Clinical trial NCT03834740
Conditions: Glioblastoma Multiforme Glioma of Brain
Keywords: recurrent GBM brain tumor GBM glioma
Sponsor: St. Joseph's Hospital and Medical Center, Phoenix
Start date: 2019-01-19; Completion date: 2022-02-18
Enrollment: 27 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
In the proposed trial, patients will be administered ribociclib+everolimus prior to surgical resection of their tumor. Recurrent GBM patients will be randomized into one of the three time-interval cohorts for the first two dose levels.

In the lead-in dose escalation study, the first six subjects (lead-in) will receive ribociclib 400 mg and everolimus 2.5 mg orally-administered in 5 daily doses with the last dose. If one or less patient experiences DLT among the 6 patients, this regimen with ribociclib 400 mg and everolimus 2.5mg will be considered safe and we will continue with the dose escalation phase of the study up to Level 3.

Four dose escalation levels:

Level 0: ribociclib 400mg and everolimus 2.5

Level 1: ribociclib 600mg and everolimus 2.5mg

Level 2: ribociclib 600mg and everolimus 5mg

Level 3: ribociclib 600mg and everolimus 10mg

Detailed description:

Arms: arm 1: Three to fourteen patients will receive ribociclib and everolimus orally-administered in 5 daily doses with the last dose being administered at one of 3 intervals before brain tumor resection:

• Cohort 1: last ribociclib+everolimus dose 1 to 3 hours prior to craniotomy for tumor resection arm 2: Three to fourteen patients will receive ribociclib and everolimus orally-administered in 5 daily doses with the last dose being administered at one of 3 intervals before brain tumor resection:

• Cohort 2: last ribociclib+everolimus dose 7 to 9 hours prior to craniotomy for tumor resection arm 3: Three to fourteen patients will receive ribociclib and everolimus orally-administered in 5 daily doses with the last dose being administered at one of 3 intervals before brain tumor resection:

• Cohort 3: last ribociclib+everolimus dose 23 to 25 hours prior to craniotomy for tumor resection
Interventions: intervention 1: Ribociclib intervention 2: Everolimus
Intervention descriptions: intervention 1: Ribociclib administered orally in 5 daily doses prior to resection intervention 2: Everolimus administered orally in 5 daily doses prior to resection

Protocol documents:
Prot_SAP_000.pdf: 


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Table of contents 
Table of contents .........................................................................................................................2 
List of figures ..............................................................................................................................5 
List of tables ................................................................................................................................5 
List of abbreviations ...................................................................................................................6 
1 
Background ..........................................................................................................................8 
1.1 
Overview of glioblastoma pathogenesis, epidemiology and current treatment ..8 
1.1.1 Glioblastoma 8 
1.1.2 Rb-Positive and mTOR-positive tumors ........................................................... 8 
1.2 
Introduction to investigational treatment(s) and other study treatment(s) ..........9 
1.2.1 Overview of Ribociclib ..................................................................................... 9 
1.2.2 Overview of everolimus (RAD001/Afinitor).................................................. 20 
1.2.3 Ribociclib in combination with everolimus .................................................... 23 
2 
Rationale ............................................................................................................................26 
2.1 
Study rationale and purpose ..............................................................................26 
2.2 
Rationale for the protocol design ......................................................................27 
2.3 
Rationale for dose and regimen selection .........................................................28 
3 
Objectives and endpoints ...................................................................................................30 
4 
Protocol design ..................................................................................................................32 
4.1 
Description of protocol design ..........................................................................32 
4.1.1 Phase 0 
32 
4.1.2 Phase 2 Dose expansion .................................................................................. 35 
4.2 
Timing of interim analyses and design adaptations ..........................................36 
4.3 
Definition of end of the Study ..........................................................................36 
4.4 
Early Termination .............................................................................................37 
5 
Population ..........................................................................................................................37 
5.1 
Patient population .............................................................................................37 
5.2 
Inclusion criteria ...............................................................................................37 
5.3 
Exclusion criteria ..............................................................................................39 
6 
Treatment ...........................................................................................................................42 
6.1 
Protocol treatment .............................................................................................42 
6.1.1 Phase 0 Dose Escalation Schedule .................................................................. 42 
6.1.2 Phase 0 Dose Limiting Toxicity (DLT) and Maximum Tolerated Dose (MTD)43 
6.1.3 Dose Limiting Toxicity for Phase 0 or Phase 2 .............................................. 44 
6.1.4 Dosing regimen 
46 


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6.1.5 Guidelines for continuation of treatment beyond tumor resection (Optional 
Phase 2) 
47 
6.1.6 Treatment duration 48 
6.2 
Dose modification post-tumor resection (Phase 2) ...........................................48 
6.2.1 General guidelines for dose modifications ..................................................... 48 
6.2.2 Dose modification and dose delay of ribociclib+everolimus ......................... 49 
6.2.3 Follow-up for toxicities................................................................................... 50 
6.3 
Concomitant medications..................................................................................62 
6.3.1 Permitted concomitant therapy ....................................................................... 63 
6.3.2 Permitted concomitant therapy requiring caution and/or action with ribociclib64 
6.3.3 Prohibited concomitant therapy with ribociclib and everolimus .................... 65 
6.4 
Patient numbering, treatment assignment .........................................................67 
6.4.1 Patient numbering 67 
6.4.2 Treatment assignment ..................................................................................... 67 
6.4.3 Treatment blinding 68 
6.5 
Study drug preparation and dispensation ..........................................................68 
6.5.1 Study drug packaging and labeling ................................................................. 68 
6.5.2 Drug supply and storage ................................................................................. 68 
6.5.3 Study drug compliance and accountability ..................................................... 68 
6.5.4 Disposal and destruction ................................................................................. 69 
7 
Visit schedule and assessments ..........................................................................................69 
7.1 
Protocol flow and visit schedule .......................................................................69 
7.1.1 List of Efficacy/Pharmacokinetic/Pharmacodynamics and 
Pharmacometabolomics Measurements .................................................... 73 
7.2 
Assessment types ..............................................................................................82 
7.2.1 PK, PD, and pharmacometabolomics assessments ......................................... 82 
7.2.2 Safety and tolerability assessments ................................................................. 82 
8 
Safety monitoring and reporting ........................................................................................84 
8.1 
Adverse events ..................................................................................................84 
8.1.1 Definitions and reporting ................................................................................ 84 
8.1.2 Laboratory test abnormalities ......................................................................... 86 
8.1.3 Adverse events of special interest (AESI) ...................................................... 86 
8.2 
Serious adverse events ......................................................................................86 
8.2.1 Definitions 
86 
8.2.2 Reporting 87 
8.3 
Emergency unblinding of treatment assignment...............................................88 


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8.4 
Pregnancies .......................................................................................................88 
8.5 
Warnings and precautions .................................................................................88 
8.6 
Data and Safety Monitoring Board ...................................................................88 
8.6.1 Dose Escalations 
89 
9 
Data collection and management .......................................................................................89 
9.1 
Site monitoring..................................................................................................89 
9.2 
Data confidentiality, collection, management, and quality control ..................89 
9.3 
Analysis sets......................................................................................................89 
9.3.1 Full Analysis Set 
89 
9.4 
Patient demographics/other baseline characteristics .........................................89 
9.5 
Primary objective ..............................................................................................90 
9.6 
Secondary and exploratory objectives ..............................................................90 
9.6.1 Statistical hypothesis, model, and method of analysis .................................... 91 
9.6.2 Safety objectives 
91 
9.6.3 Adverse Events (AEs) ..................................................................................... 91 
9.7 
Statistical Methods ............................................................................................91 
9.7.1 Objectives, endpoints, analysis, and sample size justification........................ 91 
9.7.2 Statistical considerations for accrual .............................................................. 92 
10 Ethical considerations and administrative procedures .......................................................93 
10.1 
Regulatory and ethical compliance ...................................................................93 
10.2 
Informed consent procedures ............................................................................93 
10.3 
Discontinuation of the study .............................................................................93 
10.4 
Publication of the study and results ..................................................................93 
10.4.1 Communication and Publication of Clinical Trial Results ............................. 93 
10.5 
Study documentation, record keeping and retention of documents ..................93 
10.6 
Confidentiality of study documents and patient records ..................................94 
10.7 
Audits and inspections ......................................................................................94 
10.8 
Financial disclosures .........................................................................................94 
11 Protocol adherence .............................................................................................................94 
11.1 
Amendments to the protocol .............................................................................94 
12 References ..........................................................................................................................95 
13 Appendices .........................................................................................................................98 
Appendix 1: ECOG Performance Status Scale .............................................................98 
Appendix 2: List of prohibited concomitant medications and concomitant 
medications requiring caution ...........................................................................99 




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List of abbreviations 
ADME 
absorption, distribution, metabolism and excretion  
AE 
adverse event 
AESI 
adverse event of special interest 
ALK 
anaplastic lymphoma kinase 
ALT 
alanine transaminase 
ANC 
absolute neutrophil count 
AST 
aspartate transaminase 
AUC 
area under the curve 
AUC0-12 
area under the curve over the first 12 hours 
AUC0-24 
area under the curve over the first 24 hours 
AUC0-t 
area under the curve over the period of time to X hours
BCRP 
breast cancer resistance protein 
BLRM 
Bayesian logistic regression model 
BNI 
Barrow Neurological Institute 
BSEP 
bile salt export pump 
CERT 
Center for Education and Research on Therapeutics 
CI 
confidence interval 
CL 
clearance 
Cmax 
maximum concentration 
CrCL 
creatinine clearance 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DBP 
diastolic blood pressure  
DDI 
drug-drug interactions 
DHEA 
dehydroepiandrosterone 
DLT 
dose-limiting toxicities 
DS&E 
Drug Safety and Epidemiology 
EC 
ethics committee 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ERK 
extracellular signal-regulated kinase 
EIAED 
enzyme inducing anti-epileptic drug  
FIH 
first in human 
FMO3 
flavin-containing monooxygenase 3 
GBM 
glioblastoma multiforme  
GI 
gastrointestinal 
HED 
human equivalent dose 
hERG 
human Ether-a-go-go Related Gene 
IHC 
immunohistochemistry 
IUD 
intrauterine device 
IUS 
intrauterine system 


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LFT 
liver function test 
MATE1 
multidrug and toxin extrusion protein 1 
MCL 
mantle cell lymphoma 
MEK 
mitogen-activated protein kinase kinase 
MTD 
maximally tolerated dose 
mTOR 
mammalian target of rapamycin 
Non-EIAED non-enzyme inducing anti-epileptic drug 
NSCLC 
non-small cell lung cancer  
OATP1B1 
organic anion transporting polypeptide 1B1 
OCT1 
organic cation transporter 1 
OCT2   
organic cation transporter 2 
OTC 
over-the-counter 
P-gp
P-glycoprotein
PD
pharmacodynamics
PG
pharmacogenetic
PIK3
phosphoinositide 3-kinase
pRB
retinoblastoma protein
PK
pharmacokinetic
PO
by mouth
PPIs
proton pump inhibitors
PXR
pregnane X-receptor
QD
daily
RDE
research development and extension
RP2D
recommended phase 2 dose
SAE
serious adverse event
SBP
systolic blood pressure
SUSARs
Suspected Unexpected Serious Adverse Reactions
T1/2
terminal elimination half-life
Tmax
time to reach maximal plasma concentrations
ULN
upper limit of normal


