A Phase I/II Study of Ribociclib, a CDK4/6 Inhibitor, Following Radiation Therapy in Children With Newly Diagnosed Non-biopsied Diffuse Pontine Gliomas (DIPG) and RB+ Biopsied DIPG and High Grade Gliomas (HGG)
Phase: PHASE1
Conditions: High Grade Glioma, Diffuse Intrinsic Pontine Glioma, Bithalamic High Grade Glioma
Sponsor: Children's Hospital Medical Center, Cincinnati

 
 A Phase I/II Study of Ribociclib, a CDK4/6 Inhibitor, following radiation therapy in Children with 
Newly Diagnosed non-biopsied Diffuse Pontine Gliomas (DIPG) and RB+ biopsied DIPG and High Grade 
Gliomas (HGG) 
 
 
NCT02607124 
 
 
Protocol version date October 27, 2016 

Protocol #: CLEE011XUS17T 
Version Date: October 27 2016 
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Protocol #: 
CLEE011XUS17T 
TITLE: A Phase I/II Study of Ribociclib, a CDK4/6 Inhibitor, following radiation therapy in 
Children with Newly Diagnosed non-biopsied Diffuse Pontine Gliomas (DIPG) and RB+ biopsied 
DIPG and High Grade Gliomas (HGG) 
Coordinating Center: 
     Cincinnati Children’s Hospital Medical Center 
Sponsor Investigator/ 
Study Chair  
Mariko DeWire, M.D. 
Cincinnati Children’s Hospital Medical Center 
Cancer and Blood Diseases Institute 
MLC 7018 
3333 Burnet Ave, 
Cincinnati, OH 45229 
TEL: (513) 636-1849 
FAX: (513) 636-3549 
EMAIL: mariko.dewire@cchmc.org  
Co-Chair 
Maryam Fouladi, M.D., M.S. 
Cincinnati Children’s Hospital Medical Center 
Cancer and Blood Diseases Institute 
MLC 7018 
3333 Burnet Ave, 
Cincinnati, OH 45229 
TEL: (513) 803 0721  
FAX: (513) 636-3549 
 EMAIL: maryam.fouladi@cchmc.org 
Co-Investigators 
Lionel Chow, M.D., PhD 
Trent Hummel, M.D. 
Ralph Salloum, M.D. 
Charles Stevenson, M.D 
Christine Fuller, MD 
David Witte, M.D. 
Rachid Drissi, PhD 
Richard Lu, PhD 
Neuroradiology Co-Investigators   Jim Leach, M.D. 
Division of Neuroradiology 
Department of Radiology 
Radiation Oncology Coordinator John Breneman, M.D. 
Luke Pater, M.D. 
University of Cincinnati 
Biostatistician 
Adam Lane, PhD 
Department of Biostatistics 

Protocol #: CLEE011XUS17T 
Version Date: October 27 2016 
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Biology Correlative Study 
Laboratories 
Lionel Chow, MD, PhD 
Cancer and Blood Diseases Institute 
Cincinnati Children's Hospital 
Medical Center  
240 Albert Sabin Way 
Cincinnati, OH 45229-3039 
Telephone: (513) 803-1369 
Email:  lionel.chow@cchmc.org  
 
Rachid Drissi, PhD  
Cancer and Blood Diseases Institute 
Cincinnati Children's Hospital 
Medical Center  
240 Albert Sabin Way 
Cincinnati, OH 45229-3039 
Telephone: (513) 803-0674 
Email: rachid.drissi@cchmc.org  
 
Qing Lu, PhD 
Cancer and Blood Diseases Institute 
Cincinnati Children's Hospital 
Medical Center  
240 Albert Sabin Way 
Cincinnati, OH 45229-3039 
Telephone: (513) 636-7684 
 Email:  Richard.Lu@cchmc.org 
 
 
 
Coordinating Center 
Cincinnati Children’s Hospital 
Medical Center 
Clinical Management & Research 
Support Core (CMRSC) 
Contact:  Lori Backus 
Sr. Specialist Project Manager 
Telephone:  (513) 636-2047 
Email:  Lori.backus@cchmc.org 
 
 
 
 
This protocol is for research purposes only, and should not be copied, redistributed or used for any other purpose.  
The procedures in this protocol are intended only for use by clinical oncologists in carefully structured settings, 
and may not prove to be more effective than standard treatment.  A responsible investigator associated with this 
clinical trial should be consulted before using or attempting any procedure in this protocol. Contents of this 
document may not be extracted without permission from the Study Chair. 
 
 
Novartis Supplied Agent:
 
 
 

Protocol #: CLEE011XUS17T 
Version Date: October 27 2016 
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Protocol Abstract and Schema  
Rationale for Study 
The prognosis for patients diagnosed with diffuse intrinsic pontine gliomas (DIPG) remains dismal. 
Although radiotherapy can extend survival by 2-3 months, no adjuvant therapy has proven effective.  
Similarly, high-grade gliomas (HGG), particularly those which are not resectable and/or are Grade IV, have 
a poor outcome, with standard of care remaining upfront radiotherapy.  Despite clinical trials testing a 
multitude of chemotherapeutic agents, no major advances have been made in the treatment of children with 
DIPG and HGG for several decades and DIPG/HGG remain the leading cause of brain cancer death in 
children and young adults.1,2  
 
 
 
  
 
 
 
  
 
 
 
 
 Tissue for the RB 
screening may be obtained from an outside institution or from a diagnostic biopsy/surgery performed at 
CCHMC to determine if RB is present prior to initiation of therapy with Ribociclib. However, patients 
diagnosed with DIPG will have the option to have a diagnostic biopsy but is not required for eligibility as 
over 70% of patients with DIPG have been reported to have an intact RB (RB+). 6,10,11   
 
 
 
Description 
 
This is an early phase II study to determine: 1) feasibility of Ribociclib administered once daily at the 
recommended phase II dose (RP2D) (350 mg/m2/day) for 21 days followed by a 7-day break every 28 days 
following completion of radiation therapy for at least 6 courses and up to 12 courses in patients with newly-
diagnosed non-biopsied DIPG and RB+ biopsied DIPG and HGG, 2) early efficacy of Ribociclib defined 
by the 1-year overall survival (OS) separately in two strata for newly-diagnosed patients with DIPG and 
HGG treated with the proposed therapy.  
 
