Conditions: CNS Embryonal Tumor, Not Otherwise Specified Malignant Glioma Recurrent Atypical Teratoid/Rhabdoid Tumor Recurrent Childhood Ependymoma Recurrent Diffuse Intrinsic Pontine Glioma Recurrent Medulloblastoma Refractory Diffuse Intrinsic Pontine Glioma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 22
Healthy volunteers: no

Brief summary:
This phase I trial studies the side effects and best dose of ribociclib and everolimus and to see how well they work in treating patients with malignant brain tumors that have come back or do not respond to treatment. Ribociclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as everolimus, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ribociclib and everolimus may work better at treating malignant brain tumors.

Detailed description:
PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) and/or the recommended phase II dose (RP2D) of ribociclib and everolimus in children with refractory or recurrent central nervous system (CNS) tumors. (Phase I) II. To describe the toxicity profile and define the dose-limiting toxicities (DLTs) of ribociclib and everolimus in children with refractory or recurrent CNS tumors. (Phase I) III. To characterize the pharmacokinetics of ribociclib and everolimus in children with refractory or recurrent CNS tumors, and the potential for drug-drug interactions between the two compounds in this population. (Phase I) IV. To characterize ribociclib concentrations in tumor, and plasma in children with refractory or recurrent CNS malignancies undergoing neurosurgical procedures. (Surgical Study)

SECONDARY OBJECTIVES:

I. To describe the response rate of relapsed and refractory malignant brain tumors to ribociclib and everolimus in the context of a phase I study. (Phase I) II. To explore the effect of ribociclib treatment on Ki-67 by immunohistochemistry (IHC) by comparing archival and post-treatment tumor tissue. (Surgical Study)

TERTIARY OBJECTIVES:

I. To increase knowledge of the genomic landscape of treatment-refractory pediatric CNS tumors, including mechanisms of resistance and response.

OUTLINE: This is a dose-escalation study.

Patients receive ribociclib orally (PO) once daily (QD) on days 1-21 of course 1 and subsequent courses and days 2-21 of course 2, and everolimus PO QD on days 3-28 of course 1 and days 1-28 of subsequent courses. Patients who are undergoing surgery also receive ribociclib PO QD on days 7-10 before surgery. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity. Patients with stable disease after 13 courses may continue receiving ribociclib and everolimus every 28 days for up to 13 additional courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days.

Arms:
arm 1: Patients receive ribociclib PO QD on days 1-21 of course 1 and subsequent courses and days 2-21 of course 2, and everolimus PO QD on days 3-28 of course 1 and days 1-28 of subsequent courses. Patients who are undergoing surgery also receive ribociclib PO QD on days 7-10 before surgery. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity. Patients with stable disease after 13 courses may continue receiving ribociclib and everolimus every 28 days for up to 13 additional courses in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Everolimus intervention 2: Laboratory Biomarker Analysis intervention 3: Pharmacological Study intervention 4: Ribociclib
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies intervention 3: Correlative studies intervention 4: Given PO

Protocol document:
Prot_SAP_000.pdf: 
NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
 
 
NCI Protocol #: 
PBTC-050 
 
Local Protocol #: 
PBC-050 
 
ClinicalTrials.gov Identifier: NCT03387020 
 
TITLE:  A Phase I and Surgical Study of Ribociclib and Everolimus (RAD001) in Children with 
Recurrent or Refractory Malignant Brain Tumors 
 
 
Coordinating Center: 
Operations, Biostatistics and Data Management Core (OBDMC) for the 
Pediatric Brain Tumor Consortium (PBTC), St. Jude Children’s 
Research Hospital 
 
Principal Investigator: 
Mariko DeWire-Schottmiller, M.D. 
 
 
 
 
 
 
 
Co-Investigator: 
Maryam Fouladi, M.D. 
 
 
 
  
 
 
 
 
PBTC Biostatistician 
Haitao Pan, Ph.D.  
 
 
 
 
 
 
 
PBTC Biostatistician 
Tong Lin, PhD 
 
 
 
 
 
 
 
 
PBTC Protocol Coordinator 
Stacye Richardson, MSHS 
 
 
 
 
 
 
 
 
 
 
 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
PBTC Neuroimaging Center 
Tina Young Poussaint, M.D. 
 
 
 
 
 
 
 
  
 
Pathology and 
Pharmacodynamics Correlates 
Laboratory 
Christine Fuller, MD 
 
 
 
 
 
 
 
 
  
 
Pharmacokinetics Laboratory 
Clinton Stewart, PharmD 
 
 
 
 
 
 
 
 
 
 
Genomics Correlates Laboratory 
Donald W.(Will) Parsons, M.D, PhD 
 
 
 
 
 
 
 
 
 
Investigational Pharmacist 
Denise Lagory, PharmD 
 
 
 
 
 
 
 
Nursing Committee Representative 
Michele Anton, RN BSN CPN  
 
 
 
 
 
 
 
 
CRA Committee Representative 
Emily Sparks, MS 
 
 
 
 
 
 
 
 
 
 
 
 
NCI-Supplied Agent(s): NA   
 
Other Agent(s):  
• Ribociclib, NSC # 794613, supplied by Novartis 
• Everolimus (RAD001), NSC # 733504, supplied by Novartis 
  
IND #:  128405 
IND Sponsor:  Mariko DeWire-Schottmiller, MD, 
  
 
Protocol Type / Version #3.1 / Version Date: September 26, 2018 
 
 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
Pediatric Brain Tumor Consortium Institutions and Principal Investigators 
Arzu Onar-Thomas, Ph.D.* 
 
 
 
 
 
 
 
 
Ira Dunkel, M.D. 
 
 
 
 
 
 
Patricia Baxter, M.D. 
 
 
 
 
 
 
 
Girish Dhall, MD 
 
  
 
 
 
 
 
 
Kathleen Dorris, MD 
 
 
 
 
 
 
Michelle Monje, M.D PhD 
 
 
 
 
 
 
Maryam Fouladi, M.D. 
 
 
 
 
 
  
 
 
Stewart Goldman, M.D. 
 
 
 
 
 
 
 
Eugene Hwang, M.D. 
 
 
 
 
 
 
 
Tobey MacDonald, MD 
  
 
 
 
 
 
 
Giles Robinson, MD 
 
 
 
 
 
 
 
Kathy Warren, M.D. 
 
 
 
 
 
 
 
 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
Ian Pollack, M.D. 
 
 
 
 
 
 
 
*Does not have patient care responsibilities 
 
 
 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
Abstract and Schema 
This is Phase I and Surgical study for children with retinoblastoma protein 1 (Rb1) positive recurrent or 
refractory central nervous system tumors.  
 
Brain tumors are the leading cause of cancer-related death in children.  Though cures for some are possible 
using conventional therapeutic approaches, outcome for highly malignant and recurrent brain tumors 
remains poor, despite aggressive multimodal therapy.  Improved understanding of the inherent tumor 
biology and genomic landscape of brain tumors has spurred development of novel therapeutics aimed at 
targeted inhibition of important cancer-promoting pathways. 
 
Aberrant cell cycle regulation and activation of the PI3K/Akt/mTOR pathway represent two highly 
important mechanisms of malignant potential in pediatric brain tumors.  Joint inhibition of CDK4/6 and 
mTOR is promising due to strong biologic rationale, non-overlapping single-agent toxicities, and 
preliminary clinical experience in adults that suggests tolerability of this combination. Additionally, 
increased exposure of RAD001 in the presence of ribociclib, as observed in pharmacokinetic profiling of 
samples from adults receiving the combination, suggest that lower doses of both drugs may also be used 
in the pediatric population.   
 
Ribociclib is an orally available cyclin-dependent kinase (CDK) inhibitor targeting cyclin D1/CDK4 and 
cyclin D3/CDK6 cell cycle pathway, with potential antineoplastic activity. Overexpression of CDK4/6, 
as seen in certain types of cancer, causes cell cycle deregulation. Ribociclib specifically inhibits CDK4 
and 6, thereby inhibiting retinoblastoma (Rb) protein phosphorylation. Inhibition of Rb phosphorylation 
prevents CDK-mediated G1-S phase transition, thereby arresting the cell cycle in the G1 phase, 
suppressing DNA synthesis and inhibiting cancer cell growth.  
 
Everolimus is an inhibitor of selective mammalian target of rapamycin (mTOR), the effects of which 
specifically target the mTOR-raptor signal transduction complex 1 (mTORC1). The PI3K/AKT/mTOR 
pathway is dysregulated in the majority of human cancers and is the object of many targeted agents.  
Inhibition of mTORC1, an essential regulator of global protein synthesis downstream on the 
PI3K/AKT/mTOR pathway, reduces tumor cell proliferation, glycolysis and angiogenesis.  
 
Both ribociclib and everolimus will be supplied by Novartis for PBTC-050 study.  
 
Schema: 
This is Phase I and Surgical Study of ribociclib and everolimus given in combination in children with 
recurrent or refractory malignant brain tumors.   
 
Phase I 
The primary objective of the Phase I component is to estimate the MTD and/or the recommended phase 
II dose (RP2D) of ribociclib and everolimus in children. Ribociclib and everolimus will be given in 
combination either in oral with drug-in-capsule versus liquid formulation or via gastric tube (liquid 
formulation). Ribociclib will be administered once a day for 21 days on/7 days off on a 28-day cycle and 
everolimus will be administered once a day for 28 days. One course is therefore equivalent to 28 days. 
Therapy may continue for up to a year (13 courses) in the absence of disease progression or unacceptable 
toxicity. Patients who have at least clinically and radiographically stable disease at the end of course 13 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
may be able to participate in the extended therapy for up to an additional 13 courses (total maximum 
duration of treatment is 26 courses). 
 
Dose Escalation Schedule Table 
Dose Level 
Ribociclib  
(mg/m2/day PO days 1- 21) 
Everolimus  
(mg/m2/day PO days 1-28) 
BSA Restriction 
-1 
75 mg/m2/day 
1 mg/m2/day 
BSA≥0.55m2 
-0.5*  
120 mg/m2/day 
1 mg/m2/day 
BSA≥0.75m2 
0 
75 mg/m2/day 
1.2 mg/m2/day 
BSA≥0.55m2 
1(starting dose) 
120 mg/m2/day 
1.2 mg/m2/day 
BSA≥0.75m2 
2 
170 mg/m2/day 
1.2 mg/m2/day 
BSA≥0.45m2 
3 
170 mg/m2/day 
1.5 mg/m2/day 
BSA≥0.45m2 
*Dose reduction if toxicities clearly attributable to Everolimus 
 
Surgical Cohort 
The primary objective of the Surgical Cohort is to characterize ribociclib concentrations in tumor and 
plasma in children with refractory or recurrent CNS tumors undergoing neurosurgical procedures. Patients 
will take ribociclib alone at the pediatric MTD (350 mg/m2/day) for 7 – 10 days prior to surgery. Following 
tumor resection and within 2-4 weeks of post-surgery period, patients enrolled on the surgical study will 
be switched over to the phase I study and be treated with ribociclib and everolimus combination at the 
assigned dose level.  
 
If the starting dose of ribociclib is intolerable or if DLTs of the starting dose of ribociclib are clearly 
attributable to the study drug, the dose will be dose de-escalated to 280 mg/m2/day. 
 
 
 
 
 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
Table of Contents 
Abstract and Schema....................................................................................................................... 5 
Table of Contents ............................................................................................................................ 7 
1 
Objectives ............................................................................................................................... 9 
1.1 
Primary Objectives ....................................................................................................... 9 
1.2 
Secondary Objectives ................................................................................................... 9 
1.3 
Exploratory Objective ................................................................................................... 9 
2 
Background ........................................................................................................................... 10 
2.1 
Study Disease ............................................................................................................. 10 
2.2 
Ribociclib (LEE011)................................................................................................... 14 
2.3 
Everolimus (RAD001) ................................................................................................ 28 
2.4 
Rationale for Proposed Pediatric Study ...................................................................... 30 
2.5 
Correlative Studies Background ................................................................................. 31 
3 
Patient Selection.................................................................................................................... 34 
3.1 
Eligibility for Screening (Phase I and surgical study) ................................................ 34 
3.2 
Eligibility Criteria: Prior to Study Enrollment ........................................................... 35 
3.3 
Exclusion Criteria ....................................................................................................... 39 
3.4 
Criteria to Start Treatment .......................................................................................... 41 
3.5 
Criteria to Start Treatment with ribociclib and everolimus combination therapy ...... 41 
3.6 
Treatment at the Primary Institution ........................................................................... 41 
4 
Registration Procedures ........................................................................................................ 42 
4.1 
CTEP Investigator Registration Procedures ............................................................... 42 
4.2 
CTSU Registration Procedures ................................................................................... 43 
4.3 
Requirements for Submitting Regulatory Documents................................................ 43 
4.4 
General Guidelines ..................................................................................................... 44 
4.5 
Enrollment Procedures ............................................................................................... 44 
5 
Treatment Plan ...................................................................................................................... 46 
5.1 
Starting Dose and Dose escalation Schedule .............................................................. 47 
5.2 
Agent Administration ................................................................................................. 48 
5.3 
Dose Limiting Toxicity .............................................................................................. 50 
5.4 
Concomitant Medications and Supportive Care Guidelines ....................................... 52 
5.5 
Duration of Therapy ................................................................................................... 54 
6 
Dosing Delays/Dose Modification ........................................................................................ 56 
6.1 
Notification of the Study Chair .................................................................................. 56 
6.2 
Hematologic and Non-hematologic Adverse Events and Management ..................... 56 
7 
Adverse Events: List and Reporting Requirements .............................................................. 63 
7.1 
Adverse Event List(s) for ribociclib (LEE011, NSC 794613) ................................... 63 
7.2 
Adverse Event List(s) for everolimus (RAD-001, NSC 733504) .............................. 64 
7.3 
Adverse Event Characteristics .................................................................................... 66 
7.4 
Expedited Adverse Event Reporting .......................................................................... 67 
8 
Agent Information ................................................................................................................. 70 
8.1 
Everolimus (RAD001) ................................................................................................ 70 
8.2 
Ribociclib.................................................................................................................... 72 
8.3 
Agent Ordering and Agent Accountability ................................................................. 74 
9 
Biomarker, Correlative and Special Studies ......................................................................... 74 
9.1 
Integral Laboratory Studies ........................................................................................ 75 


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9.2 
Pathology and Exploratory Correlative Studies ......................................................... 77 
9.3 
Neuroimaging Studies ................................................................................................ 86 
10 Study Calendar ...................................................................................................................... 87 
10.1 
Surgical Study............................................................................................................. 87 
10.2 
Phase I......................................................................................................................... 90 
10.3 
Correlative Lab Studies Calendar (Phase I) ............................................................... 91 
11 Measurement of Effect .......................................................................................................... 93 
11.1 
Antitumor Effect ......................................................................................................... 93 
11.2 
Disease Parameters ..................................................................................................... 94 
11.3 
Tumor Response Criteria ............................................................................................ 96 
12 Study Oversight and Data Reporting/ Regulatory Requirements/ Confidentiality ............... 97 
12.1 
Study Oversight .......................................................................................................... 97 
12.2 
Data Reporting ............................................................................................................ 97 
12.3 
CTEP Multicenter Guidelines .................................................................................... 98 
12.4 
Collaborative Agreements Language ......................................................................... 98 
12.5 
Participant and Data Confidentiality .......................................................................... 98 
13 Statistical Considerations ...................................................................................................... 99 
13.1 
Study Design/Endpoints ............................................................................................. 99 
13.2 
Dose Escalation/De-Escalation Rules ...................................................................... 100 
13.3 
Sample Size/Accrual Rate ........................................................................................ 102 
13.4 
Analysis of Primary endpoints ................................................................................. 103 
13.5 
Analysis of Secondary endpoints ............................................................................. 103 
14 References ........................................................................................................................... 104 
15 Appendices .......................................................................................................................... 109 
15.1 
Performance Status Criteria ...................................................................................... 109 
15.2 
Prohibited medications - Ribociclib alone or Ribociclib and Everolimus ............... 110 
15.3 
List of medications to be used with CAUTION during study drug treatment with Ribociclib 
alone or Ribociclib and Everolimus ........................................................................................ 111 
15.4 
List of prohibited medications – Everolimus ........................................................... 112 
15.5 
Dosing Tables for Ribociclib .................................................................................... 113 
15.6 
Patient Drug Information Handout ........................................................................... 115 
15.7 
Caregiver and Patient instructions for administration of everolimus dispersible tablets using a 
Dosing Cup ............................................................................................................................. 117 
15.8 
Caregiver and Patient instructions for administration of everolimus dispersible tablets using a 
Syringe 119 
 
 


NCI Protocol #: PBTC-050 
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Updated Date:  September 26, 2018 
1 OBJECTIVES 
1.1 
Primary Objectives 
Phase I 
1.1.1 To estimate the MTD and/or the recommended phase II dose (RP2D) of ribociclib and everolimus 
in children with refractory or recurrent CNS tumors  
1.1.2 To describe the toxicity profile and define the dose-limiting toxicities (DLTs) of ribociclib and 
everolimus in children with refractory or recurrent CNS tumors  
1.1.3 To characterize the pharmacokinetics of ribociclib and everolimus in children with refractory or 
recurrent CNS tumors, and the potential for drug-drug interactions between the two compounds in 
this population 
 
Surgical Study 
1.1.4 
To characterize ribociclib concentrations in tumor, and plasma in children with refractory or 
recurrent CNS malignancies undergoing neurosurgical procedures 
 
1.2 
Secondary Objectives 
Phase I 
1.2.1 To describe the response rate of relapsed and refractory malignant brain tumors to ribociclib and 
everolimus in the context of a phase I study 
1.2.2 To assess dexamethasone-based mouthwash for prevention of stomatitis in pediatric patients 
receiving everolimus therapy 
 
Surgical Study 
1.2.3 To explore the effect of ribociclib treatment on Ki-67 by IHC by comparing archival and post-
treatment tumor tissue 
 
1.3 
Exploratory Objective 
1.3.1 To increase knowledge of the genomic landscape of treatment-refractory pediatric CNS tumors, 
including mechanisms of resistance and response 
 
 


NCI Protocol #: PBTC-050 
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2 BACKGROUND 
2.1 
Study Disease 
Brain tumors are the leading cause of cancer-related death in children.  Though cures for some are possible 
using conventional therapeutic approaches, outcome for highly malignant and recurrent brain tumors 
remains poor, despite aggressive multimodal therapy. Improved understanding of the inherent tumor 
biology and genomic landscape of brain tumors has spurred development of novel therapeutics aimed at 
targeted inhibition of important cancer-promoting pathways. 
 
Cell Cycle Regulation and Cancer 
Tumor cell proliferation requires repetitive cell divisions involving doubling of DNA content (S phase) 
and halving of the genome during mitosis (M phase) that results in two identical cells. Between the S and 
M phase, the G1 (Gap 1) phase occurs during which signals either allow continuation to S phase or prompt 
cell cycle exit into the quiescence phase (G0 phase).1 During G1, cells grow and prepare for chromosomal 
replication during the S phase. Following S phase, the cell enters another gap phase (G2 phase), during 
which the cell prepares for equal division of DNA into two identical daughter cells (M phase). Checkpoints 
are transitions between various phases of the cell cycle that are tightly regulated by cyclins and cyclin-
dependent kinases (CDKs), which are aberrant in the majority of human cancers.2  
 
In mammalian cells, cyclins and CDKs are associated with various cell cycle phases, including G1 phase 
(Cyclins D1-3, E and CDKs 4, 6, 2), S phase (Cyclins A, E and CDK2), and mitosis (Cyclin A, E and 
CDK 1, 2).1,2 The “brakes” of the cell cycle are regulated by CDK phosphorylation/ dephosphorylation, 
cyclin synthesis/degradation, and availability of naturally occurring protein inhibitors, as well as 
subcellular localization of these regulatory components. Cell cycle inhibition is mediated by two families 
of proteins: INK4 and CDK inhibitor protein (CIP)/kinase inhibitor protein (KIP).1 Whereas the INK4 
inhibitors (p16INK4A and p14ARF, p15INK4B, p18INK4C, and p19INK4D) specifically inhibit CDK4/6 during G1, 
CIP/KIP (p21CIP1, p27KIP1, p57KIP2) inhibitors work against kinases and cyclins in all phases of the cell 
cycle.1  
 
G1→S phase transition is mediated by activation of the CDK4/Cyclin D complex following release of 
INK4 from CDK4/6.1 This results in hypophosphorylation of the retinoblastoma protein (Rb) and partial 
release of the E2F-DP1 transcription complex. In late G1, release of Cyclin E/CDK2 from the inhibitory 
effect of p27KIP1 results in Rb1 hyperphosphorylation and complete release of E2F-DPI complex, which 
then binds to promoter regions of genes required for S phase entry and progression (Figure 1).1   
 
 
Figure 1: The CDK4/6, p16, Rb-E2F pathway 
 


NCI Protocol #: PBTC-050 
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Cell Cycle Dysregulation in Pediatric Brain Tumors 
As in most human cancers, cell cycle dysregulation is common in malignant pediatric brain tumors.  High-
throughput sequencing studies in many tumor types have identified focal gains of CDK4, CDK6, and 
Cyclin D1-3 and/or homozygous loss of INK4a-ARF, implicating cell cycle regulation in tumor 
pathogenesis. CDK4/6 inhibitors bind CDK4/6 and inhibit Rb phosphorylation, which induces G1 cell 
cycle arrest.  Importantly, since the mechanism of CDK4/6 inhibitors is mediated through Rb, functional 
Rb protein is critical for efficacy. 
 
High-Grade Glioma and DIPG 
Cell cycle regulation has been strongly implicated in pediatric high-grade glioma (HGG) and diffuse 
intrinsic pontine glioma (DIPG).  DIPG harbors focal gains of CDK4, CDK6, or cyclin D1-3 and p16 loss 
in 35% and 20% of tumors, respectively.3,4 Paugh et al. also reported focal gains of genes encoding 
receptor tyrosine kinases (RTKs) or cell cycle regulatory genes in 24/43 (56%) of DIPG.3 Gain of CDK4, 
CDK6, or cyclin D2 has less reported incidence in non-brainstem HGG (6%), though p16 loss is observed 
at a similar frequency of 20%.5,6 Mutations of PTEN and TP53, key tumor suppressors involved in cell 
cycle regulation, have also been reported commonly in DIPG and HGG at rates of 25% and 42-70%, 
respectively.7-10 Collectively, Wu et al. implicated mutations predicted to affect cell cycle regulation in 
59% of their recently reported cohort of 127 patients with DIPG and non-brainstem HGG.8 There is wide 
variation in reports about Rb mutation or deletion in HGG and DIPG, ranging from 0-58%.6-11 
Specifically, Schartzentruber et al. reported Rb1 mutation in 5/49 (10%) HGG6, and Taylor et al. and 
Buczkowicz et al. reported Rb1 loss in 6/26 (20%) and 15/48 (31%) of DIPG, respectively.7,10  
 
Barton et al. demonstrated the efficacy of CDK4/6 inhibitor PD-0332991 in a genetically- engineered 
brainstem glioma mouse model driven by PDGF overexpression and Ink4-ARF loss. In a proliferation 
assay, the IC50 of cells derived from the Ink4a-ARF-deficient, PDGF-driven brainstem glioma model was 
2µM, compared to > 5µM for cells derived from a p53-deficient PDGF-driven brainstem glioma. Two 
daily doses of PD-0332991 given by gavage to brainstem glioma-bearing mice significantly inhibited 
tumor cell proliferation as measured by pH3, demonstrating good drug delivery across the blood-brain-
barrier.12 Aoki et al. showed that treatment of a brainstem glioma xenograft model with PD-0332991 
provides significant survival benefit relative to vehicle-treated mice.13 
 
Medulloblastoma and PNET 
In medulloblastoma, focal amplification of loci containing CDK and cyclin genes was reported by Li et 
al. in 1-5% of medulloblastoma and 25% of supratentorial primitive neuroectodermal tumor (PNET).14 A 
separate study reported CDK6 overexpression in 30% of medulloblastomas, which served as an 
independent prognostic marker of poor overall survival.15 Pfister et al. also separately reported CDKN2A 
loss in 7/21 (30%) of PNETs, including 4 with homozygous loss.16 Neither Rb1 mutation, nor loss were 
reported in a large sequencing study of medulloblastoma17 and have not been reported in PNET.18  
 
Dr. James Olson at the Fred Hutchinson Cancer Center in Seattle, WA has treated mice implanted with 
patient derived medulloblastoma flank xenografts with PD-0332991 at 150 mg/kg/day for 14 days.19 
Significant tumor regressions were observed associated with decrease in proliferation rate (), Rb1 
phosphorylation (Figure 2) and improvement in animal survival (Figure 3) compared to vehicle alone. 
Maintenance of therapy past 38 days of initial treatment resulted in persistent tumor control suggesting 
that tumors do not develop drug resistance. Decreasing dose to 75 mg/kg/day did not result in loss of 
efficacy (Figure 4). 


NCI Protocol #: PBTC-050 
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Figure 2: Medulloblastoma flank xenografts in mice treated with vehicle or PD0332991 
(150 mg/kg/day for 14 days) 
 
Figure 3: Western blot to demonstrate decrease in RB phosphorylation following 
treatment with PD-0332991 (Lanes 3, 4, and 5) compared to vehicle (lanes 1 and 2). 
Tumor from mouse in lane 5 was sacrificed at 24 hours as compared to 4 hours for those 
on lane 3 and 4. 
 
 
 
Figure 4: Survival of mice with Medulloblastoma flank tumors treated with vehicle or PD 
0332991 
 
Ependymoma 
Loss of p16 has been reported in 22/89 (25%) of ependymomas and is associated with poor prognosis.20,21 
Rb1 deletions have been reported in 22/92 (24%) of ependymomas.21 
 


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ATRT 
Cell cycle regulation plays an important role in atypical teratoid rhabdoid tumor (ATRT).  SMARCB1 
directly inhibits cyclin D1 transcription through recruitment of histone deacetylase complexes to the cyclin 
D1 promoter22, and SMARCB1 loss leads to cyclin D1 overexpression and cell proliferation.23,24 Tsikitis 
et al. demonstrated rhabdoid tumor dependence on cyclin D1 overexpression for tumor formation and that 
showed that reintroduction of SMARCB1 represses cyclin D1 and activates tumor suppressor p16INK4A, 
preventing cell cycle progression.25 Betz et al. similarly showed that SMARCB1 reintroduction into 
deficient cell lines resulted in G0/G1 arrest through strong induction of p16INK4A.26 
 
Katsumi et al. reported efficacy of CDK4/6 inhibitor PD-0332991 in malignant rhabdoid tumor, the 
pediatric SMARCB1-deficient tumor equivalent to ATRT outside of the CNS.27 In 4 of 5 MRT cell lines, 
PD-0332991 inhibited cell proliferation > 50 %, (IC50 values 0.01 to 0.6 μM) by WST-8 assay, and 
induced G1-phase cell cycle arrest, as shown by flow cytometry and bromodeoxyuridine (BrdU) 
incorporation assay.  
 
Dr. Olson also used an ATRT flank xenograft to demonstrate the efficacy of CDK4/6 inhibitor PD-
0332991 in this tumor type.19 Treatment with PD-0332991 at a dose of 150 mg/kg/day for 14 days resulted 
in excellent tumor regression (Figure 5A) and prolongation of survival of animals receiving the drug as 
compared to vehicle controls. Tumors treated with PD-0332991 showed decreased proliferation rate and 
Rb1 phosphorylation (Figure 5B: ).  
 
 
 
Role of the PI3K/Akt/mTOR Pathway in Cancer 
The PI3K/Akt/mTOR pathway is one of the most commonly activated pathways in human cancer and has 
been found to be a crucial driver of tumorigenesis.28-30 Phosphatidylinositol 3-kinase (PI3K) is activated 
by a wide range of RTKs, including EGFR, ErbB2, PDGFR and MET.  Amplification and activating 
mutations of RTK genes are frequently reported in many solid and hematologic malignancies. PI3K ligand 
binding leads to receptor dimerization, transphosphorylation, recruitment of PI3K, and generation of 
secondary messenger PIP3, which localizes downstream PH proteins to the inner surface of the plasma 
membrane. PI3K can be activated through direct mutation of PIK3CA31-33 or inactivating mutation or 
Figure 5A: Palbociclib causes complete regression of ATRT 
Figure 5B: Inhibition of CDK4/6 by Palbociclib results 
in reduced phosphorylation of Rb. 


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somatic loss of PTEN, an endogenous negative regulator of PI3K signaling. Akt, the “master-switch”, is 
activated through phosphorylation at Threonine 308 and Serine 473 and has a myriad of downstream 
effectors, which promote cell survival, inhibition of apoptosis and autophagy, proliferation, motility, and 
migration. Amplification or mutation of Akt has been described in human cancer.34 Downstream of Akt 
is the mammalian target of rapamycin (mTOR), a ubiquitous serine threonine kinase involved in cell cycle, 
angiogenesis, and apoptosis.35,36 The mTOR protein is incorporated into two multiprotein complexes, 
mTORC1 (regulates growth through S6K1 and 4E-binding protein 1) and mTORC2 (regulates cell 
survival through phosphorylation of serine 473 on Akt).37 
 
PI3K/Akt/mTOR Activation in Pediatric Brain Tumors 
High-Grade Glioma and DIPG 
A recent analysis of 53 pHGGs revealed activation of the PI3K/AKT/mTOR pathway in 42 tumors 
(79%).38 Moreover, tumor grade positively correlated with expression of p-S6 and p-4EBP1 (a surrogate 
marker of mTOR activation) in 16 pediatric HGGs, in which all grade IV tumors in the study staining 
positive for p-4EBP1 by immunohistochemistry (IHC).39  Wu et al. also described recurrent fusions 
involving neutrophin receptor genes NTRK1, NTRK2, and NTRK3 in 40% of infant non-brainstem HGGs, 
which resulted in elevated levels of phosphorylated AKT and MAPK proteins, indicating activation of the 
PI3K and MAPK pathways.8 (RTK)-PI3K-MAPK pathway activation was also seen in 69% (39/57) of 
DIPGs and 67% (47/70) of non-brainstem HGG in their cohort.  Findings by Taylor et al. and Fontebasso 
et al. support the important role of PI3K/Akt/mTOR in pediatric HGG, as 46% (12/26) of DIPG and 26% 
(10/39) of DIPG or midline non-brainstem HGG in their respective studies exhibited mutations predicted 
to activate the (RTK)-PI3K-MAPK pathway.9,10  
 
Medulloblastoma 
Several growth factor receptors are upregulated across medulloblastoma subgroups and converge on the 
PI3K/Akt/mTOR pathway, including IGF-1R, PDGFRB, ErbB2, FGFR and c-KIT. PTEN loss has also 
been identified in medulloblastomas and associated with a more aggressive clinical course.40,41 Castellino 
et al. showed that PTEN loss and resultant PI3K activation is sufficient to cause medulloblastoma tumor 
formation in granule neuron precursor cells.42 In human medulloblastoma samples, Hartmann et al. 
demonstrated phospho-AKT expression in all 22 samples evaluated, indicating prevalent 
PI3K/Akt/mTOR pathway activation in medulloblastoma.43 
 
Ependymoma 
Johnson et al. demonstrated common PI3K/Akt/mTOR pathway signaling in ependymoma, as 72% of 172 
ependymomas exhibited aberrant phospho-Akt, which also predicted poor outcome.44 
 
Atypical Teratoid Rhabdoid Tumor 
Akt/mTOR pathway activation is common in ATRT.45 Darr et al. demonstrated elevated phospho-Akt in 
SMARCB1-deficient MRT xenografts that abated with reintroduction of SMARCB1.46 Igfbp7, an insulin-
like growth factor with proposed effects on angiogenesis, was also upregulated47, implying a normally 
suppressive effect of SMARCB1 on this important paracrine signaling molecule. Reintroduction of Igfbp7 
in SMARCB1-deficient cells significantly reduced phospho-Akt and inhibited tumor growth, suggesting 
transformative capacity of both Igfbp7 and PI3K/Akt/mTOR signaling ATRT in vitro.  
 
2.2 
Ribociclib (LEE011)  
Ribociclib is an orally bio-available, highly selective small molecule inhibitor of CDK4/6 that induces 
G1-arrest at an IC50 of 0.1 μM in pRB-positive cancer cells in vitro. Ribociclib inhibits the CDK4/CCND1 


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and CDK6/cyclin-D3 enzyme complexes with IC50 values of 0.01 and 0.039 μM, respectively. This 
inhibition is selective for CDK4/6, as complexes involving CDKs 1, 2, 5 and 9 were roughly 100 to 
10,000-fold less sensitive to inhibition by ribociclib (RD-2008-50549). Extended profiling was also 
carried out against an internal kinase selectivity panel, which contains an additional 38 serine/threonine 
and tyrosine kinases (RD- 2009-00240). In these studies ribociclib was weakly active against four kinases, 
Aurora A, HER1, PKCμ and LCK with IC50 values of 2.0, 9.0, 7.8 and 7.7 mM, respectively. 
 
In Jeko-1 cells, ribociclib inhibits CDK4/6-dependent pRb phosphorylation with an average IC50 of 0.06 
μM. Consistent with the observed inhibition of pRb phosphorylation, ribociclib also inhibited G1-to-S 
phase cell cycle progression in Jeko-1 cells, as judged by inhibition of bromodeoxyuridine (BrdU) uptake 
(IC50 of 0.1 μM) and fluorescence activated cell sorting (FACS) analysis (half-maximal increase in cells 
in G1 at 0.11 μM). The effect of ribociclib on pRb phosphorylation, BrdU uptake, and cell cycle 
progression has been assessed in > 40 cell lines derived from hematological, esophageal, liposarcoma, and 
breast cancers. In pRb+ cell lines, ribociclib inhibits pRb phosphorylation with a median IC50 value of 
0.275 μM (range: 0.06 to 8.8 μM). Similarly, ribociclib interferes with G1-to-S phase cell cycle 
progression in these cells, as determined by either BrdU uptake or FACS analysis with a median IC50 value 
of 0.46 μM. In contrast, in lineage-matched pRb negative cell lines, no effect of ribociclib on either pRb 
phosphorylation or cell cycle progression is observed. Thus, ribociclib is able to impact cell cycle 
progression in cell lines derived from a variety of tumor types that harbor a diversity of genetic alterations 
in a manner dependent on intact pRb. 
 
2.2.1 Preclinical Studies 
2.2.1.1 Anti-tumor activity 
Ribociclib has demonstrated in vivo anti-tumor activity in subsets of tumor xenograft models. Consistent 
with the compound’s mechanism of action, efficacy was only observed in tumors expressing pRb. Tumor 
types in which ribociclib has demonstrated robust anti-tumor activities include, but are not limited to, 
breast, melanoma, neuroblastoma, malignant rhabdoid, lung, pancreas and hematological malignancies.  
In addition, ribociclib has shown anti-tumor activity when combined with targeted agents that inhibit 
signaling pathways known to regulate D-cyclin levels, including inhibitors of the RAF/mitogen-activated 
protein kinase (MEK)/extracellular signal-regulated kinase (ERK), phosphoinositide 3-kinase (PIK3), and 
mammalian target of rapamycin (mTOR) pathways (Figure 6). 
 


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Figure 6: The Cyclin D–CDK4/6–INK4–Rb Pathway 
 
Ribociclib In Vitro Studies 
Hematological malignancies and solid tumors that are pRb-positive and dependent on D-cyclins for 
proliferation are expected to be sensitive to ribociclib. To test this hypothesis, a variety of cancer cell lines 
were examined for their sensitivity to ribociclib, including but not limited to tumor cells derived from 
acute myeloid leukemia, breast cancer, colon cancer, liposarcoma, MCL, multiple myeloma, melanoma, 
neuroblastoma, NSCLC, rhabdoid cancer, pancreatic cancer and squamous cell esophageal cancer [(RD-
2009-50759), (RD-2012-50290), (RD-2012-50369)]. Cell lines harboring genetic aberrations in the 
CCND1 and CDK4/6 genes, as well cancers containing genetic/epigenetic changes that indirectly activate 
CDK4/6-pRb pathway, were sensitive to ribociclib as judged by the inhibition of phosphorylation of pRb, 
BrdU uptake and/or cell cycle distribution. For example, mantle cell lymphoma cells harboring cyclin D1 
translocations and liposarcoma cells with CDK4 amplifications were highly sensitive to ribociclib, 
exhibiting ~100 nM sensitivity both in terms of pRb phosphorylation and cell cycle arrest in the G1 phase. 
Similarly, the majority of breast cancer and melanoma-derived cells tested were also sensitive to ribociclib 
in terms of pRb-phosphorylation and cell cycle progression, often with IC50 values less than 1μM. 
Neuroblastoma and malignant rhabdoid cells were also very sensitive to ribociclib, which underwent 
robust growth arrest upon compound treatment [(RD-2012-50290), (RD-2012- 50369)]. Lastly, clones of 
the HCC827 NSCLC cell line which harbor the activating E746_A750 indel allele of EGFR, but which 
have been selected for resistance to the EGFR inhibitor gefitinib, are also sensitive to ribociclib. Thus, 
ribociclib may have therapeutic utility in tumors that harbor a wide array of oncogenic drivers, including 
those that have acquired resistance to other targeted therapies. 
 
In vitro CDK4/6 and mTOR inhibitor combination 
When combined with the mTOR inhibitor RAD001 (everolimus), ribociclib induced synergistic growth 
inhibitions in multiple tumor models, including cell lines derived from MCL, ER+ breast cancer, and 
MRTs (RD-2012-50383). Table 1 shows synergy scores, which demonstrate that co-treatment of 


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ribociclib and everolimus leads to synergistic growth inhibition. 
 
 
Table 1: Synergy scores for ribociclib /Everolimus combination in cancer cells 
 
Ribociclib In Vivo Studies 
Activity in neuroblastoma and rhabdoid xenograft models 
Ribociclib inhibited the in vitro growth of cell lines derived from MRTs, as well as subsets of 
neuroblastoma-derived cell lines, at concentrations below 1 μM [(RD-2012-50290), (RD- 2012-50369)]. 
This in vitro sensitivity was also observed in vivo as ribociclib induced either regressions or complete 
stasis at doses ≥150mg/kg in the CHP212 neuroblastoma and G401 rhabdoid tumor models, respectively 
Figure 7; (RD-2012-50368), (RD-2012-50371). 
 
 
 
Figure 7: In vivo activity of ribociclib in neuroblastoma and rhabdoid xenograft models 
 
Ribociclib in combination with PIK3CA inhibitor BYL719 and mTOR inhibitor Everolimus in ER 
positive/PIK3CA-mutant breast cancer xenograft model 
Activating mutations in the PIK3CA gene are oncogenic drivers in a variety of cancer types. Notable 
amongst these cancers is ER+ breast cancer, where such lesions are found in approximately 40% of all 
instances of the disease. The CDK4/6, in turn, are critical mediators of at least one key effector pathway 
downstream of the PIK3C/Protein Kinase B (AKT)/mTOR axis as activation of this pathway results in 
increased levels of CCND1 via both increased mRNA expression and protein stability. The effect of 
combining ribociclib with either the alpha-selective PIK3C inhibitor BYL719 or the mTORC1-inhibitor 
everolimus in the ER+, PIK3CA-mutant MCF-7 xenograft model was examined (RD-2013-50141). As 
demonstrated in Figure 8 (panels A and B), single agent treatments with ribociclib, BYL719, and 
everolimus resulted in modest tumor regressions of -9%, -15% and -21%, respectively. When ribociclib 
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combination treatments were well tolerated as judged by body weight loss (not shown). These data suggest 
that combining inhibitors that target the PIK3C/AKT/mTOR pathway with ribociclib may be an effective 
therapeutic strategy. 
 
 
Figure 8: Ribociclib /BYL719 and Ribociclib/RAD001 combinations leads to improved 
tumor growth delays in ER+/PIK3CA mutant breast cancer model MCF-7 in vivo. 
 
2.2.1.2 Animal Toxicity 
In vivo cardiac safety studies demonstrated a signal for QT prolongation with the potential to induce 
incidences of premature ventricular contractions (PVCs) at higher exposure levels. The effects of 
ribociclib on the bone marrow (hypocellularity), lymphoid system (lymphoid depletion), intestinal mucosa 
(atrophy), skin (atrophy), bone (decreased bone formation) and testes (atrophy) are considered to be 
related to the pharmacological inhibition of cell replication in these tissues due to CDK4/6 inhibition. An 
increased number of ovarian corpora lutea was observed in a single female dog in the 4-week toxicity 
study at the highest dose tested (20 mg/kg/day) and this effect could also be related to the pharmacology 
of ribociclib (arrest of estrous cycle). The liver, bile system and gall bladder (proliferative changes, 
cholestasis, sand-like gallbladder calculi and inspissated bile) and the kidney (concurrent degeneration 
and regeneration of tubular epithelial cells) were identified as additional target organs of toxicity which 
are not likely related to the primary pharmacology of ribociclib.  Inflammatory changes in the lungs of 
dogs were considered secondary to aspiration of test article and are indicative of the irritant potential of 
the formulated test-article in the respiratory tract. Correlating hematological and/or biochemistry changes 
were seen for the effects described in the bone marrow, lymphoid system and liver. Generally all changes 
demonstrated either reversibility or a clear tendency towards reversibility.  It can be expected that after a 
prolonged recovery time incompletely recovered findings would have totally reversed in all species. 
 
Ribociclib was well-tolerated in mice and rats with body weight loss not exceeding 12.5% at doses up to 
250 mg/kg qday po or 150 mg/kg qday po, respectively, for up to 28 days. However, myelosuppression 
was observed and correlated with pRb phosphorylation inhibition.  Treatment with ribociclib resulted in 
tumor regression in the Jeko-1 MCL xenograft model at doses ≥75 mg/kg qday po. In vivo 
pharmacokinetic (PK)/pharmacodynamic (PD) studies demonstrated dose-related inhibition of pRb 
phosphorylation in tumors, with continuous dosing over at least 3-5 days being required to achieve optimal 
target inhibition. In male nude rats, a PK/PD/efficacy study indicated that plasma levels corresponding to 
approximately 0.5 - 4 μM over a 24 h dose interval are sufficient to obtain near complete inhibition of 
pRb phosphorylation and complete regression in the Jeko-1 MCL xenograft model. 


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Non-clinical reproductive studies have demonstrated ribociclib induced embryotoxicity and fetotoxicity 
in rats and rabbits and teratogenicity in rabbits.  As of December 22, 2015, a rabbit embryo-fetal 
development study was performed. Ribociclib was administered at dose levels of 0, 10, 30, or 60 
mg/kg/day. The study was conducted at Charles River Laboratories Montreal, ULC (CR-MTL), 22022 
Transcanadienne, Senneville, Quebec, Canada, H9X 3R3.  In vitro and in vivo, ribociclib did not show an 
indication for a genotoxic potential or phototoxic potential. In the rat, there was no evidence of 
teratogenicity; however ribociclib was embryofetotoxic in the rabbit. In rabbits, ribociclib was teratogenic 
at ≥ 30 mg/kg/day (1.5 times patients exposure at the dose of 600 mg/day based on AUC) as evidenced 
by increased incidences of fetal abnormalities (malformations and external, visceral and skeletal variants). 
Fetal weights were decreased at 60 mg/kg. There was no evidence of embryo-fetal mortality. In view of 
these changes, the no-observed-effect level (NOEL) for maternal toxicity was considered to be at least 30 
mg/kg and the NOEL for the embryo-fetal development, 10 mg/kg. 
 
2.2.1.3 
Ribociclib Preclinical Pharmacokinetic Studies 
After oral ribociclib administration, bioavailability was moderate in mouse (65%) and dog (64%) and low 
to moderate in cynomolgus monkey (10 to 23%). After oral administration, maximum ribociclib plasma 
concentrations occurred between 2 and 4h across species.48  
 
Initial studies of the tissue distribution of 3H-ribociclib-derived radioactivity used quantitative whole body 
autoradiography (QWBA) in male albino rats after both intravenous and oral dosing. Total radioactivity 
was markedly distributed into the extravascular compartment, and was eliminated rapidly from most 
tissues. Radioactivity was not detected in the brain using QWBA. However, more recent studies using a 
cerebral microdialysis technique have demonstrated that at clinically relevant dosages the unbound brain 
or tumor to plasma partition coefficient (Kp,uu) for ribociclib was 0.12±0.09, 0.16±0.11, and 0.07±0.07 
for normal brain, Group 3 medulloblastoma (Grp3 MB), and diffuse intrinsic pontine glioma (DIPGx7) 
tumors, respectively.49 Although the Kp,uu for ribociclib varied among the groups studied, the median 
unbound ribociclib Cmax in all three groups was 100 nM. The median time to maximum ribociclib 
concentration (Tmax) was 2, 6, and 8 hours for normal brain, Grp3 MB, and DIPGx7, respectively.  
 
