untitled h1
untitled h2

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  
  
Updated Date: September 26, 2018  
  
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 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  
Giles Robinson, MD Kathy Warren, M.D. Kathleen Dorris, MD Michelle Monje, M.D PhD Maryam Fouladi, M.D. Stewart Goldman, M.D.  
Eugene Hwang, M.D. Tobey MacDonald, MD Updated Date: September 26, 2018 Ian Pollack, M.D. **Does not have patient care responsibilities*
untitled h1
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.
untitled h1
schema

This is Phase I and Surgical Study of ribociclib and everolimus given in combination in children with recurrent or refractory malignant brain tumors.
untitled h1
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 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                | Everolimus     | BSA Restriction |
| (mg/m2 /day PO days 1- 21)                                       | (mg/m2 /day PO days 1-28) |                |                 |
| -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 |                           |                |                 |
untitled h1
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.  
Version Date: September 4, 2018 Updated Date:  September 26, 2018.  
| Table of Contents                                                                                                                                                         |                                                                                                                                                   |                                                                                                                                                     |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------|
| Abstract and Schema                                                                                                                                                       |                                                                                                                                                   |                                                                                                                                                     |
| Table of Contents                                                                                                                                                         |                                                                                                                                                   |                                                                                                                                                     |
| Objectives ............................................................................................................................................................ 9 |                                                                                                                                                   |                                                                                                                                                     |
| l                                                                                                                                                                         | 1.1                                                                                                                                               | Primary Objectives .............................................................................................................................. 9 |
| 1.2                                                                                                                                                                       | Secondary Objectives .......................................................................................................................... 9 |                                                                                                                                                     |
| 1.3                                                                                                                                                                       | Exploratory Objective                                                                                                                             |                                                                                                                                                     |
| 2                                                                                                                                                                         | Background .                                                                                                                                      |                                                                                                                                                     |
| Study Disease                                                                                                                                                             |                                                                                                                                                   |                                                                                                                                                     |
| 2.1                                                                                                                                                                       |                                                                                                                                                   |                                                                                                                                                     |
| 2.2                                                                                                                                                                       | Ribociclib (LEE011)                                                                                                                               |                                                                                                                                                     |
| 2.3                                                                                                                                                                       | Everolimus (RAD001)                                                                                                                               |                                                                                                                                                     |
| 2.4                                                                                                                                                                       | Rationale for Proposed Pediatric Study .                                                                                                          |                                                                                                                                                     |
| 2.5                                                                                                                                                                       | Correlative Studies Background                                                                                                                    |                                                                                                                                                     |
| 3                                                                                                                                                                         | Patient Selection                                                                                                                                 |                                                                                                                                                     |
| 3.1                                                                                                                                                                       | Eligibility for Screening (Phase I and surgical study)                                                                                            |                                                                                                                                                     |
| 3.2                                                                                                                                                                       | Eligibility Criteria: Prior to Study Enrollment ...................................................................... 35                         |                                                                                                                                                     |
| 3.3                                                                                                                                                                       | Exclusion Criteria .                                                                                                                              |                                                                                                                                                     |
| Criteria to Start Treatment                                                                                                                                               |                                                                                                                                                   |                                                                                                                                                     |
| 3.4                                                                                                                                                                       |                                                                                                                                                   |                                                                                                                                                     |
| 3.5                                                                                                                                                                       | Criteria to Start Treatment with ribociclib and everolimus combination therapy ..... 41                                                           |                                                                                                                                                     |
| 3.6                                                                                                                                                                       | Treatment at the Primary Institution                                                                                                              |                                                                                                                                                     |
| 4                                                                                                                                                                         | Registration Procedures                                                                                                                           |                                                                                                                                                     |
| 4.1                                                                                                                                                                       | CTEP Investigator Registration Procedures ............................................................................. 42                        |                                                                                                                                                     |
| 4.2                                                                                                                                                                       | CTSU Registration Procedures                                                                                                                      |                                                                                                                                                     |
| 4.3                                                                                                                                                                       | Requirements for Submitting Regulatory Documents                                                                                                  |                                                                                                                                                     |