DIPG patients who choose to have a diagnostic biopsy for clinical purposes, a portion of the tissue may be 
used to evaluate RB status.  Patients without RB (negative RB) DIPG and HGG tumors will have the 
opportunity to enroll on other DIPG or HGG protocols as directed by the family and their treating physician. 
Patients with RB+ tumors and non-biopsied DIPG will receive radiation therapy followed by Ribociclib as 
maintenance therapy.  Upon completion of radiation therapy, a 2 - 4 week break will occur and then 
Ribociclib will be given orally daily for 21 days followed by a 7 day break every 28 days at the RP2D (350 
mg/m2/day) for at least 6 courses and up to 12 courses. One course is equivalent to 28 days. One intra-
patient dose-de-escalation (280 mg/m2/day) will be allowed if dose mode-modifying toxicities arise and 
may continue study treatment for up to 12 courses in the absence of disease progression or unacceptable 
toxicity.  
 
 

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Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* RB screening is required for all participants with available tissue.  For patients with DIPG or bi-
thalamic HGG may elect to have diagnostic biopsy for RB evaluation prior to starting radiation therapy.  
**All patients that have biopsy/surgery at CCHMC, will have radiation therapy at CCHMC per 
institutional guidelines without radio-sensitizers.    
** All other patients may receive radiation therapy (photons or proton) at local institution according to 
recommended guidelines without radio-sensitizers.  
 
The Long-term Feasibility/Safety Treatment Plan 
 
Maintenance Phase of Therapy (Patients ≤ 21 years of age)  
Each Course 
May receive a maximum of 12 courses 
 
Day 
1-21 
22-28 
Ribociclib starting dose 
level* 
 350 mg/m2/day 
Rest/ 
Evaluation 
Ribociclib dose reduction 
280 mg/m2/day 
*starting dose 
Maintenance Phase of Therapy (DIPG Patients > 21 years of age)  
Each Course 
May receive a maximum of 12 courses 
 
Day 
1-21 
22-28 
Ribociclib starting dose 
level* 
600 mg daily 
Rest/ 
Evaluation 
Ribociclib dose reduction 
400 mg daily 
 
 
 
Newly Diagnosed DIPG/HGG 
RB+ 
RB- 
RB Unknown 
Radiation 
Therapy** 
6-7 weeks 
Radiation 
Therapy** 
6-7 weeks 
Maintenance 
Ribociclib 
Maintenance 
Ribociclib 
2-4 week rest 
Study Enrollment 
 DIPG/HGG:  
PBTC/COG or 
national protocols 
for newly-
diagnosed DIPGs 
or HGGs or as 
directed by the 
primary oncologist.  
RB Screening* 

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TABLE OF CONTENTS 
1. 
OBJECTIVES ..................................................................................................................................... 7 
 PRIMARY OBJECTIVES ................................................................................................................... 7 
 SECONDARY OBJECTIVES .............................................................................................................. 7 
2. 
BACKGROUND ................................................................................................................................. 8 
 STUDY DISEASE(S) .......................................................................................................................... 8 
 OVERVIEW AND STUDY RATIONALE ........................................................................................... 19 
 CORRELATIVE STUDIES BACKGROUND ...................................................................................... 20 
 SUMMARY ...................................................................................................................................... 29 
3. 
PATIENT SELECTION .................................................................................................................. 30 
 ELIGIBILITY CRITERIA ................................................................................................................ 30 
 EXCLUSION CRITERIA .................................................................................................................. 34 
 INCLUSION OF WOMEN AND MINORITIES ................................................................................... 35 
4. 
GENERAL GUIDELINES ............................................................................................................... 35 
 SCREENING INFORMED CONSENT ............................................................................................... 35 
 TREATMENT INFORMED CONSENT ................................................................................................. 36 
 PATIENT /ENROLLMENT .............................................................................................................. 36 
 BIOPSY ........................................................................................................................................... 36 
 RADIATION THERAPY (6-7 WEEKS OF RADIATION WITH 2-4 WEEK REST) ................................... 37 
5. 
TREATMENT PLAN - RIBOCICLIB MAINTENANCE THERAPY ....................................... 37 
 GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ...................... 40 
 DURATION OF THERAPY............................................................................................................... 41 
 DURATION OF FOLLOW UP .......................................................................................................... 41 
 CRITERIA FOR REMOVAL FROM STUDY ..................................................................................... 42 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ............................................................................. 42 
 DOSE MODIFYING TOXICITIES (DMT) FOR RIBOCICLIB DURING MAINTENANCE THERAPY ... 42 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ....................................... 48 
 DEFINITIONS ................................................................................................................................. 48 
 DOCUMENTATION AND REPORTING OF NON-SERIOUS AES OR SARS ...................................... 49 
 ADVERSE EVENT CHARACTERISTICS .......................................................................................... 50 
 SAES OR SERIOUS SARS .............................................................................................................. 51 
7.5 REPORTING OF PROTOCOL VIOLATIONS/ DEVIATIONS AND UNANTICIPATED PROBLEMS .... 53 
7.6 PREGNANCY .................................................................................................................................. 53 
 OTHER MALIGNANCY .................................................................................................................. 53 
8. 
PHARMACEUTICAL INFORMATION ....................................................................................... 54 
 RIBOCICLIB (NOVARTIS) .............................................................................................................. 54 
9. 
CORRELATIVE AND SPECIAL STUDIES ................................................................................. 55 
 LABORATORY CORRELATIVE STUDIES ....................................................................................... 55 
 SPECIAL STUDIES .......................................................................................................................... 59 
10. 
STUDY CALENDAR ..................................................................................................................... 63 
 ENDOCRINE EVALUATIONS .......................................................................................................... 67 
 PRIOR THERAPY DATA ................................................................................................................... 67 