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1 Background 
1.1 Overview of glioblastoma pathogenesis, epidemiology and current 
treatment 
1.1.1 Glioblastoma 
Primary brain tumors are among the top 10 causes of cancer-related deaths in the United States, 
accounting for approximately 1.4% of all cancers and 2.4% of all cancer-related deaths.  About 14 
per 100,000 people in the United States are diagnosed with a primary brain tumor each year, and 6 
to 8 per 100,000 are diagnosed with a primary malignant brain tumor.  Glioblastoma Multiforme 
(GBM) is the most frequently reported malignant brain tumor histology (29.6%) in the National 
Cancer Database. The prognosis for patients who develop GBM is bleak, with average survival 
after diagnosis ranging from 12-16 months.  Although conventional treatment with surgery, 
irradiation, and temozolomide postpones tumor progression and extends patients survival, these 
tumors universally recur and unrelentingly result in patient death.  Nevertheless, the alkylating 
agent temozolomide remains the single most effective adjuvant chemotherapy available for GBM 
patients. 
Targeted therapies in glioblastoma 
Glioblastoma 
Glioblastoma is a uniformly fatal extremely heterogeneous disease. Tumor heterogeneity translates 
into histological patterns, genetic alterations and gene expression profiles. The current treatment 
for glioblastoma is maximal surgical resection, followed by radiation therapy with concurrent and 
adjuvant temozolomide (the Stupp regimen). Recent genetic molecular advances have contributed 
to a better understanding of glioblastoma pathophysiology. A multitude of potentially clinically-
relevant genetic molecular alterations have been identified as targets for further drug development.  
Currently, however, there is no FDA-approved targeted therapy with demonstrated efficacy. 
1.1.2 Rb-Positive and mTOR-positive tumors 
Defective Retinoblastoma (RB) and mTOR pathway regulation in Glioblastomas 
The mitogenic PI3K/mTOR and retinoblastoma (Rb, 13q14) pathway are two key regulatory 
machineries controlling proliferation and cell cycle progression. These 2 pathways converge on 
cyclin-D and Cyclin-dependent kinases (CDK) 4/6 regulatory complex at the G1-S phase transition 
checkpoint. CDKN2A, located on 9p21 and deleted in many cancers, encodes the Inhibitor of 
CDK4 (INK4, p16) protein, a key inhibitor of the cell cycle via inhibiting CDK4 activity, and its 
homozygous deletion is associated with WHO grade III or IV gliomas. Primary GBM often displays 
loss of the INK4A/ARF tumor suppressor gene locus along with mutations/deletions for PTEN, 
which encodes key suppressor for mTOR signaling.  Together, the RB pathway is altered in 79% 
whereas PI3K/mTOR pathway is altered in 56% in GBM patients. In GBM, although mutations 
and homozygotic deletions of the RB1 gene itself appear in only 11% of them. Instead, the RB 
pathway is preferentially altered at components that lead to RB inactivation by hyper-
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antiproliferative and immunosuppressant and at least in part reversible after a 2 or 4-week recovery 
period with the exception of the changes in male reproductive organs, most notably testes. 
Based on data generated using human liver microsomes and microsomes from cells expressing 
single human cytochrome P450s enzymes, CYP3A4 was identified as the major enzyme involved 
in the microsomal biotransformation of everolimus. Everolimus inhibited competitively the 
metabolism of the CYP3A4 substrate cyclosporine with a Ki value of 2.3 μMol/L (2204 ng/mL) 
under in vitro conditions. Further details can be found in the everolimus Investigators Brochure. 
Clinical experience 
Everolimus pharmacokinetics 
Everolimus is rapidly absorbed with a median tmax of one to two hours. The steady-state AUC0-τ is 
dose-proportional over the dose range between 5 to 70 mg when given weekly and 5 and 10 mg 
when given daily. Steady-state was achieved within two weeks with the daily dosing regimen. 
Cmax is dose-proportional between 5 and 10 mg for both the weekly and daily regimens. In healthy 
subjects, high fat meals reduced systemic exposure of a 10 mg dose of everolimus (as measured by 
AUC) by 22% and the peak plasma concentration Cmax by 54%. Light fat meals reduced AUC by 
32% and Cmax by 42%. Food had no apparent effect on the post absorption phase concentration-
time profile ([Study RAD001C2120]). 
The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 to 
5,000 ng/mL, is 17% to 73%. The amount of everolimus confined to the plasma is approximately 
20% at blood concentrations observed in cancer patients given everolimus 10 mg/day [DMPK 
R303044]. Plasma protein binding is similar in healthy patients and in subjects with moderate 
hepatic impairment (approximately 74%, [Study RAD001A2303]).
The major and nearly exclusive enzyme responsible for the metabolism of everolimus in man was 
CYP3A4 (DMPK(US)1998/005; DMPK(CH) R99-2448), (Kuhn et al. 2001). Other CYP 
isoenzymes either do not metabolize everolimus or do so at very low rates. Everolimus is a moderate 
inhibitor of P-glycoprotein-like mediated efflux systems, although the compound has a high 
intrinsic permeability when P-glycoprotein is inhibited (Crowe 1998, Laplante et al. 2002, 
[DMPK(CH) 1997/417]). Following oral administration, everolimus is the main circulating 
component in human blood and contributes the majority of the overall pharmacologic activity 
(Study W107). Everolimus was also shown to increase exposure of exemestane: In [Study 
RAD001Y2301], average exemestane Cmin and C2h were 45% and 71% higher, respectively, 
when co-administered with everolimus. 
No specific excretion studies have been undertaken in cancer patients; however, data available from 
the transplantation setting found the drug to be mainly eliminated through the feces. 
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 Everolimus in combination with endocrine therapy in HR+ breast cancer 
The combination of everolimus with hormonal therapy has been assessed in different disease 
settings in HR+ breast cancer and showed evidence of efficacy of everolimus in this patient 
population (Bachelot et al 2012; Baselga et al. 2009). 
In newly diagnosed patients with ER+ breast cancer, a neoadjuvant randomized 270-patient 
Phase II study compared the combination of everolimus 10 mg QD and letrozole 2.5 mg 
QD to letrozole alone for 16 weeks of therapy prior to surgery. The overall response rate in the 
investigational everolimus + letrozole arm was higher than that with letrozole alone: 68% 
vs.59% based on palpation (p = 0.062) and 58% vs. 47% based on ultrasound (p = 0.021) 
respectively, meeting the predetermined endpoint for efficacy. Additionally, there was a greater 
antiproliferative response in the investigational arm, with a decrease of the Ki67 proliferation index 
to <1 in 57% of patients in the everolimus arm compared to 30% of patients in the placebo arm 
(p<0.01) (Baselga et al. 2009). A randomized Phase III, double-blind, placebo-controlled study (the 
BOLERO-2 Study) demonstrated very significant improvements in treatment of HR+ breast cancer 
that had recurred or progressed on letrozole or anastrozole. Response rate, progression-free survival 
(PFS), and clinical benefit rate were all significantly improved relative to exemestane monotherapy. 
The median PFS by local assessment was 7.8 months for everolimus + exemestane versus 3.2 
months for exemestane (HR = 0.45; 95% CI: 0.38-0.54; p<.0001). Overall response rate (12.6% vs 
1.7%; p<.0001) and clinical benefit rate (51.3% vs 26.4%; p<.0001) were superior in the everolimus 
+ exemestane arm versus exemestane + placebo. Analyses by central assessment showed a median
progression free survival of 11 months with everolimus versus 4.1 months with placebo (HR = 0.38;
95% CI: 0.31 – 0.48; p<.0001) confirming the results of the primary PFS analysis (Bachelot et al.
2012).
Safety profile of everolimus 
The following AEs are considered to be class-effects of mTOR inhibitors: stomatitis/oral 
mucositis/ulcers, infections and infestations, rash and similar events, cytopenia, hemorrhages, non-
infectious pneumonitis, hyperglycemia/new-onset diabetes mellitus, renal events, and 
thromboembolism. The more common metabolic side effects reported with mTOR inhibitors result 
from inhibitory effects on mTOR-regulated lipid and glucose pathways, while infections stem from 
the immunosuppressive properties of these agents. Virtually all of the side effects associated with 
mTOR inhibitors can be managed effectively with dose modification and/or supportive 
intervention. 
The safety profile of everolimus observed in the Phase III BOLERO-2 study is consistent with prior 
experience in the oncology setting; events are predominantly low grade (grade 1 or 2). An increased 
risk of non-infectious pneumonitis, infection, and stomatitis in the everolimus plus exemestane arm 
relative to the control arm [exemestane + placebo] was observed, although each of these events can 
be effectively managed in this setting. 
The most common adverse events (AEs) suspected to be related to treatment, with an incidence 
≥10%, reported in association with everolimus plus exemestane therapy were consistent with what 
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2 Rationale 
2.1 Study rationale and purpose 
Primary brain tumors are among the top 10 causes of cancer-related deaths in the United States, 
accounting for approximately 1.4% of all cancers and 2.4% of all cancer-related deaths.  About 14 
per 100,000 people in the United States are diagnosed with a primary brain tumor each year, and 6 
to 8 per 100,000 are diagnosed with a WHO grade III or IV primary brain tumor.  Glioblastoma 
Multiforme (GBM, WHO Grade IV gliomas) is the most frequently reported malignant brain tumor 
histology (29.6%) in the National Cancer Database. The prognosis for patients who develop WHO 
Grade III or IV gliomas is bleak, with average survival after diagnosis ranging from 12-16 months. 
Although conventional treatment with surgery, irradiation, and temozolomide postpones tumor 
progression and extends patients survival, these tumors universally recur and unrelentingly result 
in patient death.  Nevertheless, the alkylating agent temozolomide remains the only effective 
adjuvant chemotherapy available for high-grade glioma patients. 
Aberrant mitogenic PI3K/mTOR signaling and cell cycle control are hallmarks of human cancers. 
In GBMs, activating mutations in PI3K/mTOR pathway including PIK3CA and mTOR as well as 
loss-of-function mutations/deletions in PTEN are found in approximately 56% of the patients. The 
pathway induces uncontrolled proliferation by activating D-type cyclins. Together D-type cyclins 
and cyclin-dependent kinases (CDK) 4/6 form complexes crucial for cell cycle progression, 
specifically the G1-S phase transition. These complexes phosphorylate Rb, a product of the 
retinoblastoma protein tumor suppressor gene. In its active form, hypophosphorylated pRb is bound 
to E2Fs inhibiting their transcriptional activity. Hyperphosphorylation of pRb renders it inactive 
and allows for the release of E2F transcription factors necessary for initiation of S-phase and cell 
cycle progression. An endogenous CDK4/6 inhibitor, p16INK4A, negatively regulates these 
processes and is frequently mutated in GBMs (~40%) (Verhaak et al., 2010). In recent years there 
have been numerous clinical trials in adults with cancer utilizing small molecule inhibitors targeting 
cell cycle regulatory genes such as CDKs. Ribociclib in particular has been approved recently by 
FDA to treat breast cancer patients. Combination therapy with ribociclib and everolimus is currently 
on-going in several solid cancers. However, combination therapy with CDK inhibitor and mTOR 
inhibitor have yet to be evaluated in adult high-grade glioma patients. Abundant preclinical 
evidence indicates that Rb-deficient cancer cells are resistant to CDK4/6 inhibition and ongoing 
trials with CDK4/6 inhibitors exclude patients with Rb-deficient tumors. Patients with Rb+ and 
mTOR+ will be selected in the trial to ensure maximal benefit from the combination therapy. 
Previous LEE011X2106 Phase-1b clinical trial tested a combination of exemestane + everolimus 
+ribociclib in breast cancer patients. This combination appeared to be safe and demonstrated 
clinical activity at the RDE of ribociclib 300 mg (3weeks on/1 week off), everolimus 2.5 mg 
daily, and exemestane 25 mg daily. PK analysis indicated that ribociclib (200 mg-350 mg) 
increased exposure of everolimus (2.5 mg) due to CYP3A4 inhibition by ribociclib. At steady-
state, everolimus exposure was largely within the exposures achieved with multiple doses of 5 
and 10 mg of single agent everolimus. (Bardia et al. 2014). Thus, triplet combination of endocrine 
therapy with mTOR and CDK4/6 inhibition is feasible, permits lower dosing of everolimus with 
acceptable dose exposure levels, and shows encouraging signs of clinical activity, including in
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patients with prior exposure to PI3K/AKT/mTOR or CDK4/6 inhibitors, suggesting that triplet 
therapy might overcome resistance to doublet therapy in a subset of patients. Therefore the 
combination therapy of ribociclib plus everolimus will be examined in this phase 0/I trial.  
Figure 3 Regulation of cell cycle checkpoint control 
Mitogenic signals converge at the level of cyclin D1 upregulation and CDK4/6 association, localization, and kinase 
activity. CDK4/6 phosphorylates and inactivates retinoblastoma (RB) tumor suppressor proteins, leading to 
dissociation of E2F transcription factors and transcriptional regulation of genes important for G1/S transition and cell 
cycle progression through the restriction point (lightning bolt). Ribociclib is a highly specific inhibitor of CDK4/6 
which blocks the cell cycle in the G1 phase. Figure adapted from (Lange and Yee 2011). 
2.2 Rationale for the protocol design 
Despite improvements in drug discovery tools, a novel agent today has only an 8% chance of 
becoming commercially available to patients, down from the historical success rate of 14% in 1985. 
Currently, conventional drug development requires up to 20 years from discovery to market, with 
recent costs ranging between $800 million and $1.8 billion.  Unfortunately, it is estimated that 90% 
of all compounds developed in the laboratory fail during human trials and the current success rate 
for oncology agents is even lower.  Specifically, only 5% of new investigational drugs applications 
submitted to the FDA for cancer therapies are ultimately successful and, for brain tumors, the rate 
of success has hovered closer to 1% during the last two decades.  Importantly, 40% of exits from 
Phase I studies are currently due to undesirable pharmacokinetic characteristics that were not 
predicted from preclinical animal models.   
Not unexpectedly, the rising costs associated with drug discovery have tilted the field towards 
industry.  However, despite recent advances in cancer genomics, the FDA has reported a downturn 
in the submission of major drug and biologic product applications since 2000.  Thus, although an 
improved molecular understanding of cancer has led to a wave of experimental targeted therapies, 
the challenge of efficiently interrogating these agents and identifying those with most promise 
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remains a significant impediment. Furthermore, even though targeted molecular pathways are often 
shared across several different cancer subtypes, mru·ket forces and the risk of CNS morbidity have 
left brain tumor patients as a comparatively low priority. 
The efficiency and success of brain tumor targeted-therapy clinical trials are expected to be greatly 
improved with increased execution of Phase O clinical trials. 
Phase O trials provide 'humanization' of preclinical models with validated phannacodynamics 
assays and clinically-relevant methodologies for tissue analysis. For targeted cancer therapies, such 
as the proposed CDK4/6 and mTOR inhibitors, the Phase O trial enables rapid interrogation of 
biomarker assays for dmg effect, as well as CNS penetration. Other established benefits include 
regulatory flexibility (through the FDA's exploratory IND mechanism), lower overall costs, more 
rapid demonstration of proof-of-concept, and endpoints that will streamline the design of 
subsequent Phase I/Will trials. For this particular study, since a Phase I dose-escalation study has 
already been completed, a Phase I component will be added for patients with demonstrated 
pharmacokinetic and pha1macodynamic response. 
The applicability of a Phase O study is most ideal in the situation of a targeted molecule, where 
there is availability of a validated biomru·ker for a well-1mderstood target and evidence for linear 
dmg kinetics. Here, we propose a set of Phase O clinical trials examining a novel targeted 
combination therapy, ribociclib+everolimus, which meets both these criteria. 
2.3 Rationale for dose and regimen selection 
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patients that have been treated with 400 mg of ribociclib and 2.5 mg of Everolimus we find that 
there is almost no detectable Everolimus in the brain/CSF and no PD effect for both Ribociclib and 
Everolimus. Based on these data and the fact that the MTD is not reached in CLEE011X2106 study 
with three combination drugs, we propose to increase both the doses of Ribociclib and Everolimus 
in our study to determine the MTD and the recommended Phase 2 dose (RP2D).     
After dosing of ribociclib at 400mg and everolimus at 2.5mg in 6 patients, the data will be reviewed 
by the DSMB. If deemed safe to continue, dose escalation will be performed to evaluate brain 
penetration for both drugs. The dose escalation levels will be pre-determined with 6 patients in each 
level using a rolling-6 design and AEs will be closely monitored. 
Due to persistent negative PK effects from everolimus, despite no adverse events limiting drug 
dosing, additional dose-levels will employ a single, high-dose administration of everolimus.  Other 
combination drug studies have suggested 70mg weekly as a maximal-tolerated dose.  As a lead-in 
to this combination dose in our study, a new dose level at 50mg once prior to surgery (in 
combination with 600mg ribociclib) will be introduced.  This lead-in dose will give rise to 60mg at 
the next level and 70mg at the final level.  Similarly, the phase 2 component of the study will reflect 
this new dosing regimen for patients with PK and PD effects from both drugs.  Specifically, a lead-
in regimen at 50mg q weekly in Phase 2 (in combination with ribociclib) will then be escalated 
towards 70mg weekly.
3 Objectives and endpoints 
Objective 
Endpoint 
Primary 
• To determine the dose-
limiting toxicity (DLT)
and maximum tolerated
dose (MTD) for study
drug when administered in
combination.
• To identify recurrent high-
grade glioma patients with
positive PK and PD
effects.
• MTD: highest dose of drug that did not
cause a DLT in > 17% of participants
• PK: total and unbound ribociclib and
everolimus concentrations in non-
enhancing and contrast-enhancing
tumor tissue samples
• PD: pRB-positive cells and pS6-
positive cells
Secondary 
• To explore safety and
efficacy in recurrent high-
grade glioma  patients
with demonstrated PK and
PD effects and determine
RP2D
• To describe PK for Phase
2 patients
• Progression-free survival (PFS)
• Overall survival (OS)
• Drug-related toxicity
• RP2D
• Systemic PK profiles of ribociclib and
everolimus when combined.
Exploratory 
• To explore evidence for
CDK4/6 and mTOR
pathway activity in tumor
tissue (as compared to
• Quantification of total and
phosphorylated forms of Rb, FoxM1,
S6, 4EBP, as well as cleaved Caspase-3
and MIB1. Expression of Cyclin D1,