The plasma protein binding of ribociclib was moderate. No major concentration dependency in the tested 
plasma concentration range (100-1000 ng/mL for mouse, rat, dog or 10-10000 for cynomolgus monkey 
and human) was observed. The unbound fractions in plasma (fu) ranged between 20 ± 1% to 32 ± 6 % 
(human: 30 ± 2%). The plasma volume of distribution at steady-state (Vss) was large across species (7.9 
to 28 L/kg).48  
 
Extensive in vitro drug metabolism studies have been conducted using mouse, rat, dog, monkey, and 
human hepatocytes. The primary metabolites formed included the M4 metabolite (LEQ803; N-
demethylation at the amide moiety; all species), M8 (sulfation; rat and human), M6 (oxidation and 
glucuronidation; humans), and M13 (CCI284; N-hydroxylation; humans). Other metabolites are formed, 
but they are either in minor amounts (≤ 10% of 3H-AUC0-24h) or are not pharmacologically active. The 
LEQ803 metabolite is an active metabolite.48  
 
In male rats, ribociclib was eliminated mainly by metabolism with minor contributions of direct biliary 
and renal clearance. The major metabolic route was sulfation of ribociclib to M8 and its excretion into the 
bile. The cumulative recovery of ribociclib in the urine, bile, and feces of bile duct-cannulated male rats 
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ribociclib was primarily excreted with bile (~61% of dose). The proportion of the dose excreted in the 
urine of bile duct cannulated male rats ranged from ~5% after oral dosing to ~16% after i.v. dosing.  
 
Based upon results of in vitro studies, ribociclib is primarily metabolized by CYP3A4 (hydroxylation and 
N-demethylation) and to a lesser extent (15 to 26%) the polymorphic enzyme FMO3 (hydroxylamine 
metabolite). The oxidative metabolic clearance of ribociclib is likely to be affected by co-administration 
of drugs that inhibit or induce CYP3A4. For example, the metabolism of 3H-ribociclib in human liver 
microsomes was strongly inhibited by ketoconazole and azamulin (both CYP3A4 inhibitors), and partly 
by methimazole (FMO3 inhibitor).48  
 
In vivo pharmacokinetics (PK)/pharmacodynamics (PD) studies demonstrated dose-related inhibition of 
pRb phosphorylation in tumors, with continuous dosing over at least 3-5 days being required to achieve 
optimal target inhibition. In male nude rats, a PK/PD/efficacy study indicated that plasma levels 
corresponding to approximately 0.5 - 4 μM over a 24 h dose interval are sufficient to obtain near complete 
inhibition of pRb phosphorylation and complete regression in the Jeko-1 MCL xenograft model. 
 
2.2.1.4 Ribociclib Safety and Pharmacology Studies 
Ribociclib was profiled in a safety pharmacology receptor/enzyme panel and showed activity against 
PDE4D (IC50 0.88 μM and 0.39 μM). Ribociclib did not induce vasculitis or cardiovascular toxicity in 
the toxicology studies performed so far (up to 15 weeks). Rat safety pharmacology studies did not reveal 
any effects on CNS or respiratory functions. In the in vitro manual patch clamp assay, ribociclib had an 
IC50 of 53 μM and LEQ803, a metabolite of ribociclib that represents 6 to 10% of the parent drug in dogs, 
had an IC50 of 4.5 μM. In the dog telemetry study, prolongation of the average QT and QTc was observed 
with the potential to induce incidences of PVCs at higher exposure levels. Ribociclib and LEQ803 likely 
contributed to the QT prolonging effects seen in vivo.  Cardiac (ECG) monitoring in patients should be 
performed. 
 
Oral single dose toxicity studies were performed in dogs only. Oral multiple dose toxicity studies were 
performed in rats and dogs (up to 15 weeks). In rats and dogs, effects on bone marrow, lymphoid tissue 
(thymus, spleen, lymph nodes, gut-associated lymphoid tissues), hepatobiliary system, testes and lungs 
were observed. In addition, in dogs, effects on intestinal mucosa, skin, bone/ribs and ovaries were also 
reported. In the 15-week rat study, the kidney was identified as an additional target organ of toxicity. The 
effects of ribociclib on the bone marrow (hypocellularity), lymphoid system (lymphoid depletion), 
intestinal mucosa (atrophy), skin (atrophy), bone (decreased bone formation) and testes (atrophy) can be 
regarded as related to the pharmacological inhibition of cell replication in these tissues due to CDK4/6 
inhibition. An increased number of ovarian corpora lutea was observed in a single female dog at the 
highest dose tested (20 mg/kg/day) and this effect could also be related to the pharmacology (arrest of 
estrous cycle). The hepatobiliary system (proliferative changes, cholestasis, sand-like gallbladder calculi, 
and inspissated bile) and the kidney (concurrent degeneration and regeneration of tubular epithelial cells) 
were identified as additional target organs of toxicity, which are not likely related to the primary 
pharmacology of ribociclib. Inflammatory changes in the lung of dogs and the increase of alveolar 
macrophages in the rat studies were considered secondary to aspiration of test-article and are indicative 
of the irritant potential of the formulated test-article in the respiratory tract. Correlating hematological 
and/or biochemistry changes were seen for the effects described in the bone marrow, lymphoid system 
and liver.  Generally, all changes demonstrated either reversibility or a clear tendency towards 
reversibility. It can be expected that after a prolonged recovery time incompletely recovered findings 


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would have totally reversed in both species. 
 
It is advised to monitor carefully hematological, hepatobiliary and kidney parameters, as well as 
gastrointestinal effects in patients treated with ribociclib.  In vitro and in vivo, ribociclib did not show an 
indication for a genotoxic potential.  In vitro, ribociclib did not show a phototoxic potential.  In conclusion, 
multiple biological effects were observed in toxicology studies up to 15 weeks duration in rats and dogs. 
The observed toxicities can be considered clinically manageable. The critical nature of many of these 
effects and the potentially severe consequences for patients, however, warrant careful monitoring. 
 
2.2.2 Adult Clinical Trials 
2.2.2.1 Adult Phase 1 Studies 
As of April 2015, 132 patients have been treated with single agent ribociclib in the first-in-human phase 
I study; 85 patients have been treated in the dose escalation part and 47 patients in the dose expansion part 
of the study.  Patients with advanced solid tumors or lymphomas were treated with increasing doses of 
ribociclib orally, once daily (qday) for 21 days followed by a 1-week rest (28-day cycle). Doses ranging 
from 50 mg to 1200 mg were evaluated on this schedule. In addition, continuous dosing of ribociclib at 
600 mg was evaluated (qday for 28 days of a 28-day cycle). Doses tested include, 50 mg (n=4), 70 mg 
(n=2), 140 mg (n=4), 260 mg (n=4), 280 mg (n=4), 350 mg (n=5), 400 mg (n=5), 600 mg (n=67), 600 mg 
continuous (n=7), 750 mg (n=14), 900 mg (n=13), and 1200 mg (n=3). The median age of patients was 
60 years (22 to 84), the male/female ratio was 1, and the distribution of Eastern Cooperative Oncology 
Group (ECOG) performance status of 0/1 at baseline was 47/84 patients, respectively. The most common 
cancer types were liposarcoma (33), ER+ breast cancer (20), head and neck (including salivary gland) 
cancer (16), colon cancer (14), lung cancer (8), and lymphoma (8). Treatment has been discontinued in 
111 (84%) patients; the primary reasons for treatment discontinuation were: disease progression (96 [72%] 
patients); AEs (8 [6%] patients); withdrawal of consent (3 [2%] patient); and loss to follow up (1 [1%] 
patient). 
 
A total of 10 events meeting DLT criteria were observed at the indicated doses in the 70 patients evaluable 
for dose determination and include Grade 3 mucositis/stomatitis (later determined to be due to herpes 
simplex virus infection) (n=1) at 50 mg, Grade 3 pulmonary embolism (n=1) at 280 mg, Grade 3 
hyponatremia (asymptomatic and corrected with saline infusion) (n=1) and prolonged Grade 3/4 
neutropenia (n=1) at 400 mg, prolonged Grade 2 elevated creatinine (n=1) at 600 mg, Grade 4 
thrombocytopenia (n=1) at 750 mg, Grade 3 asymptomatic QTcF prolongation with Grade 3 neutropenia 
(n=1) at 900 mg and Grade 4 febrile neutropenia (n=1) and Grade 4 thrombocytopenia (n=1) at 1200 mg. 
There was also one DLT, prolonged Grade 3 neutropenia (n=1) at 600 mg on the continuous dosing 
schedule. 
 
The most frequently reported AEs (>10%), regardless of grade, causality and ribociclib dose were: fatigue 
(53.8%); nausea (50.8%); neutropenia (47.7%); leukopenia (46.2%); anemia (37.1%); vomiting (34.8%); 
thrombocytopenia (34.1%); diarrhea (32.6%); lymphopenia (30.3%); decreased appetite, hyperglycemia 
(21.2% each); constipation (19.7%); hypoalbuminemia (18.9%); dyspnea (18.2%); cough (16.7%); fever, 
increased creatinine (15.9% each); abdominal pain, AST increase, edema, headache (15.2% each); back 
pain (14.4%); dizziness (13.6%); ECG QT prolonged (11.4%); blood alkaline phosphatase increased and 
hypocalcemia (10.6% each). 
 
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Day 15, reaching a nadir in the third or fourth week with recovery during the week of drug holiday. Some 
patients require additional time for recovery (7 to 14 days). QT changes become evident in the first cycle 
by Day 8 and later (once steady state is reached), are associated with the maximum drug levels between 1 
to 8 h post-dose, and remain stable or improve in subsequent cycles. 
 
As of April 2015, asymptomatic Grade 2 QTcF prolongation was observed with increasing frequency 
when increasing the dose starting at 600 mg: twelve patients (18%) in the 600 mg cohort, three patients 
(21%) in the 750 mg cohort, four patients (31%) in the 900 mg cohort, and two patients (67%) in the 1200 
mg cohort. Two patients (3%) at 600 mg and two patients (15%) at 900 mg had asymptomatic QTcF 
prolongation that resulted in a QTcF interval of 500 ms or more. As compared to baseline value, QTcF 
prolongation was at least 30 msec in 2 patients (50%) at 250mg, 2 (40%) at 350 mg and 400 mg, 46 (73%) 
at 600 mg, 10 (71%) at 750 mg, 11 (85%) at 900 mg and 2 (67%) at 1200 mg; and at least 60 msec as 
compared to baseline in respectively 16%, 0%, 39% and 67% of patients at 600 mg, 750 mg, 900 mg and 
1200 mg. One grade 1 atrioventricular block of first degree was reported as related to ribociclib given at 
the dose of 140 mg. No other cardiac abnormalities were observed as related adverse events in any patient. 
 
Paired skin biopsies from 55 patients treated with ribociclib at doses ranging from 50 to 900 mg and paired 
tumor biopsies from 20 patients (16 patients at 600 mg, 2 patients at 900 mg, and 1 patient each at 70 and 
750 mg) were assessed for changes in Ki67 and pRb levels. Preliminary results indicate the following: in 
skin biopsies, reductions in Ki67 from baseline were observed across all dose levels with a more consistent 
trend from 400 mg onwards; in tumor biopsies, reductions in Ki67 from baseline were observed in 18/20 
patients; however, limited samples and varied tumor types prevent conclusions about any dose-response 
relationship from being drawn. Changes in pRb were not significant or consistent in either skin or tumor 
samples, possibly due to varied tumor types. 
 
Out of the 114 evaluable patients, 3 partial responses were observed at the 600 mg dose level; one each in 
BRAF/NRAS wild type with CCND1 amplified melanoma, and head and neck acinar carcinoma with 
CDKN2A loss (both on the 3 weeks on/1 week off regimen), and ER+/HER2-, PIK3CA mutant, CCND1 
amplified breast cancer (on the continuous daily dosing regimen).  This study is currently evaluating a 
dosing schedule with ribociclib 400 mg continuous dosing, as well as the safety and PK of the oral solution 
formulation. The MTD of ribociclib in adults is 900 mg qday with a 3 weeks on/1 week off schedule. The 
RP2D for future development is 600 mg qday with a 3 weeks on/1 week off schedule, which has an 
acceptable safety profile, lower risk for QT prolongation, adequate exposures, and preliminary evidence 
of clinical activity.  There have been no deaths related to study drug reported on study 
CLEE011X2101.The following serious adverse events shown in Table 2 have been reported with a 
suspected causal relationship in study CLEE011X2101 as of August 2014. 
 
A complete list of AEs, all grades and Grade 3/4 occurring in at least 10% of patients and suspected to be 
related to ribociclib are shown in Table 3. 
 


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Table 2:  Serious adverse events with suspected causal relationship with Ribociclib 
 
 


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Table 3: All grades and Grade 3 or 4 adverse events (occurring in at least 5% or more) 
suspected to be related to ribociclib by preferred term and treatment group.  (data as of 
April 2014) (CLEE011X2101) 
 
2.2.2.2 Phase II Studies 
Phase Ib/II trial of Ribociclib + Everolimus (RAD001) + Exemestane in postmenopausal women with 
ER+/HER2 negative locally advanced or metastatic breast cancer 
In the ongoing Phase Ib/II clinical trial (CLEE011X2106), as of August 2015, 77 patients treated with the 
triplet combination, ribociclib (200–350 mg 3 weeks on, 1 week off), everolimus (most at 2.5 mg), and 
exemestane (25 mg), the median number of prior regimens was 4, and 18 (23%) patients had received 
prior PI3K/AKT/mTOR or CDK4/6 inhibitors for metastatic disease. 
 
(1) Ribociclib (600 mg) + exemestane (25 mg), n=3 


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(2) Ribociclib (200 mg) + everolimus (RAD001) (2.5 mg) + exemestane (25 mg) 
(3) Ribociclib (250 mg) + everolimus (RAD001) (2.5 mg) + exemestane (25 mg)  
(4) Ribociclib (300 mg) + everolimus (RAD001) (2.5 mg) + exemestane (25 mg) 
 
All patients experienced at least one AE. The most frequent AEs (>10%), regardless of grade, causality 
and Ribociclib dose, were anemia, leukopenia and neutropenia (75.0% each); thrombocytopenia (68.8%); 
alanine aminotransferase increased, aspartate aminotransferase increased, fatigue and stomatitis (43.8% 
each); lymphopenia (37.5%); blood alkaline phosphatase increased, hypophosphatemia and nausea 
(31.3% each); diarrhea, edema, hyperglycemia and hypokalemia (25% each); constipation, dyspnea, 
headache, hypocalcaemia, insomnia and rash (18.8% each); decreased appetite, dermatitis acneiform, 
dysgeusia, dyspepsia, electrocardiogram QT prolonged, hypoalbuminaemia, hypomagnesaemia, 
hyponatraemia, pneumonia and sinusitis (12.5% each). The most common CTCAE Grade 3 or 4 AEs 
(>2%), regardless of causality and Ribociclib dose, were neutropenia (50.0%); leukopenia (31.3%); 
hypophosphatemia (18.8%); thrombocytopenia, alanine aminotransferase increased, aspartate 
aminotransferase increased, fatigue, stomatitis, lymphopenia, dyspnea, dermatitis acneiform, 
hyponatraemia and pneumonia (6.3% each). Grade 3/4 treatment-related AEs (≥5% patients) were 
neutropenia (45.7%), leukopenia (8.6%), and thrombocytopenia (5.7%). 17 patients (23%) experiences 
QTcF > 450 ms, 3 (4%) had QtcF > 480 ms and 2 (3%) had QtcF > 500 ms.  Five (7%) patients 
discontinued due to AEs. Grade 3 AST/ALT AEs were appreciated in 4 patients, febrile neutropenia and 
hypophosphatemia (1 patient), oral mucositis (1 patient), rash and thrombocytopenia (1 patient), and 
thrombocytopenia with bleeding (1 patient). The RP2D was declared at ribociclib 300 mg 3 weeks on, 1 
week off, everolimus 2.5 mg daily (continuous) and exemestane 25 mg daily (continuous). This 
combination dose appeared to be tolerable and safe. The following serious adverse events shown in Table 
4 have been reported with a suspected causal relationship in study CLEE011X2106. 
 
 
Table 4: Serious adverse events with a suspected causal relationship with ribociclib in 
combination with everolimus (RAD001) and exemestane. 
 
As of August 2015, when results of the combination of ribociclib + everolimus (RAD001) + Exemestane 
were presented at the San Antonio Breast Cancer Symposium (SABCS), 77 patients were evaluable for 
response.  Seven patients (9%) had a confirmed partial response, 39 (51%) patients had stable disease, and 
10 (13%) patients had neither complete response nor progressive disease.  The median duration of stable 
disease was 115 days (range: 44-460) and 21 patients experienced stable disease for > 4 cycles.  The 
median (range) duration of treatment exposure was 6 (1-15) months and 4 (1-17) months in patients with 
(n=11) and without (n=48) CCND1-amplification response resulting in a trend for longer duration of 
response in patients with CCND1 amplification. Six patients with partial responses had available genetic 


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data including the following alterations (amplifications/ mutations): PIK3CA (n=3), TP53 (n=2), 
amplification MDM2 (n=2), amplification MYC (n=2), ATM mutation (n=2) as well as alterations in 
KRAS, EGFR, FGFR, and ESR1 (n=1 each).  One patient with a p16 (CDKN2A) deletion and cyclin D1 
(CCND1) and insulin-like growth factor receptor 1 (IGFR1) amplification treated with ribociclib 200 mg 
+ EVE 2.5 mg + EXE had SD >6 months.   
2.2.2.3 Ribociclib Adult Pharmacokinetics  
PK for Single Agent Ribociclib in Adults 
As of June 2015, PK data were available from approximately 128 patients from the first-in-human study 
CLEE011X2101. Following oral dosing, Ribociclib was rapidly absorbed with median Tmax ranging 
from 1 to 5 hours. Ribociclib plasma exposure exhibited slightly over-proportional increases in exposure 
across the dose range tested (50 to 1200 mg), with no clear evidence of time-dependent auto-inhibition of 
its clearance. Steady-state was generally reached by Day 8, and the mean effective T1/2 based on 
accumulation ratio (i.e., T1/2,acc) ranged from 15.9 to 32.6 hours across the dose range tested. The 
accumulation ratio based on AUC obtained in a dosing interval (Racc) across the studied doses ranged 
from 1.55 to 2.52. 
 
Ribociclib Food and Drug Interactions 
A food effect study in 24 healthy subjects indicated that ribociclib administered as a drug-in-capsule 
formulation can be taken without regards to meals. The presence of food did delay the rate of absorption 
somewhat, but the extent was unaffected as predicted based upon the solubility characteristics of 
ribociclib.51  
An additional study in healthy subjects (CLEE011A2103) demonstrated bioequivalence between the film-
coated tablets formulation and capsule formulation. The study demonstrated no clinically important effect 
of high-fat, high-calorie meal on ribociclib exposure following oral administration of the film coated 
tablets formulation. Ribociclib exposure under fed conditions was similar to that under fasted conditions.51  
 
Ribociclib is unlikely to be the object of a clinical drug interaction, with the exception of strong CYP3A4 
inhibitors or inducers, which may markedly affect the exposure of ribociclib based on data from a clinical 
DDI study with ritonavir and rifampicin (CLEE011A2101). 
 
A drug-drug interaction (DDI) study with ritonavir (a strong CYP3A4 inhibitor) and rifampicin (a strong 
CYP3A4 inducer) was conducted in 48 healthy subjects (CLEE011A2101). Compared to ribociclib alone, 
ritonavir (100 mg bid for 14 days) increased ribociclib Cmax and AUCinf by 1.7-fold and 3.2-fold, 
respectively, following a single oral dose of 400 mg ribociclib. Cmax and AUClast for LEQ803 decreased 
by 96% and 98%, respectively. In addition, compared to ribociclib alone, rifampicin (600 mg daily for 14 
days) decreased LEE011 Cmax and AUCinf by 81% and 89%, respectively, following a single oral dose 
of 600 mg ribociclib. LEQ803 Cmax increased 1.7-fold and AUCinf decreased by 27%, respectively.  
 
PK of Ribociclib, Everolimus and Exemestane in Adults 
In an ongoing Phase Ib clinical trial CLEE011X2106, 2.5 mg of everolimus (RAD001) (qday) + 25 mg 
exemestane (qday) was administered with 200 or 300 mg ribociclib (qday, 3 weeks on/1 week off). As of 
March 2014, data for Cmax and AUC0-24h for ribociclib (300 mg, qday, 3 weeks on/1 week off) and 
everolimus (2.5 mg qday) were available on Day 1 (n=4) and after multiple doses on Day 15 (n=3). A 
dose-dependent drug interaction (DDI) was observed between ribociclib and everolimus based on clinical 
PK analyses in a separate dose escalation trial, where everolimus exposure increased 2- to 4-fold in the 
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of 300 mg ribociclib, everolimus (2.5 mg qday) exposure (AUC0-24h) was increased and was 
approximately similar to exposure following 5 to 7.5 mg everolimus when compared to historical single 
agent data.52,53  
 
2.2.3 Pediatric Clinical Trials  
2.2.3.1  Phase I Trial of Ribociclib 
Novartis has completed a phase I, multi-center, open-label study of ribociclib in children with recurrent 
malignant rhabdoid tumors (MRTs) and neuroblastoma (NB) or other tumors with cyclin D–CDK4/6 
pathway aberrations (NCT01747876).54 The initial treatment schema was as follows: 
 
Dose Level 
Ribociclib (mg/m2/day x 21 days) 
1 (starting dose) 
280 mg/m2/day 
2 
350 mg/m2/day 
3 
470 mg/m2/day 
 
Fourteen patients had NB, 15 had MRT (13 primary CNS and two primary extra-CNS), 1 had CDK4-
amplified rhabdomyosarcoma, and 1 had anaplastic meningioma with CDKN2A/B loss.  Five patients 
received 280 mg/m2, 14 received 350 mg/m2, and 12 received 470 mg/m2 of ribociclib 1. Of 31 eligible 
patients, 24 (77%) have discontinued treatment for reasons that include disease progression (n=21), 
withdrawal of consent (n=2), or DLT.  Four DLTs were reported, including 1 patient with grade 3 fatigue 
at 280 mg/m2 and 3 patients with grade 4 thrombocytopenia at 470 mg/m2. The most common (≥10%) 
grade 3/4 AEs suspected to be related to the study drug were neutropenia (61%), leukopenia (32%), and 
thrombocytopenia (29%).  Adverse events were manageable and reversible upon discontinuation of 
ribociclib.  Newly occurring post-baseline values of QTc ≥450 ms were observed in 6 patients (19%; all 
Grade 1), including 3 at 350 mg/m2 and 3 at 470 mg/m2.  No treatment-related deaths were reported. Seven 
patients were still receiving treatment at the time of data cut-off on June 23, 2014.  The MTD and RP2D 
were determined to be 470 mg/m2 (adult equivalent dose ≈ 800 mg/day) and 350 mg/m2 (adult equivalent 
dose ≈ 600 mg/day), respectively, on a 3-weeks-on/1-week-off dosing schedule, consistent with adult data.  
Three patients received ribociclib for ≥4 cycles, and stable disease was the best response observed.  
 
2.2.3.2 Ribociclib Pediatric Pharmacokinetics 
The pharmacokinetics of single agent ribociclib are being evaluated in an ongoing phase clinical trial in 
children (ages 1 to 21) with malignant rhabdoid tumors, neuroblastoma, and advanced solid tumors/ 
lymphoma. Patients received escalating ribociclib dosages (280, 350, and 470 mg/m2) daily for 3 weeks 
and then 1 week off. Pharmacokinetic studies were conducted on days 1 and 15 of cycle 1 (pre-dose, 1, 2, 
4, and 8 hr post-dose), and other samples collected in subsequent times/cycles. The preliminary 
noncompartmental pharmacokinetic results are presented in the table below. 
 
Dosage (mg/m2) 
AUC0-24h (ng/mL*hr) 
Cmax (ng/mL) 
280 
13800 
1110 
350 
24500 
2010 
470 (MTD) 
29100 
2500 
 
Other preliminary pharmacokinetic results included median time to maximum plasma concentration 
across cohorts ranged from 2 to 4 hours, and the median half-life ranged from 30 to 41 hours. The mean 
systemic exposure in children dosed with the 350 mg/m2 was equivalent to the mean exposure observed 


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in adults at 600 mg. Based upon safety, tolerability, and pharmacokinetics, the MTD was determined as 
470 mg/m2 once a day for 3 weeks on and 1 week off. 
 
2.3 
Everolimus (RAD001) 
RAD001 (everolimus) is a rapamycin analog and highly specific small-molecule mTOR inhibitor that 
functions by binding mTOR (when associated with raptor and mLST8 as part of the mTORC1 complex) 
and FK506-binding protein 12, leading to G1 phase cell cycle arrest and apoptosis.55 The anti-cancer 
effects of everolimus are multifaceted and include transcriptional regulation of cyclin D1 and c-Myc, as 
well as antiangiogenic effects mediated by down-regulation of hypoxia inducible factor 1 alpha (HIF1), 
which decreases vascular endothelial growth factor (VEGF).55,56 Rapamycin analogs have also been 
reported to inhibit mTORC2, preventing downstream signaling through Akt.57 
 
2.3.1 Preclinical Studies 
Everolimus has potent activity in many types of human cancer and has been intensely studied in vitro and 
in vivo.58,59 Rapamycin analogs have been shown effective in rhabdomyosarcoma, neuroblastoma, 
medulloblastoma/PNET, and pediatric HGG cell lines with IC50s ranging from 0.37 to 4,680 ng/mL.60,61 
Rapamycin was extensively tested in the Pediatric Preclinical Testing Program, including in combination 
with cytotoxic agents.56,62 It induced 50% cell death in 10 of 23 pediatric cell lines at nanomolar 
concentrations and showed ‘intermediate or high activity’ against 14 of 31 solid tumor xenograft models, 
including partial responses in rhabdoid tumor, rhabdomyosarcoma, and osteosarcoma.56 Another 
rapamycin analog, CCI-779, was shown to inhibit growth in vitro and in vivo in medulloblastoma, PNET, 
and GBM with synergistic effect noted with cytotoxic agents, such as cisplatin and camptothecin.63 
 
Rapamycin analogs are highly lipophilic and have been shown in preclinical studies to cross the blood-
brain barrier.63 This property of everolimus has also been demonstrated nicely in clinical practice, as it 
has been shown efficacious against certain brain tumors, such as subependymal giant cell astrocytoma 
(SEGA).64,65 Preclinical studies with ribociclib showed enhanced antitumor activity in combination with 
everolimus and exemestane versus each agent alone.51,66 Everolimus crosses the blood- brain barrier in a 
non-linear manner with the dose.  Pre-clinically, the brain/blood concentration ratio at 2 hours post-dose 
was 0.2 after a 0.1 mg/kg intravenous dose but progressively increased to 3.1 after a 30 mg/kg intravenous 
dose where everolimus blood levels are far above the therapeutic concentration range.66  
 
2.3.2 Everolimus (RAD001) Adult Clinical Studies 
Everolimus has gone through multiple adult phase I, II, and III clinical trials and received its first FDA-
approval for advanced renal cancer in 2009. It has since been FDA-approved for other indications, 
including SEGA associated with tuberous sclerosis in 2010 and in combination with exemestane for 
advanced hormone-positive, HER2-negative breast cancer in 2012.  Everolimus is currently being studied 
in multiple adult combination studies with other targeted agents, such as dual PI3K/mTOR inhibitor 
BEZ235 (NCT01482156) and CDK4/6 inhibitor LEE011 + exemestane (CLEE011X2106).   
 
2.3.3 Pediatric Studies 
2.3.3.1  Phase I/II Studies 
Fouladi et al. published a phase I study of everolimus in children with recurrent solid tumors and 
established the pediatric MTD as 5 mg/m2 continuous daily administration.67 At 3 mg/m2, DLTs included 
reversible grade 4 hypokalemia (n=1) and grade 3 hypophosphatemia (n=2). No DLTs were observed at 
5mg/m2. At 6.5 mg/m2, DLTs included grade 3 ALT elevation (n=1), mucositis (n=1), and diarrhea (n=1).  


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Pharmacokinetic findings of this phase I study are listed in Table 5. Population estimates for clearance 
(Cl)/F, V/F, and ka were 12.4 L/h/m2, 45.5 L, and 1.66 h−1, respectively. Interindividual variability in Cl/F, 
V/F, and ka was 47%, 46%, and 45% as determined by the percent coefficient of variation, respectively. 
Median apparent Cls for the 2.1, 3, 5, and 6.5 mg/m2 dosage levels were 12.1 L/h/m2 (range, 9.1 to 24.2 
L/h/m2), 9.3 L/h/m2 (range, 4.3 to 28.5 L/h/m2), 15.2 L/h/m2 (range, 14.4 to 16.0 L/h/m2), and 16.3 L/h/m2 
(range, 13.9 to 18.7 L/h/m2), respectively. 
 
 
Table 5: Summary of everolimus pharmacokinetic parameters. 
 
No objective responses were seen among 18 evaluable patients, but 6 patients exhibited prolonged stable 
disease, including one patient each with gliomatosis cerebri (low grade glioma; 14 cycles), osteosarcoma 
(8 cycles), brainstem glioma (5 cycles), peripheral PNET (5 cycles), anaplastic astrocytoma (4 cycles), 
and EPN (4 cycles). Inhibition of phosphorylated AktS473 was observed at the MTD.   
 
Krueger et al. published a phase I/II study of everolimus in patients > 3 years old with tuberous sclerosis 
and SEGA.68 Everolimus was administered at 3 mg/m2 and dose adjusted to achieve a trough concentration 
of 5 to 15 ng/mL.  The median dose of everolimus at 3 and 6 months was 4.7 mg/m2 and 5.6 mg/m2, 
respectively. Stomatitis and upper respiratory infection were the most common adverse events.  Four 
patients experienced severe adverse events, including upper respiratory infection (grade 3), pneumonia 
(grade 3), and convulsions (n=2; grades 2 and 4).  Increases in total cholesterol, low-density lipoprotein 
cholesterol, and triglycerides were noted.  Of 28 eligible patients (median age 11 years), 21 patients and 
9 patients achieved at least 30% and 50% tumor reduction, respectively. 
 
Kieran et al. reported a phase II study of everolimus in non-NF1 pediatric low-grade glioma (LGG), in 
which 23 patients (median age 9 years) were given everolimus 5 mg/m2/day in 28-day cycles.69 Four 
patients experienced partial response, and 13 had stable disease after a median of 10 cycles.  Six patients 
experienced disease progression by 1 year.  One patient discontinued therapy due to toxicity (mouth sores). 
PK was similar to that previously reported in children, and PD markers (phospho-S6 kinase, 4E-BP1 
phosphorylation, and cMyc expression) were decreased by day 14 of therapy. 
 
Geoerger et al. published a phase II study of single-agent temsirolimus (weekly oral administration at 75 
mg/m2), a rapamycin analog, in children with recurrent HGG, neuroblastoma, and rhabdomyosarcoma.70 
Only one patient with neuroblastoma had a PR, though prolonged disease stabilization (3 months) was 
observed in 7 of 17 (41%) of patients with HGG (including 5 DIPG, 1 GBM, and 1 anaplastic 
astrocytoma), suggesting potential utility if used in combination. 
 


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2.3.3.2  Phase III Studies 
Franz et al. published an international phase III study confirming the efficacy of everolimus in patients 
with tuberous sclerosis and SEGA.64 This study randomized 117 patients (median age 9.5 years in 
everolimus group and 7.1 years in placebo group) to receive everolimus (4.5 mg/m2/day to trough 
concentration of 5 to 15 ng/mL) or placebo.  The most common adverse events were mouth ulceration 
(32% everolimus, 5% placebo), stomatitis (31% everolimus, 21% placebo), convulsions (23% everolimus, 
26% placebo), and pyrexia (22% everolimus, 15% placebo). Twenty-seven patients (35%) had a t least 
50% reduction in the volume of SEGA versus none in the placebo group.   
 
2.3.3.3 Pediatric Combination Studies including mTOR inhibitors 
Wagner et al. published results of a phase II combination study with temsirolimus and cixutumumab, a 
monoclonal antibody against insulin-growth factor type 1 receptor (IGF-1R), in patients < 30 years old 
with recurrent solid tumors.71 Temsirolimus (8 mg/m2 with dose escalation to 10 mg/m2 for subsequent 
cycles if tolerable in first cycle) and cixutumumab (6 mg/kg) were administered once weekly for 4 week 
cycles and were generally well tolerated.  The most common toxicities were electrolyte abnormalities, 
mucositis, and myelosuppression. There were no objective responses. 
 
Yalon et al. reported a feasibility and phase II study of rapamycin (0.8 mg/m2/dose twice daily for trough 
concentration of 10 to 15 ng/mL) in combination with erlotinib (65 mg/m2 daily continuous dosing), an 
EGFR inhibitor, in pediatric low-grade glioma.72 Nineteen patients were evaluable. No DLTs were noted 
in the feasibility portion of the study. The most common toxicities were rash (n=11), oral apthous ulcers 
(n=9), and GI complaints (n=7). One patient (with NF1) had a PR and 6 patients remained on therapy for 
the planned 12 courses, while 10 patients progressed on therapy. 
Becher et al. reported a feasibility Phase I study with combination of perifosine (AKT inhibitor) and 
temsirolimus (mTOR inhibitor) in patients with recurrent CNS/solid tumors.  Twenty-three patients were 
treated.  Diagnosis included DIPG (n=8), HGG (n=6), medulloblastoma (n=2), ependymoma (n=1), 
neuroblastoma (n=4) and rhabdomyosarcoma (n=2).73 No DLTs were noted.  The most common toxicities 
were thrombocytopenia (38.1%), neutropenia (23.8%), lymphopenia (23.8%), and hypercholesterolemia 
(19%).  Stable disease was noted in 9 of the 11 patients diagnosed with DIPG or HGG. No partial or 
complete responses were achieved.73  
 
2.4 
Rationale for Proposed Pediatric Study 
Aberrant cell cycle regulation and activation of the PI3K/Akt/mTOR pathway represent two highly 
important mechanisms of malignant potential in pediatric brain tumors.  Joint inhibition of CDK4/6 and 
mTOR is promising due to strong biologic rationale, non-overlapping single-agent toxicities, and 
preliminary clinical experience in adults that suggests tolerability of this combination. Additionally, 
increased exposure of everolimus in the presence of ribociclib, as observed in pharmacokinetic profiling 
of samples from adults receiving the combination, suggest that lower doses of both drugs may also be 
used in the pediatric population.  
 
We propose a phase I and surgical study of ribociclib and everolimus in children ≥ 1 and ≤ 21 years of 
age with recurrent, progressive or refractory HGG, DIPG, medulloblastoma, CNS embryonal tumor 
(NOS), Ependymoma, or ATRT with evidence of an intact Rb1 protein assessed on formalin fixed paraffin 
embedded tumor tissue (preferably from the most recent recurrence). DIPGs will not require molecular 
screening if tissue is not available since biopsy of DIPG is not currently standard of care and since they 


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frequently harbor cell cycle aberrations and activation of the PI3K/Akt/mTOR pathway, as detailed in the 
background section. 
 
The proposed dose of ribociclib for the surgical study is the recommended single agent phase 2 dose 350 
mg/m2/dose which is a higher dose in comparison of ribociclib dose in combination with everolimus. Pre-
clinical data reveals ribociclib crosses the blood brain barrier providing support for the surgical study. PK 
modeling and extrapolation will be completed.  Administering the higher dose within the surgical cohort 
will provide information regarding exposure in the blood, tumor, and CSF generating knowledge of the 
RP2D. Initial evaluation at the surgical MTD (350 mg/m2) will result PK of CSF, tumor, and plasma.  For 
the proposed combination study with ribociclib and everolimus, we will evaluate plasma PK and 
extrapolate the PK in comparison to the surgical study PK analysis. The recommended time from dosing 
to surgery T max is 2-4 hours. Although ribociclib may cause myelosuppression, the timing of 
myelosuppression is usually after at least 3 weeks of therapy.  However, we will have strict platelet 
requirements for this cohort pre-operatively. Ribociclib has not been reported to be associated with 
delayed wound healing.  Following tumor resection and recovery from surgery (~2 weeks), patients 
enrolled on the Surgical study will be switched over to the phase I study and be treated with ribociclib + 
everolimus at the assigned dose level. Tumors resected following treatment with ribociclib will be 
assessed for Ki67 for ribociclib effect on archival tumor and recurrent tumor. 
 
Primary Hypothesis: We hypothesize that ribociclib and everolimus will be safe and tolerable in children 
with recurrent malignant CNS tumors. 
 
Secondary Hypothesis: We hypothesize that ribociclib will achieve adequate intra-tumoral drug 
concentration in children with recurrent malignant CNS tumors. 
 
2.5 
Correlative Studies Background 
 
2.5.1 Rationale for Biology Studies 
2.5.1.1 Hypothesis 
Molecular markers and targeted genomics or RNA sequencing may predict sensitivity or mechanism of 
response to CDK4/6 inhibitors such as ribociclib and mTOR inhibitors such as everolimus. 
 
2.5.1.2 Preclinical and Clinical Data 
Mutations that dysregulate the cell cycle and the PI3-kinase/AKT/mTOR pathway are frequently 
encountered in adult glioblastoma7 as well as in pediatric glioblastoma albeit at lower frequencies.63  
Dysregulation of these two critical pathways may also occur in the absence of genetic mutations, for 
example evidence for PI3-kinase/AKT/mTOR pathway activation in 80% of pediatric glioblastoma has 
been presented.64 Furthermore, the PI3-kinase/AKT pathway can regulate cell cycle progression in an RB-
dependent manner.65 There are multiple potential mechanisms for crosstalk between these two core 
glioblastoma pathways including AKT-mediated phosphorylation and inhibition of GSK-3β leading to 
Cyclin D1 accumulation, direct phosphorylation and inhibition of the CDK2 inhibitors p21 and p27 by 
AKT, and AKT-mediated phosphorylation and inhibition of FOXO transcription factors which are known 
to promote p27 expression.   Recent genomic studies also suggest the importance of cell cycle regulation 
in the oncogenesis of pediatric HGG, including TP53 mutations and Rb mutations, which were reported 
in 42-70% and 14-58% of pediatric HGG, respectively.7-10 Wu et al. also reported amplification of G1 
checkpoint regulators CCND1, CCND2, CCND3, CDK4, and CDK6 in 25% (14/57) of DIPGs and 


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collectively implicated mutations predicted to affect cell cycle regulation in 59% of pediatric HGG in their 
cohort.8 Mutations of PTEN, a tumor suppressor gene involved in cell cycle regulation, were also recently 
reported by Buczkowicz et al. in 25% (9/36) of DIPGs.7 Findings by Taylor et al. and Fontebasso et al. 
support the important role of PI3K/Akt/mTOR in pediatric HGG, as 46% (12/26) of DIPG and 26% 
(10/39) of DIPG or midline non-brainstem HGG in their respective studies exhibited mutations predicted 
to activate the (RTK)-PI3K-MAPK pathway.9,10  
 
In this study, we will explore the relationships between the activation status of the cell cycle and PI3-
kinase/AKT/mTOR pathways in patient samples. We will correlate our findings to the results from other 
correlative biological studies as well as to response to treatment and patient outcome.  
 
2.5.2 Rationale for Pharmacokinetic Studies 
2.5.2.1 Hypothesis 
The pharmacokinetics and tolerability of ribociclib and everolimus in pediatric patients with 
recurrent/progressive brain tumors may differ from prior studies of ribociclib and everolimus in the adult 
population and may be affected by prior treatment, age, body surface area, steroid use or concomitant 
medications. 
 
2.5.2.2 Ribociclib Preclinical Pharmacokinetic Studies 
Because the pharmacokinetics of these agents in combination are relatively unknown in the pediatric 
population, this information will be essential for evaluating toxicity and disease response and for refining 
dosing in future combination clinical trials of ribociclib. The results of these studies will provide the basis 
for assessing the relationship between the disposition of ribociclib when administered in combination with 
everolimus in adult and children.  Mandatory pharmacokinetic studies are needed to characterize the 
disposition of ribociclib and everolimus in this patient population.  
 
In an ongoing Phase Ib clinical trial CLEE011X2106, 2.5 mg of everolimus (RAD001) (qday) + 25 mg 
exemestane (qday) was administered with 200 or 300 mg ribociclib (qday, 3 weeks on/1 week off). A 
dose-dependent drug interaction (DDI) was observed between ribociclib and everolimus based on clinical 
PK analyses in a separate dose escalation trial, where everolimus exposure increased 2- to 4-fold in the 
presence of ribociclib. Cmax and AUC0-24h for everolimus at steady-state suggested that in the presence 
of 300 mg Ribociclib, everolimus (2.5 mg qday) exposure (AUC0-24h) was increased and was 
approximately similar to exposure following 5 to 7.5 mg everolimus when compared to historical single 
agent data.52,53 
 
Our pre-clinical work on Group 3 medulloblastoma (Grp3 MB), and diffuse intrinsic pontine glioma 
(DIPGx7) tumors reported the median unbound ribociclib Cmax in all three groups was 100 nM 
confirming distribution across the blood brain barrier.49 
 
2.5.3 Rationale for Dexamethasone mouthwash 
mTOR inhibitor associated stomatitis results in dose delays, reductions or discontinuation of the therapy 
resulting in compromise of duration and intensity of therapy.  Anecdotal reports have suggested that 
topical steroids may improve healing of everolimus-associates apthous ulcers.74,75  In a prior Phase 3 trial 
(BOLERO-2 trial) of everolimus and exemestane therapy for patients with hormone receptor-positive, 
HER2-negative metastatic breast cancer, all grade stomatitis occurred in 67% of patients including grade 
2 or worse in 33% and grade 3 severity in 8%.76  89% of all grade stomatitis was most prominent within 


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8 weeks of starting the everolimus.76  The SWISH trial was recently published in the Lancet Oncology.  
This is a multicenter, single-arm, phase 2 study of postmenopausal women who received everolimus and 
exemestane for hormone receptor-positive metastatic breast cancer and were evaluated  for prevention of 
everolimus-related stomatitis with dexamethasone mouthwash compared to data from the BOLERO-2 
trial as a historical control cohort for comparisons.  After 8 weeks of receiving dexamethasone oral 
solution four times daily in addition to everolimus and exemestane, the incidence of grade 2 or worse 
stomatitis was 2% vs 33% in BOLERO-2 study.  The most frequently reported grade 3 and 4 adverse 
events in the safety cohort included hyperglycemia (8%), rash (4%) and dyspnea (3%).  The adverse events 
associated with the dexamethasone mouthwash were minimal (2 patients developed oral candidiasis).77  
Given the minimal toxicities related to dexamethasone mouthwash and significant decrease in everolimus 
associated stomatitis, we will incorporate using dexamethasone in our patient population for at least the 
first 2 courses of therapy and monitor closely for dexamethasone associated toxicities in addition to 
prevention of stomatitis.  
 
 


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3 PATIENT SELECTION 
All subjects must meet the following inclusion and exclusion criteria.  No exceptions will be given. 
Imaging studies to establish eligibility must be done within 3 (three) weeks prior to enrollment. All other 
clinical evaluations to establish eligibility must be done within 7 days prior to enrollment. Subjects 
enrolled on the surgical study, will be re-assessed following guidelines in Section 10.1 prior to starting 
the combination of ribociclib and everolimus. 
 
3.1 
Eligibility for Screening (Phase I and surgical study) 
All subjects must meet the following screening criteria without exception.   
 
3.1.1 Tumor 
• Patients with a histologically confirmed diagnosis of HGG, medulloblastoma, CNS embryonal 
tumor (NOS), Ependymoma, or ATRT that is recurrent, progressive or refractory.  
• Patients with recurrent DIPG with typical radiographic appearance who have undergone biopsy 
are eligible provided there is histologic confirmation of malignant glioma WHO II-IV. Rb1 
screening for these patients is required only if adequate tissue is available. 
• Patients with recurrent brainstem tumors with an atypical presentation who have undergone biopsy 
are eligible provided there is histologic confirmation of malignant glioma WHO II-IV. These 
patients must undergo Rb1 screening. These patients must have radiographic evidence of 
progression. 
• Patients with secondary malignant gliomas will be eligible for this study but should conform to all 
other eligibility requirements. Patients with low-grade gliomas are excluded.  
 