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11. 
MEASUREMENT OF EFFECT ................................................................................................... 67 
 TUMOR RESPONSE CRITERIA ...................................................................................................... 67 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS .................................................... 69 
 IRB APPROVAL AND REQUIRED DOCUMENTATION ................................................................... 69 
 CATEGORIES OF RESEARCH RECORDS ....................................................................................... 69 
 REGULATORY AND COMPLIANCE MONITORING ............................................................................ 69 
 DATA AND SAFETY MONITORING PLAN ...................................................................................... 70 
 PRIVACY ........................................................................................................................................ 70 
 CONFIDENTIALITY ........................................................................................................................ 70 
13. 
STATISTICAL CONSIDERATIONS .......................................................................................... 71 
 STUDY DESIGN/ENDPOINTS. ........................................................................................................ 71 
 EARLY EFFICACY ......................................................................................................................... 72 
 PROJECTED ACCRUAL RATE AND STUDY DURATION ................................................................ 73 
 SECONDARY OBJECTIVES: ........................................................................................................... 73 
REFERENCES .......................................................................................................................................... 75 
APPENDIX A ............................................................................................................................................ 81 
APPENDIX B (GIRLS) ............................................................................................................................ 82 
APPENDIX B (BOYS) .............................................................................................................................. 84 
APPENDIX C ............................................................................................................................................ 86 
APPENDIX D ............................................................................................................................................ 88 
APPENDIX E ............................................................................................................................................ 89 
APPENDIX F ............................................................................................................................................ 90 
APPENDIX G ............................................................................................................................................ 95 
APPENDIX H ............................................................................................................................................ 96 

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1. OBJECTIVES 
 
 
Primary Objectives 
1.1.1 To identify safety and long-term feasibility of Ribociclib at the proposed dosing 
schedule of 350 mg/m2/day once daily for 21 days/off 7 days every 28 days for at least 
6 courses and up to 12 courses following completion of radiation therapy with newly 
diagnosed non-biopsied DIPG and Rb+ biopsied DIPG and HGG.   
1.1.2 To estimate the 1-year overall survival (OS) of DIPG and HGG separately and compare 
to historical controls.  
 
 
Secondary Objectives 
 
Biopsy  
1.2.1 To estimate the consent rate to biopsy in patients diagnosed with DIPG when therapy is 
based on biopsy results.   
1.2.2 To estimate the morbidity associated with biopsy in patients diagnosed with DIPG.  
 
Imaging  
1.2.3 To estimate the proportion of newly diagnosed DIPG/HGG patients treated on protocol 
that are determined to have experienced pseudoprogression. 
1.2.4 To explore volumetric measurements and correlate with 2-dimensional measurements 
and compare response criteria.   
1.2.5 To explore the quantitative MR measures of relative cerebral blood volume (rCBV), 
vascular permeability (Ktrans, vp, and ve values), and apparent diffusion coefficient 
(ADC) within the first six months of initiating protocol treatment to correlate with 
disease outcome and determine whether such metrics differentiate patients with 
pseudoprogression from those with true early progressive disease. 
 
Exploratory  
Biomarkers/ Biology/Genomics 
1.2.6 To explore whether RB status correlates with response to proposed therapy. 
1.2.7 To assess pharmacodynamics on paraffin sections of skin biopsy for analysis of the cell 
cycle G1/S checkpoint and the PI3K/AKT/mTOR pathway.  
1.2.8 To explore the relationships between the activation status of the cell cycle and PI3-
kinase/AKT/mTOR pathways in patient tumor samples. 
1.2.9 To examine hTERT promoter mutations and methylation, H3F3A, HIST1H3B (H3.3 
and H3.1 genes), ATRX, and DAXX mutations and examine the effects of these 
modifications using targeted gene, exome, RNA sequencing and methylation arrays of 
targeted genomic regions.   
1.2.10 To evaluate the telomere length in match samples (diagnosis/recurrence) in DIPG and 
HGG specimens. 
1.2.11 To evaluate whole genome sequencing to identify the genetic alterations in DIPG and 
HGG tissue at biopsy, and recurrence and/or autopsy if available. 
 
 
 
 
 

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Late effects  
1.2.12 To evaluate pubertal development by evaluating the gonadotropin response to and degree of 
recovery from irradiation and treated with maintenance therapy Ribociclib as evidenced by 
Tanner staging, FSH, LH and Estradiol (female) and Testosterone (male) prior to therapy with 
Ribociclib, 6 months post-completion of radiation therapy and yearly thereafter among pre-
pubertal and pubertal female and male patients diagnosed with DIPG and HGG. 
1.2.13 To evaluate the effect of proposed therapy (radiation therapy followed by maintenance therapy 
with Ribociclib) on ovarian reserve in female patients as evidenced by anti-mullerian hormone 
levels (AMH) prior to therapy with Ribociclib, 6 months post-completion of radiation therapy 
and yearly thereafter among pre-pubertal and pubertal female patients diagnosed with DIPG and 
HGG.  
 
Quality of life  
1.2.14 To assess the health-related quality-of-life of patients by parent report, and when possible, 
patient report at key points in therapy using the patient reported outcomes measurement 
information system (PROMIS) survey.  
 