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archival tissue) and 
mechanisms of resistance 
• Pharmacometabolomics:
To explore the plasma
metabolomic signature of
the exposure of ribociclib
and everolimus
• To identify resistance
mechanism and alternate
pathways
Cyclin E1, PI3K/mTOR signaling 
components  
• Plasma metabolomic profiles (i.e.,
levels of ~250 metabolites) at the
pretreatment and at predefined time
points after the combination therapy.
• Pharmacogenomics studies using RNA-
seq and Whole Exome Sequencing to
identify alterations in gene expression
and mutational profile between pre-
treatment and post-treatment tissues or
plasma.


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4 Protocol design 
The proposed Phase 0 study for ribociclib and everolimus will investigate PK, PD, and PG 
endpoints for any recurrence Rb+ high-grade glioma patients. 
The following criteria will be used to determine recurrent disease required for inclusion in the 
proposed study: 
For high-grade gliomas, the RANO criteria (published in 2010) will be utilized.  This will 
be applicable for both Grade III and IV gliomas.  
Enrollment in Phase 0 study occurs after the clinical decision is made for re-resection.  This decision 
is based upon the radiographic criteria described above, in addition to clinical assessment and 
discussion of the risks/benefits for surgical resection.  Therefore, patients enrolled in this study are 
not taken to the operating room due to study protocol. 
4.1 Description of protocol design 
4.1.1 Phase 0  
In the proposed trial, patients will be administered ribociclib+everolimus prior to surgical 
resection of their tumor. Recurrent GBM patients will be randomized into one of the three time-
interval cohorts for the first two dose levels.  
In the lead-in dose escalation study, the first six subjects (lead-in) will receive ribociclib 400 mg 
and everolimus 2.5 mg orally-administered in 5 daily doses with the last dose. If one or less patient 
experiences DLT among the 6 patients, this regimen with ribociclib 400 mg and everolimus 2.5mg 
will be considered safe and we will continue with the dose escalation phase of the study up to 
Level 6.  
Four dose escalation levels: 
Level 0: ribociclib 400mg and everolimus 2.5 
Level 1: ribociclib 600mg and everolimus 2.5mg 
Level 2: ribociclib 600mg and everolimus 5mg 
Level 3: ribociclib 600mg and everolimus 10mg  
Level 4: ribociclib 600mg daily for 5 days and everolimus 50mg given once on Day 5. 
Level 5: ribociclib 600mg daily for 5 days and everolimus 60mg given once on Day 5. 
Level 6: ribociclib 600mg daily for 5 days and everolimus 70mg given once on Day 5. 
Three to fourteen (3-14) patients will be enrolled into each level to observe AEs and DLTs. 
Detailed DLTs definition will be summarized in Table 9.  
All patients will receive ribociclib and everolimus orally-administered in 5 daily doses. 
Cohort 1: last ribociclib+everolimus dose 1 to 3 hours prior to craniotomy for tumor resection 
(n=8 patients) 










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4.4 Early Termination 
Subjects/patients may withdraw at any time or be dropped from the study at the discretion of the 
investigator should any untoward effects occur. In addition, a subject/patient may be withdrawn by 
the investigator if he/she violates the study plan or for administrative and/or other safety reasons. 
When a subject/ patient discontinues/withdraws prior to study completion, all applicable activities 
scheduled for the final study visit should be performed at the time of discontinuation. Any adverse 
experiences which are present at the time of discontinuation/withdrawal should be followed in 
accordance with the safety requirements outlined. 
Subjects/patients who discontinue from the study for reasons unrelated to the study (e.g., personal 
reasons) will be replaced as required for the study to meet its objectives.  The decision to remove a 
subject/patient and to replace dropouts will be made by the investigator and study statistician.  The 
replacement will generally receive the same treatment or treatment sequence (as appropriate) as the 
allocation number replaced.  Both the replacement and originally allocated number will be unique 
numbers. 
5 Population 
5.1 Patient population 
Patients will be accrued at up to 3 sites. 
The investigator or designee must ensure that only patients who meet all of the inclusion and none 
of the exclusion criteria are entered into this protocol. 
Patients enrolled in this protocol are not permitted to participate in additional parallel 
investigational drug or device studies while on treatment. 
Please note these are the minimum inclusion and exclusion criteria required for treatment on 
LEE011 + everolimus. Investigators should include disease and protocol specific eligibility 
criteria as applicable.  
5.2 Inclusion criteria 
Patients eligible for inclusion in this early treatment protocol have to meet all of the following 
criteria: 
1. Prior resection of histologically-diagnosed WHO Grade III or IV glioma.
A. Glioma patients who have progressed on or following standard (Stupp regimen) therapy,
which included maximal surgical resection, temozolomide, and fractionated
radiotherapy.
2. Recurrence must be confirmed by diagnostic biopsy with local pathology review or contrast-
enhanced MRI.
3. Subjects must have measurable disease preoperatively, defined as at least 1 contrast-enhancing
lesion, with 2 perpendicular measurements of at least 1 cm, as per RANO criteria.
4. For gliomas, archival tissue must demonstrate: (a) RB positivity (≥20%) on
immunohistochemistry OR no RB mutations on next-generation sequencing (NGS), (b)


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Chromosomal loss of CDKN2A/B/C OR CDK4/6 or CCND1/2 amplification on array CGH, 
(c) mTOR+: PTEN loss OR PIK3C2B or AKT3 amplification on aCGH OR mutations for
PIK3CA or PIK3R1, or mTOR or PTEN mutations using rhAMP analysis or pS6 positivity on
immunohistochemistry (≥10% for pS6). If mutations within the mTOR/PI3K pathways cannot
be accurately detected due to poor tissue quality the enrollment criteria will be determined
using RB and pS6 positivity.
5. Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (Appendix 1).
6. Patients ≥ 18 years of age.
7. Ability to understand and the willingness to sign a written informed consent document
(personally or by the legally authorized representative, if applicable).
8. Patient has voluntarily agreed to participate by giving written informed consent (personally or
via legally-authorized representative(s), and assent if applicable).
(Written informed consent for the protocol must be obtained prior to any screening procedures.
If consent cannot be expressed in writing, it must be formally documented and witnessed,
ideally via an independent trusted witness.)
9. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and
other procedures.
10. Confirmed negative serum pregnancy test (β-hCG) before starting study treatment or patient
has had a hysterectomy.
11. Patient has adequate bone marrow and organ function as defined by the following laboratory
values (as assessed by the local laboratory for eligibility):
The following laboratory criteria have been met:
•
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (recommended)
•
Hemoglobin (Hgb) ≥ 9.0 g/dL (Participants may receive erythrocyte transfusions to
achieve this hemoglobin level at the discretion of the investigator.)
•
Platelets ≥ 100 x 109/L (at the time of surgery)
•
Potassium, total calcium (corrected for serum albumin), magnesium, sodium, and
phosphorus within normal limits for the institution or corrected to within normal limits
with supplements before first dose of study medication
•
INR ≤1.5 (unless the patient is receiving anticoagulants and the INR is within the
therapeutic range of intended use for that anticoagulant within 7 days prior to the first dose
of study drug)
•
Serum creatinine < 1.5 mg/dL
•
Estimated glomerular filtration rate (eGFR) ≥ 50 mL/min
•
In the absence of liver metastases, alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) < 2.5 x ULN.
•
Serum total bilirubin <ULN, or < 3.0 x ULN in patients with well-documented Gilbert’s
syndrome
•
Serum cholesterol < 300 mg/dL or < 7.75 mmol/L AND triclycerides < 2.5 x ULN (NOTE:
in case one or both of these thresholds are exceeded, the patient can only be included after
initiation of appropriate lipid lowering medication.)
12. QTcF interval at screening < 450 msec [using Fridericia’s correction (formula = QT/(RR)0.33)]