| 4.4                                                                                                                                                                       | General Guidelines .                                                                                                                              |                                                                                                                                                     |
| 4.5                                                                                                                                                                       | Enrollment Procedures                                                                                                                             |                                                                                                                                                     |
| S                                                                                                                                                                         | T Treatment Plan .                                                                                                                                |                                                                                                                                                     |
| Starting Dose and Dose escalation Schedule                                                                                                                                |                                                                                                                                                   |                                                                                                                                                     |
| 5.1                                                                                                                                                                       |                                                                                                                                                   |                                                                                                                                                     |
| 5.2                                                                                                                                                                       | Agent Administration .                                                                                                                            |                                                                                                                                                     |
| 5.3                                                                                                                                                                       | Dose Limiting Toxicity .                                                                                                                          |                                                                                                                                                     |
| 5.4                                                                                                                                                                       | Concomitant Medications and Supportive Care Guidelines                                                                                            |                                                                                                                                                     |
| 5.5                                                                                                                                                                       | D Duration of Therapy                                                                                                                             |                                                                                                                                                     |
| 6                                                                                                                                                                         | Dosing Delays/Dose Modification                                                                                                                   |                                                                                                                                                     |
| Notification of the Study Chair                                                                                                                                           |                                                                                                                                                   |                                                                                                                                                     |
| 6.1                                                                                                                                                                       |                                                                                                                                                   |                                                                                                                                                     |
| 6.2                                                                                                                                                                       | Hematologic and Non-hematologic Adverse Events and Management .................... 56                                                             |                                                                                                                                                     |
| Adverse Events: List and Reporting Requirements ............................................................................... 63                                        |                                                                                                                                                   |                                                                                                                                                     |
| Adverse Event List(s) for ribociclib (LEE011, NSC 794613) ........................................ 63                                                                     |                                                                                                                                                   |                                                                                                                                                     |
| 7.1                                                                                                                                                                       |                                                                                                                                                   |                                                                                                                                                     |
| 7.2                                                                                                                                                                       | Adverse Event List(s) for everolimus (RAD-001, NSC 733504) ................................ 64                                                    |                                                                                                                                                     |
| 7.3                                                                                                                                                                       | Adverse Event Characteristics                                                                                                                     |                                                                                                                                                     |
| Expedited Adverse Event Reporting                                                                                                                                         |                                                                                                                                                   |                                                                                                                                                     |
| 7.4                                                                                                                                                                       |                                                                                                                                                   |                                                                                                                                                     |
| 8                                                                                                                                                                         | Agent Information                                                                                                                                 |                                                                                                                                                     |
| 8.1                                                                                                                                                                       | Everolimus (RAD001)                                                                                                                               |                                                                                                                                                     |
| Ribociclib                                                                                                                                                                |                                                                                                                                                   |                                                                                                                                                     |
| 8.2                                                                                                                                                                       |                                                                                                                                                   |                                                                                                                                                     |
| 8.3                                                                                                                                                                       | Agent Ordering and Agent Accountability                                                                                                           |                                                                                                                                                     |
| 9                                                                                                                                                                         | Biomarker, Correlative and Special Studies .                                                                                                      |                                                                                                                                                     |
| 9.1                                                                                                                                                                       | Integral Laboratory Studies                                                                                                                       |                                                                                                                                                     |  
Updated Date: September 26, 2018  
| 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 |                                                                                         |
untitled h1
1 objectives 1.1 primary objectives

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
untitled h1
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
untitled h1
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
untitled h1
surgical study

1.2.3 To explore the effect of ribociclib treatment on Ki-67 by IHC by comparing archival and posttreatment tumor tissue
untitled h1
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
untitled h1
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.
untitled h1
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 cyclindependent 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
untitled h1
cell cycle dysregulation in pediatric

As in most human cancers, cell cycle dysregulation is common in malignant pediatric brain tumors. Highthroughput 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.
untitled h1
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-brainbarrier.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
untitled h1
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).  
  