2. BACKGROUND 
 
 
Study Disease(s) 
 
Pediatric Diffuse Intrinsic Pontine Gliomas  
Diffuse intrinsic pontine glioma (DIPG) accounts for 10-15% of all new pediatric brain tumor diagnoses 
and is the leading cause of brain tumor-related death in children. 11 DIPG can affect patients of any age, 
adults 12 as well as infants/ toddlers; 13 however the median age at diagnosis is 6 to 7 years 1,2, and patients 
commonly present with cranial nerve deficits, upper motor neuron signs, and ataxia. 1 DIPG is generally 
diagnosed on the basis of clinical and radiographic findings.  Typical MRI appearance is a T1-hypointense, 
T2-hyperintense, variably contrast enhancing, expansile mass involving ≥ 50% of the pons.  Though often 
not apparent at diagnosis, several recent studies have demonstrated leptomeningeal dissemination and 
spread to proximal areas of brain at autopsy. 14,15 Prognosis for patients diagnosed with DIPG is dismal, 
with a median overall survival of less than one year. 1,2 Standard treatment at diagnosis consists of local 
radiation therapy, but this intervention is only useful to improve symptoms and prolong survival by 2 to 3 
months in some.16  Over 50 clinical trials have been investigated in the last three decades with various 
interventions including radiation therapy, high dose chemotherapy, and addition of radiation sensitizers; 
none have demonstrated benefit.2 Assuming that these aggressive tumors are generally irradiation resistant, 
and intensification of traditional chemotherapy agents failed to improve outcome, it is reasonable to 
hypothesize that novel agents that target a critical tumor-specific pathway mediating irradiation and/or 
chemotherapy resistance may be worthy of clinical investigation.   
 
Historically, histopathological diagnosis has not been routinely performed due to perceived risks of 
brainstem biopsy17 but was instead reserved for patients with atypical imaging characteristics. The 
consequence of this paradigm is scarcity of tissue and thus grave limitation of our understanding of the 
molecular biology of DIPG.  In recent years, tissue has become more available through collaborative 
determination to overcome barriers to tissue procurement.  This has been accomplished in the following 
ways: 1) efforts to study and implement safe surgical techniques for brainstem biopsy, which were 
pioneered in Europe 18-20 and have become more recently accepted in the United States 21,and 2) initiation 
of programs for tissue collection at autopsy, which have been instigated by family advocacy groups and 
physicians.22-24 
 

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High Grade Gliomas  
High Grade Gliomas (HGG) are tumors of glial origin with an aggressive infiltrative nature that account 
for 3-7% of primary brain tumors in children with a peak in incidence during adolescence. 25 Anaplastic 
astrocytoma (AA) or glioblastoma multiforme (GBM) are the more common histological variants and the 
less frequently occurring histologies include grade III anaplastic oligodendroglioma, anaplastic 
oligoastrocytoma, anaplastic ganglioglioma,  anaplastic pilocytic astrocytoma, and grade IV giant cell 
glioblastoma, gliomatosis cerebri and gliosarcoma. 
 
 
  
 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
27 
Figure 1 
2.1.1 Role of cell cycle in Cancer 
 
The cell cycle is a tightly regulated process through which cells undergo division.  DNA is doubled in S 
phase and cells undergo mitosis and division in M phase with checkpoints at G1 and G2 that say STOP or 
GO. The mammalian cell cycle is dependent on multiple checkpoints regulated by cyclins and their 
associated cyclin-dependent kinase activation (CDK). Checkpoints are transitions between various phases 
of the cell cycle when the integrity of replication and division are carefully monitored before allowing the 
cell to move to the next phase.30 In mammalian cells, cyclins and the CDKs can be divided into G1 Cyclins 

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(cyclin D1-3, and E) and CDK 4, 6, and 2; S phase cyclins (cyclins A and E) and CDK2, and mitotic cyclins 
(Cyclin A and E).3 CDK 1 and 2 are the positive regulators.30  The two main classes of inhibitors include 
inhibitor of CDK4 (INK4) family of inhibitors and the CDK inhibitor protein (CIP)/kinase inhibitor protein 
family of inhibitors. 30,31 The INK4 family of inhibitors (p16INK4A and p14ARF, p15INK4B, p18INK4C, and 
p19INK4D) specifically inhibits only CDK4/6 during G1; whereas, CIP/KIP (p21CIP1, p27KIP1, p57KIP2) are 
capable of inhibiting kinases and cyclins during all phases of the cell cycle (Figure 2). 30,31 
G1-S transition in the mammalian cell cycle is divided into the early G1 (pre-restriction point (RP) which is 
mediated by the CDK-4/cyclin D complex following release of INK4 (an inhibitor of cell cycle progression) 
from CDK4/6.30 CDK4/6 binds cyclin D1, which then phosphorylates and inactivates the Rb protein and 
releases the E2F-DPI transcriptional complex, which is then free to bind to promotor regions of E2F target 
genes required for transition into the S-phase and progression (Figure 3).30,32 Deregulation of cyclin 
expression or CDKs activation are hallmarks of tumorgenesis by causing proliferation, genomic instability, 
and invasiveness. 3 
2.1.2 Alterations in Cell Cycle regulating genes in pediatric/young adult CNS tumors 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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2.1.3.2 
In vivo activity of CDK 4/6 inhibition leads to survival benefit in brainstem 
glioma xenograft with radiation therapy 
 
 
 
 
 
 
  
 
 
 
 
2.1.3.3 
Animal Toxicity 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.1.4 Adult Clinical Trials 
2.1.4.1 
Phase I Trial of Ribociclib in Adults 
 
 

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. 
2.1.4.2 
Phase Ib/II/III Trials/Combination of LEE001 in Adults  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 

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2.1.5 Pediatric Studies 
2.1.5.1 
Phase l Trial of Ribociclib  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Overview and Study Rationale 
Survival for children with DIPG and HGG is dismal and novel therapeutic options need to be developed in 
order to improve outcome. Tumor initiation and progression is dependent on deregulation of the 
components and phases of the cell cycle. 30 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 

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All patients will receive radiation therapy.  Upon completion of radiation therapy, a 2-4 week break will 
occur and then Ribociclib will be given orally daily for 3 weeks on/1 week off every 28 days post 
completion of radiation therapy at the RP2D (350 mg/m2/day) for at least 6 months and up to 12 months. 
One course is equivalent to 28 days.  
 