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13. Resting heart rate 50-90 bpm (may be repeated up to 2x)
14. Must be able to swallow ribociclib and everolimus capsules/tablets
15. If patient is receiving tamoxifen or toremifene, a washout period of 5 half-lives prior to
enrollment is required
5.3 Exclusion criteria 
Patients eligible must not meet any of the following criteria: 
1. Archival tissue is not available for research use or there is not a sufficient quantity available to
confirm eligibility.
2. Archival tumor is not Rb-positive status and mTOR-positive status.
3. Patient has not received prior radiotherapy.
4. Co-morbid condition(s) that, at the opinion of the investigator, prevent safe surgical treatment.
5. Active infection or fever > 38.5°C that in the opinion of the investigator would be a safety risk
to the patient.
6. Active (acute or chronic) or uncontrolled severe infection, liver disease such as cirrhosis,
decompensated liver disease, and active and chronic hepatitis (i.e. quantifiable HBV-DNA
and/or positive HbsAg, quantifiable HCV-RNA).
7. Known severely impaired lung function (spirometry and DLCO 50% or less of normal and O2
saturation 88% or less at rest on room air).
8. Active, bleeding diathesis.
9. Patients with known hypersensitivity to any of the excipients of ribociclib or mTOR inhibitors
(sirolimus or everolimus), including peanut, soy and lactose.
10. Patients with a clinically significant hypersensitivity to everolimus or to other rapamycin
derivatives.
11. Prior therapy with ribociclib or any CDK4/6 inhibitor (e.g. palbociclib, abemaciclib), or with
everolimus. Prior therapy is defined as a therapeutic dosing.
12. Patient who has received radiotherapy ≤4 weeks or limited field radiation for palliation ≤2
weeks prior to starting study drug, and who has not recovered to grade 1 or better from related
side effects of such therapy (exceptions include alopecia or other toxicities not considered a
safety risk for the patient at investigator’s discretion) and/or in whom ≥25% of the bone marrow
(Ellis, 1961) was irradiated.
13. Patient has a concurrent malignancy or malignancy within 3 years prior to starting study drug,
with the exception of adequately treated, basal or squamous cell carcinoma, non-
melanomatous skin cancer or curatively resected cervical cancer.
14. Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting,
diarrhea, malabsorption syndrome, or small bowel resection).
15. Patient has a known history of HIV infection (seropositivity; testing not mandatory).
16. Patients who have received live attenuated vaccines within 1 week of start of everolimus and
during the study. Patient should also avoid close contact with others who have received live
attenuated vaccines. Examples of live attenuated vaccines include intranasal influenza, measles,
mumps, rubella, oral polio, BCG, yellow fever, varicella and TY21a typhoid vaccines.


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17. Patient has any other concurrent severe and/or uncontrolled medical condition that would, in
the investigator’s judgment, cause unacceptable safety risks, contraindicate patient participation
in the clinical study or compromise compliance with the protocol (e.g. chronic pancreatitis,
chronic active hepatitis, active untreated or uncontrolled fungal, bacterial or viral infections,
etc.)
18. Uncontrolled diabetes mellitus as defined by HbA1c >8% despite adequate therapy as indicated
by the medical history. Patients with a known history of impaired fasting glucose or diabetes
mellitus (DM) may be included, however blood glucose and antidiabetic treatment must be
monitored closely throughout the trial and adjusted as necessary.
19. Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormalities,
including any of the following:
• History of acute coronary syndromes (including myocardial infarction, unstable angina
pectoris, coronary artery bypass grafting, coronary angioplasty, or stenting) or
symptomatic pericarditis within 6 months prior to screening . 
• History of documented congestive heart failure (New York Heart Association functional
classification III-IV). 
• Documented cardiomyopathy.
• Left Ventricular Ejection Fraction (LVEF) <50% as determined by Multiple Gated
acquisition (MUGA) scan or echocardiogram (ECHO) at screening.
• Clinically significant cardiac arrhythmias (e.g. ventricular tachycardia), complete left
bundle branch block, high-grade AV block (e.g. bifascicular block, Mobitz type II and
third-degree AV block). 
• Long QT syndrome or family history of idiopathic sudden death or congenital long QT
syndrome, or any of the following:
•
Risk factors for Torsades de Pointe (TdP) including uncorrected
hypokalemia or hypomagnesemia, history of cardiac failure, or history of
clinically significant/symptomatic bradycardia.
•
Concomitant use of medication(s) with a known risk to prolong the QT
interval and/or known to cause Torsades de Pointe that cannot be
discontinued (within 5 half-lives or 7 days prior to starting study drug) or
replaced by safe alternative medication.
•
Inability to determine the QT interval on screening (QTcF, using Fridericia’s
correction).
• Systolic blood pressure (SBP) >160 mmHg or <90 mmHg at screening (may be repeated
up to 2x). 
20. Patient is currently receiving any of the following medications and cannot be discontinued 7
days prior to starting study drug (see Appendix 2 for details):
• Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit hybrids,
pomelos/pummelos, star-fruit, pomegranates or pomegranate juice and Seville oranges.
• That have a narrow therapeutic window and are predominantly metabolized through
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• Herbal preparations/medications, dietary supplements known as strong inhibitors or inducers
of CYP3A4 or those with a known risk of QT prolongation. (Does not include Ca, Mg, Vit D
or KCl supplements).
• Known strong inhibitors or inducers of P-gp.
21. Patients taking ACE inhibitors.
22. Patient is currently receiving warfarin or other coumarin-derived anticoagulant for treatment,
prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH) or
fondaparinux is allowed.
23. Participation in a prior investigational study within 30 days prior to enrollment or within 5 half-
lives of the investigational product, whichever is longer.
24. Patient has had major surgery within 14 days prior to starting study drug or has not recovered
from major side effects (tumor biopsy is not considered as major surgery).
25. Patient has not recovered from all toxicities related to prior anticancer therapies to NCI-CTCAE
version 4.03 Grade ≤2 (Exception to this criterion: patients with grade 1 taxane-induced
neuropathy, any grade of alopecia, amenorrhea or other toxicities not considered a safety risk
for the patient as per investigator’s discretion, are allowed to enter the study.).
26. Patient with a Child-Pugh score B or C.
27. Patient has a history of non-compliance to medical regimen or inability to grant consent.
28. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after
conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
29. Women of child-bearing potential, defined as all women physiologically capable of becoming
pregnant, unwilling to use highly effective methods of contraception during dosing and for 3
months after the last dose of study treatment. Highly effective contraception methods include:
•
Total abstinence (when this is in line with the preferred and usual lifestyle of the subject.
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and
withdrawal are not acceptable methods of contraception.
•
Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of
oophorectomy alone, only when the reproductive status of the woman has been confirmed
by follow up hormone level assessment.
•
Male sterilization (at least 6 months prior to screening) with the appropriate post-vasectomy
documentation of the absence of sperm in the ejaculate. For female subjects on the study
the vasectomized male partner should be the sole partner for that subject.
•
Use of oral, injected or implanted hormonal methods of contraception or placement of an
intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal
contraception that have comparable efficacy (failure rate <1%), for example, hormone
vaginal ring or transdermal hormone contraception.
•
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.
•
Note: Oral contraceptives are allowed but should be used in conjunction with a barrier
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0 out of 3 
Enter 3 patients at the next dose level. 
>2
Dose escalation will be stopped.  This dose level will be declared 
the maximally administered dose (highest dose administered). 
Three (3) additional patients will be entered at the next lowest dose 
level if only 3 patients were treated previously at that dose. 
1 out of 3 
Enter at least 3 more patients at this dose level. 
•
If 0 of these 3 patients experience DLT, proceed to the next dose
level.
•
If 1 or more of this group suffer DLT, then dose escalation is
stopped, and this dose is declared the maximally administered dose.
Three (3) additional patients will be entered at the next lowest dose
level if only 3 patients were treated previously at that dose and the
lower dose level demonstrated positive PK/PD results (OBD).
<1 out of 6 at highest dose level below the 
maximally administered dose 
This is generally the recommended phase 2 dose (RP2D). 
If Dose Level 3 is reached, <1 out of 6 have experienced DLTs and 
the dose level has demonstrated positive PK/PD results, the time 
cohort will be expanded.  
If one patient develops a DLT out of three, then the cohort will be expanded to include a total of 6 
patients.  If greater than or equal to two patients develop DLT, then that dose level will be 
considered the maximum administered dose (MAD) and further dose escalation will be terminated. 
A total of 6 patients will be treated at the next lower dose.  The maximum tolerated dose (MTD) 
will be the dose at which no more than 1 patient develops DLT when at least 6 patients have been 
treated.   
At the time of dose escalation, a written report will be submitted to the DSMB Chair (or qualified 
alternate) describing the cohorts, dose levels, adverse events, safety reports and any DLTs observed. 
The DSMB Chair will review the report and provide a written authorization to proceed or request 
more information within 2 business days. Approval for the dose escalation must be obtained prior 
to implementation. 
Optimal Biological Dose (OBD) 
If positive tumor PK and PD effects are observed in patients treated at a specific dose, but no DLT 
is observed, dose escalation will continue as planned in order to demonstrate whether an increase 
in biological effect can be observed with increasing dosage or if such effect is maximized (ie, the 
OBD is attained).  If the OBD has been achieved with <2 DLTs out of 6 patients, the OBD cohort 
will be expanded to an additional 8 patients to assure safety and to evaluate time course of PK and 
PD effects at 2 time cohorts (i.e., 2 ± 1 h and 24 ± 1 h), with 4 patients in each time cohorts, 
following the administration of the final dose on Day 5. 
6.1.3 Dose Limiting Toxicity for Phase 0 or Phase 2 
Dose limiting toxicity (DLT) will be defined as adverse event(s) which is/are attributable to the 
study treatment and unrelated to disease, disease progression, inter-current illness, or concomitant 
medications during the first 5 days in Phase 0 or in the first cycle (28 days) of Phase 2. The 
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6.1.4 Dosing regimen 
Ribociclib + Everolimus 
The Barrow Neurological Institute / St. Joseph’s Hospital and Medical Center will purchase 
commercially available supplies of ribociclib (Kisqali®) and everolimus (Afinitor®).  
Ribociclib+everolimus will be administered orally once daily on a 5-day dosing schedule during 
Phase 0 and a 28-day dosing schedule (3 weeks on, 1 week off) during Phase 2. The investigator 
must instruct the patient to take the treatment exactly as prescribed. 
•
Patients should take ribociclib+everolimus once daily at approximately the same time each
day with a large glass of water (~ 250 ml) at the same time each day, in the morning,
afternoon, or evening.  The dose taken on the day of surgery will vary depending upon the
planned time of the resection (see Section 4.1).
•
Patients can take ribociclib+everolimus without regard to meals; however, dietary habits
around the time of dosing should be as consistent as possible throughout the study.
•
Patients should be instructed to swallow the ribociclib tablets whole and not to chew, crush or
open them
•
If vomiting occurs during the course of treatment, no re-dosing of the patient is allowed
before the next scheduled dose.
•
Any doses that are missed (not taken within 6 hours of the intended time) should be skipped
and should not be replaced or made up on a subsequent day.
•
Patients must avoid consumption of grapefruit, grapefruit hybrids, pomelos/pummelos, star-
fruit, pomegranates or 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 known as strong inhibitors or inducers of CYP3A4 or those
with a known risk of QT prolongation are permitted, due to potential interactions with
ribociclib and everolimus; multivitamins are allowed.
•
In Phase 2, Dose Levels 0-2, patients will take ribociclib+everolimus for 21 consecutive days
followed by 1 rest week.
•
In Phase 2, Dose Level 3, patients should take everolimus in two 5mg doses, approximately
12 hours apart (BID) for a total of 10mg. In Phase 0, the dose is 10mg given in one dose per
day (qd).
•
In Phase 2, Dose Level 4+, patients should take everolimus in one dose weekly. Ribociclib
will be taken for 21 consecutive days followed by 1 rest week.