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.  
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
untitled h1
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 PD0332991 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: ).
untitled h1
figure 5a palbociclib causes complete

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 Updated Date: September 26, 2018 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
untitled h1
pi3k/akt/mtor activation in pediatric brain

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
untitled h1
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
untitled h1
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
untitled h1
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 insulinlike 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*.
untitled h1
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 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.
untitled h1
2.2.1 preclinical studies 2.2.1.1 anti-tumor

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).
untitled h1
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 [(RD2009-50759), (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.
untitled h1
in vitro cdk4/6 and mtor

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 ribociclib and everolimus leads to synergistic growth inhibition.
untitled h1
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).
untitled h1
ribociclib in combination with pik3ca

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 was combined with everolimus, tumor regressions increased to 49%. Moreover, single agent and 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. 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. 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; Ndemethylation 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 accounted for 18.2% of the total plasma clearance.  
50 Results from a rat ADME study showed that tritiated 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.
untitled h1
2.2.1.4 ribociclib safety and pharmacology

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
untitled h1
would have totally reversed in

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.
untitled h1
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). For either continuous or intermittent dosing, the onset of neutropenia (most frequently Grade 2) occurs by Updated Date: September 26, 2018 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.  
| LEE011   |
|----------|
| 50 mg
N=4          |
| All      |
| grades   |
| n (%)    |
| 3 (75.0) |
| 0        |
| 2 (50.0) |
| 0        |
| 0        |
| o        |
| o        |
| o        |
| o        |
| 0        |
| o        |
| o        |
| 0        |
| o        |
| 0        |
| 0        |
| 1 (25.0) |
| 1 (25.0) |
| 0        |  
| Preferred term       |
|----------------------|
| -Total               |
| Neutropenia          |
| Fatigue              |
| Leukopenia           |
| Nausea               |
| Thrombocytopenia     |
| Anaemia              |
| Vomiting             |
| Lymphopenia          |
| Diarrhcea            |
| Electrocardiogram    |
| Prolonged            |
| Increased creatinine |
| Decreased Appetite   |
| Hypoalbuminaemia     |
| Aspartate            |
| Aminotransferase     |
| Increased            |
| Dizziness            |
| Stomatitis           |
| Fever                |
| Headache             |  
Version Date: September 4, 2018 Updated Date:  September 26, 2018  
|  Serious suspected adverse events which have occurred with LEE011 ( single agent)                                       |                               |
|-------------------------------------------------------------------------------------------------------------------------|-------------------------------|
| System Organ Class Preferred Term                                                                                       | Preferred Term                |
| Blood and lymphatic system disorders                                                                                    | Anaemia, Febrile neutropenia, |
| Neutropenia, Thrombocytopenia                                                                                           |                               |
| Gastrointestinal disorders                                                                                              | Diarrhoea, Nausea             |
| General disorders and administration site conditions                                                                    | Generalized oedema            |
| Infections and infestations                                                                                             | Herpes simplex                |
| Investigations                                                                                                          | Blood creatinine increased    |