3.1.2 Pre-trial tumor tissue availability:   
Formalin fixed paraffin embedded tumor tissue (preferably from the most recent recurrence) must be 
available to assess Rb1 protein status prior to enrollment on Phase I or surgical study. If the subject has 
results from prior Rb1 IHC testing in a CLIA-certified laboratory the requirement for screening to assess 
Rb1 protein status is waived. In these cases, patients will not be required to sign a screening consent.   
 
Patients with recurrent diffuse intrinsic brain stem glioma (DIPG) that has an atypical presentation must 
also submit the tumor tissue for Rb1 protein status confirmation or provide previous testing results from 
a CLIA certified laboratory.  Patients who have been biopsied for atypical DIPG but do not have sufficient 
tissue for Rb1 screening are not eligible. 
 
3.1.3 Age 
Patient must be ≥ 1 but ≤21 years of age at the time of enrollment. 
 
3.1.4 BSA 
• Patients enrolled on dose level -1 must have BSA≥0.55m2 
• Patients enrolled on dose level  -0.5 must have BSA≥0.75m2 
• Patients enrolled on dose level 0 must have BSA≥0.55m2 
• Patients enrolled on dose level 1 must have BSA≥ 0.75m2 
• Patients enrolled on dose level 2 and 3 must have BSA≥ 0.45m2 
3.1.5 Screening Consent 
Patients who are candidates for enrollment for the phase I or surgical studies must sign a screening consent 
and provide pre-trial tumor material for Rb1 testing unless testing is not needed due to diagnosis or the 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
availability of prior Rb1 IHC results. The screening consent is to be obtained according to institutional 
guidelines.  
 
3.1.6 Potential Eligibility for Study Enrollment 
Patients screened for this trial should be expected to meet the criteria for treatment as outlined in Section 
3.2.  
 
3.2 
Eligibility Criteria: Prior to Study Enrollment  
(applicable for Phase I and surgical cohort) 
 
3.2.1 Rb1 Status 
Patient has intact Rb1 protein confirmed either from previous results or screened tissue. All testing must 
be performed in a CLIA certified laboratory. DIPG patients with radiographically typical appearance will 
be waived from this requirement. 
 
3.2.2 Diagnosis 
3.2.2.1 Phase I (Stratum 1) 
• Patients with Recurrent or Refractory CNS tumors   
Patients with a histologically confirmed diagnosis of a primary CNS tumor that is recurrent, progressive, 
or refractory. All tumors must have histologic verification of HGG, medulloblastoma, CNS embryonal 
tumor (NOS), Ependymoma, or ATRT. Patients with low-grade gliomas are excluded. 
 
• Patients with DIPG  
Patients with progressive DIPG, as defined by progressive neurologic abnormalities or worsening 
neurologic status not explained by causes unrelated to tumor progression (e.g., anticonvulsant or 
corticosteroid toxicity wean, electrolyte disturbances, sepsis, hyperglycemia, etc.), OR an increase in the 
bi-dimensional measurement, taking as a reference the smallest disease measurement recorded since last 
treatment, OR the appearance of a new tumor lesion since diagnosis.   
Please note: 
o Patients with a radiographically typical DIPG, defined as a tumor with a pontine 
epicenter and diffuse involvement of more than 2/3 of the pons, are eligible without 
histologic confirmation.  
 
o Patients with pontine lesions that do not meet these radiographic criteria will be eligible if 
there is histologic confirmation of malignant glioma WHO II-IV. These patients must have 
radiographic evidence of progression. 
 
3.2.2.2 Surgical Study (Stratum 2) 
• Patients must have recurrent or refractory disease with a histological diagnosis at either the time 
of diagnosis or at the time of recurrence of one of the following:  
o HGG 
o medulloblastoma,  
o CNS embryonal tumor (NOS),  
o Ependymoma, or  
o ATRT  
 


NCI Protocol #: PBTC-050 
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• Patients for whom surgical intervention is clinically indicated (gross total resection or sub-total 
resection) at recurrence and are amenable to receiving ribociclib for 7 – 10 days prior to 
resection 
▪ Note: Patients with DIPG are excluded from the surgical study. 
 
3.2.3 Age 
Patient must be ≥ 1 and ≤ 21 years of age at the time of enrollment. 
 
3.2.4 BSA 
• Patients enrolled on dose level -1 must have BSA≥0.55m2 
• Patients enrolled on dose level  -0.5 must have BSA≥0.75m2 
• Patients enrolled on dose level 0 must have BSA≥0.55m2 
• Patients enrolled on dose level 1 must have BSA≥ 0.75m2 
• Patients enrolled on dose level 2 and 3 must have BSA≥ 0.45m2 
 
3.2.5 Prior Therapy 
Patients must have received prior therapy other than surgery and must have fully recovered from the acute 
toxic effects of all prior anti-cancer therapy (≤Grade 1 with the exception of alopecia) and must meet the 
following minimum duration from prior anti-cancer directed therapy prior to enrollment.  If after the 
required timeframe, the defined eligibility criteria are met, e.g. blood count criteria, the patient is 
considered to have recovered adequately.   
 
3.2.5.1 Myelosuppressive chemotherapy 
Patients must have received their last dose of known myelosuppressive anticancer therapy at least 21 days 
prior to enrollment or at least 42 days if nitrosourea. 
 
3.2.5.2 Investigational/Biologic Agent 
• Biologic or investigational agent (anti-neoplastic):  
Patient must have recovered from any acute toxicity potentially related to the agent and received their last 
dose of the investigational or biologic agent ≥ 7 days prior to study enrollment. 
o For agents that have known adverse events occurring beyond 7 days after administration, 
this period must be extended beyond the time during which adverse events are known to 
occur. 
• Monoclonal antibody treatment and agents with known prolonged half-lives: At least three half-
lives must have elapsed prior to enrollment. 
Note: A list of the half-lives of commonly used monoclonal antibodies is available on the PBTC webpage 
under Generic Forms and Templates. 
 
3.2.5.3 Radiation 
Patients must have had their last fraction of:  
• Craniospinal irradiation (>24Gy) or total body irradiation > 12 weeks prior to enrollment.   
• Focal irradiation > 2 weeks prior to enrollment 
 
3.2.5.4 Stem Cell Transplant 
Patient must be: 
• ≥ 3 months since autologous bone marrow/stem cell transplant prior to enrollment 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
 
3.2.6 Inclusion of Women and Minorities 
Both males and females of all races and ethnic groups are eligible for this study 
 
3.2.7 Neurologic Status 
• Patients with neurological deficits should have deficits that are stable for a minimum of 1 week 
prior to enrollment.   
• Patients with seizure disorders may be enrolled if seizures are well controlled on an anti-epileptic 
drug that is not a strong inducer or inhibitor of CYP3A4/5 are eligible.  
 
3.2.8 Performance Status 
Phase I 
Karnofsky Performance Scale (KPS for > 16 years of age) or Lansky Performance Score (LPS for ≤ 16 
years of age) assessed within one week of enrollment must be ≥ 50.  
 
Surgical Study 
Karnofsky Performance Scale (KPS for > 16 years of age) or Lansky Performance Score (LPS for ≤ 16 
years of age) assessed within one week of enrollment must be ≥ 60.  
 
Patients who are unable to walk because of neurologic deficits, but who are up in a wheelchair, will be 
considered ambulatory for the purpose of assessing the performance score. 
 
3.2.9 Organ Function 
Patients must have adequate organ and marrow function as defined below:  
• Absolute neutrophil count ≥ 1.0 x 109 cells/ L 
• Platelets ≥ 100 x 109 cells/ L (unsupported, defined as no platelet transfusion within 7 days) 
• Hemoglobin ≥ 8g/dl (unsupported) 
• Total bilirubin ≤ 1.5 times institutional upper limit of normal (ULN)  
• ALT(SGPT) ≤ 3 x institutional upper limit of normal (ULN) 
• AST (SGOT) ≤ 3 x institutional upper limit of normal (ULN) 
• Albumin ≥ 2 g/dl 
• Serum creatinine based on age/gender as noted in Table 6. Patients that do not meet the criteria 
in but have a 24 hour Creatinine Clearance or GFR (radioisotope or iothalamate) 
≥70mL/min/1.73m2 are eligible.  
 Table 6 
 Table 6 
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 


NCI Protocol #: PBTC-050 
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Updated Date:  September 26, 2018 
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. 
 
3.2.10 Corticosteroids 
Patients who are receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior 
to enrollment. 
 
3.2.11 Growth Factors 
Patients must be off all colony- forming growth factor(s) for at least 1 week prior to enrollment (i.e. 
filgrastim, sargramostim or erythropoietin).  2 weeks must have elapsed if patients received long-acting 
formulations. 
 
3.2.12 Pregnancy Status 
Female patients of childbearing potential must have a negative serum or urine pregnancy test.   
 
3.2.13 Pregnancy Prevention 
Patients of childbearing or child fathering potential must be willing to use a medically acceptable form of 
birth control while being treated on this study.   
“Women of child-bearing potential” is defined as all women physiologically capable of becoming 
pregnant, unless they are using highly effective methods of contraception throughout the study and for 8 
weeks after study drug discontinuation. Highly effective contraception methods include: 
• Total abstinence 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 
• Combination of any of the two following (a+b or a+c or b+c) 
o 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 
o Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
o Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) 
with spermicidal foam/gel/film/cream/ vaginal suppository 
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.   
 
Female patients must agree not to breastfeed their infants while on study. 
 
Patients of child fathering potential (defined as > Tanner stage 2) must use a condom during intercourse 
while taking the drug during treatment, for 8 weeks 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. 
 
3.2.14 Informed Consent 
The patient or parent/guardian is able to understand the consent and is willing to sign a written informed 
consent document according to institutional guidelines. Assent, when appropriate, will be obtained 
according to institutional guidelines.  


NCI Protocol #: PBTC-050 
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Updated Date:  September 26, 2018 
 
3.3 
Exclusion Criteria 
3.3.1 Surgery 
Patients who are otherwise deemed clinically unsuitable for surgical resection (applicable for surgical 
study only) 
 
3.3.2 Breast feeding 
Patients who are breast feeding.  
 
3.3.3 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, put them at additional risk for toxicity or would interfere with 
the study procedures or results. 
• Patients with any other current malignancy, except patients with a secondary brain tumor if the 
patient’s first malignancy has been in remission for at least 5 years from the end of treatment.   
 
3.3.4 Concurrent Therapy 
• Patients who are receiving any other anticancer or investigational or/and anti-neoplastic 
therapies, including chemotherapy, immunotherapy, target therapy, biological response 
modifiers. 
• Previous treatment with CDK4/6 inhibitors (such as PD-0332991, abemaciclib) and/or mTOR 
inhibitors (such as sirolimus, temsirolimus or everolimus).  
• Patients who are currently receiving treatment with agents that are known to cause QTc 
prolongation or induce Torsades de Pointes (see Appendix 15.2 and 15.4). 
• Known need for major surgery within 14 days of the first dose of ribociclib and everolimus. 
Please note: Gastrostomy, insertion of a G tube, Ventriculo-peritoneal shunt, endoscopic 
ventriculostomy and central venous access are NOT considered major surgery.   
 
3.3.5 Concomitant Medications 
Patient is currently receiving any of the following medications and cannot be discontinued 7 days prior to 
enrollment (see Appendix 15.2  and 15.4 for details): 
• Known strong and moderate inducers or inhibitors of CYP3A4/5, including enzyme inducing 
anti-convulsant drugs (EIACDs), grapefruit, grapefruit hybrids, pummelos, star-fruit, and Seville 
oranges 
• Substrates of CYP3A4/5 with a narrow therapeutic index 
• Herbal preparations/medications (except for vitamins) including, but not limited to: St. John’s 
wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw 
palmetto, black cohosh and ginseng. Patients should stop using all herbal medications and 
dietary supplements at least 7 days prior to enrollment.  
 
3.3.6 Cardiac disease 
Clinically significant active cardiac disease, uncontrolled heart disease and/or a 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 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
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 echocardiogram 
(ECHO)  
• 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:  
o Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia or 
hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic 
bradycardia.  
o Concomitant use of medication(s) with a known risk to prolong the QT interval and/or days 
prior to starting study drug) or replaced by safe alternative medication. 
• 12-lead Electrocardiogram (ECG)  
o QTc ≥450 msec 
• Hypertension defined as:  
o Patients 1-12 years of age with blood pressure that is > 95th percentile for age, height and 
gender at the time of enrollment.  
▪ The normal blood pressure by height, age and gender tables can be accessed in the 
Generic Forms section of the PBTC members’ webpage.   
o Patients who are ≥ 13 years of age with blood pressure > 130/80 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. 
 
3.3.7 Bleeding Disorder 
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 
as long as patient has adequate coagulation defined as:  aPTT INR ≤ 1.5 x upper limit of normal. 
 
3.3.8 Allergy 
Patient has a known hypersensitivity to ribociclib or any of its excipients as described below:  
• The capsules contain only the drug substance without any excipients.   
• The film-coated tablets consist of drug substance and compendial quality colloidal silicon 
dioxide, crospovidone, hydroxypropylcellulose, magnesium stearate and microcrystalline 
cellulose. The film-coating is a mix of compendial quality iron oxides, lecithin, polyvinyl 
alcohol, talc, titanium dioxide, and xanthan gum. Patients allergic to peanut and soy are not 
permitted to take the film-coated tablet formulation. 
• The oral solution consists of ribociclib succinate in water with an orange flavoring agent and 
common excipients such as preservatives, sweetener and pH modifier 
 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
3.3.9  Inability to Participate 
Patients with inability to return for required follow-up visits or obtain follow-up studies required to assess 
toxicity to therapy or to adhere to drug administration plan, other study procedures, and study restrictions. 
 
3.4 
Criteria to Start Treatment  
This section applies to both the Phase I study and the pre-surgical period of Surgical study. The following 
must be met prior to receiving ribociclib and everolimus combination for Phase I study or ribociclib alone 
for the Surgical study.   
• Subjects must start therapy within seven (7) days of enrollment. 
• Laboratory values must be no older than 7 days prior to the start of therapy. If a test that is 
repeated post enrollment and prior to the start of therapy is outside the limits for eligibility, it 
must be rechecked within 48 hours prior to the start of therapy. If rechecks are still outside the 
limits for eligibility, the patient may not receive protocol therapy and will be considered off 
study. 
  
3.5 
Criteria to Start Treatment with ribociclib and everolimus combination therapy  
The following must be documented for Surgical patients during the post-surgical period when switching 
to Phase I treatment  prior to receiving ribociclib and everolimus. If any of these criteria are not met, the 
patient is not eligible to start treatment. See section 10.1  for details of the assessments.  
 
3.5.1 Imaging:  
Subjects must have intra-operative or post-operative (<96 hours) MRI to document disease status.   
 
3.5.2 Ribociclib and Everolimus Combination: 
Patient amenable to receiving the drug combination therapy, ribociclib and everolimus, at least 2 weeks 
post- surgery and no later than 4 weeks post- surgery. 
 
3.5.3 Organ functions 
Laboratory parameters must meet the eligibility criteria as defined in Section 3.2.9. Laboratory values 
must be no older than 7 days prior to the start of combination therapy. If a test that is repeated post-surgery 
and prior to the start of therapy is outside the limits for eligibility, it must be rechecked within 48 hours 
prior to the start of therapy. If rechecks are still outside the limits for eligibility, the patient may not receive 
protocol therapy and will be considered off study.  
 
3.5.4 Pregnancy status:  
Female patients of childbearing potential must have a negative serum or urine pregnancy test.  
 
3.5.5 Concurrent illness:  
Patients must have recovered from surgical toxicities and cleared by Neurosurgery to start therapy.   
 
3.5.6 Neurological status:  
Patients must be neurologically stable and on stable or decreasing steroids for at least one week. 
 
3.6 
Treatment at the Primary Institution 
All experimental protocol therapy should be dispensed and all on treatment imaging studies should be 
obtained at a PBTC institution. Laboratory studies, excluding pharmacokinetic and biologic assays, may 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
be performed at a CLIA certified laboratory of the investigator’s choice. Imaging utilized to determine 
eligibility may be performed at an outside institution if all required imaging sequences are included and 
the study is deemed of adequate quality by the treating team. All required physical examinations, 
laboratory parameters need to be performed at the primary PBTC institution during the dose finding period 
of the protocol. 
4 REGISTRATION PROCEDURES 
4.1 
CTEP Investigator Registration Procedures    
 Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy require all 
individuals contributing to NCI-sponsored trials to register and to renew their registration annually. To 
register, all individuals must obtain a Cancer Therapy Evaluation Program (CTEP) Identity and Access 
Management (IAM) account (https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration 
type of Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site 
staff requiring write access to OPEN, RAVE, or acting as a primary site contact) must complete their 
annual registration using CTEP’s web-based Registration and Credential Repository (RCR) 
(https://ctepcore.nci.nih.gov/rcr).  Documentation requirements per registration type are outlined in the 
table below. 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all CTEP and 
CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and NPIVRs must list 
all clinical practice sites and IRBs covering their practice sites on the FDA Form 1572 in RCR to allow 
the following: 
• Added to a site roster 
• Assigned the training, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• Act as the site-protocol PI on the IRB approval 
• Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL). 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
https://ctep.cancer.gov/investigatorResources/default.htm.  For questions, please contact the RCR Help 
Desk by email at RCRHelpDesk@nih.gov. 
 
4.2 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
4.2.1 IRB Approval 
Each investigator or group of investigators at a clinical site must obtain IRB approval for this protocol and 
submit IRB approval and supporting documentation to the CTSU Regulatory Office before they can be 
approved to enroll patients.  Assignment of site registration status in the CTSU Regulatory Support System 
(RSS) uses extensive data to make a determination of whether a site has fulfilled all regulatory criteria 
including but not limited to the following:  
• 
An active Federal Wide Assurance (FWA) number,  
• 
An active roster affiliation with the Lead Network or a participating organization,  
• 
A valid IRB approval, and  
• 
Compliance with all protocol specific requirements.  
 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• Active registration status 
• The IRB number of the site IRB of record listed on their Form FDA 1572 
• An active status on a participating roster at the registering site. 
 
Requirements for PBTC-050 Site Registration: 
• IRB approval (For sites not participating via the NCI CIRB; local IRB approval documentation, 
an IRB-signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is accepted) 
 
4.2.2 Downloading Site Registration Documents 
Site registration forms may be downloaded directly from the CTSU members’ website.   
• Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM username and 
password 
• Click on the Regulatory tab  
• Click on the Home tab, then scroll down to the “printable CTSU Forms” section. 
• Select and download this form: 
o CTSU IRB Certification  
 
4.3 
Requirements for Submitting Regulatory Documents 
Submit completed forms along with a copy of your IRB Approval and approved Informed Consent to the 
PBTC via the PBTC document upload system. Once all documents are received, the responsible Protocol 
Coordinator listed on the study cover page will submit the regulatory documents to the CTSU Regulatory 
Office via the Regulatory Submission Portal, where they will be entered and tracked in the CTSU RSS. 
4.3.1 Delegation of Task Log (DTL)  
Each site must complete a protocol-specific DTL.  The Clinical Investigator (CI) is required to review and 
electronically sign the DTL prior to the site receiving an Approved site registration status and enrolling 
patients to the study. The DTL application is located on the CTSU members’ website at www.ctsu.org.  


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
Any individual at the enrolling site on a participating roster may initiate the site DTL.  Instructions on 
completing the DTL are embedded in the DTL application. 
 
4.3.2 Checking Site Registration Status 
You can verify your site’s registration status on the members’ section of the CTSU website.  Sites will be 
notified by the PBTC when all required documents are uploaded to the CTSU Regulatory Office.  
▪ Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM username 
and password 
▪ Click on the Regulatory tab  
▪ Click on the Site Registration tab 
▪ Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation and institutional compliance 
with protocol-specific requirements as outlined by the Lead Network. It does not reflect compliance with 
protocol requirements for individuals participating on the protocol or the enrolling investigator’s status 
with the NCI or their affiliated networks. 
 
4.4 
General Guidelines 
4.4.1 Prior to Consent 
Prior to discussing protocol entry with the patient, all site staff must verify a slot is available via the CTSU 
OPEN Slot Reservation System which is accessible through https://open.ctsu.org/open/home.open. 
 
4.5 
Enrollment Procedures 
Screening and patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available on a 24/7 basis.  To access OPEN, the site 
user must have an active CTEP-IAM account (check at < https://ctepcore.nci.nih.gov/iam>) and a 
'Registrar' role on either the LPO or participating organization roster. Registrars must hold a minimum of 
an AP registration type.  If a DTL is required for the study, the registrar(s) must also be assigned the 
OPEN Registrar task on the DTL.   
 
All site staff will use OPEN to screen and/or enroll patients to this study.  It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the patient in the PBTC 
RAVE database. OPEN can be accessed at https://open.ctsu.org or from the OPEN tab on the CTSU 
members’ side of the website at https://www.ctsu.org. To assign an IVR or NPIVR as the treating, 
crediting, consenting, drug shipment (IVR only), or investigator receiving a transfer in OPEN, the IVR or 
NPIVR must list on their Form FDA 1572 in RCR the IRB number used on the site’s IRB approval.  If a 
DTL is required for the study, the IVR or NPIVR must also be assigned the appropriate OPEN-related 
tasks on the DTL. 
 
Patients with DIPG (Rb1 screening is not required) 
For patients with DIPG who are not being screened, reservations may also be made through the CTSU 
OPEN Slot Reservation system providing time to assess the patient’s eligibility. Once a slot reservation 
confirmation is obtained, site staff may then proceed to enroll the patient on this study. Non screening 
reservations will be held for a maximum of 10 days. The patient’s reservation should be canceled as soon 
as it is determined that the patient is not eligible or that the family/patient has decided not to consent to 
the trial. 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
 
 
 
Patients with all other CNS tumors (Rb1 screening is required) 
All patients with recurrent, progressive or refractory CNS Tumors (HGG, medulloblastoma, CNS 
embryonal tumor (NOS), Ependymoma or ATRT) or with atypical presentation of DIPG must be screened 
prior to enrollment. Patients must sign the screening consent to send the pre-trial tumor tissue 
 
for Rb1 testing (see Section 9.1.1 for requirement) and have their Rb1status confirmed 
prior to enrolling in the PBTC-050 study. Only patients who have intact Rb1 will be eligible to enroll.  
 
For patients whose tumor material has previously undergone Rb1 IHC testing at another CLIA-certified 
lab, additional screening will not be required. If previous Rb1 IHC test confirms intact Rb1, then the 
patient may enroll using the same procedures as described for DIPG patients above.  
 
4.5.1 Pre-enrollment Screening 
Pre-enrollment screening will be performed for patients who are consented for screening and willing to 
provide pre-trial tumor material for Rb1 IHC testing. Sites are required to make a reservation using the 
CTSU OPEN Slot Reservation System before they ship the samples to CCHMC for screening. Screening 
is facilitated by having pre-enrollment screening questions completed by a site registrar in the Prerequisite 
screen of OPEN. The site must complete the steps up to Prerequisite to obtain the OPEN tracking number 
which will be used for labeling the slides. Patient enrollment will not proceed from the Prerequisite screen 
until the CCHMC pathology lab receives the tumor material, analyzes the tissue and enters the Rb1 result 
into the PBTC ProtoLab database. 
 
Completing the Prerequisite screen sends an automatic email to the CCHMC pathology lab and site 
registrar with information on the screening process. Once the Rb1 result is entered in ProtoLab by 
CCHMC pathology lab, an automatic email will be sent to the site registrar and the responsible PBTC 
Protocol Coordinator indicating that enrollment may proceed. Based on the communicated Rb1 screening 
result, the site registrar must return to OPEN and complete the process – either to complete enrollment of 
a patient for treatment who has passed the screening, or to remove the reservation of the patient who failed 
the screening. 
 
Sites will be notified of the results of the Rb1 testing within 2 weeks. All screened patients who are eligible 
for participating in the PBTC-050 study must be enrolled via OPEN within 10 days of the site 
notification of a patient’s Rb1 status as stated in the email notification. 
 
4.5.2 Patient Enrollment  
Patient enrollment for this study will be facilitated using the Slot-Reservation System in conjunction with 
the Registration system in the Oncology Patient Enrollment Network (OPEN).  Prior to discussing 
protocol entry with the patient, all site staff must use the CTSU OPEN Slot Reservation System to insure 
that a slot on the protocol is available to the patient.  Once a slot- reservation confirmation is obtained, 
site staff may then proceed to enroll the patient to this study. 
 
Patients must be enrolled prior to any protocol treatment. Prior to accessing OPEN, site staff should verify 
the following: 
▪ All eligibility criteria have been met within the protocol stated timeframes.  


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
▪ All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable). 
 
Note:  The OPEN system will provide the site with a printable confirmation of registration and treatment 
information.   Please print this confirmation for your records.  
 
Further instructional information is provided on the OPEN tab of the CTSU members’ side of the CTSU 
website at https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
5 TREATMENT PLAN 
Treatment may be administered on an outpatient basis.  Reported adverse events and potential risks are 
described in Section 7. Appropriate dose modifications are described in Section 6.  No investigational or 
commercial agents or therapies other than those described below may be administered with the intent to 
treat the patient's tumor. Timing of protocol therapy administration and response assessment studies are 
based on schedules derived from the experimental design or on established standards of care. Minor 
unavoidable departures (up to 72 hours) from protocol directed therapy and/or disease evaluations for 
valid clinical, patient and family logistical, or facility, procedure and/or anesthesia scheduling issues are 
acceptable.   
 
Phase I Study: 
This study will enroll patients with recurrent or refractory malignant brain tumors to define the 
MTD/RP2D of ribociclib and everolimus.  
 
Surgical study:  
The surgical study will enable us in a small population of patients to measure the ribociclib concentration 
in brain tumor tissue and in plasma samples collected approximately at the same time. The surgical study 
will involve treatment of eligible patients with ribociclib alone at the pediatric MTD (350 mg/m2/day) for 
7-10 days prior to tumor resection of their recurrent tumor, since the half- life of ribociclib in pediatric 
patients is approximately 30-41 hours.  Following tumor resection and recovery from surgery (~2 weeks, 
maximum 4 weeks), patients enrolled on the surgical study will be switched over to the phase I study and 
be treated with ribociclib and everolimus at the assigned dose level.  
 
 
Pre-surgery  


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
For surgical patients, the period from enrollment until initiation of surgery will be considered ‘pre-
surgery’. Ribociclib should be initiated within 7 days of enrollment and surgery should be performed after 
7-10 days of ribociclib treatment.   
 
Post-surgery  
“Post-surgery” is defined as the period after surgery until the initiation of combination treatment with 
ribociclib and everolimus on Phase I study (2 weeks – 4 weeks). During the recovery period, patients will 
be re-assessed per section 3.5 criteria prior to switching to Phase I study. The combination drug treatment 
must be commenced within 2-4 weeks of post- surgery period.  
 
Switching to Phase I component 
The dose level assigned for Phase I study will be determined based on the slot availability and the number 
of currently enrolled patients experiencing dose-limiting toxicities on the Phase I component. Each 
eligible surgical patient for Phase I will start treatment at the dose level that is recommended based on the 
available data and the Rolling 6 design. The potential dose for Phase I will be reviewed by the Study 
Chair, the protocol coordinator and the statistician and this dose will be made available as part of the 
patient’s study record. This process may take about 1 – 2 days. Site should email the protocol coordinator 
to initiate the assignment of a dose level during the post-surgical recovery period (approximately week 2 
– week 3) after re-confirmation of eligibility for Phase I study entry (see section 3.5). The treatment must 
start no later than 4 weeks post-surgery.   
 
5.1 
Starting Dose and Dose escalation Schedule 
5.1.1 Surgical Study 
Single agent ribociclib will be given at a dose of 350mg/m2/day daily for 7-10 days prior to tumor 
resection.  Formulation (capsule versus liquid) will be the same throughout the duration pre-operatively.   
If the starting dose of ribociclib is intolerable or if DLTs of the starting dose of ribociclib are clearly 
attributable to the study drug, the dose will be dose de-escalated to 280 mg/m2/day.  
 
Table 7: Dose De-escalation Schedule (Surgical Study) 
Dose Level 
Ribociclib (mg/m2/day) PO 
0 
280 mg/m2/day 
1 (starting dose) 
350 mg/m2/day 
 
5.1.2 Phase I 
Subjects who enroll on the Phase I trial will be assigned a dose level at the time of enrollment.  Subjects 
who enroll on the surgical study will be assigned a dose level once they meet the Phase I eligibility criteria 
during the post-surgery period.  See Table 8 below for details of dose escalation schedule. See section 6 
for dose modifications. Dosing should be adjusted based on BSA calculated at the beginning of each 
course of therapy. The dose prescribed should be rounded to the nearest deliverable dose based on the 
BSA adjustment and the available pill sizes. A Dosing Table for Ribociclib which reflects this approach 
is available in Appendix 15.5. Patients will be provided with a Medication Diary to record ribociclib and 
everolimus doses,  instructed in their use, and asked to bring the diary as well as the remaining 
capsules/liquid (in supplied bottles) with them to each appointment. The Patient Diary is available on the 
PBTC-050 webpage. The diary and returned medication will serve as confirmation of adherence to the 
protocol-prescribed dosing.   


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
 
The starting dose for everolimus will be 1.2 mg/m2/day. The starting dose of ribociclib given on a 3-
weeks-on/1-week-off dosing schedule will be 120 mg/m2 per day which is approximately 70% of the adult 
RP2D (adult RP2D = 300 mg daily) adjusted for body surface area.   
 
If the starting dosages are tolerable in combination, then dose levels 2 and 3 will be explored as tolerated.  
If the starting dosages of this combination are intolerable, then either dose level 0 or -0.5 will be explored.  
Since the toxicity profiles of ribociclib + everolimus do not generally overlap, if DLTs of the starting dose 
of the combination are clearly attributable to everolimus (e.g. mucositis, hyperlipidemia, etc.), the 
everolimus dose will be dose de-escalated (rather than the ribociclib dose) to 1 mg/m2/day continuous 
dosing. However if the toxicities observed are more consistent with ribociclib side effects then the dose 
of ribociclib will be reduced (see Table 8 below, dose levels 0 and -0.5). If dose level 0 or -0.5 are not 
tolerable, doses will be reduced as outlined in dose level -1.  
 
Patients are not allowed to take a combination of the liquid, capsules and tablets formulations for ribociclib 
within a course but may change to a different formulation when starting a new course. The dose levels in 
Table 8 have been determined in order to accommodate the smallest capsule sizes of 50 mg. While the 
increments between ribociclib dose levels are larger than 30% which is commonly used, this was necessary 
to avoid overlaps between the dosages.  
 
No intra-patient dose escalation will be permitted on the protocol. Only DLTs observed during the dose-
finding period of therapy will be used to guide dose escalation. Dose escalation will be governed by the 
statistical design as described in section 13.1 of the protocol. 
 
Table 8 - Dose Escalation Schedule (Phase I) 
Dose Level 
Ribociclib  
(mg/m2/day PO days 1- 21) 
Everolimus  
(mg/m2/day PO days 1-28) 
BSA Restriction 
-1 
75 mg/m2/day 
1 mg/m2/day 
BSA≥0.55m2 
-0.5*  
120 mg/m2/day 
1 mg/m2/day 
BSA≥0.75m2 
0 
75 mg/m2/day 
1.2 mg/m2/day 
BSA≥0.55m2 
1(starting dose) 
120 mg/m2/day 
1.2 mg/m2/day 
BSA≥0.75m2 
2 
170 mg/m2/day 
1.2 mg/m2/day 
BSA≥0.45m2 
3 
170 mg/m2/day 
1.5 mg/m2/day 
BSA≥0.45m2 
*Dose reduction if toxicities clearly attributable to Everolimus 
 
5.2 
Agent Administration 
One course consists of a 28-day cycle. Ribociclib will be administered daily for 21 days on/7 days off on 
a 28-day cycle. Everolimus will be administered daily for 28 days. Subsequent courses will immediately 
follow with no break in administration of the agents in the absence of toxicity. Duration of therapy is 
defined in Section 5.5. 
 
5.2.1 Ribociclib 
Ribociclib is supplied as 50 mg capsules and 200 mg capsules or film coated tablets. The oral solution is 
available as 30 mg/mL. The liquid formulation may be administered via g-tube or nasogastric or 
nasojejunum tube. Tablet and capsule dosing will be rounded to the nearest 50 mg.  Liquid 
formulation (30mg/mL) will be rounded to the nearest 50 mg. See Appendix 15.5 for the rounding 


NCI Protocol #: PBTC-050 
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total daily dose (mg) tables. Patients allergic to peanut and soy are not permitted to take the film-
coated tablet formulation. 
 
5.2.2 Everolimus 
Everolimus dosing for this study will utilize the dispersible tablet (also referred to as ‘tablets for oral 
suspension’) formulation which is available as a 2 mg dosage form. Dosing will be rounded to the nearest 
0.1mg. 
 
5.2.3 Treatment schedule  
The PK studies will be done during courses 1 and 2. Please follow instructions for holding study 
medications until PK samples are collected noted in Section 9.2.2. 
 
In Course 1, patients will start ribociclib on day 1 through day 21 followed by 7 days of rest and everolimus 
on day 3 through day 28 on a 28 day cycle.  
 
 
In Course 2, patients will receive everolimus on day 1 through day 28 and Ribociclib on day 2 through 
day 21 followed by 7 days of rest.   
 
 
 
For Course 3 and beyond: 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
For subsequent courses, patients will receive ribociclib once a day for 21 days followed by 7 days of rest 
and everolimus once a day for 28 days.  
 
5.2.4 Instructions for taking the study drugs 
Ribociclib and everolimus should be taken as follows: 
• Patients should be instructed to take the Ribociclib dose with a large glass of water/clear liquid 
(~250 mL) at the same time each day preferably in the morning with the everolimus dose.  
• On days when PK collection/ECG is scheduled at the clinic, patients will take ribociclib and 
everolimus in the clinic under the supervision of the investigator or designee. On all other days 
patients will take the ribociclib and everolimus combination at home. 
• Ribociclib and everolimus can be taken without regard to meals.   
• If emesis occurs within 10 minutes of administration of ribociclib and everolimus, the dose should 
be repeated.  
• A missed dose (not taken within 6 hours of the intended time) should not be replaced or made up 
on a subsequent day, but the missed dose and reason for missing the dose should be recorded in 
the diary. The completed Patient dairy will be reviewed at each subsequent clinic visits throughout 
therapy.  
• Patients must avoid consumption of grapefruit, Seville oranges or products containing the juice of 
each during the entire study and preferably 7 days before the first dose of study medication, due 
to potential CYP3A4 interaction with the study medications. Orange juice is allowed. 
• No herbal or dietary supplements. 
• Patients should be advised to drink plenty of water or take hydration fluids to avoid dehydration if 
diarrhea occurs.   
 
5.2.5 Criteria to start subsequent courses 
Patients will start each subsequent course of therapy with recovery of ANC ≥ 1.0 x 109 cells/ L and Platelet 
count ≥ 100 x 109 cells/ L (transfusion independent, no platelet transfusion for a ≥ 7 days). If a patient 
does not meet these parameters at the end of the treatment course, then ribociclib and everolimus must be 
held for 14 days until parameters are met. Drug can be held for up to 14 days in patients who undergo 
surgical procedures for reasons other than tumor progression to allow for proper wound healing. 
A course may be repeated every 28 days if the patient has at least stable disease and has again met 
laboratory parameters as defined in Section 3.2.9. If a patient does not meet these parameters at the end 
of the treatment course then ribociclib/everolimus should be held until parameters meet the eligibility 
criteria. 
 
5.3 
Dose Limiting Toxicity  
Toxicities will be graded based on CTCAE v5.0 unless otherwise specified in the protocol. Management 
and dose modifications associated with adverse events are outlined in Section 6. DLT will be defined as 
any of the events listed in this section that are at least possibly related to the investigational agent that 
occur during the dose-finding period regardless of expectedness.   
 
Management and dose modifications for toxicities which occur outside of the dose-finding period should 
also follow section 6; however these will not be considered dose limiting for the purpose of dose 
escalation. 
 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
5.3.1 Phase I - Dose-Limiting Toxicities (DLT's):  
• 
Any ribociclib/everolimus-related adverse event during the first course of therapy that leads 
to a dose reduction or results in the permanent cessation of therapy will be considered dose 
limiting. All dose modifications in all courses are to follow the guidelines provided in Section 
6.2.  
• 
Any ribociclib/everolimus -related adverse event during the first course of therapy that 
results in a delay of treatment > 14 days. 
 
5.3.1.1 Non-hematologic dose limiting toxicity is defined as: 
• 
Any grade 4 non-hematologic toxicity 
• 
Any grade 3 non-hematologic toxicity with the exception of: 
o Grade 3 nausea and vomiting that respond to intervention within  5 days 
o Grade 3 fever or infection lasting fewer than 5 days in duration without the use of 
growth factors 
o Grade 3 hypophosphatemia, hypokalemia, hypocalcemia or hypomagnesemia   
responsive   to   oral   supplementation 
o Grade 3 anorexia 
o Grade 3 hyperlipidemia (hypercholesterolemia, hypertriglyceridemia) 
• 
Any ≥ Grade 3 AST/ALT and/or bilirubin (see Table 9 for specific modifications) 
Any ≥ 2 Grade QTc (see Table 10 and  
• 
Table 11 for specific modifications) 
• 
Any ≥ Grade 2 mucositis (see Table 12 for specific modifications) 
• 
Any ≥ Grade 2 pneumonitis 
• 
Any grade 2 non-hematologic toxicity that persists for > 7 days and is considered medically 
significant or sufficiently intolerable by the patient as to warrant treatment interruption 
and/or dose reduction will be considered dose limiting. 
 
5.3.1.2 Hematologic dose limiting toxicity is defined as: 
• 
Grade 4 thrombocytopenia 
• 
 Grade 3 thrombocytopenia (platelet count < 50 x109 cells/L) with clinically significant 
bleeding, petechiae or grade 3 thrombocytopenia that persists for ≥ 7 days or that requires 
platelet transfusion on ≥ 2 separate days within a 7-day period 
• 
Grade 4 neutropenia lasting >7 consecutive days 
• 
Myelosuppression that causes a delay greater than 14 days between treatment cycles  
 
5.3.2 Surgical study - Dose-Limiting Toxicities (DLT's):  
• 
Any ribociclib-related adverse event defined below in sections 5.3.2.1 and 5.3.2.2 during the 
pre-operative (7-10 days prior to surgery), intra-operatively (during surgery) and post-
operatively (2-4 weeks post- surgery). 
 
5.3.2.1 Non-hematologic dose limiting toxicity is defined as: 
• 
Any grade 4 non-hematologic toxicity 
• 
Any grade 3 non-hematologic toxicity with the exception of: 
o Grade 3 nausea and vomiting that respond to intervention within  5 days 
o Grade 3 fever or infection lasting fewer than 5 days in duration 


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o Grade 3 hypophosphatemia, hypokalemia, hypocalcemia or hypomagnesemia   
responsive   to   oral   supplementation 
o Grade 3 anorexia 
o Grade 2 liver enzyme elevation, including ALT/AST OR total bilirubin that 
returns to Grade ≤ 1 or baseline within 14 days.  
• 
Any ≥ Grade 3 AST/ALT and/or bilirubin (see Table 9 for specific modifications) 
Any ≥ 2 Grade QTc (see Table 10 and  
• 
Table 11 for specific modifications) 
• 
Any Grade 2 non-hematologic toxicity that persists for > 7 days and is considered medically 
significant or sufficiently intolerable by the patient as to warrant treatment interruption 
and/or dose reduction will be considered dose limiting. 
 
5.3.2.2 Hematologic dose limiting toxicity is defined as: 
• 
Grade 4 thrombocytopenia 
• 
 Grade 3 thrombocytopenia (platelet count < 50 x109 cells/L) with clinically significant 
bleeding, petechiae or grade 3 thrombocytopenia that persists for ≥ 7 days or that requires 
platelet transfusion on ≥ 2 separate days within a 7-day period 
• 
Grade 4 neutropenia lasting >7 consecutive days 
• 
Myelosuppression that causes a delay greater than 14 days between treatment cycles 
 
5.3.3 Dose-finding period (Phase I) 
The dose finding period of Phase I begins with the initial dose of ribociclib and ends on the last day of 
course 1. Should there be a delay starting the subsequent course, dose finding will complete on the start 
date of the subsequent course.  
 
5.3.4 Dose Escalation/ De-escalation 
Dose escalation will begin with dose level 1 and will be governed by the Rolling-6 design as described in 
section 13.1. No intra-patient dose escalation will be permitted on the protocol. Only DLTs observed 
during the dose-finding period of therapy will be used to guide dose de-escalation. 
 
5.4 
Concomitant Medications and Supportive Care Guidelines 
5.4.1 Steroids 
Corticosteroids should be used at the lowest dose to control symptoms of edema and mass effect, and 
discontinued, if possible. Use of corticosteroids should be recorded in the Rave database. 
 
5.4.2 Anticonvulsants 
Anticonvulsants drugs should be used, if indicated. Use of anticonvulsants should be recorded in the Rave 
database. Note: Use of enzyme inducing anti-convulsants is prohibited on this trial.  
 
5.4.3 Growth Factors 
Routine use of growth factors (e.g. G-CSF, GM-CSF and erythropoietin) is not permitted.  However, 
therapeutic use of G-CSF or GM-CSF in patients with serious neutropenic conditions, such as sepsis, may 
be considered at the investigator’s discretion. Use of growth factors should be recorded in the Rave 
database. 
 


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Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
5.4.4 Anti-emetics 
Patients may receive ondansetron or granisetron during therapy with CAUTION while taking ribociclib. 
The use of additional anti-emetics will be at the treating physician’s discretion.  Use of anti-emetics should 
be recorded in the Rave database. 
 
5.4.5 Febrile neutropenia 
Febrile neutropenia should be managed according to the local institutional guidelines.  Measures include 
laboratory testing, blood cultures, and institution of broad spectrum antibiotics. 
 
5.4.6 Pneumocystis jiroveci pneumonia (PJP) prophylaxis 
The use of medication (i.e., Trimethoprim-sulfamethoxazole) for PJP prophylaxis in patients on chronic 
steroids is recommended, but is at the investigator’s discretion. 
 
5.4.7 Mucositis prophylaxis 
Mouth care will be per standard institutional guidelines with the mandatory addition of dexamethasone 
and salt water rinses.  
 
Overview of dexamethasone:  Dexamethasone steroid-based oral solution comprised of 0.5 milligrams 
per 5mL of alcohol free dexamethasone.  
 
Dexamethasone administration:  All patients will be given 0.5 mg/5 mL dexamethasone steroid 
mouthwash. The patient will initiate the dexamethasone steroid mouthwash on the same day that they 
initiate the combination study treatment (Course 1 Day 3).  
The alcohol-free, 0.5 mg/5 mL dexamethasone steroid mouthwash should be administered based on the 
following instructions: 
• 5-10 mL of mouthwash swish and spit 3 times daily (TID). The mouthwash is to be held in 
mouth and swished around mouth to come in contact with entire buccal mucosa surface for a 
minimum of two minutes, and then spit out. If the patient is unable to hold mouthwash in mouth 
for 2 minutes, may spit out prior to 2 minutes or may use swab sponge.   
• Patient should remain NPO (no food, no drinks, nothing in mouth) for at least an hour after 
administering mouthwash, with the exception of Nystatin (or another topical antifungal). 
 
Dexamethasone treatment regimen 
Course 1 Day 3 (C1D3) is the day the patient initiates the mouthwash regimen and study drugs.  
Patients should use mouthwash regimen for two consecutive treatment cycles. Patients may continue for 
subsequent cycles, but this will not be mandated.   
 
Salt water mouth rinse 
The Salt water mouth rinse will only be administered once the onset of Grade 1 stomatitis has been noted. 
Salt water mouth rinse (0.9%): administered as 10mL swish and spit TID and must be done prior to the 
dexamethasone mouthwash. The patient should administer the salt water (0.9%) mouth rinse (swish and 
spit) and wait for 10-15 minutes before administering the dexamethasone mouthwash. 
• If the patient is unable to swish and spit mouthwash, swab sponge may be used.   
 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
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5.4.8 Neurosurgical or other surgical procedures 
If a neurosurgical procedure or other surgical procedure is required for a reason other than tumor 
progression (i.e. the onset of hydrocephalus), these procedures should be documented, but will not 
constitute criteria for declaring the patient “off therapy”.  Ribociclib and everolimus should be held until 
the patient is clinically stable and has recovered from the acute effects of surgery. 
 