The long- term feasibility component of the study will assess Ribociclib at the defined RP2D 350 
mg/m2/day once daily for 3 weeks on/one week off every 28 days following radiation therapy for at least 6 
courses and up to 12 courses.  Safety monitoring and stopping rules will be instituted to ensure that serious 
treatment-related toxicities are reported and study continuation re-evaluated. Follow-up will be for 2 years 
following the last dose of Ribociclib. Any Ribociclib related adverse event as outlined in section 6.1 during 
the maintenance therapy will lead to one intra-patient dose reduction. Therapy will be discontinued if a 
dose modifying toxicity occur after one dose modification and will be considered infeasible.  
 
 
Correlative Studies Background 
 
2.3.1 Rationale for diagnostic biopsy in DIPG 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 

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 Rationale for Imaging Studies 
 
 
 
 
 
 
 
 

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2.3.3 Rationale for Exploratory Correlatives 
 
 
 
 
 
 
 
  
 
 
  
 
2.3.3.1 
Molecular markers may predict sensitivity to CDK4/6 inhibitors such as 
Ribociclib 
 
 
  
    
 
 
  
 
 
 
 
 
 
 
 
  
 
2.3.3.2 
Surrogate pharmacodynamics studies confirm inhibition of the molecular target 
 
 
 
 
 
 
 
 
 

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2.3.3.3 
Molecular correlates of telomerase activity: H3F3A (H3.3 gene), ATRX, and 
DAXX mutations/DNA methylation sequencing  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.3.3.4 
The genomic landscape of pediatric HGG and DIPG differs from adult HGG 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 

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2.3.4.1 
Rationale for correlative gonadal function in patients 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
 
 

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2.3.5 Quality of Life Studies 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
   
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
  
 

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3. PATIENT SELECTION 
Patients may be recruited at the participating institutions.  The investigational nature and objectives of this 
trial, the procedures, and treatments involved and their attendant risks and discomforts and benefits, as well 
as potential alternative therapies will be carefully explained to the patient or the patient’s parents or guardian 
if he/she is a child, and a signed informed consent document will be obtained.  Consent will be obtained by 
the site PI or a delegated sub- investigator on the trial.  Where deemed appropriate by the clinician and the 
child’s parents or guardian, the child will also be included in all discussions about the trial.  Requirement 
for documentation of assent will be determined by the local IRB.  
 
 
Eligibility Criteria  
The eligibility criteria listed below are to be interpreted literally and cannot be waived. All clinical and 
laboratory data required to determine eligibility of a patient enrolled on this trial must be available in the 
patient’s medical or research record. 
 
3.1.1 Age  
 
Patients must be ≥ 12 months of age and ≤ 30 years of age at the time of study entry for 
 
patients diagnosed with DIPG.  
 
 
Patients must be ≥ 12 months of age and ≤ 21 years of age at the time of study entry for 
 
patients diagnosed with HGG.  
 
3.1.2 RB status  
 
Diagnostic stereotactic biopsy:  Patients diagnosed with DIPG may choose to have a 
 
stereotactic biopsy prior to starting radiation therapy.   
 
 
 
Screening for RB applies to all patients with available tissue except for patients 
 
diagnosed with DIPG and bi-thalamic tumors.   
 
 
If resection occurred at an outside institution, eligibility and treatment MRI evaluations in 

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addition to RB testing must be formally evaluated at CCHMC.   
 
3.1.3 Tumor 
 Diffuse Intrinsic Pontine Glioma (DIPG) 
Patients with newly diagnosed diffuse intrinsic pontine gliomas (DIPGs), defined on 
neuroimaging as tumors with a pontine epicenter and diffuse intrinsic involvement of the pons, 
are eligible without histologic confirmation.   
 
Patients with brainstem tumors that do not meet these criteria or not considered to be typical 
intrinsic pontine gliomas will only be eligible if the tumors are biopsied and proven to have + 
RB and be the following according to the 2016 World Health Organization Classification of 
Tumors of the Central Nervous System 97:   
Anaplastic astrocytoma (IDH mutant, IDH wildtype, or NOS) 
Glioblastoma (IDH mutant, IDH wildtype or NOS) 
Diffuse midline glioma, H3 K27M mutant or H3 K27M negative 
Diffuse astrocytoma (IDH mutant, IDH wildtype, or NOS)  
 
  
Note: Patients with juvenile pilocytic astrocytoma, pilomyxoid astrocytoma, pleomorphic 
xanthoastrocytoma with or without anaplasia, gangliogliomas, or other mixed gliomas without 
anaplasia are not eligible. 
 
Patients with diffuse intrinsic brain stem glioma (DIPG) can be enrolled without the need for 
available tumor tissue for RB protein status confirmation.  If DIPG or bi-thalamic patients have 
been biopsied and if available tissue, RB status will be tested.  These must be RB+ to be eligible 
for enrollment.   
  