| Events in italic font indicate those events which are newly included since the previous edition of the reference safety |                               |
| information.                                                                                                            |                               |  
Table 2:  Serious adverse events with suspected causal relationship with Ribociclib  
| Grade    |
|----------|
| 3/4      |
| n (%)    |
| 1 (25.0) |
| 0        |
| 0        |
| o        |
| o        |
| o        |
| o        |
| 0        |
| o        |
| 0        |
| 0        |
| o        |
| 0        |
| o        |
| o        |
| 0        |
| 1 (25.0) |
| 0        |
| 0        |  
| LEE011   |       |
|----------|-------|
| 70 mg
N=2          |       |
| All      | Grade |
| grades   | 3/4   |
| n (%)    | n (%) |
| 2 (100)  | 0     |
| 0        |       |
| 0        |       |
| 2 (100)  | 0     |
| 0        | o     |
| 1 (50.0) | 0     |
| o        |       |
| 0        |       |
| 0        | 0     |
| 1 (50.0) | o     |
| o        | o     |
| 0        | 0     |
| o        | o     |
| o        | o     |
| 0        | 0     |
| o        | o     |
| o        | o     |
| o        |       |
| 10       |       |
| 1 (50.0) | 0     |
| 0        | 0     |
| 0        | 0     |  
| LEE011     | LEE011   |          |          |
|------------|----------|----------|----------|
| 140 mg     | 200 mg   |          |          |
| N=4        | N=4      |          |          |
| All        | Grade    | All      | Grade    |
| grades     | 3/4      | grades   | 3/4      |
| n (%)      | n (%)    | n (%)    | n (%)    |
| 3 (75.0)   | 0        | 4 (100)  | 1 (25.0) |
| 0          |          |          |          |
| 0          | 0        | 0        |          |
| 3 (75.0)   | 0        | 4 (100)  | 0        |
| o          | 0        | 1 (25.0) | 0        |
| o          | 0        | 0        | 0        |
| 0          | 0        |          |          |
| o          | 0        |          |          |
| o          | 0        | 0        | 0        |
| o          | 0        | 0        | o        |
| o          | 0        | 2 (50.0) | o        |
| 0          | 0        | 0        | o        |
| o          | 0        | 0        | 0        |
| o          | 0        | 0        | o        |
| 1 (25.0) 0 | 10       | 0        |          |
| o          | 0        | 1 (25.0) | 0        |
| 1 (25.0)   |          |          |          |
| o          | 0        | 0        |          |
| o          | 0        | 0        | 0        |
| o          | 0        | 1 (25.0) | o        |
| o          | 0        | 0        | o        |
| o          | o        |          |          |
| 0          | 0        |          |          |  
| LEE011   | LEE011   |            |          |
|----------|----------|------------|----------|
| 200 mg   | 350 mg   |            |          |
| N=4      | N=5      |            |          |
| All      | Grade    | All        | Grade    |
| grades   | 3/4      | grades     | 3/4      |
| n (%)    | n (%)    | n (%)      | n (%)    |
| 4 (100)  | 1 (25.0) | 4 (80.0)   | 1 (20.0) |
| 1 (25.0) | 0        | 1 (20.0)   | 0        |
| 1 (25.0) | 0        | 1 (20.0)   | 0        |
| 1 (25.0) | 0        | 2 (40.0)   | 0        |
| 2 (50.0) | 0        | 2 (40.0)   | 0        |
| 1 (25.0) | 0        | 0          | o        |
| 0        | 0        | 2 (40.0)   | 0        |
| o        | 0        | 2 (40.0)   | 10       |
| 1 (25.0) | 1 (25.0) | 1 (20.0)   | 1 (20.0) |
| 1 (25.0) | 0        | 1 (20.0)   | 0        |
| 0        | 0        | 0          | o        |
| 3 (60.0) |          |            |          |
| o        | 0        | 0          |          |
| 2 (50.0) | 0        | 1 (20.0) 0 |          |
| o        | 0        | 1 (20.0)   | o        |
| 0        |          |            |          |
| o        | 0        | o          |          |
| 0        |          |            |          |
| 0        | 0        | o          |          |
| 1 (25.0) | 0        | 0          | o        |
| 0        | o        | 0          | o        |
| o        | 0        | 0          | 0        |  
| LEE011        |          |
|---------------|----------|
| 400 mg        |          |
| N=5           |          |
| All           | Grade    |
| grades        | 3/4      |
| n (%)         | n (%)    |
| 5 (100)       | 2 (40.0) |
| 2 (40.0)      | 1 (20.0) |
| 1 (20.0)      | 0        |
| 1 (20.0)      | 0        |
| 1 (20.0)      | 0        |
| 1 (20.0)      | 0        |
| 2 (40.0)      | 10       |
| 2 (40.0)      | 0        |
| o             | 0        |
| 0             | 0        |
| o             | o        |
| 1 (20.0)      | 0        |
| o             | 0        |
| o             | 0        |
| o             | 0        |
| 2 (40.0)    0 |          |
| 0             | 0        |
| o             | 0        |
| 0             | 0        |  
  