5.4.9  Concomitant therapy  
Because there is a potential for interaction of ribociclib and everolimus with other concomitantly 
administered drugs through the cytochrome P450 system, the local health care providers should be alerted 
if this patient is taking any agent known to affect or with the potential to affect selected CYP450 
isoenzymes.  Medications to be used with caution during in this study are listed in Appendix 15.3. This 
list is not comprehensive and is only meant to be used as a guide.  
 
The heart’s electrical activity may be affected by ribociclib. The study doctor should be concerned about 
QTc prolongation and any other medicine that is associated with greater risk for having QTc prolongation.   
 
The case report form (CRF) must capture the concurrent use of all other drugs, over-the-counter 
medications, or alternative therapies.  The study team should check a frequently-updated medical 
reference for a list of drugs to avoid or minimize the use of while receiving  ribociclib and everolimus.    
 
Medications which should be excluded from patient use if possible are listed in Appendices 15.2 and 15.4. 
If they must be given based on the investigator’s judgment, then use with caution and consider a ribociclib 
and everolimus interruption if the concomitant medication is only needed for a short time. The Study Chair 
should be contacted if there are additional questions regarding concomitant medications.   
 
The Patient Drug Information Handout and Wallet Card (Appendix 15.6) should be provided to patients. 
 
5.5 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s) or disease progression, treatment will continue 
for 13 courses (approximately 1 year) or until one of the Off Treatment Criteria applies noted in Section 
5.5.4.  
 
5.5.1 On Study Data Submission Schedule 
Pre-treatment, on-study and off-treatment data, as well as patient response data are to be recorded in the 
electronic data collection screens using the Rave database.  See the Required Data and Timetable for 
Submission form located on the PBTC-050 Protocol webpage for the schedule.  For assistance, contact 
the PBTC Protocol Coordinator listed on the cover page. An optional roadmap is located on the PBTC-
050 Protocol Webpage.  
 
5.5.2 Extended Therapy 
Ribociclib and everolimus will be available beyond 13 courses of therapy for patients who have at least 
clinically and radiographically stable disease at the end of course 13 and the investigator and subject agree 
to continue treatment with ribociclib and everolimus for up to an additional 13 courses (total maximum 
duration of treatment is 26 courses).  
 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
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5.5.3 Data Submission during Extended Therapy 
For patients who are eligible for extended therapy (section 5.5.2), they will be followed during this 
additional period for dates of drug administration, adverse events that are possibly, probably or definitely 
related to study drug, laboratory results,  date and result of disease evaluations by MRI, date of disease 
progression, and date of last follow up and date of death. At the completion of the additional 13 courses  
of therapy the patient is considered to have completed protocol therapy and should be taken off treatment 
(per protocol section 5.5.4). At the completion of the appropriate follow up period (per protocol section 
5.5.6), the patient should be considered off study. 
 
5.5.4 Off Treatment Criteria 
At the discontinuation of treatment, the “Off Treatment Date” is to be recorded in the eCRF and is to be 
consistent with the reason given for going off treatment. The “Last Treatment Date” is defined as the last 
date that the patient received protocol based therapy.  Date of “off treatment” must be the greatest of the 
date of last treatment, date of procedure, date of patient assessment, notification of patient/family decision, 
or decision made by the physician that resulted in the patient being taken off protocol treatment.  The 
reason for discontinuation of treatment must be documented by the attending investigator in the medical 
record and recorded in the eCRF.  
 
Patients will be considered Off Treatment for the following reasons: 
▪ Development of unacceptable toxicity as outlined in section 5.3. See 7 for specific reporting 
requirements. 
▪ Progressive disease (PD) as described in section 11.3.4.  
▪ Development of a medical or psychiatric illness that in the investigator's judgment renders the 
patient incapable of further therapy on this protocol or the treating physician determines 
continuation on this study is not in the patient’s best interest.  
▪ The patient, parent or legal guardian refuses further treatment on this protocol. In this case the 
investigator should clarify if the family also wishes to withdraw consent for continued 
participation for data collection purposes.  
▪ The patient was required to start a prohibited medication as noted in the exclusion criteria (Section 
3.3.5).   
▪ Completion of all protocol defined treatment 
▪ Pregnancy 
▪ Non Compliance that in the opinion of the investigator does not allow for ongoing participation. 
▪ For surgical study participants, failure to meet criteria to start treatment within four (4) weeks of 
surgery 
 
Patients who are off protocol therapy must be followed until an “Off Study Criterion” is met. 
 
5.5.5 Data Submission Schedule for Patients Off Treatment 
All patients will be followed until resolution (or return to baseline) of all adverse events considered at 
least possibly related to ribociclib and/or everolimus occurring while on treatment and/or within 30 days 
of the last administration of study drug. Toxicities that are ongoing at the end of day 30 of last treatment 
date will be followed until resolution or return to baseline or until the patient is off study.  
 
Patients whose treatment is interrupted or permanently discontinued due to a ribociclib or everolimus 
related adverse event (AE), including abnormal laboratory value, should be followed at least once a week 


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for 4 weeks and subsequently at 4-week intervals until resolution to baseline or < Grade 2, whichever 
comes first. 
 
5.5.6 Criteria for Removal from Study 
The date and reason for the patient coming off study must be documented in the eCRF and the Operations, 
Biostatistics and Data Management Core must be notified according to standard reporting guidelines (see 
sections 7, 5.5.7, 12, and the Required Data and Timetable Submission from located on the PBTC-050 
protocol webpage).  
• Patient determined to be ineligible. 
• Parent, patient, or guardian withdraws consent for continued participation. 
• Patient death while on study. The IRB, Study Chair and OBDMC must be notified as per section 
7.4. 
• Initiation of another anti-cancer therapy 
• Patients has been observed for the resolution of all toxicities occurring while on treatment and 
for 30 days following the last administration of study drug.   
o If the patient was found to be ineligible after starting treatment, the 30 day follow-up 
would still be necessary unless the patient commences a different anti-cancer therapy. 
• Patients who have completed all protocol therapy or  are removed from treatment for reasons 
other than withdrawal of consent, PD or Death will be followed until one of the following 
occurs: 
o Commencement of additional anticancer therapy   
o Progressive disease  
- If PD occurs within less than 30 days of off-treatment date, then follow-up should 
continue until 30 days from off-treatment date or until commencement of additional 
anticancer therapy, whichever occurs first. 
- If the off treatment reason is toxicity and the patient is subsequently found to have PD, 
then follow-up should continue for 30 days from the off-treatment date or until the 
toxicity resolves or returns to baseline, whichever is longer. If the patient commences 
new anticancer therapy within this specified follow-up period however, he/she will be 
taken off study on the date the new therapy is initiated. 
  
5.5.7 Data Submission for Patients Off study 
No data will be collected documenting treatment or reporting events or disease status that occur 
subsequent to the official “off study” date with the exception of adverse events with an attribution of 
possible, probable, or definite that occur after the “off study” date for agents being studied under an IND 
(see section 7).   
6 DOSING DELAYS/DOSE MODIFICATION 
6.1 
Notification of the Study Chair 
The study chair or co-chair must be notified of any dosage modifications, prior to the implementation of 
the dose modification. 
 
6.2 
Hematologic and Non-hematologic Adverse Events and Management 
Each patient is allowed a maximum of two dose reductions as outlined in section 6.2.2, 6.2.3 and 6.2.4.  


NCI Protocol #: PBTC-050 
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Updated Date:  September 26, 2018 
If toxicity does not resolve to meet eligibility parameters within 14 days of drug discontinuation, the 
patient must be removed from protocol therapy.   
If a dose-limiting toxicity occurs in a patient who has resumed treatment at a reduced dose, the patients 
may have a second dose reduction to a lower dose level if available.   
If a dose-limiting toxicity occurs in a patient who has had two dose reductions, or for whom there is no 
lower dose level available (i.e.  At dose level -1), the patient must be removed from protocol therapy.   
A dose-dependent drug-drug interaction (DDI) was observed between ribociclib and everolimus based on 
clinical PK analyses in a separate dose escalation trial among adults, where everolimus exposure increased 
2- to 4-fold in the presence of ribociclib. If a dose adjustment of both ribociclib and everolimus are 
required, a dose reduction in ribociclib is considered as a method to reduce exposure to both drugs since 
everolimus exposure is increased with increased ribociclib doses through a DDI.  However, if attribution 
is clearly due to everolimus, everolimus will be initially decreased.   
First dose reduction will occur with ribociclib. However, if the attribution is clearly due to everolimus 
only, the everolimus dose will be reduced. The second dose reduction will occur for everolimus if the first 
dose reduction was ribociclib or will occur for ribociclib if the first dose reduction was everolimus. For 
patients enrolled in dose level 2, two dose level reductions are allowed.  
 
6.2.1 Ribociclib specific dose reduction guidelines 
For patients requiring a dose reduction enrolled on Dose Levels 2 and 3 (both at 170 mg/ m2/ day 
ribociclib) with BSA between 0.45 m2 and 0.73m2, the ribociclib dose will be reduced to 120 mg/ m2/ 
day (first reduction) then to 75 mg/ m2/ day (second reduction) if needed. Ribociclib dose reduction will 
be based on the actual calculated dose and will not use the monograms in Appendix 15.5. The calculated 
dose will be rounded to the nearest 0.1 mL (or 3 mg).  
 
For example: A patient with a BSA 0.5 m2 enrolled at dose level 2 (170 mg/ m2/ day). The first dose 
reduction will be 120 mg/ m2/ day.  The patient calculated dose reduction will be 60 mg (120 x 0.5) or 2 
mL Ribociclib solution (30 mg/mL).  If second dose reduction is needed, the second reduced dose will be 
37.5 mg (or 1.2 mL) Ribociclib solution (30 mg/mL). 
 
Patients enrolled on dose levels 2 or 3 with  a BSA of at least 0.74m2  or higher, will follow the nomograms 
in appendix 15.5  for dose reductions.  
 
6.2.2 Dose modifications for non-hematologic toxicities 
Protocol therapy will be discontinued if a non-hematologic dose limiting toxicity occurs after two dose 
modifications. 
 
If a patient experiences a dose-limiting non-hematological toxicity, as defined in Section 5.3, study drug 
should be withheld. Unless otherwise stated below, if the toxicity resolves to meet on study parameters 
within 14 days of drug discontinuation, the patient may resume treatment at the next lower dose level. For 
patients enrolled at Dose Level 1, the dose should be reduced to Dose Level 0 or -0.5 pending attributions. 
Patients already receiving Dose Level -1 at the time of dose limiting toxicity must be removed from study. 
Doses reduced for toxicity will not be re-escalated, even if there is minimal or no toxicity with the reduced 
dose. 
 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
6.2.3 Dose modifications for hematologic toxicities 
≥ Grade 3 thrombocytopenia: Platelet transfusion is permissible and strongly encouraged for patients with 
dose-modifying thrombocytopenia to minimize risk of intra-tumoral hemorrhage. Ribociclib and 
everolimus should not be restarted until platelet count has recovered to ≥ 100 x 109 cells/ L (transfusion 
independent for 7 days).  
 
Patients with grade 4 neutropenia (during any time throughout the course) may receive filgrastim (G-CSF) 
support (Investigator’s discretion) only for documented Grade 3 or greater infection and/or sepsis. 
Ribociclib and everolimus should not be restarted until the ANC is ≥ 1.0 x 109 cells/ L and for at least 48 
hours without G-CSF support. Patients should start the subsequent course at one lower dose level without 
G-CSF support. 
 
In the event of hematological DLT, complete blood counts should be repeated twice weekly for any 
hematological toxicity described above until counts recover to meet criteria for starting subsequent course 
of maintenance therapy. Missed doses will not be made up if drug was held for a DLT.  A patient who 
experiences any DLT at dose level -1 will be removed from study. 
 
If a patient experiences myelosuppression (i.e. thrombocytopenia or neutropenia) that causes a delay of 
>14 days between treatment cycles, counts should be checked every 3-4 days for thrombocytopenia and 
for neutropenia during this period. Once neutropenia or thrombocytopenia has resolved to eligibility 
criteria, the patient may resume treatment at the next lower dose level for ribociclib and everolimus dose 
will remain the same. For patients on dose level -1, the patient must be removed from protocol therapy. 
Doses reduced for toxicity will not be re-escalated. 
 
If a dose-limiting toxicity occurs in a patient who has had two dose reductions, or for whom there is 
no lower dose level available ( i.e. if already at dose level -1), the patient must be removed from 
protocol therapy. 
 
6.2.4 Dose modifications for specific toxicities 
 
Table 9: Guidance for dose modifications for hepatic toxicities 
Total bilirubin  OR ALT/AST increased above baseline value 
Grade 3  
Dose interruption of ribociclib and everolimus  
• 
If resolved to ≤ grade 1 in ≤14 days, 
lower 1 dose level of ribociclib and 
maintain everolimus dose 
 
Repeat liver enzymes and bilirubin tests twice 
weekly for 2 weeks after dose resumption 
 
Grade 4 (>20.0 x ULN) 
Discontinue ribociclib and everolimus 
Confounding factors and/or alternative causes for increase of total bilirubin should be excluded before dose 
interruption/reduction. 
AST or ALT and concurrent Bilirubin 
For patients with normal ALT or AST or total 
bilirubin at baseline: AST or ALT ≥ grade 2 
combined with total bilirubin >1.5-3 x ULN 
without evidence of cholestasis 
Discontinue ribociclib and everolimus 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
 
Additional Follow-up for Hepatic Toxicities 
Increase in transaminases combined with total bilirubin (TBIL) increase may be indicative of drug-
induced liver injury (DILI), and should be considered as clinically important events.  
 
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL value; 
patients meeting any of the following criteria will require further follow-up as outlined below: 
• For patients with normal ALT or AST or TBIL value at baseline: AST or ALT Grade 3 combined 
with TBIL Grade 3.  
• For patients with elevated AST or ALT or TBIL value at baseline: (AST or ALT > 2 x baseline 
AND > Grade 3) OR (AST or ALT Grade 3), whichever is lower, combined with (TBIL > 2 x 
baseline AND Grade 2). 
 
In the absence of cholestasis, these patients should be immediately discontinued from study drug 
treatment, and repeat Liver Function Tests (LFTs) as soon as possible, preferably within 48 hours from 
the awareness of the abnormal results. The evaluation should include laboratory tests, detailed history, 
physical assessment and the possibility of obstructions/compressions, etc. 
Hepatic toxicity monitoring includes the following LFTs: albumin, ALT, AST, total bilirubin, direct and 
indirect bilirubin, alkaline phosphatase (fractionated if alkaline phosphatase is grade 2 or higher), 
creatine kinase, prothrombin time (PT/INR) and GGT. For patients with Gilbert Syndrome: total and 
direct  bilirubin  must  be  monitored,  intensified  monitoring  applies  to  changes  in  direct bilirubin 
only. 
 
Close observation is recommended in case of AST, ALT, and/or bilirubin increase requiring dose 
interruption, which involves: 
• Repeating liver enzyme and serum bilirubin tests two or three times weekly. Frequency of re-
testing can decrease to once a week or less if abnormalities stabilize or return to normal values. 
• Obtaining a more detailed history of prior and/or concurrent diseases, including history of any 
pre-existing liver conditions or risk factors. 
• Obtaining a history of concomitant drug use (including non-prescription medications, herbal and 
dietary supplements), alcohol use, recreational drug use, and special diets. 
• Ruling out acute viral hepatitis types A, B, C, D, and E; hepatotropic virus infections (CMV, 
EBV or HSV); autoimmune or alcoholic hepatitis; Nonalcoholic steatohepatitis (NASH); 
hypoxic/ischemic hepatopathy; and biliary tract disease. 
• Obtaining a history of exposure to environmental chemical agents. 
• Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, direct bilirubin). 
• Considering gastroenterology or hepatology consultations. 
• Assessing cardiovascular dysfunction or impaired liver oxygenation, including hypotension or 
right heart failure as possible etiologies for liver dysfunction. 
 
Liver biopsy as clinically indicated to assess pathological change and degree of potential liver injury. 
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no other 
alternative cause for LFT abnormalities identified, should be considered as “medically significant”, thus 
met the definition of SAE (section 7.4.2) and reported as an SAE with a comment using the term “potential 
drug-induced liver injury”. All events should be followed up with the outcome clearly documented. 
 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
Table 10: Guidance for Dose modifications for QT prolongation 
Grade  
Dose Modification 
All Grades 
1. Check the quality of the ECG and the QT value and repeat if 
needed.   
2. Perform analysis of serum electrolytes (K+, Ca++, Phos, Mg++).  
If outside of the normal range,  interrupt ribociclib administration, 
correct with supplements or appropriate therapy as soon as 
possible, and repeat electrolytes until documented as normal.   
3. Review concomitant medication usage for the potential to inhibit 
CYP3A4 and/or to prolong the QT interval.  
4. Check compliance with correct dose and administration of 
ribociclib.   
1 (QTc 450- 480 ms) 
Perform Steps 1-4 as directed in “For All Grades”.   
No dose adjustment required. 
2 (QTc 481-500 ms) 
Interrupt ribociclib and everolimus.  
Perform steps 1-4 as directed in “For All Grades.” 
Perform a repeat ECG  within one  hour after the first QTc of ≥481 ms 
• If QTc <481 ms, restart ribociclib by 1 dose level. Refer to Table 8 
for dosing schedule..  
• If QTc remains ≥481 ms, repeat ECG within 14 days until the QTc 
returns to <481 ms. Hold ribociclib and everolimus. Restart 
ribociclib reduced by 1 dose level and everolimus at the same dose 
level.  
• If QTc ≥481 ms recurs, ribociclib should be reduced again by 1 
dose level and everolimus at same dose 
• Repeat ECGs 7 days and 14 days after dose resumption (then as 
clinically indicated) for any patient who has therapy interrupted 
due to QTc ≥481 ms  
3 (QTc ≥ 501 ms on at least 
two separate ECGs) 
Interrupt ribociclib and everolimus  
• Perform a repeat ECG within one hour of the first QTc of ≥501 ms.  
• If QTc remains ≥501 ms, consult with a cardiologist (or qualified 
specialist) and repeat cardiac monitoring as indicated until the QTc 
returns to <481 ms.  
• If QTc returns to <481 ms within 14 days, ribociclib should be 
reduced by 1 dose level and maintain everolimus dose.  
• If QTc remains ≥ 481ms after performing steps 1-2 as directed in 
“for all grade,” discontinue Ribociclib and everolimus. 
• Repeat ECGs 7 days and 14 days after dose resumption for any 
patient who has therapy interrupted due to QTc ≥501 ms  
• If QTc of ≥501 ms recurs, discontinue ribociclib and everolimus 
4 (QT/QTc ≥ 501 or > 60 ms 
change from baseline)  
and 
(Torsades de pointes or 
polymorphic ventricular 
tachycardia, or 
signs/symptoms of serious 
arrhythmia) 
Discontinue Ribociclib and everolimus and removal from study 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
 
Table 11: Guidance for dose modification and management for cardiac dysfunction 
Adverse drug reaction 
Severity 
Dose adjustment and management 
recommendations 
 
Cardiac - Left 
Ventricular Systolic 
Dysfunction 
Asymptomatic, 
resting ejection fraction 40-
50%; 
or 10-20% drop from baseline 
Maintain dose level, and continue 
ribociclib and everolimus with 
caution. 
Repeat LVEF within 4 weeks or as 
clinically appropriate. 
Symptomatic, 
responsive to intervention, 
ejection fraction 20-39% 
or >20% drop from baseline 
Hold ribociclib and everolimus until 
resolved, then reduce ribociclib by 
one dose level; 
LVEF measurement to be repeated, if 
not resolved within 28 days 
permanently discontinue ribociclib 
and everolimus if applicable. 
 
6.2.5 Dose Modifications for Everolimus related toxicities 
 
Table 12: Dose modification and management for Mucositis  
Adverse drug 
reaction 
Severity 
Dose adjustment and management 
recommendations 
Mucositis 
characterized 
by ulceration 
or 
inflammation 
of the oral 
mucosa 
Grade 1  
 
Asymptomatic or mild 
symptoms; intervention not 
indicated 
No dose adjustment required. 
Manage with non-alcoholic steroid mouthwash and salt 
water (0.9%) mouthwash four times a day (section 
5.4.7). 
Grade 2 
 
Moderate pain or ulcer that 
does not interfere with oral 
intake; modified diet 
indicated 
Interrupt everolimus and ribociclib until recovery to 
grade 1 within 14 days. 
• 
Re-initiate study treatment at the same dose. 
• 
If stomatitis recurs, interrupt ribociclib and 
everolimus until recovery to grade 1.  
• 
Re-initiate everolimus at a one dose lower.  
 
Manage with topical analgesic mouth treatments (e.g. 
benzocaine,butyl minobenzoate, tetracaine 
hydrochloride, menthol or phenol) with or without 
topical corticosteroids (i.e. triamcinolone oral paste). 
 
Grade 3 
 
Severe pain; interfering 
with oral intake 
Interrupt everolimus and ribociclib until recovery to 
grade ≤1. 
• 
Re-initiate everolimus at a reduced dose level 
and maintain ribociclib dosing 
• 
If reoccurs, interrupt ribociclib and everolimus 
until recovery to grade ≤1. 
• 
Re-initiate ribociclib at reduced dose level and 
maintain everolimus dosing. 
 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
Adverse drug 
reaction 
Severity 
Dose adjustment and management 
recommendations 
Manage with topical analgesic mouth treatments (i.e. 
benzocaine, 
butyl 
aminobenzoate, 
tetracaine 
hydrochloride, menthol or phenol) with or without 
topical corticosteroids (i.e. triamcinolone oral paste). 
 
Grade 4 
Life-threatening 
consequences; urgent 
intervention indicated 
Hold ribociclib and everolimus and provide appropriate 
medical therapy.  
• 
If recovered to ≤grade 1 within 14 days, Re-
initiate everolimus at a reduced dose.  
• 
If reoccurs, interrupt ribociclib and everolimus 
until recovery to grade ≤1.  
• 
Re-initiate ribociclib at reduced dose level and 
maintain everolimus reduced dosing  
 
Table 13: Dose modification and management for Hypertension 
Hypertension is to be reported as ‘Vascular disorders-Other, Pediatric Hypertension” and graded as 
defined in Table 13. 
 
Adverse drug reaction 
Dose Adjustment and management recommendations 
Grade 1 
Children 1-13y: 
Elevated BP: ≥90th percentile to <95th 
percentile or 120/80 mm Hg to <95th 
percentile (whichever is lower) 
No dose modifications 
Children ≥13y 
Elevated BP: 120/<80 to 129/<80 mmHg 
Grade 2 
Children 1-13y 
Stage 1 Hypertension (HTN): ≥95th 
percentile to <95th percentile + 12 mm 
Hg, or 130/80 to 139/89 mm Hg 
(whichever is lower) 
No dose modifications 
Children ≥13y 
Stage 1 HTN: 130/80 to 139/89 mm Hg 
Grade 3 
Children 1-13y 
Stage 2 HTN ≥95th percentile + 12 mm 
Hg or ≥140/90 mm Hg (whichever is 
lower) 
Hold ribociclib and everolimus and follow up blood 
pressure if the toxicity resolves to meet on study 
parameters within 14 days of drug discontinuation, the 
patient may resume treatment at the next lower dose level.  
 
If Grade 3 hypertension reoccurs, hold ribociclib and 
everolimus and follow up blood pressure if the toxicity 
resolves to meet on study parameters within 14 days of 
drug discontinuation, the patient may resume treatment at 
the next lower dose level (2 dose levels lower than 
starting dose).   
Children ≥13y 
Stage 2 HTN: ≥140/90 mm Hg 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
 
If Grade 3 hypertension reoccurs after 2 dose level 
reductions, ribociclib and everolimus will be 
discontinued.   
Grade 4 – All Ages 
Life-threatening consequences; urgent 
intervention indicated 
Discontinue ribociclib and everolimus. 
7 ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The following list 
of AEs (Section 7.1 and 7.2) and the characteristics of an observed AE (Section 7.3) will determine 
whether the event requires expedited reporting via the CTEP Adverse Event Reporting System (CTEP-
AERS) in addition to routine reporting. The coding of attribution in the Rave database pertains to adverse 
events related to ribociclib and everolimus. 
 
• Baseline Abnormalities 
Any baseline (pretreatment) abnormalities observed during the initial physical examination should be 
recorded in the Rave database. 
 
• Treatment or within 30 days of treatment 
Only record adverse events grades 1 and 2 if the attribution is at least possibly related to ribociclib and 
everolimus. Record all adverse events grades 3 through 4 and deaths), regardless of attribution on the 
electronic case report forms. 
 
7.1 
Adverse Event List(s) for ribociclib (LEE011, NSC 794613) 
Adverse events suspected to be related to ribociclib –  
Adverse events considered to be expected with ribociclib (3 weeks on 1 week off dosing regimen) for 
reporting purposes. May also refer to the most current version of the Ribociclib Investigator Brochure 
(available on the PBTC-050 webpage) for additional expected adverse events.  
 
 
MedDRA system organ 
class 
Event 
Frequency category* 
all grades 
 
Frequency category* 
grade 3/4 
 
Blood 
and 
lymphatic 
system disorders 
Anemia 
Very common 
common 
Febrile neutropenia 
 common 
 common 
Eye Disorders 
Dry eye 
Common 
Not reported 
Watering eyes 
Common 
Not reported 
Gastrointestinal disorders 
Abdominal pain 
Very common 
common 
Constipation 
Very common 
common 
Diarrhea 
Very common 
common 
Dyspepsia 
Common 
Not reported 
Mucositis oral 
Very common 
Uncommon 
Nausea 
Very common 
common 
Vomiting 
Very common 
common 
General disorders and 
administration site 
conditions 
Fatigue 
Very common 
Common 
Edema limbs 
Very common 
Not reported 
Fever 
Very common 
Uncommon 
Hepatobiliary disorders 
Hepatic Failure 
Uncommon 
Uncommon 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
Infections 
Urinary tract infection 
Very common 
Uncommon 
Investigations 
Electrocardiogram QT corrected 
interval prolonged 
common 
Uncommon 
Alanine aminotransferase 
increased 
Very common 
Common 
Aspartate aminotransferase 
increased 
Very common 
Common 
Alkaline phosphatase increased 
Very common 
Common 
Blood creatinine increased 
Common 
Uncommon 
White blood cells decreased 
Very Common 
Very Common 
Neutrophil count decreased 
Very common 
Very Common 
Lymphocyte count decreased 
Very Common 
Very Common 
Platelet count decreased 
Common 
Uncommon 
Weight decreased 
Common 
Uncommon 
Metabolism and nutrition 
disorders 
 
 
 
Hypokalemia 
Common 
common 
Hypophosphatemia 
Common 
common 
Hypocalcemia 
Common 
Common 
Anorexia 
Very common 
Common 
Musculoskeletal and 
connective tissue 
disorders 
Back pain 
Very common 
common 
Nervous System 
Disorders 
Headache 
Very common 
Uncommon 
Syncope 
Common 
Common 
Dysgeusia 
Common 
Uncommon 
Psychiatric disorder 
Insomnia 
Very Common 
Uncommon 
Respiratory, thoracic and 
mediastinal disorders 
 
 
 
Dyspnea 
Very common 
common 
Epistaxis 
Common 
Not reported 
Skin and subcutaneous 
tissue disorders  
Rash maculo-papular 
Very common 
Uncommon 
Pruritus 
Very common 
uncommon 
Erythema 
Common 
Not reported 
Alopecia 
Very common 
Not reported 
*Frequency category for each adverse drug reaction is based on the following:  
Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); 
very rare (<1/10,000). Unknown - insufficient data to determine the frequency of the ADR; none reported – for this 
event no grade 3-4 events have been reported, 
 
The adverse drug reactions frequencies are determined from the data from study CLEE011A2301 (a 
double-blinded randomized placebos controlled trial) and where reasonable evidence of a possible causal 
relationship with ribociclib was proven. 
Note:  Ribociclib in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent.   
 
7.2 
Adverse Event List(s) for everolimus (RAD-001, NSC 733504) 
Adverse Events considered to be expected with everolimus for Reporting Purposes. Refer to most current 
version of everolimus Investigator Brochure located on the PBTC-050 webpage for additional expected 
adverse events.  
 
 
MedDRA system organ class 
Event 
Frequency category* all grades 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
Blood and lymphatic system disorders 
Anemia 
Very common 
Gastrointestinal disorders 
Abdominal pain 
Common 
Dry mouth 
Common 
Oral pain 
Common 
Dysphagia 
Common 
Constipation 
Common 
Diarrhea 
Very common 
Mucositis oral 
Very common 
Nausea 
Very common 
Vomiting 
Very common 
Dyspepsia 
Common 
General disorders and administration site 
conditions 
Fatigue 
Very common 
Edema limbs 
Very common 
Fever  
Common 
Non-cardiac chest pain 
Uncommon 
Immune System Disorders 
Allergic reaction 
Uncommon 
Anaphylaxis 
Uncommon 
Infections and Infestations 
Infections1 
Very common 
Injury, poisoning and procedural complications 
Wound complication2 
Uncommon 
Investigations 
 
Weight loss  
Very common 
Alanine aminotransferase increased 
Common 
Aspartate aminotransferase increased 
Common 
Alkaline phosphatase increased 
Common 
Hypercholesterolemia 
Very Common 
Blood creatinine increased 
Common 
White blood cell decreased 
Common 
Lymphocyte count decreased 
Common 
Neutrophil count decreased 
Common 
Platelet count decreased 
Common 
Metabolism and nutrition disorders 
Hypertriglyceridemia 
Common 
Anorexia 
Very common 
Hyperglycemia 
Very common 
Hypophosphatemia 
Common 
Diabetes mellitus 
Common 
Hyperlipidemia 
Common 
Hypokalemia 
Common 
Dehydration 
Common 
Musculoskeletal and connective tissue 
disorders 
Arthralgia 
Common 
Pain in extremity 
Common 
Back pain 
Common 
Nervous System Disorders 
Headache 
Very common 
Dysgeusia 
Very common 
Psychiatric disorders 
Insomnia 
Common 
Respiratory, thoracic and mediastinal disorders 
Pneumonitis3 
Very common 
Epistaxis 
Very common 
Cough 
Very common 
Dyspnea 
common 
Renal and Urinary disorders 
Proteinuria 
Common 
Renal Failure 
Common 
Acute kidney injury 
Uncommon 
Urinary frequency (daytime) 
Uncommon 
Reproductive system and breast disorders 
Irregular menstruation 
Common 
Amenorrhea 
Uncommon 
Skin and subcutaneous tissue disorders 
Rash maculo-papular 
Very common 
Pruritus 
Very common 
Dry Skin 
Common 
Nail Disorder 
Common 
Acne 
Common 
Angioedema 
Rare 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
Erythema 
Common 
Hand-foot syndrome4 
Common 
Vascular disorders 
Hypertension 
Common 
Deep vein thrombosis 
Uncommon 
Thromboembolic event – Pulmonary 
embolism 
Uncommon 
Acute Respiratory Distress Syndrome 
Rare 
Bleeding 
Hemorrhage5 
Common 
*Frequency category for each adverse drug reaction is based on the following:  
Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). 
1 Infection includes all reactions within the ‘infections and infestations’ system organ class including common: pneumonia, urinary tract 
infection; uncommon: bronchitis, herpes zoster, sepsis, abscess and isolated cases of opportunistic infections (e.g. aspergillosis, candidiasis, and 
hepatitis B) and rare: viral myocarditis. 
2 Everolimus delays wound healing and increases the occurrence of wound-related complications like wound dehiscence, wound infection, 
incisional hernia, lymphocele, and seroma.   
3Includes common:  pneumonitis, interstitial lung disease, lung infiltration, and rare: alveolitis, pulmonary alveolar hemorrhage and pulmonary 
toxicity.   
4 Reported as palmar-plantar erythrodysesthesia syndrome 
5 Includes different bleeding events from different sites not listed individually 
   
 
 
7.3 
Adverse Event Characteristics 
7.3.1 CTCAE term (AE description) and grade: 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 5.0 will be utilized for AE reporting with the exception of grading for 
Hypertension .  Hypertension will be reported as “Vascular disorders – Other, pediatric hypertension”, 
and is to be graded according to the definitions outlined in Table 14. All appropriate treatment areas should 
have access to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be downloaded 
from the CTEP web site http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
In 2017, Flynn JT et al reported new clinical practice guidelines for high blood pressure in children and 
adolescents. 78 Definitions of  blood pressure categories and stages have been redefined as noted in Table 
14. These definitions are not aligned with CTCAE version 5.0 as the 99th percentile for pediatric pressure 
no longer exists in the definition of hypertension in children. Stage 2 hypertension is defined as the 95th 
percentile + 12mmHg.  Per CTCAE version 5, the definition of Grade 3 hypertension in pediatrics is 
systolic and/or diastolic > 5mmHg above the 99th percentile.   
 
Table 14: Updated Definitions of BP Categories and Stages 
Grade 
For Children Aged 1-13 years 
For Children Aged ≥13 years 
Normal Normal BP: <90th percentile 
Normal BP: <120/<80 mm Hg 
1 
Elevated BP: ≥90th percentile to <95th percentile or 120/80 
mm Hg to <95th percentile (whichever is lower) 
Elevated 
BP: 
120/<80 
to 
129/<80 mm Hg 
2 
Stage 1 Hypertension (HTN): ≥95th percentile to <95th 
percentile + 12 mm Hg, or 130/80 to 139/89 mm Hg 
(whichever is lower) 
Stage 1 HTN: 130/80 to 139/89 
mm Hg 
3 
Stage 2 HTN ≥95th percentile + 12 mm Hg or ≥140/90 mm 
Hg (whichever is lower) 
Stage 2 HTN: ≥140/90 mm Hg 
4 
Life threatening consequences (e.g. malignant hypertension, transient or permanent 
neurologic deficit, hypertensive crisis); urgent intervention indicated 
 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
7.3.2 Attribution of the AE: 
• 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. 
 
7.4 
Expedited Adverse Event Reporting 
Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event Reporting System), 
accessed via the CTEP Web site (https://eapps-ctep.nci.nih.gov/ctepaers).  The reporting procedures to be 
followed are presented in the “NCI Guidelines for Investigators: Adverse Event Reporting Requirements 
for DCTD (CTEP and CIP) and DCP INDs and IDEs” which can be downloaded from the CTEP Web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm. 
 
These 
requirements are briefly outlined in the tables below (Section 7.4.2). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be made to the PBTC 
operation office by telephone at 901-595-7793.  Once Internet connectivity is restored, the 24-hour 
notification phoned in must be entered electronically into CTEP-AERS by the original submitter at the 
site. 
 
7.4.1 Distribution of Adverse Event Reports 
CTEP-AERS is programmed for automatic electronic distribution of reports to the following individuals:  
Principal Investigator and the responsible Protocol Coordinator at the PBTC, the local treating physician, 
and the Reporter and Submitter.  CTEP-AERS provides a copy feature for other e-mail recipients. 
 
The following must be copied on expedited reports (24-hour notification and the complete report) 
submitted via CTEP-AERS: 
Study Chair and IND Holder: 
Mariko DeWire-Schottmiller, MD 
 
 
 
 
 
 
 
PBTC OBDMC: 
Stacye Richardson, MSHS 
 
 
 
 
 
 
 
 
Regulatory Affairs: 
Renee Doughman, PhD 
 
 
 
 
 
 
 
 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
The OBDMC will email and/or fax the SAE /CTEP-AERS report, within 24 hours of their awareness of 
the event to Novartis (fax#: 1- 877- 778- 9739). 
 
The IND holder, 
 shall notify the FDA of any event that is 
both a serious suspected adverse reaction and unexpected in accordance with FDA rules and regulations 
(21 CFR 312.32). Follow-up information to a safety report will be submitted, as requested. 
 
The IND Sponsor or designee will submit a report of the unexpected, suspected adverse event to the FDA 
using the FDA’s reporting form (FDA 3500A MedWatch Form) and guidelines. The report should 
describe the event as fully as possible. Supporting documentation (lab reports, summary notes, and 
autopsy report) should accompany the report. A fatal or immediately life-threatening suspected adverse 
event will be reported to the FDA within 7 calendar days of the receipt of the initial report by the IND 
sponsor. A non-fatal, non-life threatening unexpected, suspected, serious adverse event will be reported 
to the FDA within 15 calendar days of receipt of the initial report by the IND Sponsor.  
 
The PBTC OBDMC will post all IND Safety Letters on the PBTC-050 webpage. Sites will be notified via 
email of the receipt of the IND Safety Letter(s) and instructed to submit these to their local IRB in 
accordance with the institution‘s requirements. 
 
A copy of the Annual Progress Reports is submitted by the IND holder as required by FDA, by the 
sponsor-investigator. This submission will be cross referenced according to local regulations to the 
Novartis product number at the time of submission.  
 
Any SAEs experienced after this 30 days period should only be reported to Novartis if the investigator 
suspects a causal relationship to the study treatment. Recurrent episodes, complications, or progression of 
the initial SAE must be reported as follow-up to the original episode within 24 hours of the investigator 
receiving the follow-up information. An SAE occurring at a different time interval outside the 30-day 
period post last dose and related to therapy should be reported separately as a new event. 
 
7.4.2 Expedited Reporting Guidelines 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial registration on all 
reports. 
Note:  A death on study requires both routine and expedited reporting, regardless of causality.  
Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in the system 
organ class (SOC)  “General disorders and administration site conditions”.  Evidence that the death was 
a manifestation of underlying disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) should be submitted.  
 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse Events that 
Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor /NCI  ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic 
submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, rounded 
UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above applies after this 
reporting period. 
Effective Date:  May 5, 2011 
 
7.4.3 Additional Protocol Specific Expedited Adverse Event Reporting Exclusions 
For this protocol only, the AEs/grades listed below do not require expedited reporting via CTEP-AERS.  
However, they still must be reported through the routine reporting mechanism (Section 7.4): 
 
CTCAE 
SOC 
Adverse 
Event 
Grade Hospitalization/ 
Prolongation of 
Hospitalization 
Attribution 
Comments 
Blood/Bone 
Marrow 
Lymphopenia 
≤4 
 
Regardless 
Any 
Expedited reporting is 
not required. 
 
7.4.4 Routine Adverse Event Reporting 
All Adverse Events must be reported in routine study data submissions.  AEs reported expeditiously 
through CTEP-AERS must also be reported in routine study data submissions. 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are done to 
ensure the safety of patients enrolled in the studies as well as those who will enroll in future studies using 
similar agents.  AEs are reported in a routine manner at scheduled times during the trial using Medidata 
Rave.  For this trial the Adverse Event CRF is used for routine AE reporting in Rave. 
 
7.4.5 Pregnancy 
Although not an adverse event in and of itself, pregnancy as well as its outcome must be documented via 
CTEP-AERS.  In addition, the Pregnancy Information Form included within the NCI Guidelines for 
Adverse Event Reporting Requirements must be completed and submitted to CTEP.  Any pregnancy 
occurring in a patient or patient’s partner from the time of consent to 90 days after the last dose of study 
drug must be reported and then followed for outcome.  Newborn infants should be followed until 30 days 
old.  Please see the “NCI Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD 
(CTEP 
and 
CIP) 
and 
DCP 
INDs 
and 
IDEs” 
(at 
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm) for more details on how to report 
pregnancy and its outcome to CTEP.  
 
7.4.6 Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment with 
investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is not considered 
a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an NCI 
IND/IDE be reported expeditiously via CTEP-AERS. Three options are available to describe the event:  
 
• Leukemia secondary to oncology chemotherapy such as acute myelocytic leukemia (AML)  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be reported via 
the routine reporting mechanisms outlined in each protocol. 
 
7.4.7 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a metastasis 
from the initial malignancy).  Second malignancies require ONLY routine AE reporting unless otherwise 
specified. 
8 AGENT INFORMATION 
A list of the adverse events and potential risks associated with the investigational and commercial agents 
administered in this study can be found in Section 7.1 and 7.2. 
 
8.1 
Everolimus (RAD001) 
 
Chemical Name: (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-
12-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl]-19,30-


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-
16,24, 26,28-tetraene-2,3,10,14,20-pentaone 
 
Other Names: RAD001, Afinitor 
 
Classification: mTOR inhibitor 
 
CAS Registry Number: 159351-69-6 
 
Molecular Formula:  C53H83NO14  
M.W.: 958.2 
 
Mode of Action: Everolimus is an inhibitor of selective mammalian target of rapamycin (mTOR), the 
effects of which specifically target the mTOR-raptor signal transduction complex 1 (mTORC1). Inhibition 
of mTORC1, an essential regulator of global protein synthesis downstream on the PI3K/AKT/mTOR 
pathway, reduces tumor cell proliferation, glycolysis and angiogenesis. The PI3K/AKT/mTOR pathway 
is dysregulated in the majority of human cancers and is the object of many targeted agents. 
 
Description: White to faintly yellow powder 
 
How Supplied: Everolimus will be supplied by Novartis or its designee as dispersible tablets (also 
referred to as ‘tablets for oral suspension’) and is available as a 2 mg dosage forms. Each box of 28 tablets 
contains 4 blister cards of 7 tablets each.  
 
Extent of absorption of everolimus through topical exposure is not known. Caregivers are advised to avoid 
contact with suspensions of everolimus.  Wash hands thoroughly before and after preparation of the 
suspension. All dosages prescribed and dispensed to the patient and all dose changes during the study 
must be recorded. 
 
Dispersible 
tablets 
contain 
butylhydroxytoluene/butylated 
hydroxytoluene 
(BHT), 
cellulose 
microcrystalline/microcrystalline cellulose, crospovidone, hypromellose/hydroxypropyl methylcellulose, 
lactose monohydrate, magnesium stearate, mannitol/D-mannitol, silica colloidal anhydrous/colloidal 
silicon dioxide.  
 
Everolimus will be packaged in bottles. They will include storage conditions for the drug but no 
information about the patient. The study drug will be labeled and packaged under the responsibility of the 
Novartis drug supply management department. The medication will be supplied as open label supply to 
the site in a way that allows the patient to take medication at home. 
 
Storage: Store at 25°C (77°F). Excursions permitted between 15 to 30°C (59 to 85°F).  
If a storage temperature excursion is identified, promptly return everolimus to controlled room 
temperature and quarantine the supplies.  Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the excursion) to Novartis for determination of 
suitability. 
 
Storage of the prepared oral suspension: The suspension should be discarded if not administered within 
60 minutes of preparation. 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
 
Stability: Refer to the clinical labels for current shelf life, in-use, expiration date and proper storage 
condition. Store tablets in the original container and protect from light and moisture. 
 
Stability or BUD (beyond-use date) of the prepared oral suspension: The oral suspension of 
everolimus prepared in an oral syringe or in a small drinking glass should be administered immediately 
after preparation.  The oral syringe or glass should be rinsed with the same volume of water and the rinse 
should be completely swallowed to ensure that the entire dose is administered and there is no drug residue 
remaining in the oral syringe or glass.  
 
Route and Method of Administration: Oral administration. The dispersible tablet is prepared as a 
suspension of undissolved medicine that is mixed with water, and then taken by mouth. The suspension 
can be prepared in an oral syringe or small drinking glass. Everolimus dispersible tablet is an ad-hoc drug 
compounding. Patient and/or guardian will be taught how to prepare the oral suspension by research 
nursing staff.  A patient/caretaker educational template is available  on the PBTC-050 webpage for step-
by-step ad-hoc drug preparation and administration guidance for Everolimus dispersible tablet in the home 
settings and included in the protocol as Appendices 15.7 and 15.8. 
 
They can be taken with or without food, but should be taken consistently the same time every day. If a dose 
is missed, it can still be taken up to 6 hours after the usual time of administration. Missed doses more than 6 
hours late should be skipped for that day. 
 
Potential Drug Interactions: 
Everolimus is a substrate of CYP3A4 and P-glycoprotein (PgP). Concomitant treatment with strong 
inhibitors or inducers of CYP3A4 or PgP should be avoided. Use caution when everolimus is given 
concomitantly with moderate inhibitors or inducers of CYP3A4 and PgP.  Consult the protocol document 
or study investigator prior to making any dose adjustments related to potential drug-drug interactions. 
 
In vitro, everolimus is a competitive inhibitor of CYP3A4, a mixed inhibitor of CYP2D6, an inhibitor of 
transport proteins, OATP1B1 and OATP1B3 and a moderate inhibitor of P-gp. Exercise caution when 
everolimus is taken in combination with orally administered substrates of these enzymes and transporters, 
in particular, CYP3A4 and 2D6 substrates with a narrow therapeutic index. Everolimus does not appear 
to affect CYP 2C8 or 2C9 activity according to in vitro studies using reference substrates. 
 