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Additional Dosing Guidelines for Pharmacokinetic Sampling / ECG / 
Chemistry panel / Lipid Panel Collection  
On days with PK, ECG sampling, chemistry panel and/or lipid panel sampling, the following 
additional guidelines should be followed:  
•
On a day when PK blood collection is scheduled at the clinic, patients must take study
treatment in the clinic under the supervision of the Investigator or designee. On all other
days, patients may take the study treatment at home.
•
On a day of chemistry panel and/or lipid panel sampling, patients should be fasting from food
and drink for at least 8 hours overnight; however, it will not be considered a deviation if the
patient is not fasting. Water is allowed during all fasting periods; however, coffee, tea and
juice are not permitted during the fasting period. Patients must also take study treatment in
the clinic under the supervision of the Investigator or designee. On all other days, patients
may take the study treatment at home.
•
Pre-dose samples should be drawn prior to dosing. The sampling time of the PK samples and
the dosing time must be precisely recorded in the CRF. Furthermore, the dosing date and
time the study medication was taken on the day before the PK assessment must be precisely
recorded in the CRF.
•
Post-dose PK samples should be collected after dosing of the study treatment and precisely
recorded in the CRF.
•
If a pre-dose PK sample should be obtained, then the sample should be collected after the
ECG and before dosing of the study treatment when possible; or allow approximately 30
minutes after the sample is drawn before obtaining the ECG.
6.1.5 Guidelines for continuation of treatment beyond tumor resection (Optional 
Phase 2) 
Patients with positive PK and PD responses will be provided the option of continuing on therapy 
until tumor progression.  PK data evaluates the drug concentration in enhancing and non-
enhancing region of the tumor. PD analysis evaluates the biomarker response after 5-day treatment 
and compares this with archival tissue. If both are positive the patients will be enrolled into Phase 
2 portion of the trial with the same dose level taken during Phase 0 (unless there is more than one 
DLT observed in Phase 2, see Section 4.1.2). If the PD data is not conclusive due to treatment 
effect or limited tissue samples from the surgery, the PK data would be the primary guidance on 
deciding phase 2 enrollment. 
Some anticipated risks and safety considerations of the ribococlib+everolimus combination will 
be closely monitored. Preclinical and Phase I clinical data available from ongoing studies with 
ribociclib and everolimus separately suggest few overlapping toxicities for the proposed 
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combinations. Special attention will be paid to blood counts (cytopenias), mucositis, liver function 
test abnormalities and QTc prolongation. Clinical data from the [CLEE011X2101] study do not 
show marked accumulation in ribociclib with time, suggesting that it does not substantially inhibit 
its own metabolism or clearance. Everolimus and ribociclib are in vitro inhibitors and substrates 
of CYP3A4, and the latter is also a time-dependent CYP3A4 inactivator. The available preclinical 
and clinical data therefore suggest the possibility of a drug interaction, specifically one that may 
increase exposure to everolimus. Based on simulation using Simcyp software (Simcyp Version 12, 
release 1), the projected increase in the AUCleac 0-6h of everolimus was 3.5-fold following the 
starting daily dose of 200 mg ribociclib co-administered with 2.5 mg of everolimus for 14 days. 
No significant effect on ribociclib metabolism was predicted when co-administered with 
everolimus. Appropriate eligibility criteria, dose modification guidelines and stopping rules are 
included in this protocol. 
6.1.6 Treatment duration 
All Phase 0 patients will receive a 5-day regimen as described above.  Patients with Rb+ mTOR+ 
tumors will be provided the option of continuing on therapy until tumor progression.  In Phase 2 
continuation therapy, patients will receive RP2D daily schedule (28 day cycle). 
 
6.2 Dose modification post-tumor resection (Phase 2) 
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patients to continue the ribociclib+everolimus treatment. See Table 
10 for dose reductions. Any changes in ribociclib+everolimus administration must be recorded. 
6.2.1 General guidelines for dose modifications 
•
For grade 1 and tolerable grade 2 treatment-related toxicities, with the exception of
pneumonitis, patients may continue at the current dose of ribociclib+everolimus treatment.
•
For intolerable grade 2 treatment-related toxicities as those that are irreversible (e.g.,
neurotoxicities, ocular toxicities, or cardiac toxicities) or prolonged grade 2 toxicities (i.e.,
those lasting longer than 14 days), or any grade 3 toxicities, with the exception of pneumonitis,
dosing should be interrupted until resolution to grade 1 or lower followed by resumption of a
new 28 days regimen. Dosing reductions could also be considered after grade 3 toxicities
(Table 11).
•
For any grade 4 toxicity, dosing should be interrupted and the patients should be followed until
the toxicity resolution to baseline levels, grade 1, or become stable. Following recovery from
grade 4 events, no additional ribociclib+everolimus treatment should be given to the patient
except for neutropenia and thrombocytopenia (details in Table 11).
More detailed ribociclib and everolimus dose modification guidelines are described in Section 
6.2.2 respectively for selected toxicities. Any variance from these guidelines in view of patient 
safety must first be discussed with the Sponsor unless there is an urgent need for action. 
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Guidelines for the follow-up of laboratory hematologic abnormalities 
In case of any occurrence of febrile neutropenia, neutropenia ≥ grade 3, or thrombocytopenia ≥ 
grade 3, hematology tests must be performed weekly (or more frequently if clinically indicated) 
until the event resolves to ≤ grade 2. Subsequent monitoring must be performed every 3 weeks. 
(See Table 12) 
Guidelines for the follow-up of laboratory liver abnormalities 
In patients with any clinically relevant laboratory liver abnormality, as defined below, hepatic 
toxicity monitoring must include ALL of the following liver function tests (LFTs): albumin, ALT, 
AST, total bilirubin (fractionated if total bilirubin > 2.0 x ULN), indirect bilirubin, alkaline 
phosphatase (fractionated if alkaline phosphatase is grade 2 or higher), creatine kinase, 
prothrombin time (PT) or INR  and GGT. Note: for patients with Gilbert Syndrome, total and 
direct bilirubin must be monitored, but intensified monitoring applies to changes in direct bilirubin 
only. (See Table 12) In case of any occurrence of ALT/AST/total bilirubin increase to grade 2 the 
LFTs must be monitored weekly (or more frequently if clinically indicated) until the event resolves 
to ≤ grade 1. Thereafter monitoring must be continued every 2 weeks (or more frequently if 
clinically indicated) for two additional cycles (e.g. 6 weeks). If there is no recurrence of ≥ grade 2 
ALT/AST/total bilirubin elevations during this period, subsequent monitoring must be performed 
every 3 weeks. 
In case of any occurrence of ALT/ AST/ bilirubin increase to grade 3 or 4, LFTs must be monitored 
weekly (or more frequently if clinically indicated) until the event resolves to ≤ grade 1. Thereafter 
monitoring must be continued every 2 weeks (or more frequently if clinically indicated) for four 
additional cycles (e.g. 12 weeks). If there is no recurrence of ≥ grade 2 ALT/AST/total bilirubin 
elevations during this period, subsequent monitoring must be performed every 3 weeks. 
Patients who discontinue ribociclib+everolimus treatment due to liver toxicity must be monitored 
weekly (or more frequently if clinically indicated) until the event resolves to ≤ grade 1 or 
stabilization occurs (no CTCAE grade change over 3 weeks). (See Table 12) 
Guidelines for the follow-up of laboratory renal abnormalities 
In case of any occurrence of serum creatinine results of grade 2 or greater, tests must be performed 
weekly (or more frequently if clinically indicated) until the event resolves to ≤ grade 1. Subsequent 
monitoring must be performed every 3 weeks. 
In case of any occurrence of serum creatinine ≥ grade 3, tests must be performed twice weekly (or 
more frequently if clinically indicated) until the event resolves to ≤ grade 1. Subsequent monitoring 
must be performed every 3 weeks. (See Table 12) 
Guidelines for the treatment of study drug induced diarrhea 
Mild to moderate diarrhea has been observed frequently in patients treated with ribociclib. 
Patients  should  be  monitored  for  diarrhea  and  given  appropriate  supportive  care  with 
diagnostic or therapeutic intervention, including interruption of therapy with ribociclib as 
appropriate. If a patient has experienced ribociclib-related diarrhea, and it is considered 
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sufficiently severe to warrant the use of prophylactic anti-diarrhea therapy, then prophylaxis may 
be instituted in that patient with subsequent treatment. 
Guidelines for the treatment of study drug induced nausea and vomiting 
Preclinical studies have identified vomiting as an AE of ribociclib administration in dogs. Nausea 
and vomiting are the most common non-hematologic adverse reactions observed with ribociclib; 
the majority of cases are mild to moderate. Hence, prophylactic treatment with anti-emetics is 
not required when starting therapy with ribociclib. However, all patients should be carefully 
monitored for the development of nausea and/or emesis, and if they occur, treatment with anti-
emetics may be instituted. If a patient has experienced ribociclib-related nausea and/or 
vomiting, and it is considered sufficiently severe to warrant the use of prophylactic anti-emetic 
therapy, then prophylactic therapy may be used in that patient with subsequent treatment. 
Table 12 Follow-up evaluations for selected toxicities 
Toxicity 
Follow-up evaluation* 
Investigations 
(hematologic) 
Febrile neutropenia, neutropenia or thrombocytopenia ≥ CTCAE Grade 3 
Test weekly (or more frequently) until ≤ Grade 2 
Subsequent monitoring must be performed every 3 weeks 
Investigations 
(hepatic) 
Total ALT/AST/total bilirubin Grade 2: 
Test weekly (or more frequently) until ≤ Grade 1 
Thereafter, continue to test every 2 weeks (or more frequently) for 2 cycles (6 weeks). If 
no recurrence of ≥ Grade 2 event, continue monitoring every cycle (3 weeks) 
Total ALT/AST/total bilirubin ≥ Grade 3: 
Test weekly (or more frequently) until ≤ Grade 1 
Thereafter, continue to test every 2 weeks (or more frequently) for 4 cycles (12 weeks). If 
no recurrence of ≥ grade 2 event, continue monitoring every cycle (3 weeks) 
Discontinuation due to liver toxicity: 
Test weekly (or more frequently) until ≤ Grade 1 or stabilization 
Investigations (renal) 
Serum creatinine Grade 2: 
Test weekly (or more frequently) until Grade 1 
Thereafter, test every cycle (3 weeks) 
Serum creatinine ≥ Grade 3: 
Test twice weekly (or more frequently) until ≤ Grade 1 
Thereafter, test every cycle (3 weeks) 
Investigations 
(Metabolic) 
Hyperglycemia ≥ Grade 3 
Test weekly (or more frequently) until Grade 1 
*Note: this table refers only to the evaluation schedule to monitor selected toxicities. Refer to Table 11 Criteria for post-tumor resection 
interruption and re-initiation of ribociclib+everolimus treatment 
6.3 Concomitant medications 
In general, the use of any concomitant medication/therapy deemed necessary for the care of the 
patient (e.g., anti-emetics, anti-diarrheal agents) is permitted, except when specifically prohibited. 
Anesthesia may use medications that would otherwise be prohibited when deemed clinically 
necessary, but if possible should be avoided. 
The patient must be told to notify the investigational site about any new medications he/she takes 
after the start of the ribociclib+everolimus treatment. All medications, including herbal/natural 
medications (excluding ribociclib treatment and prior antineoplastic treatments and blood 
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transfusions), surgeries and procedures (including physical therapy) administered within 28 days 
prior to the first dose of administration of ribociclib treatment through 30 days after the last dose 
of treatment will be recorded. Medications include not only physician prescribed medications, but 
also all over-the counter (OTC) medications, herbal medications (prohibited, see Section 6.3.3), 
food or vitamin supplements, and blood transfusions. 
For up to date information on prohibited medications please refer to the following websites: 
•
Medication with a known risk of prolonging the QT interval or inducing Torsades de Pointes
(please refer to http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm )
•
Strong inhibitors or strong inducers of CYP3A4/5 (please refer to
http://medicine.iupui.edu/flockhart/table.htm or http://www.druginteractioninfo.org)
•
Medications with a low therapeutic index that are primarily metabolized by CYP3A4/5,
CYP2C8 and/or CYP2C9 (please refer to http://medicine.iupui.edu/flockhart/table.htm or
http://www.druginteractioninfo.org)
6.3.1 Permitted concomitant therapy 
Medications required to treat AEs, manage cancer symptoms, concurrent diseases and supportive 
care agents, such as pain medications, anti-emetics and anti-diarrheal are allowed. 
The patient must be told to notify the investigational site about any new medications he/she takes 
after the start of the study treatment. All medications (other than study drugs) and significant non-
drug therapies (including vitamins, herbal medicines, physical therapy and blood transfusions) 
administered within 30 days of study entry and during the study must be listed on the Concomitant 
medications/Significant non-drug therapies eCRF. 
If patients take concomitant medications chronically, any change in dose schedule of concomitant 
medication throughout the study period should be clearly documented. 
Palliative radiotherapy 
In Phase 2 Palliative radiation is permitted. It should not be delivered to a target lesion and it 
should not encompass more than 25% of irradiated bone marrow. 
If palliative radiotherapy is initiated after the start of study treatment, the reason for its use must 
be clearly documented and progression as per RECIST 1.1 must be ruled out. 
No dose modification of study treatment is needed during palliative radiotherapy. 
Refer to the ribociclib Investigators Brochure and other drug package insert and Appendix 2 for 
information on possible interactions with other drugs. 
Use of antiemetic medications 
Ribociclib has low to minimal emetogenic potential according to a definition of antineoplastic 
agent emetogenicity (Grunberg et al, 2010). Antiemetic therapy can be used according to clinical 
guidelines for antineoplastic medications with low to minimal emetogenic potential for treatment 
and/or prevention of nausea and vomiting as a result of study treatment (NCCN Clinical Practice 
Guidelines in Oncology. Antiemesis, 2016; Roila F et al, 2016).  
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Potential drug interaction between ribociclib/placebo and antiemetic medications should always 
be taken into consideration. Example of prohibited antiemetic medication is intravenously 
administered ondansetron that in combination with ribociclib may precipitate TdP. Refer to 
Sections 6.3.1, 6.3.2 and 6.3.3 for list of medications that are prohibited or allowed to be used with 
ribociclib+everolimus.   
If a clinical decision to use ondansetron is made in order to treat the patient, this will be recorded 
in the concomitant medications but will not be recorded as a deviation. Efforts to not utilize 
ondansetron should be made.  
6.3.2 Permitted concomitant therapy requiring caution and/or action with 
ribociclib 
Medications to be used with caution during ribociclib and everolimus in this study are listed below 
(see Appendix 2). This list is not comprehensive and is only meant to be used as a guide. These 
medications should be excluded from patient use if possible. If they must be given, then use with 
caution and consider a ribociclib interruption if the concomitant medication is only needed for a 
short time.  
•
Moderate inhibitors or inducers of CYP3A4/5 (may increase or decrease ribociclib exposure,
respectively)
•
Moderate P-gp inhibitors and inducers
•
Sensitive substrates of CYP3A4/5 that do not have narrow therapeutic index (ribociclib may
increase exposure to these medications)
•
Strong inhibitors of BSEP (based on in vitro data co-administration with ribociclib may lead
to intrahepatic cholestasis)
•
Medications that carry a possible risk for QT prolongation (may precipitate QT prolongation
and TdP)
•
Sensitive substrates of the renal transporters, MATE1,  OCT2 and BCRP (has a potential to
increase exposure to substrates of these transporters, although no animal or clinical data are
available to support these statements)
Hematopoietic growth factors 
Prophylactic use of WBC growth factors with ribociclib is not recommended. 
Corticosteroids 
Chronic dosing of corticosteroids such as dexamethasone and prednisone is known to lead to 
induction of CYP3A enzymes, thereby potentially increasing the risk of reducing ribociclib drug 
exposure to subtherapeutic levels. Systemic corticosteroid treatment should not be given during 
the study, except for: 
•
Topical applications (e.g., rash), inhaled sprays (e.g., obstructive airways diseases), eye drops
or local injections (e.g., intra-articular);
•
A short duration (< 5 days) of systemic corticosteroids ≤ to the anti-inflammatory potency of
4 mg dexamethasone (e.g. for chronic obstructive   pulmonary disease, or as an antiemetic);