Grade LEE011
260 mg  
  
  
| Increased                |                  |           |          |                   |           |                   |           |            |            |           |            |           |
|--------------------------|------------------|-----------|----------|-------------------|-----------|-------------------|-----------|------------|------------|-----------|------------|-----------|
| Rssh                     | o                | 1 (25.0)  | 2 (50.0) |                   |           |                   |           |            |            |           |            |           |
| LEE011
600 mg                          |                  |           |          |                   |           |                   |           |            |            |           |            |           |
| LEE011                   | 28d              | LEE011    | LEE011   | LEE011            | AI        |                   |           |            |            |           |            |           |
| 600 mg
N=67                          | cont.
N=7                  | 750 mg
N=14           | 900 mg
N=13          | 1200 mg           | subjects  |                   |           |            |            |           |            |           |
| N=3                      | N=132            |           |          |                   |           |                   |           |            |            |           |            |           |
| All                      | All              | All       | All      | All               |           |                   |           |            |            |           |            |           |
| Grade                    | Grade            | Grade     | Grade    |                   |           |                   |           |            |            |           |            |           |
| grades                   | Grade 3/4 grades | 3/4       | grades   | 3/4               | grades    | 3/4               | grades    | 3/4        | All grades | Grade 3/4 |            |           |
| Preferred term           | n (%)            | n (%)     | n (%)    | n (%)             | n (%)     | n (%)             | n (%)     | n (%)      | n (%)      | n (%)     | n (%)      | n (%)     |
| -Total                   | 63 (94.0)        | 33 (49.3) | 7 (100)  | 6 (85.7)          | 14 (100)  | 7 (50.0)          | 12 (92.3) | 8 (61.5)   | 3 (100)    | 3 (100)   | 124 (93.9) | 63 (47.7) |
| Neutropenia              | 31 (46.3)        | 19 (28.4) | 6 (85.7) | 5 (71.4)          | 8 (57.1)  | 5 (35.7)          | 9 (69.2)  | 5 (38.5)   | 2 (66.7)   | 1 (33.3)  | 60 (45.5)  | 36 (27.3) |
| Fatigue                  | 2 (32.8)         | 2 (3.0)   | 5 (71.4) | 1 (14.3) 5 (35.7) | 0         | 10 (76.9)         | 0         | 3 (100)    | 0          | 59 (44.7) | 3 (2.3)    |           |
| 31 (46.3)                |                  |           |          |                   |           |                   |           |            |            |           |            |           |
| Leukopenia               | 13 (19.4)        | 6 (85.7)  | 5 (71.4) | 6 (42.9)          | 9 (69.2)  | 4 (30.8)          | 0         | 57 (43.2)  | 2 (16.7)   |           |            |           |
| Nausea                   | 30 (44.8)        | 1 (1.5)   | 3 (42.9) | 8 (57.1)          | 1 (7.1)   | 6 (46.2)          | o         | 3 (100)    | 0          | 56 (42.4) | 2 (1.5)    |           |
| Thrombocytopenis         | 23 (34.3)        | 6 (9.0)   | 2 (28.6) | 0                 | 5 (35.7)  | 3 (21.4) 6 (46.2) | 0         | 2 (66.7)   | 1 (33.3)   | 40 (30.3) | 10 (7.6)   |           |
| Anaemia                  | 19 (28.4)        | 2 (3.0)   | 2 (28.6) | 0                 | 3 (21.4)  | 1 (7.1)           | 3 (23.1)  | o          | 3 (100)    | 1 (33.3)  | 34 (25.8)  | 4 (3.0)   |
| Vomiting                 | 17 (25.4)        | 2 (28.6)  | 4 (28.6) | 3 (23.1)          | 3 (100)   | 0                 | 34 (25.8) |            |            |           |            |           |
| Lymphopenia              | 15 (22.4)        | 12 (17.9) | 3 (42.9) | 2 (28.6)          | 6 (42.9)  | 1 (7.1)           | 4 (30.8)  | 4 (30.8)   | 0          | 32 (24.2) | 21 (15.9)  |           |
| 0                        |                  |           |          |                   |           |                   |           |            |            |           |            |           |
| Diarrhoea                | 18 (26.9)        | 2 (3.0)   | 0        | 4 (28.6)          | 5 (38.5)  | 2 (66.7)          | 0         | 31 (23.5)  | 2 (1.5)    |           |            |           |
| Electrocardiogram        | 6 (9.0)          | 2 (14.3)  | 4 (30.8) | 2 (15.4)          | 2 (66.7)  | 14 (10.6)         | 2 (1.5)   |            |            |           |            |           |