Co-administration with angiotensin-converting enzyme (ACE) inhibitors may increase the risk for 
angioedema.  
 
Patient Care Implications: Patients taking everolimus should avoid the use of live vaccines and close 
contact with those who have received live vaccines. Examples of live vaccines include intranasal influenza, 
measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines. 
 
8.2 
Ribociclib 
 
Chemical Name: 7-Cyclopentyl-N, N-dimethyl-2-[[5-(piperazin-1-yl) pyridin-2-yl]amino]-
7Hpyrrolo[2,3-d]pyrimidine-6-carboxamide succinate (1:1) 
 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
Other Names: LEE011, KISQALI 
 
Classification: cyclin-dependent kinase (CDK) inhibitor 
 
CAS Registry Number: 1211441-98-3 (free base) 
 
Molecular Formula: C23H30N8O.C4H6O4 
 
M.W.: 434.55 
 
Mode of Action: An orally available cyclin-dependent kinase (CDK) inhibitor targeting cyclin D1/CDK4 
and cyclin D3/CDK6 cell cycle pathway, with potential antineoplastic activity. Ribociclib specifically 
inhibits CDK4 and 6, thereby inhibiting retinoblastoma (Rb) protein phosphorylation. Inhibition of Rb 
phosphorylation prevents CDK-mediated G1-S phase transition, thereby arresting the cell cycle in the G1 
phase, suppressing DNA synthesis and inhibiting cancer cell growth. Overexpression of CDK4/6, as seen 
in certain types of cancer, causes cell cycle deregulation. 
 
Description:  Light tan to yellow powder 
 
How supplied: Ribociclib will be supplied by Novartis or its designee.  The available formulations are 50 
mg (capsules) and 200 mg (capsules or film-coated tablets) and a 30mg/mL in 100 mL placed in a 180 ml 
glass bottle (oral solution) provided as an individual patient supply packaged in bottles.  All dosages 
prescribed and dispensed to the patient and all dose changes during the study must be recorded. 
 
Ribociclib capsules/tablets and the liquid form will be packaged in bottles. They will include storage 
conditions for the drug but no information about the patient. The study drug will be labeled and packaged 
under the responsibility of the Novartis drug supply management department. The medication will be 
supplied as open label supply to the site in a way that allows the patient to take medication at home. 
 
Ribociclib may be administered orally in different ways based upon available formulations and capsule or 
tablet sizes: 
• Capsule: swallow whole or open capsule and pour contents onto semi-solid food or dissolve 
contents of opened capsule in water or Ora-Sweet (or equivalent) and administer orally or via 
feeding tube (e.g. nasogastric or gastric) 
• Liquid formulation: Since ribociclib did not show pH-dependent solubility in biorelevant media, 
the exposure/bioavailability is not expected to be limited by its dissolution rate due to different 
dosage form of administration. Liquid may be administered via feeding tube (e.g. nasogastric 
(NG)/nasojejunal (NJ)/gastric). 
 
Storage:  The shelf life of the drug product is established based on ongoing stability studies and may be 
extended during the clinical study. The capsules are stored in HDPE bottles. Storage for the capsules is 
“Do not store above 25 °C, protect from moisture”. The oral solution is stored in brown glass bottles.  
Storage for the oral solution is “store at 2-8 degrees C, do not freeze”.  Refer to the clinical labels for 
current shelf-life, in-use and storage conditions for the capsules, film-coated tablets and oral solution. 
 
Stability: 
Stable for at least 2 years after receipt when stored at -20°C 
 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
Route and Method of Administration:   Ribociclib can be taken by mouth or NG/NJ/G-tube at the 
approximate same time daily for 3 weeks followed by one week off without regard to meals.  
 
8.3 
Agent Ordering and Agent Accountability 
 
8.3.1 Agent Ordering 
Ribociclib and Everolimus may be requested by the Principal Investigator (or their authorized designee) 
at each participating institution.  All regulatory documents, as required by the PBTC, must be current and 
up to date prior to requesting the study drugs. Drug request form can be found on the PBTC-050 protocol 
and resources webpage. The form can be emailed to Novartis. In general, sites may order initial agent 
supplies when a subject is being screened for enrollment onto the study.  
 
8.3.2 Agent Inventory Records 
The investigator, or a responsible party designated by the investigator, must maintain a careful record of 
the receipt, dispensing, use and disposal of ribociclib and everolimus received from Novartis using the 
appropriate NCI Investigational Agent (Drug) Accountability Record (DARF) available on the CTEP 
forms page. Store and maintain separate the Investigational Agent Accountability Records for each agent, 
strength, formulation and ordering investigator on this protocol. 
 
Any unused/used/expired study drug and containers may be destroyed according to the institutional 
standard operating procedure. The method and the record of destruction must be documented and 
maintained at the site. 
 
8.3.3 Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  https://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:   RCRHelpDesk@nih.gov  
• CTEP Identity and Access Management (IAM) account: https://ctepcore.nci.nih.gov/iam/  
• CTEP  IAM account help email: ctepreghelp@ctep.nci.nih.gov. 
9 BIOMARKER, CORRELATIVE AND SPECIAL STUDIES 
This section contains the collection, shipping and handling information for all planned biomarker and 
exploratory correlative studies, neuropathology review and research imaging.  The table below identifies 
the tests, sample type and amount, analyzing laboratory and whether it is required or optional.  For 
additional details, please review the associated section below. 
 
Tissue Requirements: Tissue for CLIA-certified Rb1 expression assessment for screening will be 
required for patients to enroll with the exception of DIPG patients. Prior testing for Rb1 IHC in a CLIA-
certified laboratory will be accepted in lieu of tissue submission. For the Phase I study, tissue for 
exploratory correlative studies will be strongly recommended but not required.  
 
Phase I  
 
Test Name 
 
Sample Type and Amount 
Analyzing 
Laboratory 
Required or 
Optional 
Section 
ID 
Screening: 
Assessment of Rb1 
expression  
(FFPE) tumor tissue - 2 unstained slides + 1 
H&E stained slide 
Christine 
Fuller, MD 
CCHMC 
Required*  
9.1.1 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
Pharmacokinetics 
Plasma – 1 mL per sample 
 
Stewart 
Laboratory 
Required 
9.2.2 
Pharmacokinetics 
Serial or single CSF – 2 mL  
Stewart 
Laboratory 
Optional 
9.2.3 
Genomics- Whole-
exome sequencing 
and RNA 
sequencing 
 
Frozen tumor tissue or FFPE and PBMCs**  
 
 
Will Parsons, 
MD 
Texas 
Children’s 
Hospital 
Optional 
9.2.5 
PBTC 
CRB 
Repository Samples 
20 unstained slides and blood for future 
research  
PBTC CRB at 
CHLA 
Optional 
9.2.1 
*Required for HGG, medulloblastoma, CNS embryonal tumor (NOS), Ependymoma, ATRT or with atypical presentation of 
DIPG. Patients with typical DIPG appearance who have biopsied may also submit tissue if available. If there is known Rb1 
status, screening will not be required.   
**In all cases, frozen tissue is preferable to FFPE, but either will be accepted. 
 
Surgical Study 
Rb1 testing will be completed on diagnostic tissue PRIOR to enrollment for the surgical study.   
The PK sample collection requirements for patients enrolled on the surgical study are noted below.  
Surgical study patients should still be invited to participate in the optional genomics studies and 
submission of repository samples as noted in the Phase I table.  
 
Test Name 
 
Sample Type and Amount 
Analyzing 
Laboratory 
Required or 
Optional 
Section 
ID 
Screening: 
Assessment of Rb1 
expression  
(FFPE) tumor tissue - 2 unstained slides + 1 
H&E stained slide 
Christine 
Fuller, MD 
CCHMC 
Required*  
9.1.1 
Intratumoral 
Pharmacokinetics 
Tumor tissue (collected during surgery)*** 
Stewart 
Laboratory 
Required 
9.2.2 
Pharmacokinetics 
Plasma – 1 mL per sample 
Stewart 
Laboratory 
Required 
9.2.2 
Pharmacokinetics 
CSF – 2 mL  
Stewart 
Laboratory 
Optional 
9.2.3 
Pharmacodynamics 
 FFPE – 2 unstained slides FFPE (1 FFPE each 
from pre-treatment tumor and post-treatment 
tumor***)  + 1 H&E OR tumor block  
Christine 
Fuller, MD 
CCHMC 
Optional 
9.2.4 
*Required for HGG, medulloblastoma, CNS embryonal tumor (NOS), Ependymoma, ATRT. If there is known Rb1 status, 
screening will not be required.   
*** For patients who consent to participate in the PD study, post-surgery tissue should be split between intra-tumoral PK and 
PD studies. Site should ensure sufficient tissue is sent per protocol requirement to each lab.   
 
9.1 
Integral Laboratory Studies 
9.1.1 Assessment of Retinoblastoma (Rb1) expression 
All diagnostic tumor samples will be evaluated for Rb protein by immunohistochemistry (IHC) in a CLIA 
certified lab – either at 
) or local Lab. Tumor 
samples will be sent to  CCHMC  if the tissue has not been previously tested locally. Additionally, left 
over tumor samples will be stored after required studies are completed for future research with participant 
consent. 
 
Formalin fixed paraffin embedded (FFPE) tumor tissue will be collected from all patients prior to 
enrollment (except for those with DIPG who have not undergone previous biopsy). Unstained slides and 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
a corresponding H & E stained slide will be prepared from the original and/or recurrent surgery by sites 
and sent to CCHMC for Rb immunohistochemistry and interpretation.  Unstained sections should be cut 
to 5µm in thickness on (+) slides from a section containing at least 50% tumor cells. The turn-around time 
for this test is approximately 7-10 days.  Tumor RB protein status will be denoted as “positive” if ≥ 20% 
of tumor cells have positive nuclear staining.  Rb+ endothelial cells will serve as an internal positive 
control.  All slides will be centrally reviewed by the Neuro-pathologist at CCHMC.   
 
9.1.1.1 Assay Method 
Immunohistochemistry for Rb will be performed as previously described79 using a mouse monoclonal 
anti-RB antibody (G3-245; BD Biosciences, San Jose, CA) and an automated IHC staining process 
(Benchmark XT; Ventana Medical Systems, Inc, Tucson, AZ). Briefly, antigen retrieval will be performed 
in Tris, pH 8.0 at 95C for 1 hour, followed by incubation in 3% H2O2 for 16 minutes and primary antibody 
at 1: 100 at room temperature for 60 minutes.   Immunohistochemistry will be scored as follows:  0, 
denotes expression in less than 20% of tumor cells; 1, denotes expression ins 20% to 50% of tumor cells; 
and 2, indicate positive expression in more than 50% of tumor cells.  At least three 20x-fields will be 
evaluated per case.  The assay is performed and interpreted in a laboratory that is CLIA certified 
(CCHMC) to perform high complexity testing. 
 
9.1.1.2 Collection and shipping of Specimen(s) 
Two unstained slides for FFPE material will be collected along with one H & E stained slide prepared 
from the same block will be submitted to CCHMC.   
 
Slides must be shipped to CCHMC within 3 days of reservation. Sites will be notified of the results of the 
Rb1 testing within 2 weeks. All screened patients who are eligible for participating in the PBTC-050 study 
must be enrolled via OPEN within 10 days of the site notification of a patient‘s Rb1 status. Slides must 
be labeled with the PBTC enrollment tracking number (OPEN tracking #) and protocol number. Samples 
should be shipped Monday through Thursday using the PBTC-050 FedEx account. Weekend deliveries 
are not permitted. The sample shipping date must be documented in the eCRF by the sites.  All specimens 
should be shipped at room temperature.  
 
Send the following to CCHMC: 
• 2 unstained slides  
• 1 H&E stained slide 
• Completed PBTC-050 specimen transmittal form  
   
Attn: Christine Fuller, MD 
 
 
 
 
 
 
  
 
9.1.1.3 Site(s) Performing Correlative Study 
Christine Fuller, MD 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
 
 
 
9.2 
Pathology and Exploratory Correlative Studies 
The Biorepository (CRB)’s function is to collect, distribute and store specimens for planned correlative 
studies which support the laboratory objectives of this protocol.   
 
The CRB will also serve as a central repository for specimens collected for future research and left over 
specimens (tumor tissue, blood, urine or CSF) returned to the repository following the planned analysis 
from patients who consent to long term storage of unused specimen.  These samples will be stored in the 
repository for undefined future studies which support the mission of the PBTC.  If the patient does not 
consent to participation in the repository, correlative study samples should be submitted following 
the guidelines in the appropriate correlative study section below. If the patient does not consent to 
long term storage, remaining correlative study samples will be destroyed once the PBTC-050 
analysis is complete. 
 
9.2.1 PBTC CRB Submission Guidelines  
If the patient consents to provide slides for submission to the repository at the time of participation in a 
PBTC trial the following should be submitted:  
 
• Tumor material 
Slides from the original and/or recurrent surgery should be prepared for storage. The site should provide 
up to twenty (20) unstained sections cut at 4µm in thickness on (+) slides from the most representative 
section. For patients who have consented to other  correlative studies (e.g. genomics, pharmacodynamics 
studies) on this protocol that require slides,  these submitted  slides will be used for the  conduct  of studies 
outlined in the corresponding sections below (9.2.4, 9.2.5).  Fewer unstained sections may be submitted 
based on size and availability of tissue.  Preference is for tissue that has not previously been frozen.   The 
corresponding pathology report (s) including immunohistochemical, special stains, and molecular/genetic 
results is to be uploaded to the PBTC using the secure File Upload system.  These reports will be made 
available to the pathologist via a link in the ProtoLab. 
 
Suitability of sections would be established by preparing one (1) H&E to ensure that the sections meet the 
following criteria:  
o histologically representative of the reported lesion 
o contain at least 60% viable tumor 
o no more than 40% necrosis 
 
Slides submitted by patients who have consented to the PBTC CRB will undergo neuro-pathology review. 
Central pathology review is not required for this study. Pathologist review for this study will include the 
following elements:  
o Examination of H&E stained slides. For each subject one (1) H&E stained slide per one 
representative block from the brain tumor, removed either at initial diagnosis or relapse, 
should be submitted for review. 
o Review of the corresponding pathology report(s) of the immunohistochemical, special 
stains, and molecular/genetic results from current and/or original primary tumor 
o If necessary, review of immunohistochemical or special stained slides.  


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
 
Slides submitted to the PBTC CRB will be digitized to 40X. H&E stained sections will be retained and 
filed at the CRB.  Original immunohistochemical or special stain slides will be returned to the submitting 
institution. 
 
• Peripheral Blood Mononuclear Cells 
PBMC may be collected by processing a 2-5mL whole blood specimen with Ficoll or collecting the 
specimen in a BD Vacutainer™ CPT™ Cell Preparation Tube with Sodium Citrate as noted below. Once 
separated, all pellets must be snap frozen and stored at least at -20oC prior to dry ice shipment 
 
Specimen Collection and Processing by Ficoll tube 
• Collect 2 - 5mL of fresh blood into an EDTA tube. 
• Transfer blood into a sterile 50-mL tube and add double the amount of PBS. MIX GENTLY. 
• Set up another tube containing half of its total volume of Ficoll. For example, if there is 15 mL of 
blood + PBS, then use 7.5 mL of Ficoll (2:1 ratio). 
 
At very slow pace (approx. 2 mL/minute), layer the blood + PBS mixture onto the Ficoll so that the 
solutions DO NOT MIX. Spin the blood/Ficoll at 750 g in slow mode for 30 minutes @ 25ºC. After spin 
you will see four distinct layers: plasma (top layer), white fluffy ring (2nd layer), Ficoll (3rd layer), and 
blood (bottom layer). 
• Remove plasma layer down to about 1 mL above the white fluffy ring and discard.  
• Collect the entire white fluffy ring. If ring is hard to see, also take extra liquid above. Then discard 
everything else. 
• Place this fraction of white blood cells into a fresh 50 mL sterile tube with 20 mL of PBS.  Spin 
down for 10 minutes @ 25ºC, 750 g in fast mode. Remove the supernatant. Add back to pellet 1 
mL of PBS and spin for 5 min. at 4°C at 10000rpm. Remove supernatant.  
• Freeze the pellet of WBCs and store at -80ºC until shipment. 
• Ensure that all tubes are clearly labeled with the PBTC patient accession number. Please ensure 
that the labeling system used is designed to withstand temperatures down to -80oC. Samples should 
be stored at -80ºC until shipment. For short term storage (2-3 weeks) -20ºC is acceptable. NOTE 
4ºC IS NOT ACCEPTABLE STORAGE.  
 
If it is not possible to collect the PBMC by Ficoll gradient then separation of PBMC can be conducted 
using CPT tube separation as an alternative. However the PBMC pellet MUST BE frozen immediately 
and stored at -80oC. 
 
Collection and Processing by CPT tube 
• Peripheral blood should be collected in a BD Vacutainer CPT™ Cell Preparation Tube with 
Sodium Citrate or similar tube which is available locally. 8 mL and 4 mL CPT tubes can be 
obtained from Fisher Scientific (Cat# 02-685-125, 02-688-81) or Becton-Dickinson (BD 
No.362761, 362760).  The 8 mL tubes have a 6 mL minimum draw and the 4 mL tubes have a 3 
mL minimum draw.  
• Centrifuge the CPT™ tube at 1500 x g for 30 minutes at room temperature (20o C to 25o C). DO 
NOT APPLY THE BREAK ON THE CENTRIFUGE.  Use acceleration 5, brake 0 (“slow mode”).   
• It may be necessary to spin the tube longer to ensure that all of the red blood cell components have 
been separated from the plasma layer through the polyester gel barrier. 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
• The tube should be removed immediately from the centrifuge. The mononuclear layer and plasma 
lie above the polyester gel plug. 
• Using a sterile pipette, remove as much of the plasma component (upper half of the CPT tube) 
without disturbing the mononuclear layer if possible and discard. 
• Transfer mononuclear cell layer (and some residual plasma layer) to a labeled 15- mL conical 
centrifuge tube and add 5 mL sterile room temperature magnesium or calcium-free phosphate 
buffered saline (PBS) to fill the conical tube and recap. 
• Centrifuge at 450 x g for 10 minutes at room temperature (20o C to 25o C).  Use acceleration 9, 
brake (“fast mode”).  
• Remove supernatant, being careful not to aspirate the cellular pellet at the bottom of the tube.  
• Add 1 mL of sterile PBS to the pellet and gently re-suspend by pipetting up and down. Transfer 
the entire suspended pellet to the labeled cryovial.   
• Centrifuge the cryovial at 450 x g for 5 minutes (or spin down the microcentrifuge tube at 1300 x 
g for 5 minutes) at room temperature. Discard the supernatant. Store the cell pellet cryovial frozen 
at -80ºC. For short term storage (2-3 weeks) -20o C is acceptable. 
 
If the patient consents to other secondary correlative studies as outlined in sections 9.2.4, 9.2.5), the 
following specimens may also be submitted to the CRB for distribution and storage. 
• Fresh-frozen tissue: approximately 100 micrograms = pea-sized portion of tumor, frozen in foil 
in liquid nitrogen and stored at -70°C until time of shipping 
• Peripheral blood mononuclear cells: quantity and schedule of collection as outlined in section 
9.2.1. 
 
9.2.1.1 Handling of Specimens 
• Slides are to be labeled with the study ID and the patient PBTC Accession # and these slides should 
be designated as PBTCR # (where the # assigned from 1 to 20, or the highest number of unstained 
sections prepared, sequentially) or PBTCR H&E for the H&E stained section.  
 
• Frozen tumor tissue or Formalin Fixed, Paraffin Embedded (FFPE) tumor materials are to be 
labeled with the PBTC Accession # and the PBTC study for which the sample is provided.  When 
fresh frozen tumor (FFT) sample is available, we would additionally request a minimum amount 
of 20 mg.  In the event that genomic DNA (gDNA) has already been extracted from tumor material, 
this can be submitted in lieu of FFT sample and we would request a minimum of 250 ng of gDNA.   
 
9.2.1.2 Shipment of Specimens 
Samples collected for the repository should be sent to the PBTC CRB overnight via FedEx by completing 
the 
Internet 
form 
at 
http://www.fedex.com/us/ 
and 
requesting 
FedEx 
to 
e-mail 
at 
researchsupportbiorepository@chla.usc.edu. FedEx user ID and password for pathology shipping can be 
found at PBTC-050 protocol webpage. Weekend deliveries are not permitted. Receipt and processing of 
biological materials will be recorded in ProtoLab, as appropriate, by staff at the PBTC CRB. The sites 
sending the materials must document sample collection and shipping dates in the eCRF.   
 
Samples should be shipped in the appropriate environment as described below: 
• Fresh frozen tumor sample should be shipped in a separate box on dry ice.  
• FFPE tumor material should be shipped at room temperature. 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
• Blood samples should be shipped in a separate box with cold pack (1-10 degrees C), unless 
otherwise specified. 
 
Samples are to be shipped to: 
PBTC CRB 
 
 
 
 
 
   
 
 
9.2.2 Plasma Pharmacokinetics 
 
Phase I Study 
Pharmacokinetic studies for ribociclib and everolimus will be performed on all patients enrolled on the 
Phase I component of the trial (including surgical patients who are eligible to initiate Phase I treatment). 
The pharmacokinetics of these agents alone and in combination are unknown in the setting of pediatric 
CNS neoplasia, and because various agents commonly used in patients with brain tumors (e.g., 
corticosteroids) can alter the disposition of these agents, this information will be useful for evaluating 
toxicity and disease response and for refining dosing in future clinical trials. Moreover, since both these 
agents are metabolized by CYP3A4 and studies in adults have suggested that the disposition of at least 
one of the agents is altered, it will be important to know if either of these agents alter the systemic 
disposition of the other in the setting of pediatric brain tumor therapy. Thus, patients will begin  ribociclib 
therapy two days earlier than the everolimus so that we can perform ribociclib pharmacokinetic studies to 
gain a baseline of the ribociclib disposition, and then during Course 2 to hold the ribociclib dose on day 1 
so that we can perform everolimus pharmacokinetic studies to gain a baseline of the everolimus 
disposition.  
 
9.2.2.1 Sampling Strategy for Phase I Pharmacokinetic Study  
Mandatory plasma pharmacokinetic studies will be obtained from all patients enrolled on this study on 
days 1, 2, 3, and 17 and 18 of Course 1, and days 1 and 2 of Course 2 to evaluate the pharmacokinetics of 
ribociclib and everolimus alone and the pharmacokinetics of the combination. A single dose of ribociclib 
will be administered on Day 1 of Course 1 to obtain a baseline ribociclib pharmacokinetic study with 
which to compare the effect of everolimus on ribociclib when they are administered in combination (i.e., 
Course 1 day 17/18). Moreover, the effect of ribociclib on everolimus will be evaluated by comparing the 
Course 2 day 1 (and 2) everolimus (without ribociclib) baseline when they are administered in 
combination (i.e., C1 day 17/18). 
 
• Ribociclib Serial Sampling Strategy 
On Day 1 of Course 1:  
Beginning on day 1 of Course 1, serial whole blood samples for ribociclib pharmacokinetic studies will 
be collected in a labeled lavender-top K2-EDTA Vacutainer tube at the following times: pre-dose and at, 
1, 2, 4, 8 (±1), 24 (±4), 32 (±4), and 48 (±4) hours after the oral dose (8 mL total). The ribociclib dose 
on day 2 should be held during course 1 and resumed on day 3 after the 48 hour time point 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
pharmacokinetic sample has been obtained.  It is crucial that the 48-hour time point be obtained 
prior to administration of either drug (ribociclib or everolimus) on Day 3.  
 
• Ribociclib and Everolimus Serial Sampling Strategy 
On day 17 (± 2 days) of Course 1:  
On day 17 ± 2 days, serial whole blood samples for ribociclib and everolimus pharmacokinetic studies 
will be collected at the following times: pre-dose and at, 1, 2, 4, 8 (±1), and 24 (±4)  (immediately prior 
to the next dose) hours after the dose (12 mL total). Because these samples will be used for both ribociclib 
and everolimus, 2 mL of whole blood will be collected in a labeled lavender-top K2-EDTA Vacutainer 
tube at each time point. The sample will be split and 1 mL of blood will be processed to plasma for 
ribociclib, and 1 mL of whole blood will be used for the everolimus studies. 
 
• Everolimus Serial Sampling Strategy  
On day 1 of Course 2: 
 Whole blood samples for everolimus pharmacokinetic studies will be collected into a labeled lavender-
top K2EDTA Vacutainer tube at the following times: pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 (±1), and 24 (±4)  
(immediately prior to the next dose) hours after the oral dose (9 mL total). The ribociclib dose on day 1 
should be held and day 2 should be delayed until the last everolimus sample is collected. 
 
Surgical Study   
9.2.2.2 Sampling Strategy for Ribociclib Neurosurgical Study  
Mandatory plasma and fresh frozen tumor tissue will be obtained from all patients enrolled on this aspect 
of the clinical trial after continuous ribociclib therapy of 7-10 days to determine the ribociclib plasma and 
brain tumor concentrations.  
 
• Ribociclib Plasma and Brain Tumor Sampling Strategy  
After 7 – 10 days of continuous ribociclib dosing, a 1 mL whole blood sample will be collected into a 
labeled lavender-top K2-EDTA vacutainer tube at the following times:.  
 
• Prior to starting ribociclib (Day -7 or Day -10) 
• Prior to dose on Day -5 (±1 day) 
• Prior to dose on Day -2 (±1 day) 
• On the day of surgery (Day 0) 
• During surgery at time tumor tissue is collected 
 
Record the exact time of day the sample is acquired and the time of the last dose of ribociclib on the 
Pharmacokinetic Data Collection Form.  
 
During the neurosurgical procedure, brain tumor tissue will be acquired at the time of tumor resection. 
Record the time and day of sample acquisition, the anatomical location from which the tumor sample was 
acquired, and the condition of the sample at the time of acquisition (e.g., viable tumor material, necrotic 
tumor material). Each separate piece of tumor tissue should be placed into an appropriately labeled tube.  
 
9.2.2.3 Collection and Handling of Specimens 
• Ribociclib Plasma Sample Collection and Processing Instructions:   


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
Collect the ribociclib blood samples according to institutional policies and procedures, ensuring that where 
applicable, sterile discard volume is returned to the patient after the blood sample is obtained. At times 
specified, 1 mL of whole blood should be drawn into an appropriately labeled lavender-top EDTA 
vacutainer tube. The samples should be inverted several times to mix, immediately aliquoted to 
microcentrifuge tubes, and centrifuged at 10,000 rpm for 2 minutes. For participating facilities equipped 
with lower speed centrifuges, samples may be centrifuged at 1,000 - 1,300 x g for 10 minutes (see vendor 
specific rotor instructions for rpm to rcf conversion). The plasma supernatant should then be transferred 
to an appropriately labeled, screw-capped polypropylene tube and stored at -80°. (Record the exact time 
that the sample is drawn along with the exact time that the drug is administered on the Pharmacokinetic 
Data Collection Form. Refer to the Pharmacokinetics Laboratory section with the Clinical Operations 
Manual for detailed instructions for the collection, handling, and processing of pharmacokinetic samples.) 
 
• Everolimus Whole Blood Sample Collection and Processing Instructions:   
At each time point, the designated amount of blood (see the amounts of blood collected in Section 9.2.2.1 
and Correlative lab studies calendar 10.3) will be collected into appropriately labeled amber tubes 
containing K2-EDTA.  One (1) mL of blood is needed for bioanalysis. The Pharmacokinetic Data 
Collection Form should be completed with the exact time that the sample is drawn as well as the exact 
time that the drug is administered.  The Pharmacokinetic Data Collection Form is located on the PBTC-
050 webpage.  The samples should be labeled with the PBTC Accession number and the Course, Day and 
Time information for each sample.  
 
• Tumor Sample Collection and Processing Instructions for surgical study 
Approximately 50 to 100 mg of fresh flash-frozen tumor material will be collected into an appropriately 
labeled 15-mL conical tube. All samples (i.e., plasma and tumor) should be shipped on dry ice.  
 
9.2.2.4 Shipping of Specimens 
At the start of the study, each participating institution will receive a Pharmacokinetics (PK) kit from Dr. 
Clinton Stewart for the collection of samples.  
 
Samples should be shipped for delivery Monday through Thursday with a generous amount of dry ice 
enclosed to safeguard against shipping delays. Weekend and holiday deliveries should be avoided. Sites 
should contact the Stewart Laboratory 
 to 
request a Pharmacokinetics Kit for each patient enrolled on the study. 
 
Samples should be shipped within 30 days of the last sample being taken. The site should use the PBTC-
050 PK FedEx account details, located on the PBTC member website. Ship all pharmacokinetic samples 
on dry ice, along with a completed Pharmacokinetics Sample Transmittal Form located on the PBTC-050 
webpage to: 
 
Stewart Laboratory 
 
 
 
 
   
 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
 
 
Samples must be shipped from the site to the respective laboratory within 30 days of last sample collection 
in order to receive cost reimbursement. The sample collection and shipping dates must be documented in 
the eCRF. 
 
9.2.2.5 Site Performing Correlative Study 
Stewart Laboratory 
 
 
 
 
9.2.3 Cerebrospinal Fluid (CSF) Pharmacokinetic Studies   
 
Phase I 
Pharmacokinetic studies for ribociclib, everolimus, or the combination of the two drugs will also be 
performed in all research participants with access to CSF who agree to participate.   
9.2.3.1 Serial CSF Studies 
• Ventricular CSF (0.5 mL) should be obtained in a screw-top tube pre-dose and at 1, 4, and 8 
hours after drug administration on Course 1, Day 1 (C1D1); Course 1, Day 17 (C1D17) and 
Course 2, Day 1 (C2D1).   
• The exact time that the CSF sample is obtained should be recorded along with the exact time 
that the drug is administered on the Pharmacokinetic Data Collection Form. 
 
9.2.3.2 Single CSF Studies 
• A single CSF sample may be available for collection where CSF is collected as part of the best 
clinical practice at any time during treatment (e.g., those requiring CSF diversion or VP shunt 
revision during therapy, or research participants requiring shunt externalization for infection), 
therapy should be preferentially continued without interruption, and all attempts should be 
made to obtain a sample of CSF for pharmacokinetic studies.  
• A simultaneous plasma sample should be obtained at the time of all CSF sample collection(s). 
 
Surgical study 
If a CSF sample is obtained during a surgical procedure from a patient receiving ribociclib, the ribociclib 
concentration in that sample will be determined.  
9.2.3.3 Collection and Handling of Specimen(s) 
Phase I 
Collect 0.5 milliliters of CSF in a screw-top tube along with concomitant plasma sample. Record the exact 
time that the CSF and plasma samples were obtained along with the exact time of drug administration on 
the CSF Pharmacokinetic Data Collection Form located on the PBTC-050 webpage in the “Protocol 
Specific Instructions/Forms” section. Samples should be labeled with the PBTC Accession number and 
the Course, Day information for each sample. Samples should be stored at -80°C until shipped.  
 
Surgical Study 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
CSF will be obtained (2 mL in a screw-top tube) at the time of surgery after 7-10 days of daily 
administration of ribociclib (at steady state). Samples should be labeled with the PBTC Accession number 
and the Course, Day information for each sample. Samples should be stored at -80°C until shipped. 
 
9.2.3.4 Shipping of Specimen(s) 
The sample collection and shipping dates must be documented in the eCRF.  All samples should be 
forwarded via FedEx, Monday through Thursday, by completing the internet form at 
http://www.fedex.com/us/ and requesting FedEx to email the laboratory. Fed Ex account information for 
the shipment of samples can be obtained on the PBTC -050 website.  Weekend deliveries are not 
permitted.  
 
In no instance should any CSF sample remain at a participating site for more than 30 days after its 
acquisition unless prior approval is obtained by Dr. Clinton Stewart or his designee.  All CSF samples 
should be shipped on dry ice, along with a completed CSF PK Transmittal Form located on the PBTC-
050 webpage to: 
 
Stewart Laboratory 
 
 
 
 
 
 
 
9.2.3.5 Site Performing Correlative Study 
Stewart Laboratory 
 
 
 
9.2.4 Pharmacodynamics (Only applicable for surgical study)  
The rationale for this test is to look at change in Ki67 by comparing pre-treatment (prior to ribociclib) and 
post-treatment (after 7-10 days of ribociclib) tissue. Surrogate pharmacodynamics studies for a drug that 
targets the cell cycle can be performed on pre-treatment tumor and post-treatment tumor.  Ki67 is a marker 
of cellular proliferation. In the adult clinical studies with Ribociclib, pharmacodynamics markers were 
tested in skin and tumor biopsies by IHC assessment of p-Rb and Ki67.  A ≥ 50% reduction was observed 
a doses of 400 mg and higher. The study currently continues in the expansion phase for further assessment 
of toxicity and efficacy.48  
 
For the Surgical Study, Ki67 will be evaluated in pre-treatment tumor (diagnostic) and post-treatment 
tumor (recurrent) tissue in consenting patients.   
 
9.2.4.1 Collection of Specimen(s) 
The following will be collected from representative (diagnostic and recurrent) tumor tissue:  
• 2 (Two) unstained FFPE slides [1 each from pre-treatment tumor (diagnostic) and post-treatment 
tumor (recurrent) tissue] + 1 H&E  
• OR tissue block from tumor material  


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
 
9.2.4.2 Handling of Specimens(s) 
The samples should be labeled with the PBTC Accession number and the Course, Day information for 
each sample. 
 
9.2.4.3 Shipping of Specimen(s) 
The sample collection and shipping dates must be documented in the eCRF.  All samples should be 
forwarded via FedEx, Monday through Thursday, by completing the internet form at 
http://www.fedex.com/us/ and requesting FedEx to email the laboratory. Fed Ex account information for 
the shipment of samples can be obtained on the PBTC website.  Weekend deliveries are not permitted. 
Specimens should be shipped in the room temperature, along with a completed PD Specimen Transmittal 
Form located on the PBTC-050 webpage to: 
 
PBTC CRB 
 
 
 
 
 
   
 
 
9.2.4.4 Site Performing Correlative Study 
Christine Fuller, MD 
 
 
 
 
9.2.5 Genomic Studies 
As an ancillary/exploratory study in consenting patients, tumor tissue in the form of formalin fixed, 
paraffin embedded tumor material (FFPE) or frozen tumor, if available, from any previous surgical 
excision/biopsy of the primary tumor or recurrent tumor(s), and any additional resected tumor if surgery 
is performed while the subject is on study, will be analyzed as described above in 9.1.1, and 9.2.4.   
 
For all tissue specimens submitted for genomics analysis, an additional 5 mL of blood should be collected 
prior to treatment, as a normal control for sequencing studies. This blood study is mandatory for those 
subjects who also consent to the tumor tissue genomics studies and have tissue available.  The blood 
sample should be collected and processed as described in Section 9.2.1 Peripheral Blood Mononuclear 
cells. 
 
After analysis, left over material will be stored at the PBTC specimen repository. Assays performed on 
FFPE  and PBMCs will be undertaken in combination with the Biology and Pathology Committee and 
CRB on material that may include: 
• Survey methylome analysis using Illumina 450k methylation array profiling of tumor tissue to 
confirm histological diagnosis, ascertain intra-diagnosis molecular subgroup, and evaluate copy 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
number gains/losses, including those in genes involved in cell cycle regulation, PI3K/mTOR 
signaling, or related cancer pathways (see Exploratory Objective in section 1.3) 
• Targeted DNA/RNA panel analysis and/or whole exome sequencing of matched tumor and normal 
(blood) tissue to identify genetic alterations targeting cancer genes, including those in genes 
involved in cell cycle regulation, PI3K/mTOR signaling, or related cancer pathways that are 
known to be mutated in cancer and in pediatric brain tumors in particular.   
• Other genomic tests including targeted deep sequencing, transcriptome (RNA) sequencing, or 
whole genome sequencing in order to identify cancer gene mutations, copy number alterations, 
structural rearrangements, and other types of genetic alterations. 
 
9.2.5.1 Shipping of Specimen(s) 
• Fresh frozen tissue tumor material should be rapidly transferred (without thawing) from long term 
storage to a Styrofoam box filled with dry ice.  
• FFPE slides/blocks should be shipped at ambient temperature. 
• PBMCs -  Once separated, all pellets must be snap frozen and stored at least at -20°C until shipped.  
Samples should be shipped overnight in a separate box with a 2-day supply of dry ice. 
 
The sample collection and shipping dates must be documented in the eCRF.  All samples should be 
forwarded via FedEx, Monday through Thursday, by completing the internet form at 
http://www.fedex.com/us/ and requesting FedEx to email at researchsupportbiorepository@chla.usc.edu. 
Fed Ex account information for the shipment of samples can be obtained on the PBTC-050 website.  
Weekend deliveries are not permitted. Genomic specimens should be shipped as described in Section 
9.2.5.1, along with a completed Genomics Specimen Transmittal Form located on the PBTC-050 webpage 
to: 
 
PBTC CRB 
 
 
 
 
 
   
 
 
9.2.5.2 Site(s) Performing Correlative Study  
Will Parsons, MD, PhD 
 
 
  
 
9.3 
Neuroimaging Studies 
Patients will have MRI Brain with and without contrast performed prior to therapy, after courses 2, 4, 6 
then every 12 weeks thereafter until time of progression or completion of treatment.  MRI Spine should 
be performed prior to therapy and at the same time points as standard MRI Brain, if clinically indicated.  
 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
Standard MR imaging will include Sagittal T1 MPRAGE, axial FLAIR, axial T2, post gadolinium sagittal 
T1 MPRAGE (with reconstructions) and axial T2 images.  Standard MR Spine imaging protocol is Sagittal 
T1 images after gadolinium (slice thickness 3mm skip 0). Axial T1 images are after gadolinium (slice 
thickness 3mm skip 0). Axial T2 images are optional. Standard MR Spine imaging protocol is Sagittal T1 
images after gadolinium (slice thickness 3mm skip 0). Axial T1 images are after gadolinium (slice 
thickness 3mm skip 0). Axial T2 images are optional. The standard MR parameters are listed on the PBTC 
NIC 
web 
page 
located 
at 
http://www.childrenshospital.org/research-and-innovation/research-
labs/pediatric-brain-tumor-consortium-neuroimaging-center under Neuroimaging Studies/ Specific MR 
Imaging Sequences- Open PBTC Protocols.  There is also a link to the same PBTC-NIC webpage from 
the PBTC-050 protocol study page. 
 
Volumetric analyses will be done at the Neuroimaging Center (NIC, Children’s Hospital Boston) via the 
Vitrea (Vitrea™) workstation, from the axial FLAIR and T1-weighted post-contrast brain images. 
 
9.3.1 Neuroimaging Review 
All patient specific data are stripped from the images and replaced with PBTC Accession numbers prior 
to transmitting the images to the NIC. All image data transfer is accomplished using PGP (pretty-good-
privacy) 128-bit encryption which meets industry standard for secure communication. 
Only scans showing a response, the confirmation scan obtained approximately 8 weeks later if available 
and the corresponding baseline scan will be electronically transferred to the PBTC Neuroimaging Center 
(NIC) for central review scan for confirmation. 
 
Local review of MR imaging studies at each site and central review of the MR imaging studies will be 
conducted through the PBTC Neuroimaging Center (NIC).  NIC review will include assessment of 
response to therapy (as feasible). The director and one neuroradiologist of NIC will review the imaging 
studies at study completion. If the local and central review are not in agreement the NIC neuroradiologist 
will confer with the participating site to determine why there is a discrepancy via conference call. 
10 STUDY CALENDAR 
Data is to be submitted according to the Data submission timelines located on the PBTC-050 webpage. 
 
10.1 Surgical Study 
 
 
Screening 
Pre- Enroll 
- 
Enrollment 
Pre-
surgery 
Surgery 
Post-
surgery 
Switch to Phase 
I 
(see 10.2) 
Visit Window 
Week -5  
Week -3   Week -2 
Week 0 
Week 2 - 
week 4 
> Week 2-4 
OPEN registration system 
X 
X 
 
 
 
 
Screening consent 
X 
 
 
 
 
 
Informed consent  
 
XA 
 
 
 
XB 
Confirmation of intact Rb1 required for  
HGG, medulloblastoma, CNS embryonal 
tumor (NOS), Ependymoma, or ATRT 
X 
 
 
 
 
 
Ribociclib administration C  
 
 
X  
 
 
 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
 
Screening 
Pre- Enroll 
- 
Enrollment 
Pre-
surgery 
Surgery 
Post-
surgery 
Switch to Phase 
I 
(see 10.2) 
Physical Assessments 
 
 
 
 
 
 
Medical history  
 
X 
 
 
X 
 
Physical exam /height/weight 
 
X 
 
 
X 
 
Vital signs 
 
X 
 
 
X 
 
Performance status 
 
X 
 
 
X 
 
Neurologic exam  
 
X 
 
 
X 
 
Review of eligibility assessments,  AE, 
concomitant meditations, prior therapy 
assessment 
 
X 
 
 
X 
 
Laboratory Evaluations 
 
 
 
 
 
 
CBC  
WBC, HgB, Hct, Platelets, ANC, ALC   
 
X 
 
 
X 
 
Serum Chemistry  
Sodium, 
Potassium, 
Bicarbonate, 
Chloride, Calcium, BUN, Creatinine, 
Glucose, 
Phosphorous, 
Magnesium, 
Albumin, Total Protein, SGPT(ALT), 
SGOT(AST), Total Bilirubin    
 
X 
 
 
X 
 
Lipid profile (fasting)  
Triglycerides, total cholesterol, HDL, 
LDL 
 
X 
 
 
 
 
Serum or Urine pregnancy test (for 
females of childbearing potential)  
 
X 
XD 
 
XD 
 
CSF cytology (if clinically indicated) 
 
X 
 
 
 
 
Other assessments 
 
 
 
 
 
 
12-lead EKG 
 
X 
 
 
 
 
ECHO 
 
X 
 
 
 
 
Imaging Assessments 
 
 
 
 
 
 
Brain MRI (standard) with diffusion 
 
X 
 
XE 
XE 
 
Spinal MRI (if clinically indicated) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Correlatives 
 
 
 
 
 
 
PK Blood 
 
 
XF 
XF 
 
 
PK Tumor tissue 
 
 
 
XG 
 
 
CSF PK (if consented) 
 
 
 
XH 
 
 
PD (if consented) 
 
 
 
X 
 
 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
 
Screening 
Pre- Enroll 
- 
Enrollment 
Pre-
surgery 
Surgery 
Post-
surgery 
Switch to Phase 
I 
(see 10.2) 
A. Informed consent for surgical study 
B. Informed consent for Phase I 
C. Ribociclib will be administered 7 – 10 days prior to surgery. 
D. Within 72 hours prior to starting study drug(s)  
E. Intraoperative OR post- operative (<96 hours) MRI 
F. PK blood – obtain 1 mL each prior to dose on day -7 or day -10, day -5, Day -2, on the day of surgery, and during 
surgery. See section 9.2.2.2.  
G. 50 to 100 mg of fresh flash-frozen tumor will be collected at the time of surgery. See section 9.2.2.3. 
H. CSF PK – obtain 2 mL at the time of surgery 
 
 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
10.2 Phase I  
 
 
Pre-
therapy 
Course 1 
Courses 2- 
Course 13 
Courses 
14-26 
Completion/ 
Discontinuation 
Of Treatment 
Study drugs administration  
(ribociclib + everolimus) 
 
X 
X 
X 
 
Medical history  
X 
Weekly 
X 
X 
X 
Physical exam /height/weight 
X 
Weekly 
X 
X 
X 
Vital signs 
X 
Weekly 
X 
X 
X 
Performance status 
X 
Weekly 
X 
X 
X 
Neurologic exam  
X 
Weekly 
X 
X 
X 
CBC  
WBC, HgB, Hct, Platelets, ANC, ALC A,B 
X 
WeeklyA 
WeeklyA,B 
XB 
X 
Serum Chemistry  
Sodium, Potassium, Bicarbonate, Chloride, 
Calcium, 
BUN, 
Creatinine, 
Glucose, 
Phosphorous, Magnesium, Albumin, Total 
Protein, SGPT(ALT), SGOT(AST), Total 
Bilirubin  
X 
XB 
XB 
XB 
X 
Lipid profile (fasting)  
Triglycerides, total cholesterol, HDL, LDL C 
X 
 
XC 
XC 
X 
Serum or Urine pregnancy test (for females of 
childbearing potential) B 
X 
XB 
XB 
XB 
X 
CSF cytology (if clinically indicated) 
X 
 
 
 
 
12-lead EKG D 
X 
XD 
XD 
XD 
X 
ECHO 
X 
 
XE 
XE 
XE 
Imaging Assessments 
 
 
 
 
 
Brain MRI (standard) with diffusion F 
X 
 
XF 
XF 
XF 
Spinal MRIF (if clinically indicated) G 
X 
 
XG 
XG 
X 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
 
Pre-
therapy 
Course 1 
Courses 2- 
Course 13 
Courses 
14-26 
Completion/ 
Discontinuation 
Of Treatment 
A. CBC with differential at baseline and q weekly during each cycle for the first 3 cycles; consideration can be given to 
increase interval to q 2 weeks from course 4 onwards if the patient did not DLT in the previous cycle.  If patient 
develops Grade 4 neutropenia or thrombocytopenia, then CBCs should be checked every 3-4 days until recovery to 
Grade 3.  
B. Within 72 hours prior to starting the next course 
C. Lipid profile is to be obtained every other course (prior to course 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26) 
D. 12-lead EKG at baseline, days 15 of cycle 1 and prior to cycles 2 and 3.  Thereafter, EKG should be done prior to the 
start of every 3rd cycle (prior to 6, 9, 12, 15, 18, 21, 24 and end of treatment).  For patients with QTc  481 ms at any 
time, interrupt study treatment and follow the procedures described in  Table 10Error! Reference source not found. 
EKG must be completed within 7 days prior to starting next course of ribociclib and everolimus.   
E. ECHO must be obtained within 7 days prior to anticipated start of therapy of course 3.  Additional studies may be 
done as clinically indicated at the investigator’s discretion. 
F. Standard imaging with diffusion is to be done every 8 weeks (after courses 2, 4, 6, and then every 12 weeks thereafter 
through the 26 courses of treatment or progression).  All required imaging dates are to be entered in the database. 
However, only scans showing a partial response or complete response, and the corresponding baseline scan, will be 
uploaded. 
G. MRI Spine should be done at the indicated time and when clinically indicated. 
 