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•
Patients may be given dexamethasone alcohol-free mouthwash when starting everolimus
treatment prophylactically for stomatitis;
•
As determined by the investigator for clinical treatment.
Corticosteroid usage for CNS-related symptoms must be recorded, but are allowed.
Drugs that are metabolized by CYP450 enzymes 
In vitro drug metabolism studies show that the metabolism of ribociclib is mediated by P450 
enzymes CYP1A2, CYP2E1, and CYP3A4.  Ribociclib is a time-dependent CYP3A4/5 inhibitor. 
Clinical studies have not yet been performed to confirm the potential effect of ribociclib on 
substrate drugs metabolized by these enzymes in patients.  
Concomitant treatment of ribociclib with weak inhibitors or inducers of CYP3A4/5 is permitted. 
Caution is advised when ribociclib is co-administered with drugs that are moderate inhibitors or 
inducers of CYP3A4/5 (Appendix 2). Duration of concomitant treatment should be kept as short 
as possible, or completely avoided whenever possible. Patients receiving such medications must 
be monitored closely for any potentiation of toxicity or decrease of clinical benefit due to any 
individual concomitant medications, and may require dose titration or adjustment. Note that co-
administration of ribociclib with strong inducers of CYP3A4/5 is prohibited (Section 6.3.3.4). 
Concomitant treatment of ribociclib with medications known to be metabolized by CYP1A2 and 
CYP2E1is allowed with caution (Appendix 2), except for drugs which have narrow therapeutic 
index/sensitive substrates for these CYP isoforms (Section 6.3.3.5 and Appendix 2). 
Gastric protection agents 
The use of gastric protection agents including antacids, H2-antagonists, and proton pump 
inhibitors (PPIs; Appendix 2) is allowed. 
6.3.3 Prohibited concomitant therapy with ribociclib and everolimus 
Patient must be able to stop receiving any of the following medications 7 days prior to starting 
study drug:  
•
Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit
hybrids, pomelos/pummelos, star-fruit, pomegranates or pomegranate juice and Seville
oranges.
•
That have a narrow therapeutic window and are predominantly metabolized through
CYP3A4/5.
•
Strong P-gp inhibitors and inducers.
•
Herbal preparations/medications, dietary supplements known as strong inhibitors or
inducers of CYP3A4 or those with a known risk of QT prolongation.
•
Concomitant use of medication(s) with a known risk to prolong the QT interval and/or
known to cause Torsades de Pointe that cannot be discontinued (within 5 half-lives or 7
days prior to starting study drug) or replaced by safe alternative medication are
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Other anticancer therapy 
Anticancer therapy (chemotherapy, targeted therapy, biologic therapy, or radiation therapy (except 
palliative radiotherapy as described in Section 6.3.1.1), and anti-cancer surgery) other than the 
ribociclib treatment must not be given to patients while they are enrolled in the treatment trial (i.e.: 
during the initial 5-day regimen). If such agents are required then the patient must be permanently 
discontinued from the treatment portion of the study. 
Hematopoietic growth factors 
Hematopoietic 
growth 
factors 
may 
be 
used 
according 
to 
ASCO 
guidelines. 
(http://jco.ascopubs.org/content/early/2015/07/08/JCO.2015.62.3488.full) 
 Other investigational therapies 
Other investigational therapies must not be used while the patient is on the study. 
Strong CYP3A inhibitors and inducers 
In vitro metabolism studies suggest that oxidative metabolism of ribociclib is predominantly 
mediated by CYP3A4/5. 
Strong inhibitors or inducers of CYP3A4/5 are prohibited, with the exception of phenytoin and 
carbamazepine. Patients receiving other concomitant medications known to strongly inhibit and/or 
induce CYP3A4/5 that are deemed medically necessary should be excluded from the study. Refer 
to Appendix 2 for a list of these medications. Please note that this list may not be comprehensive. 
Patients should stop using medications at least 7 days prior to first dose of treatment. 
Medications that are CYP2C8, CYP2C9 and CYP3A4/5 substrates with 
narrow therapeutic index 
Ribociclib is a potent inhibitor of drugs metabolized by the cytochromes CYP2C8, CYP2C9 and 
CYP3A4/5 in vitro. Because of the potential risk for drug-drug interactions, using concomitant 
medications known to be metabolized by these enzymes and that have a low therapeutic index is 
not permitted in the study. Refer to Appendix 2 for a list of these medications. Please note that this 
list may not be comprehensive. Patients should stop using medications at least 7 days prior to first 
dose of treatment. 
Herbal medications 
Herbal preparations/medications are not allowed throughout the study, as a potential drug-drug 
interaction is always possible. These herbal medications include, but are not limited to: Cannabis 
Oil, St. John’s wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), 
yohimbe, saw palmetto, and ginseng. 
Patients should stop using herbal medications at least 7 days prior to first dose of treatment. 
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6.4.3 Treatment blinding 
This study is open-label; therefore, the patient, the investigator's site personnel and Sponsor-
Investigator are not blinded to treatment.  Drug identity (name, strength) is included in the label 
text; disclosure envelopes are not provided. 
6.5 Study drug preparation and dispensation 
6.5.1 Study drug packaging and labeling 
Clinical supplies will be obtained commercially by the Sponsor-Investigator and/or site 
investigator(s).    
6.5.2 Drug supply and storage 
Ribociclib/everolimus must be received by designated personnel at the study site, handled and 
stored safely and properly, and kept in a secured location to which only the investigator and 
designated site personnel have access. Upon receipt, the study treatment should be stored 
according to the instructions specified on the product label(s).  
6.5.3 Study drug compliance and accountability 
Clinical supplies must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designated 
assistants have access.  Clinical supplies are to be dispensed only in accordance with the protocol. 
The investigator is responsible for keeping accurate records of the clinical supplies received, the 
amount dispensed to and returned by the subjects/patients, and the amount remaining at the 
conclusion of the study.  In accordance with Good Pharmacy Practices, gloves should always be 
worn by study personnel if directly handling tablets or capsules that are returned (i.e., when 
counting returns).  At the end of the study, all clinical supplies including partial and empty 
containers must be destroyed per institutional policies. 
Study drug compliance 
During Phase 0 of the trial, patients will receive 5 consecutive doses of ribociclib+everolimus and 
their compliance measure will be assessed by the study research nurse and principal investigator 
at each patient visit and information provided by the patient and/or caregiver. The same will apply 
when patients enroll in the Phase 2 continuation trial where patients receive 21 consecutive daily 
doses (3 weeks on / 1 week off). 
Study drug accountability 
The study research nurse and principal investigator will maintain study drug accountability for the 
duration of the proposed study. Records of study medication used, dosages administered, and 
intervals between visits and the completion of the study should be captured in the Drug 
Accountability Form. 
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Handling of other study treatment 
Clinical supplies should be kept in a secured location; storage conditions: according to the product 
label(s).  The clinical supplies storage area at the site must be monitored by the site staff for 
temperature consistency with the acceptable storage temperature range specified in this protocol 
or in the product label attached to the protocol.  Documentation of temperature monitoring should 
be maintained. 
6.5.4 Disposal and destruction 
The study drug supply can be destroyed at the institution or third party, as appropriate, if permitted 
by local regulations, policies and authorized by IBTC. 
7 Visit schedule and assessments 
7.1 Protocol flow and visit schedule 
Table 13 lists all of the assessments and indicates when they are performed. Each post-surgical 
Phase 2 treatment cycle in patients is 28 days (the 28 days cycle length is fixed regardless of 
whether the dose of ribociclib+everolimus is withheld). All visits are to be scheduled according to 
the appropriate number of calendar days from Cycle 1 Day 1 of ribociclib+everolimus drug 
administration post-surgery. A visit window of ±1 in Cycle 1 Days 8, 15, 22 and ±3 days in Cycle 
2 onward is allowed. PK sampling on Day 4/5 post-dose will have ±5 min window for 0.5hr and 
1 hour samples and ±15min window for remaining samples (2, 4, 7h).  
Note: If treatment with ribociclib+everolimus is withheld at any time during the post-
surgical phase (Phase 2), all study visits, and safety assessments should continue according 
to the appropriate number of calendar days from Cycle 1 Day 1 as per the schedule of 
assessments. 
Surveillance imaging will adhere to current clinical standards, which include MR imaging at a 
minimum of every 3 months for Grade III/IV recurrent gliomas.
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7.1.1 List of Efficacy/Pharmacokinetic/Pharmacodynamics and 
Pharmacometabolomics Measurements 
Pharmacokinetic (PK) Measurements 
Sample collection and processing: All patients will donate approximately a total of nine 6 mL 
blood samples (approximately 48ml of blood) the day before the surgery and during the surgery 
as noted in Table 13. If intravenous vein (IV) blood collection utilized, the approximate total 
volume of blood will be 58mL of blood. See the Ivy Brain Tumor Center Laboratory Manual for 
details regarding collection, processing, packaging and shipment.  
PK sample analysis: The total and unbound concentrations of ribociclib and its active metabolite, 
LEQ803, in plasma, CSF, and tumor tissues (including contrast-enhancing and non-enhancing 
regions) will be determined by a validated LC-MS/MS method as described previously by us (Bao 
X, J Pharmaceutical and Biomedical Analysis, 2019).  The total and unbound concentrations of 
everolimus in whole blood, CSF, and tumor tissues (including contrast-enhancing and non-
enhancing regions) will be determined by a validated LC-MS/MS method.  All analyses will be 
performed at the KCI Pharmacology Core Laboratory. 
Pharmacometabolomics 
Rationale: Novel metabolomics technologies allow high-throughput assessment of a large number 
of endogenous metabolites, which provide powerful tools for mapping biochemical pathways 
implicated in disease and in response to drug treatment.  Pharmacometabolomics is an emerging 
field that applies metabolomics to define metabolic signature of drug exposure, thereby enabling 
identification of biochemical pathways implicated in drug efficacy and adverse drug reactions.  By 
defining metabolite profiles both at baseline (prior to) and post drug exposure, 
pharmacometabolomics has the potential to provide early insights into mechanism of drug action 
and molecular basis for variation in drug response. 
The plasma metabolic signatures of ribociclib plus everolimus exposure in patients will be 
defined using a LC-MS/MS based targeted metabolomics platform, which has been established 
in the Karmanos Cancer Institute Pharmacology Core (Bao X, J Clin Pharm, 2019).   
We will identify the plasma metabolites that are significantly altered by ribociclib and everolimus 
exposure, which may provide insights into the mechanism of drug action.  In addition, we will 
explore the associations between the metabolite changes and PK/PD parameters, toxicity, or 
clinical response.  This may help identify potential metabolic biomarkers for the early prediction 
of clinical outcome. 
Pharmacometabolomic 
samples: 
No 
extra 
sample 
collection 
is 
required 
for 
pharmacometabolomic study.  Metabolomic profiling will be performed using the plasma PK 
samples collected at pretreatment and following the combination therapy at 2, 7, and 24 h.  
LC-MS/MS based targeted metabolomics: Metabolites in plasma samples will be quantitatively 
profiled using a LC-MS/MS based targeted metabolomics platform in the Karmanos Cancer 
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Institute Pharmacology Core, as described previously (Bao X, J Clin Pharm, 2019).  This platform 
can quantitatively measure about ~250 metabolites that are involved in major human metabolic 
pathways.  All LC-MS/MS analyses were performed on an AB SCIEX QTRAP 6500 LC-MS/MS 
system.  Analyst® 1.6 software was used for system control and data acquisition and MultiQuant 
3.0 software was used for data processing and quantitation.   
Metabolomic data analysis: Metabolomics data analyses were performed using the 
MetaboAnalyst web-based statistical package (http://www.metaboanalyst.ca/).  Features (i.e., 
Metabolites) with >50% missing values were removed from the analysis, and the remaining 
missing values were replaced by the minimum value of a feature. To meet the normality 
assumption, individual metabolite concentrations were log-transformed and then auto-scaled 
(mean-centered and divided by the standard deviation of each metabolite). A one-way analysis of 
variance (ANOVA), if significant, followed by Fisher’s LSD post-hoc analysis was performed to 
identify significantly changed metabolites among groups.  The study of metabolic signature of the 
drug exposure in patients was intended to be hypothesis-generating and thus a false discovery rate 
(FDR) adjusted p-value < 0.2 along with unadjusted p-value < 0.05 was used to identify plasma 
metabolites significantly changed. A heat map was used to visualize metabolic signatures of 
ribociclib plus everolimus exposure, with significantly changed metabolites ranked in ascending 
order according to the FDR adjusted p-values from the ANOVA test.  
Pharmacodynamic (PD) Measurements 
See the Ivy Brain Tumor Center Laboratory Manual for details regarding collection, processing, 
packaging and shipment. 
Identification of a positive PD effect (as defined by a significantly >30% decrease in the percentage 
of phospho-RB+ cells as well as phospho-S6+ cells) will be based upon comparative analysis of 
archival and post-treatment tumor tissue. Tumor tissues will be analyzed for pRB and total RB by 
immunohistochemistry (IHC). IHC analysis will be used to identify the status of pRB, RB, 
pFOXM1, FOXM1, pS6, S6, p-4EBP, cleaved caspase 3 and MIB-1 (ki67) in archival versus 
ribociclib+everolimus treated GBM tissue samples. For immunohistochemistry, the staining will 
be quantified using Aperio Brightfield Toolbox Software available at Barrow Neurological 
Institute. In addition, western blotting will be performed for pRB (S780), total RB, cleaved caspase 
3 and MIB-1 on frozen treated tumor tissue and analyzed using the LiCOR Odyssey Imaging 
system. For comparison, treatment naïve tumor tissue with similar pathology from the Biobank 
will be used. The normalized average staining and/or luminescence for banked treatment naïve 
tumor will be used as a baseline to determine the pharmacodynamics of CDK4/CDK6 inhibition 
in the treated tumor tissues. 
Biomarker Evaluation in Blood Samples 
See the Ivy Brain Tumor Center Laboratory Manual for details regarding collection, processing, 
packaging and shipment. Pre-treatment blood sample will be collected for biomarker evaluation 
and baseline analysis. The tests include genetic sequencing to obtain status of the germline 
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mutations, liquid biopsy for tumor DNA or tumor secreted extra-cellular vesicles to identify 
biomarkers that will help predict drug efficacy. 
Biomarker Evaluation in Tumor Samples 
It has been shown that mTOR inhibition sometimes leads to paradoxical activation of upstream 
PI3K pathway activation. To assess this, protein from FFPE slides from pre- and post-treatment 
samples will be extracted and be analyzed by nanostring nCounter analysis system for their cancer 
panel examination. This cancer panel includes key components in the PI3K/mTOR signaling 
pathway, cell cycle pathway, MAPK as well as apoptosis pathways. The system also allows 
simultaneous comparison with protein and mRNA expression. This would allow comparison with 
surgical tissue with archival tissue.  
Additional downstream target genes for E2F1 and mTOR pathways will be analyzed. Whole 
exome sequencing and RNAseq will be performed (Novogene). RNA and DNA will be extracted 
from matched archival and treated tissues (i.e.: pre- and post-treatment) for all patients, with blood 
samples as germline normal controls. RNA-sequencing and Exome sequencing will be performed 
to analyze differences in expression, mutations and copy number variations in genes before and 
after treatment. In addition, quantitative RT-PCR analysis will be performed for downstream 
genetic targets of E2F1 involved in cell cycle (CCNA1, CCNE1, CCNB1, CDK2, and CDK1), 
DNA replication (MCM2, MCM3, MCM5, MCM7, CDT1 and CDC6) and mitosis (CDC20, 
PLK1, MAD2 and CCNB1) to assess the effect of CDK4/6 inhibition. Since mTORC1 increases 
HIF1α and phosphorylated STAT3 protein levels, we will also assess expression levels of HIF1α 
and STAT3 target genes (VEGFa, MYC, CCND1 and BIRC5).  
In addition, gliomas can be sub-classified by IHC as mesenchymal, proneural, or classical 
signatures based on the sequencing analysis and comparison to the TCGA database.   
See the Ivy Brain Tumor Center Laboratory Manual for details regarding collection, processing, 
packaging and shipment. 
Patient Derived Xenografts (PDX) 
Participant-related tissue, cells and fluids from outpatient and inpatient sources will be collected 
by St. Joseph’s Hospital and Medical Center (SJHMC); tissue will be processed, and stored by the 
IBTC team according to standard collection, processing, and storage procedures and with 
Institution Biosafety Committee (IBC) approval. The IBTC team will prepare all tissue samples 
according to approved protocols and/or standard procedures (also called Working Instructions, 
WIs) for storage, development into cell lines, creation of Patient-derived xenografts (PDXs) and/or 
preparation for histochemistry, as needed. Only SJHMC will be asked to collect tissue and provide 
to the IBTC. If a patient does not qualify for the treatment portion of the trial, the patient’s intra-
operative tissue may be collected if the patient has signed the informed consent and agrees to the 
tissue collection.  
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See the Ivy Brain Tumor Center Laboratory Manual for details regarding collection, processing, 
packaging and shipment. 
Requirements for Historical and Post-treatment Tissue Samples 
See the Ivy Brain Tumor Center Laboratory Manual for details regarding collection, processing, 
packaging and shipment.   
Historical/Archival Tissue Samples 
Pretreatment archival tissue samples will be requested to evaluate for PD and biomarkers to 
determine study eligibility after obtaining informed consent. Archival tissue will be requested from 
pathology lab.  
Request will be for approximately 3-10-micron sections of archival tissue FFPE blocks which 
contain > 3 mm x 3 mm portions of viable tumor, on 10 unstained slides, a representative H & E 
slide from this tissue, and 12 scrolls of 20-micron thickness of the pathology core tissue for (2 
scrolls per 2 ml tube), if there is adequate tissue available.  Adjustments to the request may be 
made based on the available tissue. If adjustments are necessary, the decision should be made in 
conjunction with the nursing team, pathology lab and research lab.   
Intraoperative Tissue Samples 
Post-treatment surgical tissue should be placed in formalin until taken to hospital histology lab 
where it will be prepared as a FFPE block (see Appendix 3 for tissue fixation protocol) and then 
made into approximately 3-10-micron sections of 20 unstained slides plus one H & E slide and 12 
scrolls of 20-micron thickness of the pathology core tissue for (2 scrolls per 2 ml tube), if there is 
adequate tissue available. In addition, one tumor sample (dimensions, 0.5 cm3) will be collected 
from patients and divided into two equal portions.  
The H&E slide will be examined by neuropathologist to confirm the presence of viable tumor in 
the resected tissue before proceeding with PD analysis. 
Response Assessment in neuro-oncology criteria (RANO) 
In Phase 0, RANO criteria will be used to confirm recurrence. In Phase 2, only those patients who 
have received at least one cycle of therapy and obtained an MRI in Phase 2 will be considered 
evaluable. Patients who have disease progression prior to the end of Cycle 1 will not be considered 
evaluable. The Phase 2 baseline MRI will be the first MRI taken post-operatively. Subsequent 
MRIs will be compared to the Phase 2 baseline. 
MRI scans will be evaluated using the Criteria for response assessment incorporating MRI and 
clinical factors (Chukwueke, 2018) 
 Phase 2 Evaluation of Target Lesions 
Complete Response (CR) 
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Requires all of the following: complete disappearance of all enhancing measurable and 
nonmeasurable disease sustained for at least 4 weeks; no new lesions; stable or improved 
nonenhancing (T2/FLAIR) lesions; patients must be off corticosteroids (or on physiologic 
replacement doses only); and stable or improved clinically. Note: Patients with nonmeasurable 
disease only cannot have achieved CR; the best response possible is SD.  
Partial Response (PR) 
Requires all of the following: ≥50% decrease compared with baseline in the sum of products of 
perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks; no 
progression of nonmeasurable disease; no new lesions; stable or improved nonenhancing 
(T2/FLAIR) lesions on same or lower dose of corticosteroids compared with baseline scan; the 
corticosteroid dose at the time of scan evaluation.  
Stable Disease (SD) 
Requires all of the following: Does not qualify for CR, PR or progression; stable nonenhancing 
(T2/FLAIR) lesions on the same or lower dose of corticosteroids compared with baseline scan. In 
the event that the corticosteroid dose was increased for new symptoms and signs without 
confirmation of disease progression on neuroimaging, and subsequent follow-up imaging shows 
that this increase in corticosteroids was required because of disease progression, the last scan 
considered to show SD will be the scan obtained when the corticosteroid dose was equivalent to 
the baseline dose. 
Progressive Disease (PD) 
Defined by any of the following: ≥25% increase in the sum of the products of perpendicular 
diameters of enhancing lesions compared with the smallest tumor measurement obtained either at 
baseline (if no decrease) or best response on stable or increasing doses of corticosteroids†; 
significant increase in T2/FLAIR nonenhancing lesion on stable or increasing doses of 
corticosteroids compared with baseline scan or best response after initiation of therapy† not caused 
by comorbid events (e.g., radiation therapy, demyelination, ischemic injury, infection, seizures, 
postoperative changes or other treatment effects); any new lesion; clear clinical deterioration not 
attributable to other causes apart from the tumor (e.g., seizures, medication adverse effects, 
complications of therapy, cerebrovascular events, infection, etc.) or changes in corticosteroid dose; 
failure to return for evaluation as a result of death or deteriorating condition; or clear progression 
of nonmeasurable disease. 
 Evaluation of Non-Target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions and normalization of tumor marker level.  All lymph nodes 
must be non-pathological in size (< 10 mm short axis). 
Incomplete Response/Stable Disease (SD) 
Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above 
the normal limits. 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or unequivocal progression of existing non-target 
lesions. 
 Evaluation Response 
Progression-Free Survival 
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Progression-free survival (PFS) is defined as the duration of time from the date of surgery to time 
of progression. 
 Information to be collected at screening  
Data to be collected on patient characteristics at screening include: 
•
Demography (including: date of birth, age, patient initials, gender, childbearing potential,
race and ethnicity, or as allowed by local regulations)
•
Relevant medical history
•
Diagnosis and extent of disease, including:
o
Date of diagnosis
o
Site of active disease
o
Prior antineoplastic therapies (medications, radiation, surgeries)
o
Prior and Concomitant
o
Medications, surgical and medical procedures
o
MRI
Note: All other medications taken within 28 days before the first dose of study treatment is 
administered must be recorded and updated on a continual basis if there is new change to the 
medication. 
Patients will have the following performed at screening: 
•
Physical examination*
•
Laboratory testing*:
o
Chemistry, (comprehensive metabolic panel, magnesium, phosphorus)
o
Hematology (CBC w/differential)
o
Coagulation (PT/INR, aPTT)
o
Lipid panel
o
Urinalysis
o
Serum pregnancy test (if applicable)
•
Estimated glomerular filtration rate (eGFR)
•
ECOG Performance Status
•
12-lead ECG
•
Weight*
•
Height*
•
Vital signs*
•
RANO assessment (see section 5.2)
*Assessments may be done at Day 1 predose as part of screening to determine eligibility.
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If assessments are available in the medical record at the investigator’s site or from the 
patient’s referring physician and are completed within the screening window, these may be 
utilized for eligibility review. All lab tests per protocol must be present. 
Information to be collected on screening failures 
A patient who signs an informed consent but fails to satisfy all eligibility criteria for any reason 
will be considered a screen failure.  
Treatment period 
Following completion of screening procedures and verifying patient eligibility, study treatment 
should start as soon as possible.  
Patients who discontinue study treatment should be scheduled for a visit as soon as possible and 
within approximately 7 days after the last dose of study treatment, at which time all of the 
assessments listed for the EOT visit will be performed. 
Day 1 Enrollment 
The following assessments will be performed on Day 1: 
•
Review of surgical and medical procedures
•
ECOG
•
12-lead ECG
•
Collection of AEs and Concomitant medication(s)
•
Screening assessments not previously collected as noted in section 7.1.1.9
•
Day 1 pre-dose PK sample
•
Day 1 pre-dose biomarker blood sample
•
Confirm eligibility prior to study drug administration
•
In clinic/hospital study drug administration
•
Provide the patient the following for home dosing on Days 2 and 3
o
Instructions for study medication
o
Dosing Diary
o
Symptom Diary
o
Study drug
Day 2 and 3 
Phase 0 patients will record study drug administration in the Dosing Diary and record symptoms 
in the Symptom Diary. 
Day 4  
The following assessments will be performed on Day 4: 
•
Review of medical and surgical procedures
•
Collection of AEs and Concomitant medication(s)
•
Review of home dosing diary and symptom diary