 
Bi-thalamic tumors, biopsied and noted to have intact RB. Bi-thalamic tumors that are not 
 
biopsied will be eligible to enroll on the DIPG non-biopsied arm. 42  
 
 
 
High-grade Glioma (HGG) 
Patients must have had histologically verified the following according to the 2016 World 
Health Organization Classification of Tumors of the Central Nervous System 97:   
Anaplastic astrocytoma (IDH mutant, IDH wildtype, or NOS) 
Glioblastoma (IDH mutant, IDH wildtype or NOS) 
Diffuse astrocytoma (IDH mutant, IDH wildtype, or NOS)  
AND RB+ noted on immunohistochemistry.   
 
Patients with primary spinal cord tumors are eligible. Patients with multi-focal disease within 
the cerebrum are eligible.  
 
 
Patients with a diagnosis of oligodendroglioma or oligoastrocytoma are not eligible. 
 
3.1.4 Performance Status 
 
Karnofsky ≥ 50% for patients >16 years of age or Lansky ≥ 50 for patients ≤ 16 years of age.  
 
Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be 
 
considered ambulatory for the purpose of assessing the performance score. See 
 
APPENDIX A. 
 

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3.1.5 Prior Therapy 
 
Patients must have not received any prior therapy other than surgery, radiation and/or 
 
steroids.  
 
3.1.6  Radiation therapy requirements 
• 
Patients diagnosed with DIPG: any variances in the radiotherapy dose within 10% of the 
current standard  dose (54 Gy) will be discussed with the Sponsor-Investigator to confirm 
eligibility prior to study enrollment.  
• 
Patients diagnosed with HGG: any variances in the radiotherapy dose within 10% of the 
current standard dose (59.4 Gy) will be discussed with the Sponsor-Investigator to confirm 
eligibility prior to study enrollment. 
• 
Patients diagnosed with primary spinal tumors any variances in the radiotherapy dose within 
10% of the current standard dose (54 Gy) will be discussed with the Sponsor-Investigator 
to confirm eligibility prior to study enrollment. 
 
• 
Timing of Radiation 
Radiation therapy must begin no later than 30 days after the date of radiographic 
diagnosis or definitive surgery, whichever is the later date. 
 
3.1.7 Organ Function  
 
Patients must have normal organ and marrow function documented within 7 days of study 
 
enrollment as defined below: 
 
− 
Absolute neutrophil count  
≥ 1,000 mm3  
− 
Platelets  
 
 
 
 
 
≥ 100,000/mm3 (unsupported for 7 days) 
− 
Hemoglobin  
 
 
 
 
≥ 9g/dL (unsupported) for 7 days 
− 
Total bilirubin  
 
 
 
≤ 3 times upper limit of normal (ULN) for age  
− 
ALT (SGPT) 
 
 
 
 
≤ 2.5 x ULN institutional upper limit of normal for age 
− 
AST (SGOT) 
 
 
 
 
≤ 2.5 x ULN institutional upper limit of normal for age 
− 
Albumin  
 
 
 
 
 
≥ 2g/dL 
− 
Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m2 or 
Serum creatinine based on age/gender as follows: 
 
Table 1 
Serum Creatinine for age/gender  
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 (Schwartz et al. J. 
Peds, 106:522, 1985) utilizing child length and stature data 
published by the CDC. 

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3.1.8 All patients must have recovered from all acute RT-related toxicities to ≤ grade 2 prior to 
initiating the use of Ribociclib.  
 
3.1.9 Pregnancy Status 
 
Female patients of childbearing potential, as defined in section 3.1.10, must not be pregnant 
 
or breast-feeding.  Female patients of childbearing potential must have a negative serum or 
 
urine pregnancy test.   
 
3.1.10  Pregnancy Prevention 
 
Women of child-bearing potential are defined as all women physiologically capable of 
 
becoming pregnant, unless they are using highly effective methods of contraception 
 
throughout the study and for 21 days after study drug discontinuation. Highly 
 
effective contraception have less than 1% chance of unwanted pregnancy during one year, if 
 
used appropriately according to the instructions of the manufacturer.  Examples of highly 
 
effective birth control methods are:  
• 
Total abstinence (no sexual relations) when this is in line with the preferred and usual lifestyle 
of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 
• 
Tubal ligation at least 6 weeks before taking study drug.   
• 
Male partner has had vasectomy with the appropriate documentation.  Sterilized male partner 
should be the sole partner of the female.   
• 
Use of a Combination of any of the two following (a+b or a+c or b+c) 
a. Use of oral, injected or implanted hormonal methods of contraception or other forms of 
hormonal contraception that have comparable efficacy (failure rate <1%), for example 
hormone vaginal ring or transdermal hormone contraception 
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/ vaginal suppository 
 
 
Patients of child fathering potential (defined as > Tanner stage 2) must use a condom during 
intercourse while taking the drug during treatment, for 21 days after stopping treatment and 
should not father a child in this period. A condom is required to be used also by vasectomized 
men during  intercourse with a male  or female partner in order to prevent delivery of the study 
drug via semen.  
 
 
Note: Oral contraceptives are allowed but should be used in conjunction with a barrier 
 
method of contraception due to unknown effect of drug-drug interaction. In case of use of oral 
 
contraception, women should have been stable on the same pill for a minimum of 3 months 
 
before taking study treatment.   
 
3.1.11  Female patients with infants must agree not to breastfeed their infants while on this study.  
 
3.1.12 Informed Consent 
 
Signed informed consent according to institutional guidelines must be obtained. Assent, when 
 
appropriate, will be obtained according to institutional guidelines. 
 

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Exclusion Criteria 
3.2.1 Concurrent Illness 
 
Patients with any clinically significant unrelated systemic illness (serious infections or 
 
significant cardiac, pulmonary, hepatic or other organ dysfunction) that would compromise 
 
the patient’s ability to tolerate protocol therapy or would likely interfere with 
the 
study 
 
procedures or results. 
 