10.3 Correlative Lab Studies Calendar (Phase I) 
Correlative Laboratory 
Studies 
Screening 
Pre-
therapy 
Course 1 
Course 2 
Rb1 expression (required) 
X A 
 
 
 
Pharmacokinetics blood:  
Ribociclib serial samples  
(required) 
 
 
D1 of C1 
• pre-dose, and 1, 2, 4, 8 
(±1), 24 (±4), 32 (±4), and 
48 (±4) hours after dose.B  
• 1 mL each ( 8 mL total) 
 
Pharmacokinetics blood: 
Everolimus serial samples  
(required) 
 
 
 
D1 of C2  
• pre-dose, 0.5, 1, 1.5, 
2, 4, 6, 8 (±1), and 24 
(±4)   hr after dose.C   
• 1 mL each ( 9 mL 
total) 
Pharmacokinetics blood: Both 
ribociclib and everolimus serial 
samples (required) 
 
 
D17 of C1 (+/- 2 days) 
• pre-dose, 1, 2, 4, 8 (±1), 
and 24 (±4)  hrs after dose 
• 2 mL each (12   
    mL total) 
 
PK – serial CSF (if consented) 
 
 
XD 
 
PK – single CSF (if consented) 
 
XE 
 
 
Pre-trial tumor materials and 
PBMCs for Genomics (if 
consented) 
 
X 
 
 
Tumor Tissue and blood for 
Biorepository (if consented) 
 
X 
 
 


NCI Protocol #: PBTC-050 
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A. Required for patients with HGG, medulloblastoma, CNS embryonal tumor (NOS), Ependymoma, or ATRT or with 
atypical presentation of DIPG. Tissue may be submitted if available for patients with typical presentation of DIPG 
who have undergone previous biopsy but not mandated. 
B. 48-hour time point will be obtained prior to administration of either drug (ribociclib or everolimus) on Day 3 
C. The ribociclib dose on day 1 should be held and day 2 should be delayed until the last everolimus sample is collected 
on day 2. 
D. See section 9.2.3 for details.  
E. Anytime during treatment.  See section 9.2.3 for details. 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
11 MEASUREMENT OF EFFECT 
Although the clinical benefit of ribociclib/everolimus drug(s) has not yet been established, the intent of 
offering this treatment is to provide a possible therapeutic benefit, and thus the patient will be carefully 
monitored for tumor response and symptom relief in addition to safety and tolerability.  Patients with 
measurable disease will be assessed by standard criteria.  For the purposes of this study, patients should 
be re-evaluated every 8 weeks for the first 3 courses (Courses 2, 4, 6), then every 12 weeks (Courses 9, 
12, and Course 15, 18, 21, 24, 26 during extended therapy period) thereafter until time of progression or 
completion of treatment. In addition to a baseline scan, confirmatory scans will also be obtained 8 weeks 
following initial documentation of an objective response. 
 
11.1 Antitumor Effect 
11.1.1 Definitions 
• Evaluable for Toxicity 
Patients who receive at least 1 dose of ribociclib or everolimus and are removed from treatment for toxicity 
during the dose-finding period (first 4 weeks of treatment) are evaluable for estimating the MTD. 
 
Patients who receive approximately 85% (≥18/21 doses of ribociclib and ≥22/26 doses of everolimus) of 
prescribed therapy during the dose-finding period but who progress prior to completing the course may 
be considered evaluable for estimating the MTD, 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 must 
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 MTD. 
 
Patients who have completed all therapy during the dose-finding period but who failed to comply with all 
the specified clinical and laboratory monitoring requirements for the first course may be considered 
inevaluable for estimating the MTD and replaced. 
 
Patients who receive less than 85% (<18/21 doses of ribociclib and <22/26 doses of everolimus)  doses of 
the protocol specified therapy and who go off treatment for reasons other than toxicity (e.g. progressive 
disease, withdrawal of consent etc.) during the dose finding period will be considered inevaluable for 
estimating the MTD and  will be replaced. 
 
• Evaluable for Objective Response 
Only those patients who have measurable disease present at initiation of phase I treatment, have received 
at least one dose of therapy, and have had their disease re-evaluated will be considered evaluable for 
response. These patients will have their response classified according to the definitions stated below.  
(Note:  Patients who exhibit objective disease progression prior to the next scheduled MRI will also be 
considered evaluable.) 
 
• Evaluable for PK intra-tumoral PK on the surgical study 
Patients with adequate tumor tissue (amount and quality) to be analyzable for the PK objective will be 
considered evaluable for the surgical study. Please note patients who may not be evaluable for the PK 
study may still be evaluable for the Phase I trial should they proceed to that component of the study. 
 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
11.2 Disease Parameters 
Sites should report tumor measurements in 3 dimensions in the database. In order to completely document 
the assessment of response, the measurements of the longest tumor dimension, and its perpendicular, of 
all target lesions upon which the assessments of tumor response are based should be explicitly noted in 
the radiology report for the baseline and all subsequent follow-up exams. Reports for the follow-up exams 
should reiterate the measurements obtained at baseline for each target lesion. Non-target lesions or newly 
occurring lesions should also be enumerated in these reports, and changes in non-target lesions should be 
described. The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. 
 
Tumor response criteria are determined by changes in size using the longest tumor dimension, and its 
perpendicular. FLAIR, T2 or post contrast T1 weighted images may be used - whichever gives the best 
estimate of tumor size. 
 
Since many tumors contain nonenhancing components (or, in some cases, the tumor may not enhance at 
all), both the enhancing and the non-enhancing components must be evaluated – on post contrast T1 
weighted images and on FLAIR/T2 weighted images respectively. Increase in enhancement on T1 
weighted images without accompanying increase in disease bulk on T2 or FLAIR images is not considered 
tumor progression. In return, enlarging areas of nonenhancing tumor (defined as mass effect/tissue 
thickening) are evidence of tumor progression. Conversely, decrease in enhancing tumor component 
without decrease in overall FLAIR/T2 extent may represent change in tumor permeability (commonly 
observed with antiangiogenic therapies) rather than represent tumor response. 
 
11.2.1 Method 
The following section describes the methodology. (See Figure 9 below for illustration.) 
• For MRI imaging (preferred), the longest measurement of the tumor (or width, W) should be 
determined. It can be measured from the axial plane or the plane in which the tumor is best seen 
or measured, provided the same plane is used in follow ups. . 
 
• The transverse measurement should be the longest length perpendicular to the selected W. These 
dimensions will serve as the comparator for subsequent disease response assessments.  
 
NOTE: A measurable lesion should have a minimal transverse measurement that is at least twice 
the combined thickness of the image slice and the interslice gap. For example, with a 4 mm slice 
and a 0.4 mm gap, minimal measurable lesion diameter is 8.8 mm. Smaller lesions would not be 
measurable for study purpose. 
 
• 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, and change in 
extent/thickness assessed on follow up studies. 
• Follow-up examinations should assess the same 2 largest dimensions assessed at baseline. 
 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
 
Figure 9: Tumor size measurement based on cross-sectional imaging 
 
11.2.2 Overall Response Assessment 
The overall response assessment takes into account response in both target and non-target lesion, and the 
appearance of new lesions, where applicable, according to the criteria described in the table below. The 
overall response assessment is shown in the last column, and depends on the assessments of target, non-
target, and new lesions in the preceding columns. 
 
Overall Response Assessment 
 
Target Lesions 
 
New Lesions* 
 
Overall Response 
CR 
No 
CR 
PR 
No 
PR 
SD  
No 
SD  
PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR – Complete Response; PD – Progressive Disease;  
PR – Partial Response ; IR – Incomplete Response; SD – Stable Disease 
*If CSF cytology becomes positive, it will be considered a new lesion and 
progressive disease. 
 
11.2.3 Selection of Target and Non-target Lesions 
• For most CNS tumors, only one lesion/mass is present and therefore is considered a “target” for 
measurement/follow up to assess for tumor progression/response.  
• If multiple measurable lesions are present, a minimum of the 2 largest lesions should be measured; 
a maximum of 5 should be selected as “target” lesions. Target lesions should be selected on the 
basis of size and suitability for accurate repeated measurements. All other lesions will be followed 
as non-target lesions.  
• The lower size limit of the target lesion(s) should be at least twice the thickness of the slices 
showing the tumor to decrease the partial volume effect (e.g., 8 mm lesion for a 4 mm slice). 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
 
11.3 Tumor Response Criteria  
11.3.1 Complete Response (CR) 
 Complete disappearance on MR of all evaluable tumor and mass effect, on a stable or decreasing dose of 
corticosteroids (or receiving only adrenal replacement doses), accompanied by a stable or improving 
neurologic examination, and maintained for at least 8 weeks.  If CSF was positive, it must be negative.  
 
11.3.2 Partial Response (PR) 
Greater than or equal to 50% reduction in tumor size by bi-dimensional measurement, as compared with 
the baseline measurements, on a stable or decreasing dose of corticosteroids, accompanied by a stable or 
improving neurologic examination, and maintained for at least 8  weeks.  
 
11.3.3 Stable Disease (SD) 
Neurologic exam is at least stable and maintenance corticosteroid dose not increased, and MR/CT imaging 
meets neither the criteria for PR nor the criteria for Progressive Disease.   
 
11.3.4  Progressive Disease (PD) 
Progressive Disease (PD): Progressive neurologic abnormalities or worsening neurologic status not 
explained by causes unrelated to tumor progression (e.g., anticonvulsant or corticosteroid toxicity wean, 
electrolyte disturbances, sepsis, hyperglycemia, etc.), OR a greater than 25% increase in the bi-
dimensional measurement, taking as a reference the smallest disease measurement recorded since the start 
of protocol therapy, OR the appearance of a new tumor lesion.   
 
Increasing doses of corticosteroids required to maintain stable neurological status should be strongly 
considered as a sign of clinical progression unless in the context of recent wean or transient neurologic 
change due to treatment effect.   
 
11.3.5 Progression-free Survival 
Interval of time between date of initiation of protocol treatment and minimum date of documentation of 
PD, second malignancy, death due to any cause, or date of last follow-up. 
 
11.3.5 Duration of Response 
• Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). The duration of overall 
CR is measured from the time measurement criteria are first met for CR until the first date that 
progressive disease is objectively documented. 
 
 
• Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since 
the treatment started, including the baseline measurements. 
 
 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
12 STUDY OVERSIGHT AND DATA REPORTING/ REGULATORY 
REQUIREMENTS/ CONFIDENTIALITY 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7 (Adverse 
Events: List and Reporting Requirements). 
 
12.1 Study Oversight 
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including the 
ongoing review of accrual, patient-specific clinical and laboratory data, and routine and serious adverse 
events; reporting of expedited adverse events; and accumulation of reported adverse events from other 
trials testing the same drug(s).  The Protocol Principal Investigator and statistician have access to the data 
at all times through Medidata Rave.  
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse events for 
that particular study.  This includes timely review of data collected on the electronic CRFs submitted via 
Medidata Rave. 
 
All studies are also reviewed in accordance with the Pediatric Brain Tumor Consortium's (PBTC) data 
safety monitoring plan. 
 
12.2 Data Reporting 
Data collection for this study will be done exclusively through the Medidata Rave clinical data 
management system.  Access to the trial in Rave is granted through the iMedidata application to all persons 
with the appropriate roles assigned in Regulatory Support System (RSS).  To access Rave via iMedidata, 
the site user must have an active CTEP-IAM account (check at https://ctepcore.nci.nih.gov/iam/) and the 
appropriate Rave role (Rave CRA, Read-Only, CRA (Lab Admin), SLA or Site Investigator) on either the 
LPO or participating organization roster at the enrolling site.  To the hold Rave CRA role or CRA Lab 
Admin role, the user must hold a minimum of an AP registration type.  To hold the Rave Site Investigator 
role, the individual must be registered as an NPIVR or IVR.  Associates can hold read-only roles in Rave.  
If the study has a DTL, individuals requiring write access to Rave must also be assigned the appropriate 
Rave tasks on the DTL. 
 
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned on the 
appropriate roster will be sent a study invitation e-mail from iMedidata.  To accept the invitation, site 
users must log into the Select Login (https://login.imedidata.com/selectlogin) using their CTEP-IAM user 
name and password, and click on the “accept” link in the upper right-corner of the iMedidata page.  Please 
note, site users will not be able to access the study in Rave until all required Medidata and study specific 
trainings are completed.  Trainings will be in the form of electronic learnings (eLearnings), and can be 
accessed by clicking on the link in the upper right pane of the iMedidata screen. 
 
Users that have not previously activated their iMedidata/Rave account at the time of initial site registration 
approval for the study in RSS will also receive a separate invitation from iMedidata to activate their 
account.  Account activation instructions are located on the CTSU website, Rave tab under the Rave 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
resource materials (Medidata Account Activation and Study Invitation Acceptance).  Additional 
information on iMedidata/Rave is available on the CTSU members’ website under the Rave tab at 
www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at 
ctsucontact@westat.com.  
 
Users may also contact OBDMC to get help with study specific issues including clinical forms, data entry, 
data query, data sign-offs and/or uploading of regulatory and other required documents. For complete 
OBDMC contact details, click on the OBDMC Contact Information link that is available in the Members’ 
Area of the PBTC website (http://www.pbtc.org/). 
 
12.2.1 Method 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0. A protocol and 
subject-specific CDUS “Abbreviated” data set will be submitted electronically to CTEP on a quarterly 
basis via CDUS OPEN (Oncology Patient Enrollment Network). Reports are due January 31, April 30, 
July 31, and October 31. Instructions for submitting data using the CDUS can be found on the CTEP 
website (http://ctep.cancer.gov/reporting/cdus.html). 
 
12.2.2 Responsibility for Data Submission 
The OBDMC for the PBTC is responsible for compiling and submitting CDUS data to CTEP for all 
participants and for providing the data to the Principal Investigator for review.   
 
12.3 CTEP Multicenter Guidelines 
N/A 
 
12.4 Collaborative Agreements Language 
N/A 
 
12.5 Participant and Data Confidentiality 
Participant confidentiality is strictly held in trust by the participating investigators, their staff and the 
sponsor(s) and their agents.  This confidentiality is extended to cover testing of biological samples and 
genetic tests in addition to the clinical information relating to participants.  Therefore, the study protocol, 
documentation, data and all other information generated will be held in strict confidence. No information 
concerning the study and the data will be released to an unauthorized third party without the prior written 
approval of the Pediatric Brain Tumor Consortium (PBTC).  
 
The PBTC protocol coordinators, other authorized representatives of the sponsor, regulatory 
representatives,  PBTC auditors,  representatives of the IRB or the pharmaceutical collaborator supplying 
study product may inspect all documents and records required to be maintained by the investigator, 
including but not limited to, medical records (office, clinic, or hospital) and pharmacy records for the 
participants in this study.  The clinical study site will permit access to such records. 
 
Source documents which are the original records of clinical findings, observations or activities in a clinical 
trial are to be maintained at each participating site.  Sites must upload all source documentation which 
supports the eligibility of the participant to the PBTC via the RAVE database. In the event the patient 
experiences unexpected events, additional source documentation may be requested to complete the event 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
review. These documents may include but are not limited to, hospital records, clinical and office charts, 
laboratory notes, memoranda and radiographic images.   
 
Study participant study related data, which is for purposes of statistical analysis and scientific reporting 
will be transmitted to the Pediatric Brain Tumor Consortium electronically via the RAVE database.  This 
will not include the participant's contact or identifying information.  Rather, research participants and their 
research data will be identified by a unique study identification number assigned at the time of screening 
or registration.  The study participant's contact information will be securely stored at each clinical site for 
internal use during the study.  At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by local IRB and institutional regulations. 
 
The study data entry and study management systems used by clinical sites and by the PBTC will be secured 
and password protected.  At the end of the study, all study data is maintained on a secure server.  
 
After the study is completed, the data collected will be maintained on a server and may be used by other 
investigators, including those outside the study.  With the participant's approval and as approved by local 
IRBs, biological samples labeled only with the participant's protocol specific identification number will 
be stored at the PBTC Central Review and Biorepository and could be made available to other 
investigators for future unspecified research.  Investigators conducting future studies will not have access 
to the key for stored data collected while the participant is on study.  Clinical data will be de-identified 
before it is shared with other investigators.  
 
If the participant agrees to submit a repository sample, those samples contain genetic information that may 
be used for research related to brain tumors and their treatment.  They may also be used to develop 
tests/assays to improve diagnosis and treatment of these diseases in the future.  Genetic research may 
consist of the analysis of one or more genes or the analysis of genetic markers throughout the genome. 
13 STATISTICAL CONSIDERATIONS 
13.1 Study Design/Endpoints 
 
Rolling-6 Design 
 
Phase I Study 
A ”Rolling-6” Phase I design will be used to estimate the maximum tolerated dose (MTD), where dose 
escalations are planned in cohorts of two-six patients. No intra-patient escalation will be allowed.  
 
Skolnik et al80 introduced the Rolling-6 design, motivated by the observation that most pediatric Phase I 
trials in oncology have not produced excessive toxicities. A possible explanation for this could be that 
pediatric studies are often preceded by adult trials and the knowledge gained in the latter is utilized towards 
ensuring safety in the former. The Rolling-6 design aims to shorten the duration of pediatric Phase I trials 
by minimizing the time the trial would be closed to accrual for toxicity monitoring. This is achieved by 
enrolling anywhere from 2 to 6 patients at a dose level without requiring that the DLT status of the patients 
already assigned to the same dose level are known; hence reducing the number of patients who would be 
turned away due to unavailability of open slots. The simulations in Skolnik et al. as well as Onar-Thomas 
and Xiong81 indicate that this approach decreases the duration of a Phase I trial compared to the traditional 


NCI Protocol #: PBTC-050 
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method and that the toxicity associated with the Rolling-6 design is not higher than the toxicity associated 
with the traditional method. 
 
13.2 Dose Escalation/De-Escalation Rules 
The Rolling-6 design allows for accrual of two to six patients concurrently onto a dose level. Decisions 
as to which dose level to enroll a patient are based on the number of patients currently enrolled and 
evaluable, the number of patients experiencing dose-limiting toxicities (DLT), and the number of patients 
still at risk of developing a DLT at the time of new patient entry. Dose escalation occurs if 0 of 3-6 or no 
more than 1 of 6 evaluable patients experience a DLT while being treated at a dose level; otherwise if 2 
of 2-6 patients experience DLTs the dose is declared too toxic and thus above the MTD. Once a dose is 
determined to be too toxic, further dose escalation is not allowed. The MTD is empirically defined as the 
highest dose level at which six patients have been treated with at most one patient experiencing a DLT 
and the next higher dose level has been determined to be too toxic.  
 
The following table enumerates all possible scenarios and describes escalation/de-escalation rules for the 
rolling 6 design. 
 
Dose Escalation/De-Escalation Rules for the Rolling-6 Design 
Decision when Next Patient is 
Enrolled 
# Pats 
Enrolled 
# Pats 
with 
DLTs 
# Pats w/o 
DLT 
# Pats 
with Toxicity 
Data Pending 
Not at the 
Highest 
Dose Level 
At the 
Highest 
Dose Level 
2 
0, 1 
Any 
Any 
Stay 
Stay 
2 
2 
0 
0 
De-escalate 
De-escalate 
3 
0 
0, 1, 2 
3, 2, 1 
Stay 
Stay 
3 
0 
3 
0 
Escalate 
Stay 
3 
1 
0, 1, 2 
2, 1, 0 
Stay 
Stay 
3 
≥ 2 
Any 
Any 
De-escalate 
De-escalate 
4 
0 
0, 1, 2, 3 
4, 3, 2, 1 
Stay 
Stay 
4 
0 
4 
0 
Escalate 
Stay 
4 
1 
0, 1, 2, 3 
3, 2, 1, 0 
Stay 
Stay 
4 
≥ 2 
Any 
Any 
De-escalate 
De-escalate 
5 
0 
0, 1, 2, 3, 4 
5, 4, 3, 2, 1 
Stay 
Stay 
5 
0 
5 
0 
Escalate 
Stay 
5 
1 
0, 1, 2, 3, 4 
4, 3, 2, 1, 0 
Stay 
Stay 
5 
≥ 2 
Any 
Any 
De-escalate 
De-escalate 
6 
0 
0, 1, 2, 3, 4 
6, 5, 4, 3, 2 
Suspend 
Suspend 
6 
0 
5, 6 
1, 0 
Escalate 
MTD not determined 
6 
1 
0, 1, 2, 3, 4 
5, 4, 3, 2, 1 
Suspend 
Suspend 
6 
1 
5 
0 
Escalate 
MTD not determined 
6 
≥ 2 
Any 
Any 
De-escalate 
De-escalate 


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As indicated in the above table, dose escalation occurs if 0 out of 3-6 or at most 1 out of 6 evaluable 
patients experience a DLT while being treated at a dose level; otherwise if 2 of 2-6 patients experience 
DLTs the dose is declared too toxic and thus above the MTD. Once a dose is determined to be too toxic, 
no escalation to higher dose levels is allowed.  
 
Special Considerations for Surgical Patients to Contribute to the Phase I component: 
Surgical patients will be counted towards the accrual of the Phase I trial when they initiate the combination 
treatment post-surgical recovery. Since we expect a delay of 4-6 weeks from enrollment of a surgical 
patient on the surgical study to his/her enrollment on the Phase I trial, it would be infeasible to reserve a 
slot on a given dose level for that long. Given the rarity of these patients we also do not want to miss 
enrolling a surgical patient due to unavailability of slots on the Phase 1 trial. Thus we propose the 
following contingencies for the surgical patients: 
- 
As long as accrual to the Phase I trial remains open, accrual to the surgical study will continue. 
- 
Surgical patients who meet treatment initiation criteria for the Phase 1 component post-surgical 
recovery will be enrolled on the current dose level where non-surgical patients are being enrolled (see 
section 5 for details).  
o If a slot is available at the time a surgical patient presents for Phase I enrollment, then the patient 
will count towards the maximum accrual of 6 patients at that dose level. 
o If a slot is not available at the current dose level i.e. 6 patients have been enrolled and accrual is 
temporarily on hold for DLT assessment, we will nonetheless enroll the surgical patient(s) at that 
dose level bringing the total to 7 (or more) patients. In this case, if the observed DLT rate is <0.33 
(i.e. 2 or fewer DLTs in 7 or 8 patients) then we will allow escalation. Otherwise the dose will be 
declared too toxic and de-escalation will occur. 
o Given the rarity of these patients we do not anticipate that we will enroll any more than 8 patients 
at a dose level but in the unlikely event that we do we will use 0.33 as the threshold for 
escalation/de-escalation decisions. 
 
Based on the above-outlined escalation rules, if the lowest proposed dose level is found to be too toxic, 
then the trial will be closed to accrual and the merits of amending or closing the trial permanently will be 
reconsidered. On the other hand, if the maximum dose level proposed for the study is deemed to be safe, 
then the MTD will be considered to be beyond the highest dose level and consideration may be given to 
investigate higher dose levels. Alternatively, the highest dose level may be recommended as the Phase II 
dose.  
 
Once the MTD has been estimated or the recommended Phase II dose has been determined, 6 additional 
patients will be treated at that dose level to better describe the toxicity profile of the agent. If the number 
of toxicities observed in the expansion cohort suggests that the initial estimate of the MTD is too toxic 
then we will consider de-escalating to a lower dose level and treating additional patients at that level 
including an expansion cohort in an effort to estimate the phase II recommended dose. 
 
Contingencies 
If all the dose levels are investigated with acceptable toxicity, consideration may be given to investigating 
higher dose levels. A deliberate decision will be made by the study committee and the sponsor. If a 
decision is made to not study higher doses, then the highest dose level may be recommended for further 
study in Phase II trials. 


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In the event of a single fatal toxicity, the OBDMC will suspend enrollment, pending discussion with the 
study chair, IDB and others as necessary. 
 
13.3 Sample Size/Accrual Rate 
We believe that it is unlikely we will study all 6 dose levels proposed but rather 4-5 dose levels. If 6 
patients are enrolled on each of the 5 proposed dose levels (including dose-de-escalation levels of either 
0 or -0.5 based on toxicities observed), up to 30 patients will be enrolled on the Phase I Study. Once the 
MTD has been estimated or the recommended phase II dose determined, 6 additional patients will be 
treated at that dose level to better describe the toxicity profile of this combination, bringing the total 
expected sample size for the Phase 1 component to 36 evaluable patients.   
 
Although it is difficult to estimate the number of patients who will be available for the surgical cohort, 
our past experience with PBTC studies suggests approximately 3-6 such patients may be enrolled.  In 
order for patients to be considered evaluable, tumor samples must be analyzable for the PK objectives.  
There is limited information available regarding the variability associated with intratumoral PK 
parameters and thus the desired sample size of 3-6 was chosen on pragmatic grounds and based on the 
fact that for plasma PK dose cohorts of 3-6 patients are often used in Phase I trials. Enrollment to the 
surgical cohort will continue throughout the Phase I study and will be closed when accrual to the Phase 1 
component is completed. 
 
Considering that there are always patients who enroll but are not evaluable for dose finding, we may need 
to screen as many as 70 patients for both the Phase I and surgical cohorts.  
 
13.3.1 Projected Accrual Rages and Study Duration 
The projected accrual rate is 1-2 patients per month for the Phase I Study and 2-3 patients per year for 
Surgical Study, based on knowledge of the member institutions and their commitment to the Consortium. 
With 4-5 likely dose levels, the total sample size and the study duration are expected to be 35-45 and about 
1.5-2.5 years, respectively, if four dose levels are investigated. We believe it is unlikely that both dose 
level -1 and dose level 3 will be evaluated. 
 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ Alaska Native 
0 
0 
0 
0 
0 
Asian 
0 
0 
2 
2 
4 
Native Hawaiian or Other Pacific 
Islander 
0 
0 
0 
0 
0 
Black or African American 
3 
3 
2 
2 
10 
White 
10 
11 
3 
3 
27 
More Than One Race 
1 
1 
1 
1 
4 
Total 
14 
15 
8 
8 
45 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
13.4 Analysis of Primary endpoints 
We will summarize toxicities observed on the study by dose level and by attribution in a table format. 
Similarly data from correlative studies will be reported descriptively.  Tumor PK concentrations will be 
compared to plasma PK and described descriptively as there are no data on CNS distribution of Ribociclib 
in humans and the expected sample size for the surgical trial is small.  Paired tests may also be used to 
capture any significant changes in these markers pre and post treatment.  
 
13.4.1 Statistical Analysis of Pharmacokinetics 
Plasma drug concentrations and pharmacokinetic parameters will be presented in tabular and graphical 
form. Pharmacokinetic parameters of interest, such as apparent volume of the central compartment (Vc/F), 
elimination rate constant (Ke), half-life (t1/2), apparent oral clearance (CL/F), and area under the plasma 
concentration time curve (AUC) will be estimated using compartmental methods. Dose proportionality in 
pharmacokinetic parameters will be investigated by performing one-way analysis of variance (ANOVA) 
on dose-normalized parameters. 
 
13.5 Analysis of Secondary endpoints 
Any objective responses (CR+PR) which may be observed in this trial will be described by dose and by 
histology. Prolonged stable diseases will also be reported in a descriptive fashion.  
 
Target inhibition will be descriptively defined by changes in phospho-RB1 and ki-67 via plots and 
summary statistics.  We will also descriptively summarize any associations between molecular subgroup 
designations and other biology correlates with observed response to ribociclib and everolimus if there are 
any. 
 
Prevention of stomatitis with dexamethasone-based mouthwash during course 1 and 2 will be descriptively 
defined by reporting the number of events of stomatitis and grade.   
 
In addition to estimating individual pharmacokinetic parameters, we will also estimate the population 
parameters using nonlinear mixed effects modeling methods (NONMEM). This method estimates the 
population parameters and both the inter- and intra-subject variability. Once the population parameters 
and corresponding covariance matrix are estimated, individual estimates can be obtained using post hoc 
analysis. 
 
 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
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NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
15 APPENDICES 
15.1  Performance Status Criteria 
 
MODIFIED LANSKY SCORE (Score as 0 - 100) 
A.  Normal Range 
100 = Fully active 
90 = Minor restrictions in physically strenuous play 
80 = Restricted in strenuous play, tires more easily, otherwise active 
 
B.  Mild to moderate restriction 
70 = Both greater restrictions of and less time spent in active play 
60 = Ambulatory up to 50% of time, limited active play with assistance/supervision 
50 = Considerable assistance required for any active play; full able to engage in quiet play 
 
C.  Moderate to severe restriction 
40 = Able to initiate quiet activities 
30 = Needs considerable assistance for quiet activity 
20 = Limited to very passive activity initiated by others e.g. TV) 
10 = Completely disabled, not even passive play 
  0 = Unresponsive, coma 
 
KARNOFSKY SCALE 
100 = Normal; no complaints 
90 = Able to carry on normal activities; minor signs or symptoms of disease 
80 = Normal activity with effort 
70 = Cares for self.  Unable to carry on normal activity or to do active work 
60 = Requires occasional assistance but able to care for most of his/her needs 
50 = Requires considerable assistance and frequent medical care 
40 = Disabled; requires special care and assistance 
30 = Severely disabled; hospitalization indicated though death not imminent 
20 = Very sick.  Hospitalization necessary.  Active support treatment necessary. 
10 = Moribund 
  0 = Dead 
 
 
 
 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
15.2 Prohibited medications - Ribociclib alone or Ribociclib and Everolimus 
Category 
Drug Name 
Strong CYP3A4/5 inhibitors 
Atazanavir/ritonavir, boceprevir, clarithromycin, cobicistat, conivaptan, 
danoprevir /ritonavir, darunavir/ritonavir, elvitegravir/ritonavir, grapefruit juice, 
idelalisib, indinavir, indinavir/ritonavir, itraconazole, ketoconazole, 
lopinavir/ritonavir, mibefradil, nefazodone, 
nelfinavir,ombitasvir/paritaprevir/dasabuvir/ritonavir (VIEKIRA PAK), 
posaconazole, ritonavir,  saquinavir/ritonavir, telaprevir, telithromycin, 
tipranavir/ritonavir, troleandomycinvoriconazole 
Strong CYP3A4/5 inducers 
carbamazepine3, enzalutamide, lumacaftor, mitotane, phenobarbital, phenytoin3, 
rifabutin, rifampin (rifampicin)3, St. John's wort (hypericum perforatum)2,3 
CYP3A4/5 substrates with 
NTI1 
Alfentanil, astemizole, cisapride, cyclosporine, diergotamine 
(dihydroergotamine), ergotamine, fentanyl,  pimozide, quinidine,  sirolimus, 
tacrolimus 
Medications with a known 
risk for QT prolongation4 
Amiodarone, anagrelide, arsenic trioxide, astemizole, azithromycin, 
chloroquine,  chlorpromazine, cilostazol, ciprofloxacin, cisapride, citalopram, 
clarithromycin, disopyramide, dofetilide, domperidone, donepezil, dronedarone, 
droperidol, erythromycin, escitalopram, flecainide, fluconazole, gatifloxacine, 
grepafloxacin, halofantrine, haloperidol, ibutilide, levofloxacin, 
levomepromazine, levosulpiride, methadone, moxifloxacin, ondansetron, 
oxaliplatin, papaverine HCl (intra-coronary), pentamidine, pimozide,  
procainamide, propofol, quinidine, roxithromycin, sevoflurane, sotalol,  
sulpiride, sultopride, terlipressin, terodiline,  thioridazine, vandetanib 
Herbal preparations/ 
medications 
Herbal preparations/medications known as strong inducers or inhibitors of 
CYP3A4/5 or those with a known risk of QT prolongation are prohibited 
throughout the study. These herbal medications include, but are not limited to: 
St. John’s wort, Kava, ephedra (ma huang), gingko biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. Patients 
should stop using these herbal medications 7 days prior to first dose of study 
drug. 
Other investigational and 
antineoplastic therapies 
Other investigational therapies must not be used while the patient is on the 
study. Anticancer therapy (chemotherapy, all SERMS (including raloxifene), 
biologic or radiation therapy, and surgery) other than the study treatments must 
not be given to patients while the patient is on the study medication. If such 
agents are required for a patient then the patient must be discontinued study 
drug. 
1 NTI = narrow therapeutic index drugs whose exposure-response indicates that increases in their exposure levels 
by the concomitant use of potent inhibitors may lead to serious safety concerns (e.g., Torsades de Pointes) or 
drugs which have <2-fold difference in the minimum toxic concentrations and minimum effective concentrations 
in the blood. 
2 Herbal product 
3 P-gp inducer 
4 The list provided is as of January 2018.Check https www crediblemeds.org/healthcare-providers/drug-list for the 
most updated list.  
As far as possible, avoid co-administration of QT prolonging drugs or any other drugs with the potential to 
increase the risk of drug-related QT prolongation (e.g., via a potential DDI that increases the exposure of 
ribociclib or the exposure of the QT prolonging drug). A definitive list of drugs with a known risk, possible risk, 
or conditional risk of QT prolongation and/or Torsades de Pointes (TdP) is available online at qtdrugs.org. 
Source: Novartis PK Sciences Memorandum: Drug-Drug Interactions (DDI) and Co-medication Considerations 
for Novartis Clinical Trials (January 2018), which is compiled from Indiana University “Clinically Relevant” 
Flockhart Table™, University of Washington Drug Interaction Database, and FDA Drug Development and Drug 
Interactions: Table of Substrates, Inhibitors and Inducers. 
 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
15.3 List of medications to be used with CAUTION during study drug treatment with Ribociclib 
alone or Ribociclib and Everolimus 
Category 
Drug Name 
Moderate CYP3A4/5 
inhibitors 
Aprepitant, amprenavir, asafoetida resin (Ferula asafoetida) cimetidine, crizotinib, 
diltiazem, faldaprevir,  imatinib,  isavuconazole, netupitant, nilotinib, tofisopam, 
Schisandra sphenanthera (nan wu wei zi), verapamil 
Moderate CYP3A4/5 inducers 
Bosentan, dabrafenib, efavirenz, etravirine, genistein,lopinavir5, modafinil, nafcillin, 
telotristat 
Sensitive CYP3A4/5 
substrates1 
Alpha-dihydroergocryptine,  aprepitant,  atorvastatin, avanafil, bosutinib,brotizolam, 
budesonide, buspirone,  cobimetinib,   darifenacin, dasatininb, ebastine, eletriptan, 
eplerenone, everolimus, felodipine, fluticasone, grazoprevir, ibrutnib, isavuconazole, 
ivabradine, ivacaftor, , levomethadyl (LAAM), lomitapide, lovastatin, lumefantrine, 
lurasidone, maraviroc, midazolam, midostaurin, naloxegol, neratinib, nisoldipine, 
perospirone, quetiapine, ridaforolimus, sildenafil, simeprevir, simvastatin, ticagrelor, 
tilidine,  tolvaptan, triazolam, ulipristal, vardenafil, venetoclax, vicriviroc, voclosporin 
BSEP inhibitors 
Alectinib, atorvastatin,  bromocriptine, candesartan, clobetasol, clofaziminie, 
dabigatran, dipyridamole, glyburide, grazoprevir, ledipasvir, 
mifepristone,pioglitazone, reserpine, rifamycin, simeprevir, telmisartan,timcodar, 
troglitazone, valinomycin, velpatasvir 
Medications that carry a 
possible risk for QT 
prolongation2 
Alfuzosin, apomorphine, aripiprazole, artenimol+piperaquine , asenapine, 
, atomoxetine,  bedaquiline, bendamustine, bortezomib, bosutinib, buprenorphine, 
cabozantinib, 
capecitabine, 
ceritinib, 
clomipramine, 
crizotinib,clozapine, 
cyamemazine (cyamepromazine), dabrafenib, dasatinib, degarilix, delamanid, 
desipramine, dexmedetomidine, dolasetron, efavirenz, eliglustat, epirubicin, eribulin 
mesylate, ezogabine(retigabine), famotidine, felbamate, fingolimod, flupentixol,  
gemifloxacin, granisetron, hydrocodone-ER, iloperidone, imipramine (melipramine), 
isradipine, ketanserin, lapatinib, lenvatinib, leuprolide, lithium, melperone, 
midostaurin, mifepristone, mirabegron, mirtazapine, moexipril/HCTZ, necitumumab, 
nicardipine, nilotinib, norfloxacin, nortriptyline, nusinersen, ofloxacin, osimertinib,  
oxytocin, paliperidone, palonosetron,  panabinostat, pasireotide, pazopanib, perflutren 
lipid 
microspheres, 
perphenazine, 
pilsicainide, 
pimavanserin, 
pipamperone, 
promethazine, prothipendyl,  rilpivirine, risperidone, romidepsin, sertindole, sorafenib, 
sunitinib, 
tamoxifen, 
tipiracil/trifluridine, 
tizanidine, 
tolterodine, 
toremifene,trimipramine, tropisetron, vardenafil, vemurafenib, venlafaxine, vorinostat, 
ziprasidone 
MATE1/2 substrates3 
Acyclovir, cephalexin, cimetidine, fexofenadine, ganciclovir, glycopyrronium, 
metformin, pindolol, plisicainide, ranitidine, topotecan, varenicline 
OCT1/2 substrates4 
 Amantadine,  6-beta-hydroxycortisol, carboplatin, cisplatin, cephalexin, cephradine, , 
, ,  ipratropium,  lamivudine, linagliptin, metformin, , oxyplatin, oxybutynin, 
phenformin, picoplatin, pilsicainide, pindolol, , ranitidine, sorafenib,  tropisetron, 
trospium, umeclidinium,, , and zidovudine 
BCRP substrates 
Daunorubicin, dolutegravir, doxorubicin, hematoporphyrin, imatinib, methotrexate, 
mitoxantrone, pitavastatin, rosuvastatin, irinotecan, ethinyl estradiol, simvastatin, 
sulfasalazine, sofosbuvir, tenofovir, topotecan, venetoclax 
1 Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold or higher when co-
administered with a potent inhibitor.2  The list provided is as of January 2018. Check https www 
crediblemeds.org/healthcare-providers/drug-list for the most updated list. 
3 MATE1 and MATE2 share considerable substrate specificity.  
4 OCT1 and OCT2 share considerable substrate specificity. 
5 Lopinavir is prohibited when combined with ritonavir (see Table 14-1) 
Source: Novartis PK Sciences Memorandum: Drug-Drug Interactions (DDI) and Co-medication Considerations for 
Novartis Clinical Trials (January 2018), which is compiled from Indiana University “Clinically Relevant” Flockhart 
Table™, University of Washington Drug Interaction Database, and FDA Drug Development and Drug Interactions: 
Table of Substrates, Inhibitors and Inducers. 
 
 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
 
15.4 List of prohibited medications – Everolimus 
 
Category 
Drug Name 
Strong PgP Inihibitors 
alogliptin, canaglifozin, cremophor RH40, curcumin, ketoconazole, 
lapatinib, lopinavir/ritonavir, mirabegron, 
propafenone, simepravir, valspodar, vandetanib, voclosporin 
Strong PgP/CYP3A4 dual 
inhibitors 
amiodarone, azithromycin, captopril, carvedilol, clarithromycin, 
conivaptan, diltiazem, dronedarone, elacridar, 
erythromycin, felodipine, , fluvoxamine, ginkgo (Ginkgo biloba), 
indinavir, indinavir/ritonavir, itraconazole, 
mibefradil, milk thistle (Silybum marianum), nelfinavir, nifedipine, 
nitrendipine, paroxetine, quercetin, quinidine, 
ranolazine, rifampin, ritonavir, saquinavir/ritonavir, Schisandra 
chinensis, St John’s wort (Hypericum perforatum), 
talinolol, telaprevir, telmisartan, ticagrelor, tipranavir/ritonavir, 
tolvaptan, verapamil 
Herbal 
preparations/ 
medications 
Herbal preparations/medications are prohibited throughout the study. 
These herbal medications include, but are not limited to: St. John’s wort, 
Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone 
(DHEA), yohimbe, saw palmetto, and ginseng. Patients should stop using 
these herbal medications 7 days prior to first dose of study drug. 
Other investigational and 
antineoplastic therapies 
Other investigational therapies must not be used while the patient is on the 
study. Anticancer therapy (chemotherapy, biologic or radiation therapy, 
and surgery) other than the study treatments must not be given to patients 
while the patient is on the study medication. If such agents are required 
for a patient then the patient must be discontinued study drug. 
Reference: Internal Clinical Pharmacology Drug-drug interaction (DDI) memo, updated April-2015 
which 
summarizes DDI data from three sources including the FDA’s “Guidance for Industry, Drug 
Interaction Studies”, 
the University of Washington’s Drug Interaction Database, and Indiana University School of 
Medicine's Drug 
Interaction Table. 
 
 
 
 
 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
15.5 Dosing Tables for Ribociclib 
 
Surgical Study 
• Based on 50mg and 200mg Capsules, round to the nearest 50mg. Patients allergic to peanut and 
soy are not permitted to take the film-coated tablet formulation. 
• Ribociclib liquid formulation is 30 mg/ mL. If a 1 mL syringe is used, each 0.1 mL is equivalent 
to 3 mg.   
 
 
Ribociclib Dose Level 
280 mg/m2/day 
Total Daily 
Dose (mg) 
BSA Range 
(m2) 
 Capsules Required 
Liquid  
Formulation  
Liquid total 
dose 
low 
high 
50 mg 
200 mg 
ml 
mg 
150 
0.50 
0.62 
3 
0 
5 
150 
200 
0.63 
0.80 
0 
1 
6.6 
198 
250 
0.81 
0.98 
1 
1 
8.3 
249 
300 
0.99 
1.16 
2 
1 
10 
300 
350 
1.17 
1.33 
3 
1 
11.6 
348 
400 
1.34 
1.51 
0 
2 
13.3 
399 
450 
1.52 
1.69 
1 
2 
15 
450 
500 
1.70 
1.87 
2 
2 
16.6 
498 
550 
1.88 
2.05 
3 
2 
18.3 
549 
600 
2.06 
2.23 
0 
3 
20 
600 
650 
2.24 
2.41 
1 
3 
21.6 
648 
700 
2.42 
2.50 
2 
3 
23.3 
699 
 
 
 
Ribociclib Dose Level 
350 mg/m2/day 
Total Daily 
Dose (mg) 
BSA Range 
(m2) 
 Capsules Required 
Liquid  
Formulation  
Liquid total 
dose 
low 
high 
50 mg 
200 mg 
ml 
mg 
200 
0.50 
0.62 
0 
1 
6.6 
198 
250 
0.63 
0.78 
1 
1 
8.3 
249 
300 
0.79 
0.92 
2 
1 
10 
300 
350 
0.93 
1.07 
3 
1 
11.6 
348 
400 
1.08 
1.21 
0 
2 
13.3 
399 
450 
1.22 
1.35 
1 
2 
15 
450 
500 
1.36 
1.50 
2 
2 
16.6 
498 
550 
1.51 
1.64 
3 
2 
18.3 
549 
600 
1.65 
1.79 
0 
3 
20 
600 
650 
1.80 
1.92 
1 
3 
21.6 
648 
700 
1.93 
2.08 
2 
3 
23.3 
699 
750 
2.09 
2.21 
3 
3 
25 
750 
800 
2.22 
2.35 
0 
4 
26.6 
798 
850 
2.36 
2.49 
1 
4 
28.3 
849 
900 
2.50 
2.50 
2 
4 
30 
900 
 
 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
 
Phase I Study: 
• Based on 50 mg and 200 mg Capsules, round to the nearest 50 mg. Patients allergic to peanut 
and soy are not permitted to take the film-coated tablet formulation. 
• Ribociclib liquid formulation is 30 mg/ mL. If a 1 mL syringe is used, each 0.1 mL is equivalent 
to 3 mg.   
 