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•
12-lead ECG
•
Trough PK Sample (Dose Levels 0-3)
•
Laboratory testing (may also be performed as a pre-surgical assessment on Day 5 or Day
6):
o
Chemistry, (comprehensive metabolic panel, magnesium, phosphorus)
o
Hematology (CBC w/differential)
o
Coagulation (PT/INR, aPTT)
o
eGFR
•
In clinic/hospital study drug administration
•
PK blood sampling: 0.5, 1, 2, 4, 7 hours post-dose (Dose Levels 0-3)
o
In Dose Level 4+ only, PK blood sampling will occur on Day 5 instead of Day 4.
Day 5 
•
Review of medical and surgical procedures
•
Collection of AEs and Concomitant medication(s)
•
12-Lead ECG (if not collected on Day 4)
•
In clinic/hospital study drug administration
•
Craniotomy (Day 5 for Cohort 1 & 2; Day 6 for Cohort 3)
o
PK Collection of blood, CSF and tumor
o
Biomarker tumor collection
•
Dose Level 1-3: Day 5 trough/24hrs post-dose
•
Dose Level 4+ only: PK blood sampling: pre, 0.5, 1, 2, 4, 6, 8 and 24 hours (Day 6) post-
dose
  Follow-up / EOT visit 
Phase 0 patients will have a follow up visit 7-14 days after surgery (routine post-operative visit). 
All Phase 2 patients should be scheduled for an EOT visit within 7 (±3) days following 
discontinuation of study treatment. 
The following assessments will be performed at the EOT visit: 
•
Physical exam
•
ECOG performance status
•
Weight
•
Vital signs
•
Laboratory blood collections
o
CMP, magnesium, phosphorus
o
Hematology (CBC w/differential)
o
Urine pregnancy test (if applicable)
•
12-lead ECG
•
Collection of AEs and Concomitant medication(s)
•
MRI (last standard of care MRI completed)