3.2.2 Inability to Participate 
 
Patients with inability to return for follow-up visits or obtain follow-up studies required to 
 
assess toxicity to therapy. 
 
3.2.3  Received a radiosensitizer, investigational agent or any additional adjuvant therapy during 
radiation therapy.  
 
3.2.4 Patients with disseminated disease to the spine are not eligible, and MRI of spine must be 
performed prior to enrollment if the treating physician suspects disseminated disease. 
 
3.2.5 Seizures 
 
 
Patients who are currently receiving enzyme inducing anti-epileptic drugs that are known 
 
 
strong inducers or inhibitors of CYP3A4/5 (EIAEDs) (Appendix D).  Patients with a history 
 
 
of seizures and maintained on an anti-epileptic drug that is not a strong inducers or inhibitor 
 
 
of CYP3A4/5 are eligible.  
 
3.2.6 Patient has a known hypersensitivity to Ribociclib or any of its excipients. 
 
3.2.7 Clinically significant active cardiac disease, uncontrolled heart disease and/or history  of 
cardiac dysfunction including any of the following; 
• 
History of acute coronary syndromes (including myocardial infarction, unstable angina, 
coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic 
pericarditis within 12 months prior to screening 
• 
History of documented congestive heart failure (New York Heart Association functional 
classification III-IV) 
• 
Documented cardiomyopathy 
• 
Patient has a Left Ventricular Ejection Fraction (LVEF) <50% as determined by Multiple 
Gated acquisition (MUGA) scan or echocardiogram (ECHO) at screening 
• 
History of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal arrhythmias, or 
conduction abnormality within 12 months of screening 
• 
Long QT syndrome or known family history of idiopathic sudden death or congenital 
long QT syndrome, or any of the following:  
 
Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia or 
hypomagnesemia, history of cardiac failure, or history of clinically 
significant/symptomatic bradycardia.  
Concomitant use of medication(s) with a known risk to prolong the QT interval and/or 
known to cause Torsades de Pointe that cannot be discontinued (within 5 half-lives or 7 
days prior to starting study drug) or replaced by safe alternative medication.  
• 
Hypertension defined below:  

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Patients1-17 years of age with blood pressure that is  ≥ 95th percentile for age, height and 
gender at the time of enrollment  (Appendix B) 
 
Patients who are ≥ 18 years of age  with a systolic blood pressure that is  >160 or 
diastolic > 90 mm of Hg at the time of enrollment. 
 
* Note:  If a BP reading prior to enrollment does not meet parameters, blood pressure 
should be rechecked and documented to be within eligibility range prior to patient 
enrollment.  
 
3.2.8 Inability to determine the QTc interval on the ECG (i.e.: unreadable or not interpretable) or QTc 
>480 msec as determined by screening ECG.  
3.2.9 Patient is currently receiving any of the following medications and cannot be 
 discontinued 7 days prior to starting study drug Ribociclib (see Appendix D for details): 
• 
Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit hybrids, 
pummelos, star-fruit, and Seville oranges 
• 
Medications that have a narrow therapeutic window and are predominantly metabolized 
through CYP3A4/5 
• 
Medications that have a known risk to prolong the QT interval or induce Torsades de 
Pointes  
• 
Herbal preparations/medications, dietary supplements. 
3.2.10 Patient is currently receiving warfarin or other coumadin-derived anticoagulant for treatment, 
prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH) or 
fondaparinux is allowed 
 
3.2.11 Patient has a history of non-compliance to medical regimen. 
 
3.2.12 Known need for major surgery within 14 days of the first dose of Ribociclib.  Gastrostomy, 
insertion of a G tube, Ventriculo-peritoneal shunt, endoscopic ventriculostomy and central 
venous access are NOT considered major surgery.   
 
 
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial.   
 
 
4. GENERAL GUIDELINES 
 
 
Screening Informed Consent 
 
 
 
 
  
 
 
    
 

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Treatment informed consent 
 
   
 
 
 
 
 
 
Patient /Enrollment 
   
 
 
 
 
   
 
 
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 

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4.4.1.1 
Surgical Technique for stereo-tactic biopsy in patients diagnosed with DIPG: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
 
   
 
  
 
  
 
 
 
 
   
 
 
 
 
 

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General Concomitant Medication and Supportive Care Guidelines 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
   
 
 
 
   
 
 
  
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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13. STATISTICAL CONSIDERATIONS  
 
Study Design: 
This is a “safety and preliminary efficacy” study of   Ribociclib administered orally once daily for 3 weeks, 
off one week every 28 days following radiation therapy for up to 12 courses in children with newly-
diagnosed diffuse intrinsic pontine glioma (DIPG) and RB+ high grade gliomas (HGG). The study design 
requires 24 patients evaluable for feasibility (12 in both the DIPG and HGG groups). Patients not evaluable 
for feasibility will be replaced, therefore, the enrollment sample size may be greater than 24.  DIPG patients 
will have the option to have diagnostic biopsy to evaluate RB status.  Patients with RB negative DIPG and 
HGG tumors will have the opportunity to enroll on other DIPG or HGG protocols as directed by the family 
and their treating physician. Patients with DIPG who do not consent to biopsy will be offered Ribociclib 
maintenance since over 70% of patients with DIPG have been reported to have an intact RB.  RB status 
will be identified pre-treatment on tumor tissue by immunohistochemistry. 
 
We will start with the recommended phase II dose (RP2D) 350 mg/m2/day once daily for 3 weeks, off 1 
week every 28 days and monitor for safety and toxicity for up to 12 courses upon completion of radiation 
therapy.  One intra-patient dose de-escalation is allowed in subsequent courses to 280 mg/m2 /day once 
daily for 3 weeks, off one week every 28 days.   
 