| Prolonged                | 4 (8.0)          | 1 (14.3)  | 3 (21.4) | 2 (15.4)          | 14 (10.6) |                   |           |            |            |           |            |           |
| Increased creatining     | 10               | 0         | 0        | 0                 | 0         | 0                 |           |            |            |           |            |           |
| Decreased Appetite       | 5 (7.5)          | 3 (21.4)  | 1 (7.7)  | 13 (9.8)          |           |                   |           |            |            |           |            |           |
| LEE011                   |                  |           |          |                   |           |                   |           |            |            |           |            |           |
| 600 mg
28d                          |                  |           |          |                   |           |                   |           |            |            |           |            |           |
| LEE011                   | LEE011           | LEE011    | LEE011   | All               |           |                   |           |            |            |           |            |           |
| 600 mg
N=67                          | cont.
N=7                  | 750 mg
N=14           | 90 mg
N=13          | 1200 mg
N=3                   | subjects
N=132           |                   |           |            |            |           |            |           |
| All                      | All              |           |          |                   |           |                   |           |            |            |           |            |           |
| AII                      | Grade            | All       | Grade    | AII               | Grade     | Grade             |           |            |            |           |            |           |
| grades                   | Grade 3/4        | grades    | 3/4      | grades            | 3/4       | grades            | grades    | All grades | Grade 3/4  |           |            |           |
| Preferred term           | n (%)            | n (%)     | n (%)    | n (%)             | n (%)     | n (%)             | n (%)     | n (%)      | n (%)      | n (%)     |            |           |
| n (%)                    | n (%)            |           |          |                   |           |                   |           |            |            |           |            |           |
| Hypoalbuminaemi          | 7 (10.4)         | 1 (14.3)  | 0        | 1 (7.1)           | 0         | 1 (7.7)           | 12 (9.1)  |            |            |           |            |           |
| Aspartate                | 8 (11.9)         | 1 (14.3)  | 1 (7.1)  | 0                 | 0         | 0                 | o         | 1 (8.3)    |            |           |            |           |
| Aminotransferase         |                  |           |          |                   |           |                   |           |            |            |           |            |           |
| Increased                |                  |           |          |                   |           |                   |           |            |            |           |            |           |
| Dizziness                | 6 (9.0)          | 0         | 10       | 0                 | 2 (14.3)  | 0                 | 1 (7.7)   | 10         | 10         | 1 (8.3)   |            |           |
| 2 (28.6)                 | 1 (33.3)         |           |          |                   |           |                   |           |            |            |           |            |           |
| Stomattis                | 0                | 3 (21.4)  | 0        | 1 (7.7)           | 0         | 1 (8.3)           | 1 (0.8)   |            |            |           |            |           |
| Fever                    | 1 (1.5)          | 2 (28.6)  | 0        | 2 (14.3)          | 0         | 2 (66.7)          | 0         | 8 (6.1)    |            |           |            |           |
| Headache                 | 6 (9.0)          | 2 (14.3)  | 0        | 0                 | 0         | 8 (6.1)           |           |            |            |           |            |           |
| Alanine Aminotransferase | 5 (7.5)          | 1 (1.5)   | 1 (14.3) | 1 (7.1)           | 0         | 0                 | 7 (5.3)   | 1 (0.8)    |            |           |            |           |
| Increased                |                  |           |          |                   |           |                   |           |            |            |           |            |           |
| Rash                     | 1 (1.5)          | 2 (15.4)  | 1 (33.3) | 7 (5.3)           |           |                   |           |            |            |           |            |           |  
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)
untitled h1
2.2.2 phase ii studies phase