 
Ribociclib Dose Level 
75 mg/m2/day 
Total Daily Dose 
(mg) 
BSA Range (m2) 
 Capsules Required 
Liquid 
Formulation  
Liquid 
dose 
calculation 
low 
high 
50 mg 
200 mg 
30mg/ml 
total 
50 
0.55 
1.02 
1 
0 
1.6 ml 
48 mg 
100 
1.03 
1.66 
2 
0 
3.3 ml 
99 mg 
150 
1.67 
2.33 
3 
0 
5 ml 
150 mg 
200 
2.34 
2.50 
0 
1 
6.6 ml 
198 mg 
 
 
 
 
Ribociclib Dose Level 
120 mg/m2/day 
Total Daily Dose 
(mg) 
BSA Range (m2) 
 Capsules Required 
Liquid 
formulation  
Liquid 
dose 
calculation 
low 
high 
50 mg 
200 mg 
30mg/ml 
total 
100 
0.75 
1.02 
2 
0 
3.3 ml 
99 mg 
150 
1.03 
1.45 
3 
0 
5 ml 
150 mg 
200 
1.46 
1.87 
0 
1 
6.6 ml 
198 mg 
250 
1.88 
2.29 
1 
1 
8.3 ml 
249 mg 
300 
2.30 
2.50 
2 
1 
10 ml 
300 mg 
 
 
 
 
Ribociclib Dose Level 
170 mg/m2/day 
Total Daily Dose 
(mg) 
BSA Range (m2) 
 Capsules Required 
Liquid 
formulation  
 
Liquid 
dose 
calculation 
low 
high 
50 mg 
200 mg 
30mg/ml 
total 
100 
0.45 
0.73 
2 
0 
3.3 ml 
99 mg 
150 
0.74 
1.02 
3 
0 
5 ml 
150 mg 
200 
1.03 
1.32 
0 
1 
6.6 ml 
198 mg 
250 
1.33 
1.61 
1 
1 
8.3 ml 
249 mg 
300 
1.62 
1.91 
2 
1 
10 ml 
300 mg 
350 
1.92 
2.20 
3 
1 
11.6 ml 
348  mg 
400 
2.21 
2.50 
0 
2 
13.3 ml 
399 mg 
 
 
 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
15.6 Patient Drug Information Handout 
 
Information for Patients, Their Caregivers, and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
 
The patient ____________________________ is enrolled on a clinical trial using the experimental study 
drugs, ribociclib (LEE011) and everolimus (RAD001).  This form is addressed to the patient, but includes 
important information for others who care for this patient.  
 
These are the things that you as a healthcare provider need to know:  
Ribociclib and everolimus interact with many drugs that are processed by your liver* and have an effect 
on the heart’s electrical activity (QTc prolongation)**. 
*The enzyme(s) in question are CYP3A4, FMO3, CYP2D6, and p-glycoprotein. Ribociclib and 
everolimus are broken down by these enzymes and may be affected by other drugs that inhibit or 
induce these enzymes.  
 
**The heart’s electrical activity may be affected by ribociclib. The study doctor may be concerned 
about QTc prolongation and any other medicine that is associated with greater risk for having QTc 
prolongation.   
 
To the patient: Take this paper with you to your medical appointments and keep the attached 
information card in your wallet.   
Ribociclib and everolimus may interact with other drugs which can cause side effects. For this reason, it 
is very important to tell your study doctors of any medicines you are taking before you enroll onto this 
clinical trial.  It is also very important to tell your doctors if you stop taking any regular medicines, or if 
you start taking a new medicine while you take part in this study.  When you talk about your current 
medications with your doctors, include medicine you buy without a prescription (over-the-counter 
remedy), or any herbal supplements such as St. John’s Wort.  It is helpful to bring your medication bottles 
or an updated medication list with you. 
 
Many health care providers can write prescriptions.  You must tell all of your health care providers 
(doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a clinical trial.  
 
These are the things that you and they need to know:  
Ribociclib and everolimus must be used very carefully with other medicines that use certain liver enzymes 
or transport proteins to be effective or to be cleared from your system or that may affect your heart’s 
electrical activity.  Before you enroll onto the clinical trial, your study doctor will work with your regular 
health care providers  to review any medicines and herbal supplements  that are considered strong 
inducers/inhibitors or substrates of CYP3A4, FMO3, p-glycoprotein, or any medicine associated with 
greater risk for having QTc prolongation. 
 
• Please be very careful!  Over-the-counter drugs (including herbal supplements) may contain 
ingredients that could interact with your study drug.  Speak to your doctors or pharmacist to 
determine if there could be any side effects.  


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
• Patients must avoid consumption of grapefruit, Seville oranges or products containing the juice of 
each during the entire study and preferably 7 days before the first dose of study medication, due 
to potential CYP3A4 interaction with the study medications. Orange juice is allowed. 
 
Your regular health care provider should check a frequently updated medical reference or call your study 
doctor before prescribing any new medicine or discontinuing any medicine.  Your study doctor’s name is 
__________________________ 
and 
he 
or 
she 
can 
be 
contacted 
at 
_____________________________________. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY DRUG INFORMATION WALLET CARD   
You are enrolled on a clinical trial using the experimental study  
drug Ribociclib and Everolimus. Ribociclib and Everolimus may interact 
with drugs that are processed by your liver, or use certain transport 
proteins in your body or affects the electrical activity of your heart.  
Because of this, it is very important to: 
➢ Tell your doctors if you stop taking any medicines or if you start taking 
any new medicines. 
➢ Tell all of your health care providers (doctors, physician assistants, 
nurse practitioners, or pharmacists) that you are taking part in a clinical 
trial. 
➢ Check with your doctor or pharmacist whenever you need to use an 
over-the-counter medicine or herbal supplement. 
 
 
 
Ribociclib and everolimus interacts with a specific liver enzyme called 
CYP3A4, FMO3, CYP2D6, and p-glycoprotein,, transport protein, heart’s 
electrical activity (QTc prolongation, and must be used very carefully 
with other medicines that interact with this enzyme, transporter, or 
agent.  
Before you enroll onto the clinical trial, your study doctor will work with 
your regular health care providers to review any medicines  and herbal 
supplements that are considered strong inducers/inhibitors or 
substrates of CYP3A4, FMO3, CYP2D6, and p-glycoprotein, or 
transporter; or affect the heart’s electrical activity  
Before prescribing new medicines, your regular health care providers 
should go to a frequently-updated medical reference for a list of drugs 
to avoid, or contact your study doctor.   
➢ Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.  


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
15.7 Caregiver and Patient instructions for administration of everolimus dispersible tablets using 
a Dosing Cup 
 
Please read this information before preparing and taking your study drug.  Please check with your study 
doctor or study team if you have any questions.   
 
The everolimus dispersible tablets are made to be dissolved in water creating an oral suspension of the 
study drug.   The oral suspension can be mixed in either a cup or syringe.  If drug gets into eyes, flush 
with large amount of water while holding eyelids open for at least 15 minutes.  Call your doctor or nurse 
immediately (insert phone #) and/or the Poison Control Center at (insert phone #).  If you spilled the drug 
on your skin, remove contaminated clothing. Wash the area with soap and a large amount of water.  Get 
medical attention if irritation develops or persists by calling the numbers listed above.  
 
WHAT DO YOU NEED 
• Everolimus dispersible tablets 
• Dosing cup or syringe 
• Drinking water or bottled water.  Do not use seltzer (sparkling) water or juice.   
 
HOW TO PREPARE THE EVEROLIMUS ORAL SUSPENSION - DOSING CUP 
Step 1:  Wash and dry your hands before preparing the medication. 
 
 
Step 2:  Add 5 mL of water into the dosing cup.  
 
Step 3:   
Remove the required number of dispersible tablets (              )  from 
tablet cards   
 
Step 4: 
Allow the dispersible tablets 3 minutes to disintegrate. Make sure to 
proceed further only when the 3 minutes are over and when the 
dispersible tablets have completely suspended. 
 
 
Step 5: 
Mix the content in the dosing cup by gentle swirling of the cup. 
 
The suspension is stable for up to one hour if cannot be given 
immediately.   
 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
 
Step 6:  Drink the full amount of liquid in the cup. 
 
Step 7: 
Refill the drinking glass with the same amount of water 
___________mL stir it again with the same spoon to suspend 
remaining particles and drink the full amount to ensure the entire 
dose is administered. 
 
  
Step 8: 
Rinse the dosing cup thoroughly with water.  Wipe the dosing cup 
with a clean paper towel and store it in a dry and clean place until 
next dosing. 
Step 9: 
Wash your hands. 
 
TABLET STORAGE 
The everolimus tablets should be stored at room temperature.  Store the drug away from food and out of 
reach of children and pets. 
 
RETURN OF STUDY DRUG 
All left over everolimus tablets need to be brought back to the study doctor at every clinic visit with the 
completed patient diary.   
 
 
 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
15.8 Caregiver and Patient instructions for administration of everolimus dispersible tablets using 
a Syringe 
 
Please read this information before preparing and taking your study drug.  Please check with your study 
doctor or study team if you have any questions.   
 
The everolimus dispersible tablets are made to be dissolved in water creating an oral suspension of the 
study drug.   The oral suspension can be mixed in either a cup or syringe.  If drug gets into your eyes, 
flush with large amount of water while holding eyelids open for at least 15 minutes.  Call your doctor or 
nurse immediately (insert phone #) and/or the Poison Control Center at (insert phone #).  If you spilled 
the drug on your skin, remove contaminated clothing. Wash the area with soap and a large amount of 
water.  Get medical attention if irritation develops or persists by calling the numbers listed above. 
 
 
WHAT DO YOU NEED 
• Everolimus dispersible tablets 
• Dosing cup or syringe 
• Drinking water or bottled water.  Do not use seltzer (sparkling) water or juice.   
 
HOW TO PREPARE THE EVEROLIMUS ORAL SUSPENSION - SYRINGE 
Step 1:  Wash and dry your hands before preparing the 
medication. 
Step 2:  Take a ______ml oral syringe and remove the plunger. 
Step 3:  Remove the required number of dispersible tablets    
 (                 ) from tablet cards   
Step 4: 
Re-insert the plunger into the syringe and push it inward to 
make contact with the dispersible tablets. 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
 
Step 5: 
Fill drinking glass with water and fill 5 mL of the water into 
the oral syringe by slowly pulling the plunger up. Turn the 
syringe upside-down so the tip points up. Then pull some 
additional _______ mL air. Place the filled syringe tip up in a 
glass. 
 
 
Step 6: 
Allow the dispersible tablets 3 minutes to disintegrate. Make 
sure to proceed further only when the 3 minutes are over and 
when the dispersible tablets have completely suspended. 
Step 7: 
Carefully turn the oral syringe upside down five times. 
Do not shake the oral syringe to avoid suspension leaking from 
the tip. 
 
Step 8: 
While holding the oral syringe in an upright position, carefully 
remove the excess air. 
 
Expel/dispose ________mLs of the solution in the oral syringe 
before giving to patient.   
 
Step 9: 
Dispense immediately the full content of the oral syringe 
slowly and gently into the mouth of the patient. Carefully 
remove the syringe from patient’s mouth when empty 
 
The suspension is stable for up to one hour of cannot be given 
immediately.   


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date:  September 26, 2018 
 
 
 
Step 10: 
Fill the oral syringe once more with the water by slowly 
pulling the plunger up. Turn the syringe so the tip is pointing 
up, and draw some additional mL air. Swirl the contents to 
suspend any remaining particles of the medication. While 
holding the syringe in an upright position, carefully remove 
the excess air. Then dispense the full contents of the oral 
syringe slowly and gently into the mouth of the patient. 
Step 11: 
Take apart the oral syringe and rinse all parts thoroughly with 
water. Store them in a dry and clean place until next dosing. 
Step 12: 
Wash your hands. 
 
TABLET STORAGE 
The everolimus tablets should be stored at room temperature.  Store the drug away from food and out of 
reach of children and pets. 
 
RETURN OF STUDY DRUG 
All left over everolimus tablets need to be brought back to the study doctor at every clinic visit with the 
completed patient diary.   
 
 

ICF_001.pdf: 
NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date: September 26, 2018 
1 
 
Model Consent Form – Screening Consent 
  
Study Title for Study Participants: 
Screening Test to find out the presence or absence of retinoblastoma protein (Rb1) in patients 
with brain tumors  
 
Official Study title for Internet Search on http://www.ClinicalTrials.gov  
 PBTC-050: A Phase I and Surgical Study of Ribociclib and Everolimus (RAD001) in 
Children with Recurrent or Refractory Malignant Brain Tumors 
 
“You” refers to ‘you’ or ‘your child’ throughout this document. If you are the guardian of a 
minor or of a person under legal disability who is being asked to participate in this screening 
study, you may give consent on his/her behalf. 
 
INTRODUCTION: 
This is a screening consent for a brain tumor clinical trial called PBTC-050. We are asking you 
to participate in a screening procedure for a research study and your consent to provide a tumor 
tissue sample for research.  This is not the informed consent for this clinical trial.  
 
In order to decide whether or not you agree to take part in the screening study, you should know 
enough about its risks and benefits to make your decision. 
 
The study doctor or staff will explain the screening study to you and answer your questions about 
this testing.  Screening study only include people who choose to take part. Before making your 
decision, please read the information below carefully. Please ask questions about anything you 
do not understand. 
 
Clinical trial summary 
This screening process is for the research protocol entitled: “A Phase I and Surgical Study of 
Ribociclib and Everolimus (RAD001) in Children with Recurrent or Refractory Malignant Brain 
Tumors”. You are being asked to take part in the research study because you have a brain cancer 
of either High Grade Glioma or medulloblastoma or CNS embryonal tumor (NOS) or 
Ependymoma, or ATRT or DIPG.  This study has two parts: Phase I and Surgical portion. 
Depending on which criteria you would meet, your study doctor will approach you to offer either 
Phase I or surgical portion of the study.   
  
Why is this study being done? 
The purpose of this screening consent is to perform a test on a sample of your tumor tissue which 
was removed at the time of your initial diagnostic surgery/biopsy and has been stored in a 
hospital laboratory. This screening procedure is a test, called Rb1 screening test, to see if you 
qualify to take part in a main research study of either Phase I or surgical portion.   
 
If you sign the screening consent, you are only agreeing to have this test done by allowing your 
study doctor to obtain your tissue sample from pathology. If the test result shows that you are 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date: September 26, 2018 
2 
eligible to take part in the research study, a separate informed consent will be provided to you 
describing full in details about the study and the investigational drug(s). Agreeing to have your 
tumor tissue screened does not oblige you to agree to participate in the main research study.  You 
can still decide not to participate in the main research study.   
 
In order to participate in the main research study, your study doctor must assess whether your 
tumor tissue has a specific protein called Rb1 protein. This Rb1 protein is a protein that 
suppresses your tumor from growing.  We want to find out whether your tumor has Rb1 protein 
or not so that we can consider you for participation in the main study.  Up to 70 people, between 
the ages of 1 and 21 years old, will be screened throughout the United States.  
 
Another purpose of this consent is we are asking you to let us store any leftover tumor samples 
after the screening test is completed at Cincinnati Children’s Hospital Medical Center (CCHMC) 
for possible use in future research. This is optional and only if you agree, your tumor samples 
will be kept at a central place, called the Pediatric Brain Tumor Consortium Central Review and 
Biorepository (PBTC CRB).    
 
What is involved in this screening procedure? 
This screening procedure will include sending a piece of tumor tissue collected from a previous 
surgery to a laboratory at Cincinnati Children’s Hospital Medical Center. However, if this test 
was completed at your local institution in a CLIA certified laboratory, we will be able to review 
those results to determine if additional testing is needed to confirm Rb1 status.  The Investigators 
will look for the presence of Rb1 protein in the tumor tissue. Results from this test will determine 
if you are eligible to take part in the main research study. If Rb1 protein is present, the study 
doctor or study nurse will discuss the main research study with you and you will be able to ask 
questions. If you are interested in taking part in the research study, you will be scheduled to have 
the rest of the eligibility procedures performed. You must meet all other eligibility criteria before 
you are able to participate in the main research study. 
 
How long will I be in the study? 
Since this is just a screening procedure, your involvement in this study will be minimal. The 
screening test will be done as soon as possible after you sign this consent.  The results will be 
given to your doctor who will discuss them with you and talk about the next steps.  
 
After the screening procedure is completed: 
If you are eligible and interested in taking part of the surgical study, this portion will take about 2 
months. After you complete the surgical study portion, you will also be given an option of 
joining the Phase I portion.  
The Phase I portion will take 1 to 2 years. You will receive ribociclib and everolimus for 
approximately 1 year (13 courses) and if there are no side effects, you may continue the study for 
another year (total 2 years).   
Can I stop being in the study? 
Yes, you may withdraw this consent and discontinue your participation in the screening study at 
any time. To withdraw your consent, you must contact the study doctor and tell him/her that you 
are changing your mind.  


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If you change your mind and your samples have already been tested, those results will still 
remain part of the overall research data.   
What are the possible risks, side effects, and discomforts of this screening study? 
Since your tumor tissue has already been collected during the surgery, there are no additional 
risks to you involved with this screening test.  However, there is a possibility that completing this 
test will result in exhaustion of tumor tissue.   
 
What are the benefits of participating in this study? 
There are no benefits from having this tissue testing done other than to show if you might be able 
to participate in the main research study. 
 
What other choices do I have if I do not take part in this study? 
If you decide not to take part in this study, you will not be able to take part in the main research 
study.  You do have choices. For example: 
• you may choose to take part in a different study, if one is available 
 
Is my participation in this screening procedure voluntary? 
Yes. Taking part in this screening procedure is voluntary. No matter what you decide to do, it 
will not affect the medical care you would normally receive from your doctor. 
 
Who will know about my participation in this screening study? 
Your privacy is very important to us.  The study doctors will make every effort to protect it.  The 
study doctors have a privacy permit to help protect your records if there is a court case.  
However, some of your medical information may be given out if required by law.  If this should 
happen, the study doctors will do their best to make sure that any information that goes out to 
others will not identify who you are.  
 
Some of your health information, such as your response to cancer treatment, results of study 
tests, and medicines you took, will be kept by the study sponsor in a central research database.  
However, your name and contact information will not be put in the database.  If information 
from this study is published or presented at scientific meetings, your name and other personal 
information will not be used.  
There are organizations that may look at your study records.  Your health information in the 
research database also may be shared with these organizations.  They must keep your 
information private, unless required by law to give it to another group.   
 
Some of these organizations are: 
• Your referring physician. 
• The Institutional Review Board, IRB,  is a group of people who review the research with 
the goal of protecting the people who take part in the study 
• The Pediatric Brain Tumor Consortium, which coordinates this study 
• The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), involved in keeping screening safe for people 
• Novartis and its authorized agents 


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• Governmental agencies in other countries where the study drug may be considered for 
approval 
• Cincinnati Children’s Hospital Medical Center  
 
A description of this clinical trial may be available on http://www.ClinicalTrials.gov. This Web 
site will not include information that can identify you. At most, the Web site will include a 
summary of the results.  You can search this Web site at any time. 
 
What are the costs of taking part in this study? 
The cost associated with this screening procedure will be covered by the study budget. Neither 
you nor your insurance provider will be charged. 
 
Will I be paid if I take part in this screening procedure? 
Participation in this screening procedure is voluntary. No payment for participation will be 
given. 
 
What happens if I am injured because I took part in this study? 
There is no risk of injury involved because this screening test will use previously collected tumor 
sample material.  
 
What are my rights if I take part in this study? 
Taking part in the screening procedure is your choice.  You may choose either to take part or not 
to take part in the screening procedure.  No matter what decision you make, there will be no 
penalty to you and you will not lose any regular benefits.  Your medical care will not be affected 
if you do not participate in this screening procedure.  You can still get medical care from our 
institution.    
 
Who can answer my questions about the study? 
You can talk to the study doctor about any questions or concerns you have about this study. 
Contact the study doctor (insert name of study doctor[s]) at (insert telephone number). 
 
For questions about your rights while in this study, call the (insert name of center) Institutional 
Review Board (a group of people who review the research to protect your rights) at _(insert 
telephone number). 
 
Where can I get more information? 
You may call the National Cancer Institute's Cancer Information Service at:  
1-800-4-CANCER (1-800-422-6237) 
 
You may also visit the NCI Web site at http://cancer.gov/ 
For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/. For NCI’s general 
information about cancer, go to http://cancer.gov/cancerinfo/ 
 
You will get a copy of this form.  If you want more information about this study, ask your study 
doctor. 
 


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Additional Study Section:  
This part of the consent form is about optional study that you can choose to take part in during 
the screening procedure. You will not get health benefits from this study. The researchers leading 
this optional study hope the results will help other people with cancer in the future. The results 
will not be added to your medical records and your study doctor will not know the results. 
 
You will not be billed for this optional study. You can still take part in the screening test and also 
in the main study even if you say “no” to this optional studies. If you sign up for but cannot 
complete this study for any reason, you can still take part in the main study. 
 
What is involved? 
1. 
Your leftover tumor samples after the screening test is completed at CCHMC will be sent 
to the PBTC Central Review and Biorepository (PBTC CRB).  
2. 
Your samples and some related health information may be stored in the PBTC Central 
Review and Biorepository (PBTC CRB), along with samples and information from other 
people who take part. The samples will be kept until they are used up. Information from 
your medical record will be updated from time to time. 
3. 
Qualified researchers can submit a request to use the materials stored in the Repository. 
The science committee of the PBTC and/or the National Cancer Institute, will review each 
request. Researchers will not be given your name or any other information that could 
directly identify you.  
4. 
Neither you nor your study doctor will be notified when research will be conducted or 
given reports or other information about any research that is done using your samples.  
5. 
Some of your genetic and health information may be placed in central databases that may 
be public, along with information from many other people. Information that could directly 
identify you will not be included. 
 
What are the possible risks?  
1. 
There is a risk that someone could get access to the personal information in your medical 
records or other information researchers have stored. 
2. 
There is a risk that someone could trace the information in a central database back to you. 
Even without your name or other identifiers, your genetic information is unique. The 
researchers believe the chance that someone will identify you is very small, but the risk 
may change in the future as people come up with new ways of tracing information. 
3. 
There can also be a risk in knowing genetic information. New health information about 
inherited traits that might affect you or blood relatives could be found during a study. 
The researchers believe the chance these things will happen is very small, but cannot 
promise that they will not occur. In general, we will not give you any individual results 
from the study of the samples you gave us.  This is because it will probably be a long 
time before we will know how to interpret the information accurately.  In the rare 
instance that one of the genes tested might turn out to be an important risk factor for a 
disease, and having that information could allow you to take steps to prevent, detect 
earlier, or better treat that disease, we will ask you whether you want to know those 
results. If so, we will contact you and your doctor to discuss more testing.  
4. 
 Some of your genetic and health information may be placed in central databases that 
may be public, along with information from many other people. The data resulting from 


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the genetic research may be deposited into a public or controlled access database made 
available to other researchers. Information that could directly identify you will not be 
included. However, people may develop ways in the future that would allow someone to 
link your genetic or medical information in our databases back to you. For example, 
someone could compare information in our databases with information from you (or a 
blood relative) in another database and be able to identify you (or your blood relative). It 
also is possible that there could be violations to the security of the computer systems 
used to store the codes linking your genetic and medical information to you. 
 
How will information be kept private? 
Your privacy is very important to the researchers and they will make every effort to protect it. 
Here are just a few of the steps they will take: 
1. When your sample(s) is sent to the researchers, no information identifying you (such 
as your name) will be sent. Samples will be identified by a unique code only.  
2. The list that links the unique code to your name will be kept separate from your 
sample and health information.  
3. Researchers to whom the Pediatric Brain Tumor Consortium (PBTC) sends your 
sample and information will not know who you are. They must also sign an 
agreement that they will not try to find out who you are.  
4. Information that identifies you will not be given to anyone, unless required by law. 
5. If research results are published, your name and other personal information will not 
be used. 
 
What are the possible benefits? 
You will not benefit from taking part. The researchers, using the samples from you and others, 
might make discoveries that could help people in the future. 
 
Are there any costs or payments?  
There are no costs to you or your insurance. You will not be paid for taking part. If any of the 
research leads to new tests, drugs, or other commercial products, you will not share in any 
profits. 
 
What if I change my mind? 
If you decide you no longer want research samples to be used, you can contact your study doctor 
in writing, (insert name of study doctor) who will let the researchers know. Then, any sample 
that remains in the repository will no longer be used and related health information will no 
longer be collected. Samples or related information that have already been given to or used by 
researchers will not be returned. If data has been submitted to a data repository, please include in 
your letter a request to retrieve your data.   
 
What if I have more questions? 
If you have questions about the use of your samples for research, contact your study doctor, 
(insert name of study doctor), at (insert telephone number of study doctor). 
 


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Please circle your response and then initial and date on the line provided.  
• Leftover sample storage for future research 
If you choose to take part, tumor tissue collected for the screening test but not completely used 
for the analysis will be stored in the repository for future unspecified research. The researchers 
ask your permission to store and use your tumor sample and related health information (for 
example, your response to cancer treatment, results of study tests and medicines you are given) 
for medical research. The research that may be done is unknown at this time.  
 
I agree to have my specimen collected and I agree that my specimen sample and related 
information may be used for the optional study described above. 
 
  
YES 
_______________ 
 
NO 
__________________ 
 
 


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My Signature Agreeing to Take Part in the Rb1 screening test 
The purpose of this screening consent for Rb1 test has been explained to me and all of my 
current questions have been answered. 
 
I understand that I am encouraged to ask questions about any aspect of this screening study 
during the course of this study, and that such future questions will be answered by a qualified 
individual or by the investigator(s) listed on the first page of this consent document at the 
telephone number(s) given. I understand that I may always request that my questions, concerns 
or complaints be addressed by a listed investigator. 
 
By signing this form, I agree to participate in this screening study. A copy of this consent form 
will be given to me. 
 
 
 
PATIENT NAME:  _______________________________________________________ 
(Print Name) 
 
 
___________________________________________________________________________ 
Signature of Patient or Parent or Legal Guardian or Next of Kin 
 
Date 
 
 
 
__________________________________________________________________________  
Signature of 2nd Parent or Legal Guardian 
 
 
 
 
Date 
 
 
___________________________________________________________________________ 
Signature of Investigator or Designee 
 
 
 
 
Date 
 
 
___________________________________________________________________________ 
Signature of Witness  
 
 
 
 
 
 
Date 
 


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Model Consent Form – Surgical Study 
 
Study Title for Study Participants: 
Testing ribociclib in patients with brain tumors who require surgery  
 
Official Study title for Internet Search on http://www.ClinicalTrials.gov  
PBTC-050: A Phase I and Surgical Study of Ribociclib and Everolimus (RAD001) in Children 
with Recurrent or Refractory Malignant Brain Tumors 
 
“You” refers to ‘you’ or ‘your child’ throughout this document. If you are the guardian of a minor or of 
a person under legal disability who is being asked to participate in this study, you may give consent on 
his/her behalf. 
 
This form describes your participation in a clinical trial. A clinical trial is a type of research study.  
Clinical trials include only people who choose to take part.  This consent form gives you 
information about this study, to be discussed with members of your study team.   
 
Please take time to make the decision about whether to take part.  Please discuss this decision with 
your family and friends.  If there are any questions, ask your study doctor or health care team for 
more explanation.   
 
What is the usual approach to my brain cancer? 
You are being asked to take part in this research study because you have a brain tumor that has 
grown or recurred and that will be removed through a surgical resection as a standard treatment. 
Your tumor has one of the following types - either High Grade Glioma or medulloblastoma or 
CNS embryonal tumor (NOS) or Ependymoma, or Atypical teratoid rhabdoid tumor (ATRT). 
People who are not in a study are usually treated with chemotherapy, radiation or other 
investigational agents which may or may not be FDA approved. Sometimes, combinations of these 
are used and your study doctor can explain which may be best for you.  These treatments can 
reduce symptoms and may stop the tumor from growing for several months or more. 
 
What are my other choices if I do not take part in this study? 
If you decide not to take part in this study, you have other choices. Please talk to your doctor 
about these other options.  For example: 
 You may choose to have the usual approach described above 
 You may choose to take part in a different research study, if one is available 
 or you may choose not to be treated for cancer but you may want to receive comfort care to 
relieve symptoms. 
 
Why is this study being done?  
This research study has two portions: Phase I and Surgical study. For now, we will talk to you 
about participation in the surgical portion of the study. Once you finish the surgical study, you will 
be asked again if you like to continue for participation in the Phase I study. The information about 
the participation in the Phase I study will describe more in details in the Phase I consent.   
  


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The purpose of this surgical study is to test the amount of a study drug called ribociclib in your 
tumor and blood prior and during surgery for removal of the recurrent tumor.  We have also learned 
that this study drug works better if your tumor has an intact Rb1 protein. You have been 
approached for this study because we know that you will have your brain tumor tissue removed 
within a few weeks and that this Rb1 protein is present in your tumor tissue that is removed during 
this surgery.  
 
Ribociclib has not been approved by the FDA (the U.S. Food and Drug Administration) for the 
treatment of brain cancer, therefore, is considered experimental for this trial. But it has been 
approved for other use. This drug has been tested for safety in adults and children. About 3 to 6 
people, between the ages of 1 and 21 years old, are expected to taking part in this surgical study. 
 
What are the study groups? 
There will be only one dose of the study drug, ribociclib for the surgical study. All study 
participants will get the same study drug, ribociclib in the form of either capsules or tablets or 
liquid solutions. You must take one formulation of ribociclib (i.e. liquid, capsules or tablets) prior 
to surgery.  You will take ribociclib once daily at approximately the same time every morning for 
7 to 10 days before surgery. The study doctor will tell you how many pills you should take. 
Ribociclib pills should be swallowed whole whenever possible. It is important to take the pills 
with a large glass of water at the same time every day preferably in the morning, at least an hour 
before or an hour after a meal.  
 
If you forget to take your dose and if less than 6 hours of the scheduled dose, you may replace the 
dose of ribociclib on the same day. After more than 6 hours of missed dose, the dose should be 
withheld, and you should wait to take ribociclib until the next day (do not try to make-up the 
missed dose after 6 hours). Then continue treatment with the original dosing schedule. If vomiting 
occurs within 10 minutes, the dose should be repeated. We will give you a pill diary where you 
will document information about doses taken, missed doses and reason for missing dose(s).  You 
should bring your diary to each clinic visit and your physician will review it with you.   
 
We advise that you drink plenty of water or take hydration fluids to avoid dehydration if diarrhea 
occurs. You must also avoid eating grapefruit, Seville oranges or any products containing the 
grapefruit juice or Seville orange juice. You should not take any herbal or dietary supplements. 
Check with your study doctor if you are unsure what to avoid.   
 
How long will I be in this study? 
You will receive the ribociclib for 7 to 10 days prior to the resection of your brain tumor tissue. 
During and after tumor resection, your study doctor will watch you for any significant side effects. 
The study doctor will continue to watch you and follow your condition until you are completely 
recovered from the surgery.   
 
It is expected that this surgical study will take you about 2 months to finish. You will then return 
to your doctor for re-evaluation and your doctor will also discuss with you for an option of 
switching over to Phase I study. You will be given a copy of the Phase I consent which covers 
more details about that study. If you are interested in taking part, talk to your doctor.     
 


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What extra tests and procedures will I have if I take part in this study? 
Most of the exams, tests, and procedures you will have are part of routine medical care for this 
type of cancer and may be done even if you do not join the study. On some days when you have 
labs, your doctor may tell you that you can’t have anything to eat or drink before your labs are 
drawn.  However, there are some extra tests and/or procedures that will need to be completed if 
you take part in this study. They are considered research related procedures and not part of the 
usual approach for this type of cancer.  
 
Before you begin the study: 
You will need to have the following extra tests and procedures to find out if you can be in the 
study: 
 Screening for Rb1 protein 
This study has a screening step. Because you have a type of brain tumor that is either High Grade 
Glioma or medulloblastoma or CNS embryonal tumor (NOS) or Ependymoma, or ATRT, this 
screening test was performed on your tumor tissue that was collected from a previous surgery 
and the test result showed that your tumor has an intact Rb1 protein. Based on this result, we 
know that you are eligible to see if you meet all other requirements to take part in the surgical 
study. 
 
 Electrocardiogram (EKG) 
An electrocardiogram is a simple, painless test that records the heart’s electrical activity. To assess 
the activity of your heart, your study doctor will do an EKG before you start ribociclib.  
 
 ECHO  
An echocardiogram uses sound waves to make pictures of your heart, which helps to show how 
well your heart pumps blood. An ECHO will be done before you start ribociclib.  
 
If the exams, tests, and procedures show that you can take part in the study, and you choose to 
take part, then you will need the extra tests and procedures listed in the Study Calendar. They are 
not part of the usual approach for your type of cancer. 
 
During the study: 
 
 Pharmacokinetics (PK) blood (required) 
You are required to take part in this study because determining how the body handles this drug is 
an important part of the study. The researchers would like to learn how much ribociclib stays in 
the blood for 5 specific time points after the drug is taken continuously for 7 to 10 days. This study 
will require about 1 teaspoon (5 milliliters) of blood to be collected from your arm or central line 
before you start ribociclib (day -7 or Day -10, Day -5, Day -2, on the day of surgery, during surgery 
when tumor tissue is collected).   
 
 Pharmacokinetics (PK) tumor tissue (required) 
A piece of your brain tumor tissue (about 50 to 100 mg) will be collected during the brain surgery. 
This is a required test because the researchers would want to see the amount of ribociclib that stays 
in the tumor after the drug is taken continuously for 7 to 10 days.   
   


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As a part of this study, you are providing tissue, blood and/or CSF samples and medical 
information which is labeled with a code. Traditional identifying information about you such as 
your name, address, telephone number, or social security number will not be included in your 
stored information.  If there is any remaining tissue, blood, or CSF samples, we would like your 
permission to store those samples at the  Pediatric Brain Tumor Consortium Central Review and 
Biorepository (PBTC CRB) for an unlimited period of time for future use in research related to 
cancer or, perhaps, in other research projects.  Providing these samples is optional and you can 
choose to participate at the end of this document. 
 
Test results will be identified by a unique code and the list that links the code will be kept separate 
from your sample and health information. In general, we will not give you any individual results 
from the study of the samples you gave us.  This is because it will probably be a long time before 
we will know how to interpret the information accurately.  We will tell you if we find you have a 
disease that could impact your health in the future. 
 
Your health care plan/insurance carrier will not be billed for the collection of the tissues, blood 
and CSF samples that will be used for this study.  
 
A study calendar which shows how often these tests and additional blood draws will be done is 
attached as an appendix to this consent form.  
 
What possible risks can I expect from taking part in this study?  
If you choose to take part in this study, there is a risk that: 
 You may lose time at work, school, or home and spend more time in the hospital or doctor’s 
office than usual 
 You may be asked sensitive or private questions which you do not normally discuss 
 
The study drug, ribociclib used in this study may affect how different parts of your body work 
such as the liver, kidneys, heart, and blood. Your study doctor will be testing your blood and will 
address any changes that may affect your health.  
 
There is also a risk that you could have side effects from the study drug, ribociclib.  
 
Here are important points about side effects: 
 Your study doctors do not know who will or will not have side effects. 
 Some side effects may go away soon, some may last a long time, or some may never go 
away. 
 Some side effects may interfere with your ability to have children 
 Some side effects may be serious and may even result in death. 
 
Here are important points about how to make side effects less of a problem: 
 Tell your study doctor if you notice or feel anything different so they can see if you are 
having a side effect. 
 Your study doctor may be able to treat some side effects. 
 Your study doctor may adjust the study drugs to try to reduce side effects. 
 


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The tables below show the most common and the most serious side effects that researchers know 
about. There might be other side effects that researchers do not yet know about. If important new 
side effects are found, your study doctor will discuss these with you. 
 
Side effects of ribociclib  
VERY COMMON, SOME MAY BE SERIOUS                                     
In 10 people receiving ribociclib, more than 1 may have: 
 Low number of red blood cells that can causes tiredness and shortness of breath. May 
require a blood transfusion  
 Fever  
 Low white blood cell counts which may lead to infection 
 Constipation 
 Diarrhea 
 Sores in mouth which may cause difficulty swallowing 
 Nausea 
 Vomiting 
 Tiredness 
 Decreased appetite 
 Swelling (arm/leg) 
 Change in the heart rhythm  
 Kidney infection 
 Back pain 
 Headache 
 Difficulty sleeping 
 Shortness of breath  
 Rash 
 Itching 
 Hair loss  
 Abdominal pain 
COMMON, SOME MAY BE SERIOUS                                           
In 100 people receiving ribociclib, more than 1 may have: 
 Low white blood cell count with fever 
 Low platelet count which may cause bleeding and bruising 
 Fainting episode  
 Dry eyes 
 Tears increased  
 Taste changes which may affect the way foods normally taste  
 Heartburn 
 Liver injury which may cause yellowing of eyes and skin or swelling 
 Low blood salts that may cause muscle cramping 
 Nose bleed 
 Reddening of the skin 
 Weight loss 
 Changes in heart rhythms that may cause dizziness or heart palpitations  


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Let your study doctor know of any questions you have about possible side effects. You can ask 
the study doctor questions about side effects at any time. 
 
Reproductive risks: You should not get pregnant, breastfeed, or father a baby while in this 
study. The effects of ribociclib used in this study could be very damaging to an unborn baby. If 
you are of childbearing or child fathering potential, you must agree to use at least one of the 
following methods of birth control during the study and for 8 weeks following the last dose of 
ribociclib.  
 Be sexually inactive (total abstinence) 
 Combination of any of the two following methods 
1. Use of hormonal methods (contraceptive pills, injection, implant, vaginal ring, 
transdermal) 
2. Have an Intrauterine device in place 
3. Barrier methods: Condom or Occlusive cap (diaphragm or cervical/vault caps) 
with spermicidal foam/gel/film/cream/ vaginal suppository 
 
Check with your study doctor about what types of birth control, or pregnancy prevention, to use 
while in this study. If you or your partner becomes pregnant while participating in this study, 
please notify your study doctor immediately and if you are a female, you will not be able to 
continue in the study.  
 
What possible benefits can I expect from taking part in this study? 
Taking part in this study may or may not make your health better. While researchers hope that 
once a day ribociclib for 7 to 10 days before removal of brain tumor tissue will be more useful 
against the usual treatment when compared (surgical removal of the brain tumor with or without 
ribociclib), there is no proof of this yet. We do know that the information from this study may help 
us learn more about the use of ribociclib and brain surgery as a treatment for brain tumor. This 
information may help people in the future. 
 
Can I stop taking part in this study? 
Yes.  You can decide to stop at any time.  If you are thinking about stopping or decide to stop for 
any reason, tell your study doctor and he or she will tell you how to stop safely. It is important that 
any risks from the study drug can be evaluated by your study doctor. Your study doctor may 
discuss what follow-up care and testing could be helpful for you. If the study drug is stopped, you 
can decide whether or not to let your study doctor continue to provide medical information to the 
organization running the study.   
 
Your study doctor will provide any new information or changes in the study that may affect your 
health or willingness to continue in the study. 
The doctor may decide to take you out of the study at any time if your doctor believes: 
 If your health changes and the study is no longer in your best interest 
 If new information becomes available 
 If you do not follow the study rules 
 If the study is stopped by the sponsor, IRB, Novartis (the drug supplier) or FDA. 
 


NCI Protocol #: PBTC-050 
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What are my rights in this study? 
Taking part in this study is your choice.  No matter what your decision is, and even if your decision 
changes, there will be no penalty.  You will not lose medical care or any legal rights.   
 
For questions about you rights while taking part in this study, call the (institution name) 
Institutional Review Board (a group of people who review the research to protect your rights) at 
(institution telephone number). 
 
What are the costs of taking part in this study? 
Ribociclib will be supplied at no charge while taking part in this study. The cost of getting 
ribociclib ready and giving it to you may not be paid by the study sponsor so you or your 
insurance company may have to pay for this. It is possible that ribociclib may not continue to be 
supplied while you are on the study. Although not likely, if this occurs, your study doctor will 
talk to you about other options. 
 
You or your health plan/insurance company will need to pay for all of the other costs of treating 
your cancer while in this study, including the cost of tests, procedures, or medicines to manage 
any side effects, unless your study doctor tells you certain tests are supplied at no charge. Before 
making a decision about participating in this study, you should check with your health plan or 
insurance company to find out exactly what they will pay for. 
 
You/your insurance company will not be charged for procedures that are being performed for 
research purposes only. 
 
You will not be paid for taking part in this study. 
 
What happens if I am injured because I took part in this study? 
It is important that you tell your study doctor, (Physician’s Name) if you feel that you have been 
injured because of taking part in this study.  You can tell the doctor in person or call him/her at 
(physician’s telephone number).  
 
If you are injured or hurt as a result of taking part in this study and need medical treatment, please 
tell your study doctor. The study sponsor will not offer to pay for medical treatment for injury. 
Your insurance company may not be willing to pay for study-related injury.  If you have no 
insurance, you would be responsible for any costs. 
 
Novartis will not provide payment for any medical expenses which you may incur as a result of 
your participation in this study. No other type of compensation will be provided by Novartis. 
 
If you feel this injury was a result of medical error, you keep all your legal rights to receive 
payment for this even though you are in a study. 
 
Who will see my medical information? 
Your privacy is very important to us.  The study doctors will make every effort to protect it.  The 
study doctors have a privacy permit to help protect your records if there is a court case.  
However, some of your medical information may be given out if required by law.  If this should 


NCI Protocol #: PBTC-050 
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happen, the study doctors will do their best to make sure that any information that goes out to 
others will not identify who you are.  
 
Some of your health information, such as your response to cancer treatment, results of study 
tests, and medicines you took, will be kept by the study sponsor in a central research database.  
However, your name and contact information will not be put in the database.  If information 
from this study is published or presented at scientific meetings, your name and other personal 
information will not be used.  
 
There are organizations that may look at and/or receive copies of your records. These organizations 
are required to make sure your information is kept private, unless required by law to provide 
information to another group.  
 
Some of these organizations are: 
 The Pediatric Brain Tumor Consortium (PBTC), who coordinate this study 
 Laboratories performing the required and optional research studies of tumor, blood and 
CSF samples 
 The Institutional Review Board, IRB, is a group of people who review the research with 
the goal of protecting the people who take part in the study. 
 Federal agencies such as the Food and Drug Administration, the Office of Human Research 
Protections (OHRP) and the National Cancer Institute in the U.S. 
 Governmental agencies in other countries where the study drug may be considered for 
approval. 
 The pharmaceutical company, Novartis that supplies ribociclib and its authorized agents.  
 Your insurance company or other health benefits plan (if charges are billed to these plans).  
 
The PBTC will make every effort to keep your name and identifying information confidential. 
Coded patient data and images from brain scans will be transmitted over the internet to be analyzed 
by other PBTC researchers. The PBTC has procedures (data encryption) in place to make 
electronic transmission of research information as secure as possible.  The data security involves 
coding the data in a way that only the authorized receiver can decode the data.  The method used 
to transfer information is more secure than many methods used by financial institutions when 
conducting business over the internet.   
 
Where can I get more information? 
You may visit the NCI Web site at http://cancer.gov/ for more information about studies or general 
information about cancer. You may also call the NCI Cancer Information Service to get the same 
information at: 1-800-4-CANCER (1-800-422-6237). 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Website will not include information that can identify you.  At most the 
Website will include a summary of the results.  You can search this Website at anytime 
 
Who can answer my questions about this study?  
You can talk to your study doctor about any questions or concerns related to this study.  Contact 
your study doctor (Physician’s name) at (Physician’s telephone number). 