The primary endpoint of feasibility, the two strata (DIPG and HGG) will be considered together. This is 
done since it is not expected that the two groups will differ with respect to the feasibility. The primary 
feasibility endpoints are a) toxic death or individual toxicities related to study drug resulting in 
discontinuation of study drug b) the incidence of significant delays (> 2 weeks) in the start of any course of 
maintenance therapy or discontinuation of the protocol therapy even after appropriate dose modification. 
Dose-modifying toxicities for maintenance therapy will be monitored. The primary endpoint for the early 
phase II study will be the 1-year overall survival (OS) of the two strata separately, DIPG and HGG.  Early 
efficacy will be measured by the overall survival distribution will be evaluated and compared to historical 
controls. Pharmacokinetic analysis will be stratified according to age groups:  patients ≤ 21 years of age 
and >21 years of age.   
 
 
Study Design/Endpoints. 
 
13.1.1 Feasibility 
To address the endpoint of feasibility, the two strata (DIPG and HGG) will be considered together. This 
is done since it is not expected that the two groups will differ with respect to the feasibility.  
 
 
The primary feasibility endpoints are: 
a) Toxic death or individual toxicities especially Grade 3 or 4 related to study drug resulting in 
discontinuation of study drug 
b) The incidence of significant delays (> 2 weeks) in the start of any course of maintenance therapy or 
removal from protocol therapy over any course of maintenance or discontinuation of the protocol therapy 
even after appropriate dose modification.   
 
For a patient surviving 6 months after the start of maintenance, if 5 out of 6 courses out of the first 6 months 

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are completed the drug will be deemed feasible for this patient.  This includes up to one intra-patient de-
escalation to 280 mg/m2/day once daily for 3 weeks and off one week every 28 days in this time period. If 
more than 2 out of the first 12 enrolled evaluable patients are infeasible, the study will stop and the drug 
will be considered infeasible at the RP2D (350 mg/m2/day) for this patient population. If after 24 patients 
there are fewer than 5 patients for whom the drug is infeasible the drug will be considered feasible at the 
RP2D (350mg/ m2/day). If infeasible for 6 evaluable patients enrolled at any point, the study will stop.  
Enrollment will continue after the first 12 participants are enrolled while evaluability is being determined.  
In the event of early shut down of the study, < 25% of patients with dose modifying toxicities after one 
dose level modification will be considered feasible.   
 
We anticipate enrollment of 12 DIPG patients and 12 HGG patients at the RP2D 350 mg/m2/day once daily 
for 3 weeks and off one week every 28 days for patients ≤ 21 years of age and 600 mg orally once daily for 
3 weeks and off one week every 28 days for DIPG patients > 21 years of age and evaluate the feasibility at 
6 months post completion of radiation therapy up to 12 courses of therapy.   
 
13.1.2 Definition of Evaluable Patient (Feasibility) 
Patients who receive at least 80% (5/6 courses) of the treatment regimen or are removed from treatment for 
toxicity after the dose-modification are evaluable for estimating the safety and feasibility of Ribociclib as 
long as no additional anti-cancer therapy or supportive care that would confound the interpretation of any 
observed toxicity or side effect is given. 
 
Patients who receive at least 80% of prescribed therapy during the 6 month feasibility period but who 
progress prior to completing the 12 months of therapy may be considered evaluable for safety and 
feasibility, as long as no additional anti-cancer therapy or supportive care that would confound the 
interpretation of any observed toxicity or side effect is given. Patients should have completed all of the 
clinical and laboratory monitoring requirements specified by the protocol up to the time of disease 
progression for them to be considered evaluable for safety and feasibility. 
 
Patients who receive less than 80% of the protocol specified therapy and who go off treatment for reasons 
other than toxicity (e.g. progressive disease, withdrawal of consent etc.) will be considered in evaluable for 
estimating the safety and feasibility and will be replaced.  
 
Patients who complete all therapy during the 6 month feasibility period but who fail to comply with all the 
specified clinical and laboratory monitoring requirements for the dose finding period may be considered 
inevaluable by the study chair for estimating the feasibility and may be replaced. 
 
 
Early Efficacy 
The 1-year overall survival (OS) of the two strata will be considered separately. For each, the 1-year OS 
will be estimated and 95% confidence intervals will be given. All patients enrolled will be considered 
eligible for the estimation of the 1-year OS. In our most recent HGG-01 study, OS was approximately 35% 
and 80% for DIPG and HGG, respectively. Available data report OS is 7-17 months and 12-24 months for 
DIPG and HGG respectively. 2,26,100 Conservatively assuming only 12 patients per group, this will yield 
confidence intervals with width 46% and 55%, respectively. In addition to the 1-year OS, Kaplan-Meier 
curves will be generated for each stratum. The primary objective of this part of the study will be assessed 
based on the intent-to-treat (ITT) hypothesis. That is, any eligible patient who receives any Ribociclib will 
be included in the primary analysis 
 

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13.2.1 Progression-free survival (PFS) is a secondary endpoint and is defined as the time from 
initiation of treatment to the earliest date of failure (disease progression, death from any cause, or second 
malignancy) for patients who fail and to the last assessment date for patients who have not failed. Patients 
who start other anti-cancer therapy prior to disease progression will be censored in the Kaplan-Meier 
estimate of PFS as of the date the alternative therapy began. Patients who have not failed (died) at the 
time of analyses will be censored at their last date of contact in the Kaplan-Meier estimate of the PFS 
(overall survival) distribution.  
 
13.2.2 Definition of an Evaluable Patient (Efficacy) 
All eligible patients who receive at least 1 dose of Ribociclib are evaluable for assessing overall survival, 
as well as for evaluating progression free survival and objective response rates 
 
 
Projected Accrual Rate and Study Duration 

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