPAA requirements, by study personnel to complete 
study documents, as needed. 
 
15.0 Informed Consent Procedures 
 
Informed Consent will be obtained from appropriate parents or legal guardians of all patients prior 


 
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31 
 
to beginning any study procedures. Assent will also be obtained from patients in adherence 
with University of Michigan IRB policies. 
 
16.0 Adverse Events (AEs) 
 
16.1  AE Definition: 
Adverse Events (AEs) are defined as any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom or disease temporally associated with the use of a medical treatment 
or procedure regardless of whether it is considered related to the medical treatment or procedure 
(attribution of unrelated, unlikely, possible, probable, or definite). This includes all deaths that 
occur while a subject is on a study. An adverse experience may also be referred to as an adverse 
event. Abnormalities present at baseline (before starting protocol therapy) are not adverse events, 
but for this study will be documented. (See 21 CFR 312.32. of the federal regulations covering 
investigational agents.) This study will track all AEs, regardless of attribution, for each participant. 
 
16.2  Serious AE (SAE) Definition 
A Serious Adverse Event (SAE) is any Adverse Event, occurring at any dose and regardless of 
causality that: 
• 
Results in death 
• 
Is life-threatening. Life-threatening means that the person was at immediate risk of 
death from the reaction as it occurred, i.e., it does not include a reaction which 
hypothetically might have caused death had it occurred in a more severe form. 
• 
Requires or prolongs inpatient hospitalization (i.e., the event required at least a 24-hour 
hospitalization or prolonged a hospitalization beyond the expected length of stay). 
Hospitalization admissions and/or surgical operations scheduled to occur during the 
study period, but planned prior to study entry are not considered SAEs if the illness or 
disease existed before the person was enrolled in the trial, provided that it did not 
deteriorate in an unexpected manner during the trial (e.g., surgery performed earlier 
than planned). 
• 
Results in persistent or significant disability/incapacity. Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions. 
• 
Is a congenital anomaly or birth defect; or 
• 
Is an important medical event when, based upon appropriate medical judgment, it may 
jeopardize the participant and require medical or surgical intervention to prevent one 
of the outcomes listed above. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home; blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
• 
Events not considered to be serious adverse events are hospitalizations for: 
• Routine treatment or monitoring of the studied indication, not associated with 
any deterioration in condition, or for elective procedures 
• Elective or pre-planned treatment for a pre-existing condition that did not worsen 
• Emergency outpatient treatment for an event not fulfilling the serious criteria 
outlined above and not resulting in inpatient admission 
• Respite care 
 
16.3  Expectedness 
Adverse events can be 'Expected' or 'Unexpected.' 


 
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Protocol Version: 19-Feb-2019 
 
32 
 
 
Expected Adverse Events: 
Expected adverse events are those that have been previously identified as resulting from 
administration of the agent. For the purposes of this study, an adverse event is considered expected 
when it appears in the current adverse event list, the Investigator’s Brochure, the package insert or 
is included in the informed consent document as a potential risk. 
 
Unexpected Adverse Events: 
For the purposes of this study, an adverse event is considered unexpected when it varies in nature, 
intensity or  frequency  from  information  provided  in  the  current  adverse  event  list, the 
Investigator’s Brochure, the package insert or when it is not included in the informed consent 
document as a potential risk. 
 
16.4  Attribution 
Attribution is the relationship between an adverse event or serious adverse event and the study 
treatment. Attribution will be assigned as follows: 
 
• 
Definite – The AE is clearly related to the study treatment. 
• 
Probable – The AE is likely related to the study treatment. 
• 
Possible – The AE may be related to the study treatment. 
• 
Unlikely - The AE is doubtfully related to the study treatment. 
• 
Unrelated - The AE is clearly NOT related to the study treatment. 
 
16.5  Reporting 
The investigators on this trial will assess the occurrence of AEs and SAEs at all participant 
evaluation time points during the study. All AEs and SAEs whether reported by the participant, 
discovered during questioning, directly observed, or detected by physical examination, laboratory 
test or other means, will be recorded in the participant’s medical record and on the appropriate 
study-specific case report forms. Subjects will be followed for occurrence of adverse events for 
30 days after the last dose of study treatment. 
 
The descriptions and grading scales found in the CTEP Version 4.0 of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) will be utilized for AE reporting. The CTEP 
Version 4.0 of the CTCAE is identified and located on the CTEP website at: 
 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm 
 
Any Unexpected Serious Adverse Events suspected to be possibly, probably or definitely related 
to study therapy occurring after the initial dose of study treatment, during treatment, or within 30 
days of the last dose of treatment will be reported to the University of Michigan IRB within 7 days 
of occurrence. Reporting to the University of Michigan IRB will occur on their Adverse Event 
Reporting Form. If the participant is in long term follow up, report the death at the time of 
continuing review. Serious adverse events that meet the FDA reporting requirements will be 
reported to the FDA according to 21CFR312.32(c). 
 
 
 
 


 
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Appendix A: Data and Safety Monitoring Plan 
 
Oversight Responsibilities 
Day-to-day oversight of the trial is provided by the Principal Investigator (PI), Dr. Carl 
Koschmann. Along with this study’s sub-investigators, Dr. Koschmann assures that informed 
consent is obtained prior to performing any research procedures, that all subjects meet eligibility 
criteria, and that the study is conducted according to the IRB-approved protocol. The study PI 
and sub-investigators review all study data and any adverse events (AEs) in real-time, and report all 
AEs to the IRB according to the approved DSMP.  
 
Data provided will be treated in strictest confidence. Confidentiality throughout the trial is 
maintained by a unique identifier (study number). Each subject that signs consent, from that 
point forward, wi ll  be identified by their study number. PHI will not be disclosed to the 
DSMC. Data provided to the DSMC will only be identified by the study number, when necessary. 
 
DSMC Monitoring Procedures 
This trial will be monitored in accordance with the NCI approved University of Michigan 
Comprehensive Cancer Center Data and Safety Monitoring Plan. 
 
The study team will meet quarterly or more frequently depending on the activity of the protocol. 
The discussion will include matters related to the safety of study participants (SAE/UaP reporting), 
validity and integrity of the data, enrollment rate relative to expectations, characteristics of 
participants, retention of participants, adherence to the protocol (potential or real protocol 
deviations) and data completeness. At these regular meetings, the protocol specific Data and Safety 
Monitoring Report form will be completed and signed by the Principal Investigator or by one of 
the co-investigators. 
 
Data and Safety Monitoring Reports will be submitted to the University of Michigan 
Comprehensive Cancer Center Data and Safety Monitoring Committee on a quarterly basis for 
independent review. 
 
 


 
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Appendix B. CYP3A4 Inhibitors 
 
The following list describes medications and food which are strong to moderate inhibitors of 
CYP3A4.