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
(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 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.
untitled h1
2.2.2.3 ribociclib adult pharmacokinetics pk

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 filmcoated 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.
untitled h1
pk of ribociclib everolimus and

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 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
untitled h1
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 CDK4amplified 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/m2of 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/m2and 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/m2and 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.
untitled h1
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 in adults at 600 mg. Based upon safety, tolerability, and pharmacokinetics, the MTD was determined as 470 mg/m2once a day for 3 weeks on and 1 week off.
untitled h1
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
untitled h1
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 bloodbrain 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
untitled h1
2.3.2 everolimus (rad001) adult clinical

Everolimus has gone through multiple adult phase I, II, and III clinical trials and received its first FDAapproval 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).
untitled h1
2.3.3 pediatric studies 2.3.3.1 phase

Fouladi *et al*. published a phase I study of everolimus in children with recurrent solid tumors and established the pediatric MTD as 5 mg/m2continuous 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).  
Pharmacokinetic findings of this phase I study are listed in Table 5. Population estimates for clearance
(Cl)/F, V/F, and k a were 12.4 L/h/m², 45.5 L, and 1.66 h − 1 , respectively. Interindividual variability in Cl/F,
VF, and k a 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.  
| Dosege Level                                                                                                                                               |                 |                 |                   |         |            |             |           |         |
|------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------|-----------------|-------------------|---------|------------|-------------|-----------|---------|
| 2.1 mg/m² (n = 6)                                                                                                                                          | 3 mg/m² (n = 8) | 5 mg/m² (n = 2) | 6.5 mg/m² (n = 2) |         |            |             |           |         |
| Parameter                                                                                                                                                  | Median          | Range           | Median            | Range   | Median     | Range       | Median    | Range   |
| k,, hi                                                                                                                                                     | 1.2             | 0.3-3.8         | 1.5               | 0.8-2.2 | 1.9        | 1.6-2.1     | 2.0       | 1.9-2.2 |
| 18.0                                                                                                                                                       | 15.2-19.9       | 15.9            | 13.9-22,5         | 17.7    | 15.8-19.6  | 15.2        | 14.8-15.5 |         |
| 1/2, hours                                                                                                                                                 | 94.6-197.7      | 197.6           | 59.6-249.4        | 239.6   | 2225-256.6 | 273.1-373.1 |           |         |
| AUC o … ng/mL h                                                                                                                                            | 139.8           | 323.1           |                   |         |            |             |           |         |
| Noncompartmental pharmacokinetic parameter                                                                                                                 |                 |                 |                   |         |            |             |           |         |
| n ng/ml                                                                                                                                                    | 16.1-78.5       | 68.9-108        |                   |         |            |             |           |         |
| T may hours                                                                                                                                                | 1.0             | 0.5-1.2         | 0.6-2.3           | 0.6     | 0.5-0.7    |             |           |         |
| Abbreviations: k , absorption rate constant; t , 2 , elimination half-life; AUC 0 - xx , area under the concentration-time curve from zero to infinity; C, |                 |                 |                   |         |            |             |           |         |
| verolimus concentration; T max , time at which C r                                                                                                         |                 |                 |                   |         |            |             |           |         |  
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 Akt 5473 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/m 2 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.
untitled h1
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/m2for 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/m2daily 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
untitled h1
2.4 rationale for proposed pediatric