NCI Protocol #: PBTC-050 
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You will get a copy of this form.  If you want more information about this study, ask your study 
doctor. 
 
Additional Studies Section: 
This part of the consent form is about optional studies that you can choose to take part in. You will 
not get health benefits from any of these studies. The researchers leading these optional studies 
hope the results will help other people with cancer in the future. The results will not be added to 
your medical records and your study doctor will not know the results. 
 
You will not be billed for these optional studies. You can still take part in the main study even if 
you say ‘no’ to any or all of these studies. If you sign up for but cannot complete any of the studies 
for any reason, you can still take part in the main study. 
 
What are the possible risks?  
1. The most common risks related to drawing blood from your arm are brief pain and 
possibly a bruise.  
2. There is a risk that someone could get access to the personal information in your medical 
records or other information researchers have stored. 
3. There is a risk that someone could trace the information in a central database back to you. 
Even without your name or other identifiers, your genetic information is unique. The 
researchers believe the chance that someone will identify you is very small, but the risk 
may change in the future as people come up with new ways of tracing information. 
4. There can also be a risk in knowing genetic information. New health information about 
inherited traits that might affect you or blood relatives could be found during a study. The 
researchers believe the chance these things will happen is very small, but cannot promise 
that they will not occur. In general, we will not give you any individual results from the 
study of the samples you gave us.  This is because it will probably be a long time before 
we will know how to interpret the information accurately.  In the rare instance that one of 
the genes tested might turn out to be an important risk factor for a disease, and having 
that information could allow you to take steps to prevent, detect earlier, or better treat that 
disease, we will ask you whether you want to know those results. If so, we will contact 
you and your doctor to discuss more testing.  
5. Some of your genetic and health information may be placed in central databases that may 
be public, along with information from many other people. The data resulting from the 
genetic research may be deposited into a public or controlled access database made 
available to other researchers. Information that could directly identify you will not be 
included. However, people may develop ways in the future that would allow someone to 
link your genetic or medical information in our databases back to you. For example, 
someone could compare information in our databases with information from you (or a 
blood relative) in another database and be able to identify you (or your blood relative). It 
also is possible that there could be violations to the security of the computer systems used 
to store the codes linking your genetic and medical information to you. 
 
How will information be kept private? 


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Your privacy is very important to the researchers and they will make every effort to protect it. 
Here are just a few of the steps they will take: 
1. When your sample(s) is sent to the researchers, no information identifying you (such as 
your name) will be sent. Samples will be identified by a unique code only.  
2. The list that links the unique code to your name will be kept separate from your sample 
and health information.  
3. Researchers to whom the Pediatric Brain Tumor Consortium (PBTC) sends your sample 
and information will not know who you are. They must also sign an agreement that they 
will not try to find out who you are.  
4. Information that identifies you will not be given to anyone, unless required by law. 
5. If research results are published, your name and other personal information will not be 
used. 
 
What are the possible benefits? 
You will not benefit from taking part. The researchers, using the samples from you and others, 
might make discoveries that could help people in the future. 
 
Are there any costs or payments?  
There are no costs to you or your insurance. You will not be paid for taking part. If any of the 
research leads to new tests, drugs, or other commercial products, you will not share in any 
profits. 
 
What if I change my mind? 
If you decide you no longer want research samples to be used, you can contact your study doctor 
in writing, (insert name of study doctor) who will let the researchers know. Then, any sample that 
remains in the repository will no longer be used and related health information will no longer be 
collected. Samples or related information that have already been given to or used by researchers 
will not be returned. If data has been submitted to a data repository, please include in your letter a 
request to retrieve your data.   
 
What if I have more questions? 
If you have questions about the use of your samples for research, contact your study doctor, (insert 
name of study doctor), at (insert telephone number of study doctor). 
 
For each of the optional studies below, please circle your response and then initial and date on the 
line provided. 
 
1.  Optional Sample Collection for research studies and storage.  
Researchers are trying to learn more about cancer. Much of this research is done using samples 
from your tissue, blood, urine, or other fluids. Through these studies, researchers hope to find 
new ways to prevent, detect, treat, or cure health problems. Some of these studies may be about 
genes. Genes carry information about features that are found in you and in people who are 
related to you. Researchers are interested in the way that genes affect how your body responds to 
treatment.  
 
a. Optional Sample Collection for Repository: 


NCI Protocol #: PBTC-050 
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If you choose to take part in the sample collection for the repository, tumor tissue from a 
previous surgery is needed and a blood sample is strongly encouraged to provide stored genetic 
material from your tumor and your healthy tissue. The researchers ask your permission to store 
and use your samples and related health information (for example, your response to cancer 
treatment, results of study tests and medicines you are given) for future medical research.  The 
future research that may be done is unknown at this time but may include genomic studies. These 
samples will be stored at the PBTC Central Review and Biorepository (PBTC CRB) where 
similar samples from other subjects are stored until requested for analysis.  
 
I choose to have my tumor tissue specimen collected and I agree that this tumor tissue and related 
information may be used for the test described above.  
 
YES 
 
 
 
          
NO 
 
 
 
 
I choose to have my blood specimen collected and I agree that this blood sample and related 
information may be used for the test described above.  
 
YES 
 
 
 
          
NO 
 
 
 
 
b. Leftover sample storage for future research: 
If you choose to take part, tissue, blood or CSF samples collected as a part of this study but not 
completely used for the analysis will be stored in the repository for future unspecified research. 
The researchers ask your permission to store and use your samples and related health information 
(for example, your response to cancer treatment, results of study tests and medicines you are 
given) for medical research. The research that may be done is unknown at this time.  
 
I agree to have my specimen collected and I agree that my specimen sample(s) and related 
information may be used for the laboratory study (ies) described above. 
 
 
YES 
 
 
 
          
NO 
 
 
 
 
c. Contact regarding incidental genetic findings 
If you chose to participate in genetic testing of tumor and blood samples, you may choose to be 
contacted in the future if we find incidental genetic abnormalities in your blood sample. The results 
of these studies or your choice will not affect your participation in the current study. 
 
I would like to be contacted in the future if significant incidental genetic abnormalities are found 
in my blood. 
 
YES 
 
 
 
          
NO 
 
 
 
 
 


NCI Protocol #: PBTC-050 
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4. Optional Laboratory Studies: 
 
a. Pharmacokinetic CSF Study: 
If you choose to take part in this study, your study doctor would like to collect a cerebral spinal 
fluid (CSF) sample during the surgical tumor resection. In order to get to the fluid surrounding the 
brain, a surgeon may have to place a thin tube into the fluid filled spaces of the brain (the 
ventricles). This sample will help us learn how much of the drug gets into the CSF. This study will 
require 2 mL of CSF to be collected at the time of surgery. The risks related to the collection of 
CSF during surgery may include infection, bleeding, stroke, and the risk associated with the 
anesthesia.  After surgery, the incision may become infected, which may require hospitalization 
and antibiotics.  
 
I choose to have my specimen collected and I agree that my CSF sample and related information 
may be used for the laboratory study described above. 
 
YES 
 
 
 
          
NO 
 
 
 
 
b. Tumor material for Pharmacodynamics study  
If you choose to take part, researchers would like to study tumor material that is available from a 
previous surgery and a scheduled surgery. Researchers are looking for biological markers to help 
them understand the tumors better. This study will require a piece of your tumor to be collected 
from a previous surgery and a scheduled surgery.  
 
I choose to have my specimen collected and I agree that my tumor tissue samples and related 
information may be used for the laboratory study described above. 
 
 
YES 
 
 
 
          
NO 
 
 
 
 
 
  
This is the end of the section about optional studies. 
 
 


NCI Protocol #: PBTC-050 
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SIGNATURE 
I have read this consent form or had it read to me. I have discussed it with the study doctor and 
my questions have been answered. I will be given a signed copy of this form. I agree to take part 
in the main study and any additional studies where I circled ‘yes’.  
 
 
Participant’s Name:  _______________________________________________________ 
 
 
 
 
 
(Print Name) 
 
__________________________________________________ 
 __________________ 
Signature of Participant or Parent or Legal Guardian or Next of Kin 
Date 
 
 
___________________________________________________ 
 __________________ 
Signature of 2nd Parent or Legal Guardian 
 
 
 
 
Date 
 
 
___________________________________________________ 
 __________________ 
Signature of Investigator or Designee 
 
 
 
 
Date 
 
 
___________________________________________________  
_________________ 
Signature of Witness  
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


NCI Protocol #: PBTC-050 
Version Date: September 4, 2018 
Updated Date: September 26, 2018 
Attachment 1: Study Calendar (Surgical Study) 
 
 
Before  
the study 
 
Before surgery 
Surgery 
After 
surgery 
Switch to 
Phase I 
 
Screening consent (if not 
previously tested for Rb1) 
X 
 
 
 
 
Confirmation of intact Rb1  
X 
 
 
 
 
Informed consent  
for Surgical 
study 
 
 
 
for Phase I 
Ribociclib administration 
 
1 x/day, for 7-10 
days prior surgery 
 
 
X 
Medical history 
X 
 
 
X 
 
Physical exam /height/weight 
X 
 
 
X 
 
Vital signs 
X 
 
 
X 
 
Performance status 
X 
 
 
X 
 
Neurologic exam 
X 
 
 
X 
 
Review of eligibility 
assessments,  AE, 
concomitant meditations, 
prior therapy assessment 
X 
 
 
X 
 
Laboratory Evaluations 
 
 
 
 
 
Blood Counts   
(may also be done more 
often to watch abnormalities) 
X 
 
 
X 
 
Blood Chemistries including 
liver enzymes  
X 
 
 
X 
 
Lipids (fasting) 
X 
 
 
 
 
Serum or Urine pregnancy 
test (for females of 
childbearing potential)  
X 
X 
 
X 
 
Other Assessments 
 
 
 
 
 
EKG  
(may also be done when your 
doctor thinks you need it) 
X 
 
 
 
 
Echocardiogram  
X 
 
 
 
 
Imaging Assessments 
 
 
 
 
 
Brain MRI (standard) with 
diffusion 
X 
 
X 
X 
 
Spinal MRI (if clinically  
indicated)  
X 
 
X 
X 
 
Correlative studies 
 
 
 
 
 
PK blood 
 
X 
X 
 
 
PK tumor 
 
 
X 
 
 


NCI Protocol #: PBTC-050 
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Before  
the study 
 
Before surgery 
Surgery 
After 
surgery 
Switch to 
Phase I 
 
CSF PK (if consented) 
 
 
X 
 
 
PD tumor (if consented) 
 
 
X 
 
 
 
 
 


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1 
 
 
Phase I - Model Consent Form 
 
Study Title for Study Participants: 
Testing ribociclib in combination with everolimus in patients with brain tumors 
 
Official Study title for Internet Search on http://www.ClinicalTrials.gov  
PBTC-050: A Phase I and Surgical Study of Ribociclib and Everolimus (RAD001) in Children 
with Recurrent or Refractory Malignant Brain Tumors 
 
“You” refers to ‘you’ or ‘your child’ throughout this document. If you are the guardian of a minor or of 
a person under legal disability who is being asked to participate in this study, you may give consent on 
his/her behalf. 
 
This form describes your participation in a clinical trial. A clinical trial is a type of research study.  
Clinical trials include only people who choose to take part.  This consent form gives you 
information about this study, to be discussed with members of your study team.   
 
Please take time to make the decision about whether to take part.  Please discuss this decision with 
your family and friends.  If there are any questions, ask your study doctor or health care team for 
more explanation.   
  
What is the usual approach to my brain cancer? 
You are being asked to take part in this research study because you have a brain tumor that has 
grown or recurred or has never gone away. Your tumor has one of the following types – either 
High Grade Glioma (HGG) or medulloblastoma or CNS embryonal tumor (NOS) or Ependymoma, 
or Atypical teratoid rhabdoid tumor (ATRT) or Diffuse Intrinsic Pontine Glioma (DIPG). People 
who are not in a study are usually treated with standard treatment which may have included 
surgery, chemotherapy, radiation or other investigational agents which may or may not be FDA 
approved. Sometimes, combinations of these are used and your study doctor can explain which 
may be best for you.  These treatments can reduce symptoms and may stop the tumor from growing 
for several months or more. 
 
What are my other choices if I do not take part in this study? 
If you decide not to take part in this study, you have other choices. Please talk to your doctor about 
these other options.  For example: 
 You may choose to have the usual approach described above 
 You may choose to take part in a different research study, if one is available 
 or you may choose not to be treated for cancer but you may want to receive comfort care to 
relieve symptoms. 
 
Why is this study being done?  
This research study has two portions: Phase I and Surgical study. This consent is for Phase I study 
and we will talk to you about participation in the Phase I portion of the study.  
 


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2 
 
 
The purpose of this study is to test the safety of study drugs called ribociclib and everolimus when 
given in combination. Each of these drugs has been tested in children as monotherapy but not as 
combination therapy. This study tests different doses of the drugs when given in combination to 
see which dose is safer in children.   
 
We have also learned that ribociclib works better if your tumor has an intact Rb1 protein. You 
have been approached for this study because we know that this Rb1 protein is present in your 
tumor tissue.  
 
Ribociclib and everolimus have not been approved by the FDA (the U.S. Food and Drug 
Administration) for the treatment of brain cancer; therefore, they both are considered experimental 
drugs for this trial. But they have been approved for other uses. These drugs have been tested for 
safety in adults and children.  About 45 people, between the ages of 1 and 21 years old, are 
expected to take part in this Phase I study. 
 
The goals of this study are: 
 To see if patients with brain tumors can safely take these drugs combination, and to find the 
best dose that patients can take safely  
 To learn what kinds of side effects happen in patients with brain tumors when they take 
ribociclib and everolimus in combination 
 To learn how patients with brain tumors handle the combined study drugs, ribociclib and 
everolimus (for examples, how much drugs are absorbed, how the body breaks down the 
drugs).  This is called a pharmacokinetic study, or PK study. 
 
What are the study groups? 
Different doses of the study drugs, ribociclib and everolimus will be given to several study 
participants. The first several study participants will receive the dose level that we think it is 
suitable for pediatric population. If both drugs do not cause serious side effects, they will be given 
to other study participants at a higher dose. The doses will continue to increase for every group of 
study participants until side effects occur that require the dose to be lowered. Then the dose 
escalation part of the study is stopped. Additional study participants will receive ribociclib and 
everolimus at the same dose level that had the fewest side effects. The dose you receive will depend 
on when you enroll in the study.   
 
All study participants will get the study drugs, ribociclib and everolimus. Ribociclib is available 
in the form of oral capsules, tablets and liquid solution. You may not take a combination of 
different formulations (i.e. liquid, capsules and tablets) within a course but may change to a 
different formulation before starting a next course.  Everolimus is available in the form of a 
dispersible tablet that you can dissolve in water or other liquid before taking. A dissolvable tablet 
breaks up into small particles in water and allows for small doses when administering with a dose 
dispenser or a syringe, which makes it convenient for patients who may have problems 
swallowing.  
 
You will take ribociclib once a day for 21 days followed by 7 days break and everolimus once a 
day for 28 days. This 28-day period (4 weeks) will constitute one course.  
 


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3 
 
 
Everolimus and ribociclib can be taken with or without food. The ribociclib capsule or film coated 
tablet, should be swallowed whole, not chewed and taken with water.  The everolimus tablet should 
be mixed with water. You will be provided with instruction on how to mix the drug at home and 
instructed by your physician. The amount of absorption of everolimus through exposure on the 
skin is not known. Caregivers are advised to avoid contact with suspensions of everolimus.  Wash 
hands thoroughly before and after preparation of the suspension. These drugs should be taken at 
the same time every day preferably in the morning.  
 
If you forget to take your pill(s) and if less than 6 hours of the scheduled dose, take ribociclib 
and/or everolimus on the same day. After more than 6 hours of missed dose(s), the dose(s) should 
be withheld, and you should wait to take the drug(s) until the next day (do not try to make-up the 
missed dose(s) after 6 hours). Then, continue treatment with the original dosing schedule. If 
vomiting occurs within 10 minutes, the dose(s) should be repeated. We will give you pill diary for 
each drug where you will document information about doses taken, missed doses and reason for 
missing dose(s).  You should bring your diary(s) to each clinic visit and your physician will review 
it with you. Empty bottles and any remaining pills should also be returned to your study doctor at 
each visit.  
 
We advise that you drink plenty of water or take hydration fluids to avoid dehydration if diarrhea 
occurs. You must also avoid eating grapefruit, Seville oranges or any products containing the 
grapefruit juice or Seville orange juice. You should not take any herbal or dietary supplements. 
Check with your study doctor if you are unsure what to avoid.  We will provide you a drug 
information handout and wallet card as a resource for yourself, caregivers and other health care 
providers. 
 
How long will I be in this study? 
You will receive the study drugs, ribociclib and everolimus for 13 courses (approximately 1 year).  
If you have benefited from receiving ribociclib and everolimus, and the study doctor agrees, you 
may be able to continue taking ribociclib and everolimus for another year (for a total 26 courses).  
Benefit means your disease is at least clinically and radiographically stable and you have not had 
any significant side effects. If you stop taking the study drugs due to side effects from ribociclib 
and/or everolimus, the study doctor will follow you weekly for the first 4 weeks and then every 4-
weeks until these side effects are resolved.  
 
When you finish therapy for 2 years, the study doctor will continue to watch you for side effects 
and follow your condition for 30 days after your last doses of ribociclib and everolimus. If the side 
effects that are continuing at the end of day 30, the study doctor may still follow you until they are 
resolved or until you start another cancer therapy or until your tumor grows. Follow up can be 
done by clinic visits and/or updates over the phone as determined by your study doctor.  
 
What extra tests and procedures will I have if I take part in this study? 
Most of the exams, tests, and procedures you will have are part of routine medical care for this 
type of cancer and may be done even if you do not join the study. On some days when you have 
labs, your doctor may tell you that you can’t have anything to eat or drink before your labs are 
drawn.  However, there are some extra tests and/or procedures that will need to be completed if 


NCI Protocol #: PBTC-050 
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4 
 
 
you take part in this study. They are considered research related procedures and not part of the 
usual approach for this type of cancer.  
 
Before you begin the study: 
You will need to have the following extra tests and procedures to find out if you can be in the 
study: 
 
 Screening for Rb1 protein 
This study has a screening step. Because you have a type of brain tumor that is either High Grade 
Glioma or medulloblastoma or CNS embryonal tumor (NOS) or Ependymoma, or ATRT or 
atypical DIPG which has biopsied, this screening test was performed on your tumor tissue that 
was collected from a previous surgery and the test result showed that your tumor has an intact 
Rb1 protein. Based on this result, we know that you are eligible to see if you meet all of the other 
requirements for the Phase 1 part of this study.  
 
 Electrocardiogram (EKG) 
An electrocardiogram is a simple, painless test that records the heart’s electrical activity.  
 
 ECHO  
An echocardiogram uses sound waves to make pictures of your heart, which helps to show how 
well your heart pumps blood.  
 
If the exams, tests, and procedures show that you can take part in the study, and you choose to 
take part, then you will need the extra tests and procedures listed in the Study Calendar. They are 
not part of the usual approach for your type of cancer. 
 
During the study: 
 EKG  on day 15 of course 1, day 1 of course 2, 3 and then every 3 months before you take 
drugs and at the end of study treatment  
 Echocardiogram before you take drugs on course 3, may be done more often if any 
abnormality is found during the study, and at the end of study treatment. 
 Pharmacokinetics (PK) blood (required) 
 
You are required to take part in this study because determining how the body handles this drug is 
an important part of the study. The researchers would like to learn how much ribociclib and 
everolimus alone and the combination of these drugs stay in the blood for specific time points.  
You can either choose to have multiple sticks, or have a temporary line placed in your arm to get 
these PK blood samples.   
  
For the PK study with ribociclib alone, less than ¼ teaspoon (about 1 mL) of blood will be collected 
each time before you start ribociclib, then 1, 2, 4, 8 (±1), 24 (±4),  32 (±4), 48 (±4) hours after your 
first dose of ribociclib on day 1 of Course 1. The 48-hour blood draw will be collected before your 
next dose of either ribociclib or everolimus, on day 3. A total of 8 mL (milliliters) (about 15⁄8 
teaspoon) of blood will be collected.  
 


NCI Protocol #: PBTC-050 
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5 
 
 
For the PK study with both ribociclib and everolimus combination, less than ½ teaspoon (about 2 
mL) of blood will be collected each time before your first doses of ribociclib and everolimus, then 
at 1, 2, 4, 8 (±1), and 24 (±4) hours after you take both drugs on day 17 of Course 1 (± 2 days). 
The 24 hour-blood draw will be collected immediately before your next dose (day 18 of course 1).  
A total of 12 mL (about 2 ½ teaspoon) of blood for drugs combination will be collected.   
 
For the PK study with everolimus alone, on Day 1 Course 2 less than ¼ of a teaspoon (about 1 
mL) will be collected before you start everolimus and then 30 minutes,  1, 1.5,  2, 4, 6, 8 (±1), 24 
(±4) hours after you take everolimus.  
 
It is important that you DO NOT TAKE either ribociclib or everolimus on the days of PK 
draws. Your study doctor will tell you when to take the study drug(s) on these days.  
 
As a part of this study, you are providing tissues, blood and/or CSF samples and medical 
information which is labeled with a code. Traditional identifying information about you such as 
your name, address, telephone number, or social security number will not be put included in your 
stored information.  If there is any remaining tissues, blood, or CSF samples, we would like your 
permission to store those samples at the Pediatric Brain Tumor Consortium Central Review and 
Biorepository (PBTC CRB) for an unlimited period of time for future use in research related to 
cancer or, perhaps, in other research projects.  Providing these samples is optional and you can 
choose to participate at the end of this document. 
 
Test results will be identified by a unique code and the list that links the code will be kept separate 
from your sample and health information. In general, we will not give you any individual results 
from the study of the samples you gave us.  This is because it will probably be a long time before 
we will know how to interpret the information accurately.  We will tell you if we find you have a 
disease that could impact your health in the future. Your health care plan/insurance carrier will not 
be billed for the collection of the tissues, blood and CSF samples that will be used for this study. 
 
 A study calendar which shows how often these tests and additional blood draws will be done is 
attached as an appendix to this consent form.  The correlative study calendar is also attached to 
this consent form.  
 
What possible risks can I expect from taking part in this study?  
If you choose to take part in this study, there is a risk that: 
 You may lose time at work, school, or home and spend more time in the hospital 
or doctor’s office than usual 
 You may be asked sensitive or private questions which you do not normally discuss 
 
The study drugs, ribociclib and everolimus used in this study may affect how different parts of 
your body work such as the liver, kidneys, heart, and blood. Your study doctor will be testing your 
blood and will address any changes that may affect your health.  
There is also a risk that you could have side effects from the study drugs, ribociclib and/or 
everolimus.  
 
Here are important points about side effects: 


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 Your study doctors do not know who will or will not have side effects. 
 Some side effects may go away soon, some may last a long time, or some may never go 
away. 
 Some side effects may interfere with your ability to have children 
 Some side effects may be serious and may even result in death. 
 
Here are important points about how to make side effects less of a problem: 
 Tell your study doctor if you notice or feel anything different so they can see if you are 
having a side effect. 
 Your study doctor may be able to treat some side effects. 
 Your study doctor may adjust the study drugs to try to reduce side effects. 
 
The tables below show the most common and the most serious side effects that researchers know 
about. There might be other side effects that researchers do not yet know about. If important new 
side effects are found, your study doctor will discuss these with you. 
 
Side effects of ribociclib  
VERY COMMON, SOME MAY BE SERIOUS                                     
In 10 people receiving ribociclib, more than 1 may have: 
 Low number of red blood cells that can causes tiredness and shortness of breath. May 
require a blood transfusion  
 Fever  
 Low white blood cell counts which may lead to infection  
 Constipation 
 Diarrhea 
 Sores in mouth which may cause difficulty swallowing 
 Nausea 
 Vomiting 
 Tiredness 
 Decreased appetite 
 Swelling (arm/leg) 
 Change in the heart rhythm 
 Kidney infection  
 Back pain 
 Headache 
 Difficulty sleeping 
 Shortness of breath  
 Rash 
 Itching 
 Hair loss  
 Abdominal pain 
 
COMMON, SOME MAY BE SERIOUS                                           
In 100 people receiving ribociclib, more than 1 may have: 


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 Low white blood cell count with fever 
 Low platelet count which may cause bleeding and bruising 
 Fainting episode  
 Dry eyes 
 Watering eyes 
 Taste changes which may affect the way foods normally taste  
 Heartburn 
 Liver injury which may cause yellowing of eyes and skin or swelling 
 Low blood salts that may cause muscle cramping 
 Nose bleed 
 Reddening of the skin 
 Weight Loss 
 Changes in the heart rhythm that may cause dizziness or heart palpitations  
 
 
Side effects of everolimus  
COMMON, SOME MAY BE SERIOUS   
In 100 people receiving everolimus (RAD-001), more than 20 and up to 100 may have: 
 Anemia which may require blood transfusion 
 Diarrhea 
 Sores in the mouth which may cause difficulty swallowing 
 Tiredness 
 Rash 
 Swelling of arms or legs 
 Nausea, vomiting 
 Weight loss, loss of appetite 
 Infections, especially when white blood cell count is low 
 Headache 
 Changes in taste 
 Nose bleed 
 Damage to the lungs which may cause shortness of breath 
 Rash  
 Itching 
 Cough 
 
OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving everolimus (RAD-001), from 4 to 20 may have: 


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 Pain 
 Constipation, Heartburn 
  Dry mouth 
 Fever 
 Bruising, bleeding 
 Shortness of breath 
 Dry skin, nail disorder, acne, reddening of the skin 
 Abnormal menstrual period 
 High blood pressure which may cause headaches, dizziness, blurred vision 
 Bleeding from different sites 
 
RARE, AND SERIOUS 
In 100 people receiving everolimus (RAD-001), 3 or fewer may have: 
 Non-healing surgical site 
 Kidney damage which may require dialysis 
 Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of 
breath, swelling of the face or throat 
 
Let your study doctor know of any questions you have about possible side effects. You can ask 
the study doctor questions about side effects at any time. 
 
Reproductive risks: You should not get pregnant, breastfeed, or father a baby while in this study. 
The effects of ribociclib and everolimus used in this study could be very damaging to an unborn 
baby. If you are of childbearing or child fathering potential, you must agree to use at least one of 
the following methods of birth control during the study and for 8 weeks following the last dose of 
ribociclib and everolimus.  
 Be sexually inactive (total abstinence) 
 Combination of any of the two following methods 
1. Use of hormonal methods (contraceptive pills, injection, implant, vaginal ring, 
transdermal) 
2. Have an Intrauterine device in place 
3. Barrier methods: Condom or Occlusive cap (diaphragm or cervical/vault caps) with 
spermicidal foam/gel/film/cream/ vaginal suppository 
 
Check with your study doctor about what types of birth control, or pregnancy prevention, to use 
while in this study. If you or your partner becomes pregnant while participating in this study, please 
notify your study doctor immediately and if you are a female, you will not be able to continue in 
the study.   
What possible benefits can I expect from taking part in this study? 
This study is unlikely to help you. We do know that the information from this study may help us 
learn more about the use of ribociclib and everolimus when given in combination for treatment in 
brain tumor.  This information may help people in the future. 
 
 
 


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Can I stop taking part in this study? 
Yes.  You can decide to stop at any time.  If you are thinking about stopping or decide to stop for 
any reason, tell your study doctor and he or she will tell you how to stop safely. It is important that 
any risks from the study drug can be evaluated by your study doctor. Your study doctor may 
discuss what follow-up care and testing could be helpful for you. If both drugs are stopped, you 
can decide whether or not to let your study doctor continue to provide medical information to the 
organization running the study.   
 
Your study doctor will provide any new information or changes in the study that may affect your 
health or willingness to continue in the study. 
 
The doctor may decide to take you out of the study at any time if your doctor believes: 
 If your health changes and the study is no longer in your best interest 
 If new information becomes available 
 If you do not follow the study rules 
 If the study is stopped by the sponsor, IRB, Novartis (the drug supplier) or FDA. 
 
What are my rights in this study? 
Taking part in this study is your choice. No matter what your decision is, and even if your decision 
changes, there will be no penalty. You will not lose medical care or any legal rights.   
 
For questions about you rights while taking part in this study, call the (institution name) 
Institutional Review Board (a group of people who review the research to protect your rights) at 
(institution telephone number). 
 
What are the costs of taking part in this study? 
The study drugs, ribociclib and everolimus will be supplied at no charge while taking part in this 
study. The cost of getting these study drugs, ribociclib and everolimus ready and giving them to 
you may not be paid by the study sponsor so you or your insurance company may have to pay for 
this. It is possible that the study drugs, ribociclib and everolimus may not continue to be supplied 
while you are on the study. Although not likely, if this occurs, your study doctor will talk to you 
about other options. 
 
You or your health plan/insurance company will need to pay for all of the other costs of treating 
your cancer while in this study, including the cost of tests, procedures, or medicines to manage 
any side effects, unless your study doctor tells you certain tests are supplied at no charge. Before 
making a decision about participating in this study, you should check with your health plan or 
insurance company to find out exactly what they will pay for. 
 
You/your insurance company will not be charged for procedures that are being performed for 
research purposes only. 
You will not be paid for taking part in this study. 
 
 
 
 


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What happens if I am injured because I took part in this study? 
It is important that you tell your study doctor, (Physician’s Name) if you feel that you have been 
injured because of taking part in this study.  You can tell the doctor in person or call him/her at 
(physician’s telephone number).  
 
If you are injured or hurt as a result of taking part in this study and need medical treatment, please 
tell your study doctor.  
 
The study sponsor will not offer to pay for medical treatment for injury.  Your insurance company 
may not be willing to pay for study-related injury.  If you have no insurance, you would be 
responsible for any costs. 
 
Novartis will not provide payment for any medical expenses which you may incur as a result of 
your participation in this study. No other type of compensation will be provided by Novartis.  
 
If you feel this injury was a result of medical error, you keep all your legal rights to receive 
payment for this even though you are in a study. 
 
Who will see my medical information? 
Your privacy is very important to us.  The study doctors will make every effort to protect it.  The 
study doctors have a privacy permit to help protect your records if there is a court case.  
However, some of your medical information may be given out if required by law.  If this should 
happen, the study doctors will do their best to make sure that any information that goes out to 
others will not identify who you are.  
 
Some of your health information, such as your response to cancer treatment, results of study 
tests, and medicines you took, will be kept by the study sponsor in a central research database.  
However, your name and contact information will not be put in the database.  If information 
from this study is published or presented at scientific meetings, your name and other personal 
information will not be used.  
 
There are organizations that may look at your study records.  Your health information in the 
research database also may be shared with these organizations.  They must keep your 
information private, unless required by law to give it to another group.   
 
Some of these organizations are: 
 The Pediatric Brain Tumor Consortium, who coordinate this study 
 Laboratories performing the required and optional research studies of tumor, blood and 
CSF samples 
 The Institutional Review Board, IRB, is a group of people who review the research with 
the goal of protecting the people who take part in the study. 
 Federal agencies such as the Food and Drug Administration, the Office of Human Research 
Protections (OHRP) and the National Cancer Institute in the U.S. 
 Governmental agencies in other countries where the study drug may be considered for 
approval  


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 The pharmaceutical company, Novartis that supplies ribociclib and everolimus and its 
authorized agents.  
 Your insurance company or other health benefits plan (if charges are billed to these plans).  
 
The PBTC will make every effort to keep your name and identifying information confidential. 
Coded patient data and images from brain scans will be transmitted over the internet to be analyzed 
by other PBTC researchers. The PBTC has procedures (data encryption) in place to make 
electronic transmission of research information as secure as possible.  The data security involves 
coding the data in a way that only the authorized receiver can decode the data.  The method used 
to transfer information is more secure than many methods used by financial institutions when 
conducting business over the internet.   
 
Where can I get more information? 
You may visit the NCI Web site at http://cancer.gov/ for more information about studies or general 
information about cancer. You may also call the NCI Cancer Information Service to get the same 
information at: 1-800-4-CANCER (1-800-422-6237). 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Website will not include information that can identify you.  At most the 
Website will include a summary of the results.  You can search this Website at anytime 
 
Who can answer my questions about this study?  
You can talk to your study doctor about any questions or concerns related to this study.  Contact 
your study doctor (Physician’s name) at (Physician’s telephone number). 
 
You will get a copy of this form.  If you want more information about this study, ask your study 
doctor. 
 
Additional Studies Section: 
This part of the consent form is about optional studies that you can choose to take part in. You will 
not get health benefits from any of these studies. The researchers leading these optional studies 
hope the results will help other people with cancer in the future. The results will not be added to 
your medical records and your study doctor will not know the results. 
 
You will not be billed for these optional studies. You can still take part in the main study even if 
you say ‘no’ to any or all of these studies. If you sign up for but cannot complete any of the studies 
for any reason, you can still take part in the main study. 
 
What are the possible risks?  
1. The most common risks related to drawing blood from your arm are brief pain and possibly 
a bruise.  
2. There is a risk that someone could get access to the personal information in your medical 
records or other information researchers have stored. 
3. There is a risk that someone could trace the information in a central database back to you. 
Even without your name or other identifiers, your genetic information is unique. The 


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researchers believe the chance that someone will identify you is very small, but the risk 
may change in the future as people come up with new ways of tracing information. 
4. There can also be a risk in knowing genetic information. New health information about 
inherited traits that might affect you or blood relatives could be found during a study. The 
researchers believe the chance these things will happen is very small, but cannot promise 
that they will not occur. In general, we will not give you any individual results from the 
study of the samples you gave us.  This is because it will probably be a long time before 
we will know how to interpret the information accurately.  In the rare instance that one of 
the genes tested might turn out to be an important risk factor for a disease, and having that 
information could allow you to take steps to prevent, detect earlier, or better treat that 
disease, we will ask you whether you want to know those results. If so, we will contact you 
and your doctor to discuss more testing.  
5. Some of your genetic and health information may be placed in central databases that may 
be public, along with information from many other people. The data resulting from the 
genetic research may be deposited into a public or controlled access database made 
available to other researchers. Information that could directly identify you will not be 
included. However, people may develop ways in the future that would allow someone to 
link your genetic or medical information in our databases back to you. For example, 
someone could compare information in our databases with information from you (or a 
blood relative) in another database and be able to identify you (or your blood relative). It 
also is possible that there could be violations to the security of the computer systems used 
to store the codes linking your genetic and medical information to you. 
 
How will information be kept private? 
Your privacy is very important to the researchers and they will make every effort to protect it. 
Here are just a few of the steps they will take: 
1. When your sample(s) is sent to the researchers, no information identifying you (such as 
your name) will be sent. Samples will be identified by a unique code only.  
2. The list that links the unique code to your name will be kept separate from your sample 
and health information.  
3. Information that identifies you will not be given to anyone, unless required by law. 
4. If research results are published, your name and other personal information will not be 
used. 
 
What are the possible benefits? 
You will not benefit from taking part. The researchers, using the samples from you and others, 
might make discoveries that could help people in the future. 
 
Are there any costs or payments?  
There are no costs to you or your insurance. You will not be paid for taking part. If any of the 
research leads to new tests, drugs, or other commercial products, you will not share in any profits. 
 
 


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What if I change my mind? 
If you decide you no longer want research samples to be used, you can contact your study doctor 
in writing, (insert name of study doctor) who will let the researchers know. Then, any sample that 
remains in the repository will no longer be used and related health information will no longer be 
collected. Samples or related information that have already been given to or used by researchers 
will not be returned. If data has been submitted to a data repository, please include in your letter a 
request to retrieve your data.   
 
What if I have more questions? 
If you have questions about the use of your samples for research, contact your study doctor, (insert 
name of study doctor), at (insert telephone number of study doctor). 
 
For each of the optional studies below, please circle your response and then initial and date on the 
line provided 
 
1. Optional Sample Collection for research studies and storage  
Researchers are trying to learn more about cancer. Much of this research is done using samples 
from your tissue, blood, urine, or other fluids. Through these studies, researchers hope to find new 
ways to prevent, detect, treat, or cure health problems. Some of these studies may be about genes. 
Genes carry information about features that are found in you and in people who are related to you. 
Researchers are interested in the way that genes affect how your body responds to treatment. 
 
a. Optional Sample Collection for Repository: 
If you choose to take part in the sample collection for the repository, tumor tissue from a previous 
surgery is needed and a blood sample is strongly encouraged to provide stored genetic material 
from your tumor and your healthy tissue. The researchers ask your permission to store and use 
your samples and related health information (for example, your response to cancer treatment, 
results of study tests and medicines you are given) for future medical research.  The future research 
that may be done is unknown at this time but may include genomic studies. These samples will be 
stored at the PBTC Central Review and Biorepository (PBTC CRB) where similar samples from 
other subjects are stored until requested for analysis.  
 
I choose to have my tumor tissue specimen collected and I agree that this tumor tissue and related 
information may be used for the test described above.  
 
YES 
 
 
NO 
 
 
 
 
I choose to have my blood specimen collected and I agree that this blood sample and related 
information may be used for the test described above.  
 
YES 
 
 
NO 
 
 
 
 
b. Leftover sample storage for future research: 
If you choose to take part, tissue, blood or CSF samples collected as a part of this study but not 
completely used for the analysis will be stored in the repository for future unspecified research. 
The researchers ask your permission to store and use your samples and related health information 


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(for example, your response to cancer treatment, results of study tests and medicines you are given) 
for medical research. The research that may be done is unknown at this time.  
 
I agree to have my specimen collected and I agree that my specimen sample(s) and related 
information may be used for the laboratory study (ies) described above. 
 
 
YES 
 
 
NO 
 
 
 
 
c. Contact regarding incidental genetic findings 
If you chose to participate in genetic testing of tumor and blood samples as described in section 
4(c) below, you may choose to be contacted in the future if we find incidental genetic abnormalities 
in your blood sample. The results of these studies or your choice will not affect your participation 
in the current study. 
 
I would like to be contacted in the future if significant incidental genetic abnormalities are found 
in my blood. 
 
YES   
 
NO  
 
 
 
 
4. Optional Laboratory Studies: 
 
a. Pharmacokinetic CSF Study (with Ommaya): 
If you choose to take part in this study and if you have an Ommaya reservoir, a cerebral spinal 
fluid (CSF) sample will be collected from your Ommaya for research to determine how much of 
the drug gets into the CSF.   This study will require about 2 mL (less than ½ teaspoon) to be 
collected before you take ribociclib  and 1, 4 and 8 hours after the ribociclib dose on day 1 of 
course 1, day 17 of course 1 and day 1 of course 2.  
 
I choose to have my specimen collected and I agree that my CSF sample(s) and related information 
may be used for the laboratory study described above. 
 
YES 
 
 
NO 
 
 
 
 
b. Pharmacokinetic CSF Study (without an Ommaya): 
If you choose to take part in this study but you do not have an Ommaya reservoir and have CSF 
collected at any time during study treatment for clinical purposes, your study doctor would like to 
collect an extra CSF sample from you for research to determine how much of the drug gets into 
the CSF. This study will require about 0.5 mL (about 1/8 teaspoon) to be collected at any time 
during treatment.   
 
At approximately the same time the CSF sample is collected, the research doctor would also like 
to collect a sample of blood (about 0.5 mL) to be collected.    
 
I choose to have my specimens collected and I agree that my CSF and blood sample and related 
information may be used for the laboratory study described above. 
 


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YES 
 
 
NO 
 
 
 
 
c. Genomics  
Your blood and tissue samples contain genes, which are made up of DNA and which serve as the 
“instruction book” for the cells that make up our bodies.  If you agree, a small piece of tumor 
material will be collected from a previous surgery for research. The researchers will look for 
biological markers to help them understand the tumors better.   
 
I agree to have my specimen collected and I agree that my specimen sample(s) and related 
information may be used for the laboratory study (ies) described above. 
 
 
YES 
 
 
NO 
 
 
 
 
 
 
This is the end of the section about optional studies. 
 
 


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SIGNATURE 
I have read this consent form or had it read to me. I have discussed it with the study doctor and 
my questions have been answered. I will be given a signed copy of this form. I agree to take part 
in the main study and any additional studies where I circled ‘yes’.  
 
 
Participant’s Name:  _______________________________________________________ 
 
 
 
 
 
(Print Name) 
 
__________________________________________________ 
   __________________ 
Signature of Participant or Parent or Legal Guardian or Next of Kin 
Date 
 
 
___________________________________________________ 
   __________________ 
Signature of 2nd Parent or Legal Guardian  
 
 
 
Date 
 
 
___________________________________________________ 
   __________________ 
Signature of Investigator or Designee 
 
 
 
 
Date 
 
 
___________________________________________________  
   __________________ 
Signature of Witness  
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Attachment 1: Study Calendar (Phase I) 
 
 
Pre-therapy Course 1 
Courses 2- 
Course 13 
Courses 14-26 
When finish with 
the drugs 
Screening consent (if not 
previously tested for Rb1) 
X 
 
 
 
 
Confirmation of intact Rb1  
X 
 
 
 
 
Study drugs administration  
(ribociclib – once/day x 21 days 
AND everolimus – once/day x 
28 days) 
 
X 
X 
X 
 
Medical history 
X 
Weekly 
X 
X 
X 
Physical exam /height/weight 
X 
Weekly 
X 
X 
X 
Vital signs 
X 
Weekly 
X 
X 
X 
Performance status 
X 
Weekly 
X 
X 
X 
Neurologic exam 
X 
Weekly 
X 
X 
X 
Laboratory Evaluations 
 
 
 
 
 
Blood Counts   
(may also be done more often to 
watch abnormalities) 
X 
Weekly 
Weekly 
X 
X 
Blood Chemistries including 
liver enzymes  
X 
X 
X 
X 
X 
Lipids (fasting)   
X 
 
Every other 
course  
Every other 
course  
X 
Serum or Urine pregnancy test 
(for females of childbearing 
potential)  
X 
X 
X 
X 
X 
Other Assessments 
 
 
 
 
 
EKG  
 
X 
Day 15, 
before the 
drugs 
 
Day 1 of Course 
2,3; thereafter, 
every 3rd course; 
before the drugs 
every 3rd 
course; before 
the drugs 
X 
Echocardiogram  
(may be done more often when 
your doctor thinks you need it) 
X 
 
prior to Course 3 
May be done  
X 
Imaging Assessments 
 
 
 
 
 
Brain MRI (standard) with 
diffusion 
X 
 
After every 2 
courses for the 
first 3 courses, 
then after every 
3 courses until 
tumor worsens 
every 3 courses 
until tumor 
worsens 
When finished 
with drugs or when 
tumor worsens 


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Pre-therapy Course 1 
Courses 2- 
Course 13 
Courses 14-26 
When finish with 
the drugs 
Spinal MRI (if clinically  
indicated)  
X 
 
After every 2 
courses for the 
first 3 courses, 
then after every 
3 courses until 
tumor worsens 
every 3 courses 
until tumor 
worsens 
When finished 
with drugs or when 
tumor worsens 
 
 
 
Attachment 2: Correlative Studies Calendar (Phase I) 
 
Correlative studies 
Pre-
therapy 
Course 1 
 
Course 2 
PK blood 
 
 
 
Ribociclib PK samples 
 
D1 C1 
 pre-dose, and 1, 2, 4, 8 (±1), 24 
(±4), 32 (±4), and 48 (±4) hours 
after dose.A  
 1 mL each (8 mL total) 
 
Everolimus PK samples 
 
 
D1 of C2  
 pre-dose, 0.5, 1, 1.5, 2, 4, 6, 
8 (±1), and 24 (±4)  hr after 
dose.B   
 1 mL each (9 mL total) 
Ribociclib + Everolimus PK 
samples 
 
D17 of C1 (+/- 2 days) 
  pre-dose, 1, 2, 4, 8 (±1), and 24 
(±4)  hrs after dose 
 2 mL each (12   mL total) 
 
PK – serial CSF (if consented) 
 
D1 C1, D17 C1 and D1 C2 
 pre-dose and at 1, 4, and 8 
hours after dose 
 0.5 mL each (2 mL total)  
 
PK – single CSF (if 
consented) 
 
Anytime during treatment 
Pre-trial tumor materials and 
PBMCs for Genomics (if 
consented) 
X 
 
 
Tumor Tissue and blood for 
Biorepository (if consented) 
X 
 
 
A. 48-hour time point will be collected prior to administration of either drug (ribociclib or everolimus) on Day 3.  
B. The ribociclib dose on day 1 should be held and day 2 should be delayed until the last everolimus sample is 
collected on day 2