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 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. Preclinical 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.
untitled h1
2.5 correlative studies background 2.5.1

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.
untitled h1
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 glioblastoma7as 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 RBdependent 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 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 PI3kinase/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.
untitled h1
2.5.2 rationale for pharmacokinetic studies

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.
untitled h1
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
untitled h1
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 Updated Date: September 26, 2018 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.
untitled h1
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.
untitled h1
3.1 eligibility for screening (phase

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 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.
untitled h1
3.2 eligibility criteria prior to

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.
untitled h1
- 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
- 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.
untitled h1
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 halflives 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.
untitled h1
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
untitled h1
3.2.5.4 stem cell transplant

Patient must be:
- ≥ 3 months since autologous bone marrow/stem cell transplant prior to enrollment 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.
untitled h1
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.
untitled h1
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 109cells/ L - Platelets ≥ 100 x 109cells/ 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/1.73m2are eligible.  
Table 6 Table 6 Serum Creatinine for age/gender  
| 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 |  
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.
untitled h1
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.
untitled h1
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.
untitled h1
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 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 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.
untitled h1
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.
untitled h1
3.5 criteria to start treatment

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.
untitled h1
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.
untitled h1
3.6 treatment at the primary

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 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.
untitled h1
4 registration procedures 4.1 ctep

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).  
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.
untitled h1
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
untitled h1
4.3 requirements for submitting regulatory

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. 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.
untitled h1
4.4 general guidelines 4.4.1 prior

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.
untitled h1
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.
untitled h1
patients with dipg (rb1 screening

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.
untitled h1
patients with all other cns

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.  
- 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.
untitled h1
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.
untitled h1
phase i study

This study will enroll patients with recurrent or refractory malignant brain tumors to define the MTD/RP2D of ribociclib and everolimus.
untitled h1
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.  
For surgical patients, the period from enrollment until initiation of surgery will be considered 'presurgery'. Ribociclib should be initiated within 7 days of enrollment and surgery should be performed after 7-10 days of ribociclib treatment.
untitled h1
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.
untitled h1
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.
untitled h1
5.1 starting dose and dose

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             |
untitled h1
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.  
The starting dose for everolimus will be 1.2 mg/m2/day. The starting dose of ribociclib given on a 3weeks-on/1-week-off dosing schedule will be 120 mg/m2per 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 dosefinding 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                | Everolimus     | BSA Restriction |
| (mg/m2 /day PO days 1- 21)                                       | (mg/m2 /day PO days 1-28) |                |                 |
| -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 |                           |                |                 |
untitled h1
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.
untitled h1
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 total daily dose (mg) tables. **Patients allergic to peanut and soy are not permitted to take the filmcoated 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 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 109cells/ L and Platelet count ≥ 100 x 109cells/ 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.
untitled h1
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. 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.  
5.3.2 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 postoperatively (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
untitled h1
5.3.1.2 hematologic dose limiting toxicity

- Grade 4 thrombocytopenia
-  Grade 3 thrombocytopenia (platelet count < 50 x109cells/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 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.
untitled h1
5.3.2.2 hematologic dose limiting toxicity

- Grade 4 thrombocytopenia
-  Grade 3 thrombocytopenia (platelet count < 50 x109cells/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.
untitled h1
5.4 concomitant medications and supportive

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.
untitled h1
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.
untitled h1
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. 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).
untitled h1
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.
untitled h1
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.  
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.
untitled h1
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 PBTC050 Protocol Webpage.
untitled h1
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). 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.
untitled h1
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
untitled h1
patients who are off protocol

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 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).