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Patients who have had a recurrence and who undergo an additional surgical procedure, may have 
tissue obtained and sent to the lab per Section 7.1.1.5.  
  Safety Follow Up 
All Phase 0 and Phase 2 patients will have a safety follow-up phone call 30 days after last dose 
(±7) days following discontinuation of study treatment. 
The following assessments will be performed at the safety follow-up phone call: 
•
Collection of AEs and Concomitant medication(s)
End of Phase Disposition
At a minimum, all patients who discontinue ribociclib+everolimus treatment, including those who 
refuse to return for a final visit, will be contacted for safety evaluations during the 30 days ± 7 
days following the last dose of treatment. 
Criteria for patient withdrawal 
Subjects/patients may withdraw at any time or be dropped from the study at the discretion of the 
investigator should any untoward effects occur. In addition, a subject/patient may be withdrawn 
by the investigator if he/she violates the study plan or for administrative and/or other safety 
reasons. When a subject/ patient discontinues/withdraws prior to study completion, all applicable 
activities scheduled for the final study visit should be performed at the time of discontinuation. 
Any adverse experiences which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 8.  
Subjects/patients who discontinue from the study for reasons unrelated to the study (e.g., personal 
reasons) will be replaced as required for the study to meet its objectives.  The decision to remove 
a subject/patient and to replace dropouts will be made by the investigator and study statistician.  
The replacement will generally receive the same treatment or treatment sequence (as appropriate) 
as the allocation number replaced.  Both the replacement and originally allocated number will be 
unique numbers. 
Patient death will be considered as a withdrawal from the study. Patients may also be withdrawn 
(the physician may decide to remove the patient from any further study activity) if any of the 
following occur: 
•
Adverse event(s) (see Section 8.1)
•
Drug discontinuation if their surgery is delayed by 4 or more weeks due to drug toxicity
•
Disease progression
•
Major protocol deviation
•
Technical problems
•
Physician decision
•
Non-compliance with study treatment.
•
Death
•
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Patients must be withdrawn if any of the following occur: 
•
Lost to follow-up
•
Subject/guardian decision
•
Study terminated by sponsor
•
Pregnancy (Pregnancy will be followed for outcome)
Replacement policy 
Patients who do not receive a minimum of 5 daily doses or who vomit within 4 hours of any dose 
will be replaced upon Sponsor-Investigator discretion. 
7.2 Assessment types 
7.2.1 PK, PD, and pharmacometabolomics assessments 
As described above. 
7.2.2 Safety and tolerability assessments 
Adverse experiences will be graded and recorded throughout the study according to NCI-CTCAE, 
version 4.03.  Toxicities will be characterized in terms including duration, intensity, and time to 
onset.  Safety endpoints will include all types of adverse experiences, in addition to laboratory 
safety assessments, ECOG performance scale status, and vital signs. 
Safety evaluation will include the following and may also be performed at any time based on the 
clinical judgment of the Investigator. 
Screening:  vital signs, physical examination (including height/weight), ECOG, tumor evaluation, 
ECG 
Post-Treatment:  vital signs, physical examination, ECOG 
Laboratory safety tests (e.g., INR/PT, aPTT, complete blood count, and serum chemistries) will 
be obtained and assessed per routine preoperative and/or postoperative neurosurgical protocols.   
Physical examination 
Physical examinations will include an examination as per standard of care. The exam may 
include a review of general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, 
lungs, heart, abdomen, back, lymph nodes, extremities, and a neurologic evaluation.  The 
physical exam should be completed by appropriately licensed personnel as per institutional 
guidelines or as delegated by the Investigator.   
Vital signs 
Vital signs include body temperature, blood pressure, pulse, and pulse oximetry measurements. 
Blood pressure (systolic and diastolic) and pulse should be measured after the patient has been 
sitting for five minutes. 
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Height and weight 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, 
but without shoes) will be measured. Height will be measured at screening only.   
Performance status 
ECOG performance status will be assessed as per the assessment schedule (refer to Table 13). 
Assessment of ECOG performance status will be performed within the time windows described 
above of the scheduled assessment, even if study treatment is being held. More frequent 
examinations may be performed at the investigator’s discretion, if medically indicated. (See 
Appendix 1). ECOG should be completed by a physician, nurse or other appropriately licensed 
personnel as delegated by the Investigator. 
Laboratory evaluations 
The time windows granted for laboratory evaluations are identical to the corresponding visit time 
windows for each visit (refer to Section 7.1). 
Table 14 Clinical laboratory parameters collection plan 
Test Name 
Test Category 
Hematology 
Hgb, platelets, white blood cells (WBC), red blood cells (RBC), 
differential (basophils, eosinophils, lymphocytes, monocytes, neutrophils 
[% or absolute]) 
Blood Chemistry 
Albumin, ALT, AST, calcium, corrected calcium, creatinine, total 
bilirubin, direct bilirubin (only if total bilirubin is ≥ grade 2), blood urea 
nitrogen (BUN) or urea, potassium, sodium, fasting glucose, alkaline 
phosphatase, magnesium, phosphorus 
Lipid Panel 
HDL, LDL, triglycerides, cholesterol 
Urinalysis 
Macroscopic panel (dipstick) (bilirubin, blood, glucose, ketones, WBC, 
pH, protein, specific gravity)  
Reflexive Microscopic panel (RBC, WBC, casts) 
Pregnancy test 
At screening visit, serum pregnancy test  
At subsequent cycles, urinary pregnancy test. 
Coagulation 
International normalized ration (INR) and pro-thrombin time (PT) or 
Quick Test; activated partial thromboplastin time (PTT)  
Hematology 
Hematology assessments of the parameters listed in Table 15 will be tested as per the schedule of 
assessments (Table 13). 
Clinical chemistry 
Blood chemistry assessments of the parameters listed in Table 15 will be tested as per the schedule 
of assessments (Table 13). 
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Coagulation 
International normalized ration (INR), prothrombin time (PT) and active partial thromboplastin 
time (aPPT) or Quick Test will be measured per the schedule of assessments (Table 13). 
Urinalysis 
Dipstick measurements will be performed as per Table 15 and according to the schedule of 
assessments (Table 13). Any significant findings on dipstick will be followed up with microscopic 
evaluation as per Table 15. 
Pregnancy and assessments of fertility 
During screening, a serum pregnancy test will be completed as per routine preoperative 
neurosurgical protocol prior to starting study treatment. 
Women who are determined to be of child bearing potential before the study will only be tested at 
screening. When non-child bearing potential status is determined during the study, pregnancy 
testing will not be completed. Women are considered post-menopausal if they have had 12 months 
of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, 
history of vasomotor symptoms), and otherwise not of child bearing potential if they have had 
surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks 
ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment is she considered not of child bearing potential. 
If a positive pregnancy test is performed in between study visits, the patients must immediately 
notify the investigator. 
8 Safety monitoring and reporting 
8.1 Adverse events 
8.1.1 Definitions and reporting 
An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical condition(s) that occur after patient’s signed informed consent has 
been obtained. Adverse Events that are not serious will be captured following first administration 
of study drug. 
Abnormal laboratory values or test results occurring after study drug administration are adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, require 
therapy (e.g., hematologic abnormality that requires transfusion or hematological stem cell 
support), or require changes in study medication(s). 
Information about all AEs is collected. 
Except for screening failures, adverse events that begin or worsen after the first study drug 
administration should be recorded. Conditions that were already present at the time of informed 
consent should be recorded as part of medical history. Adverse event monitoring should be 
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continued for at least 30 days following the last dose of ribociclib+everolimus treatment. Adverse 
events (including lab abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible, rather than individual underlying signs and symptoms. When a clear diagnosis 
cannot be identified, each sign or symptom should be reported as a separate Adverse Event. 
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03. 
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, and 
life-threatening, corresponding to Grades 1 - 4, will be used. CTCAE Grade 5 (death) will not be 
used in this study; rather, information about deaths will be collected through the study. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent at each visit during the study. 
Adverse events also may be detected when they are volunteered by the patient (subject) during the 
screening process or between visits, or through physical examination, laboratory test, or other 
assessments. As far as possible, each adverse event should be evaluated to determine: 
1. The severity grade (CTCAE Grade 1-4)
2. Its duration (Start and Ongoing at End of study)
3. Its relationship to the ribociclib and/or everolimus treatment (Reasonable possibility that AE
is related: No, Yes)
4. Action taken with respect to study or investigational treatment (none, dose adjusted,
temporarily interrupted, permanently discontinued, unknown, not applicable)
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy,
concomitant medication/non-drug therapy)
6. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded. 
Once an adverse event is detected, it should be followed until its resolution or until it is judged to 
be permanent, and assessment should be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the ribociclib+everolimus treatment, the 
interventions required to treat it, and the outcome. 
Progression of malignancy (including fatal outcomes), if documented, should not be reported as a 
serious adverse event. 
Events that are clearly consistent with the expected pattern of progression of the underlying disease 
should not be recorded as AEs. Events that are clearly related to surgical complications 
experienced as a result of the craniotomy and not related to study participation or the test article(s) 
should not be recorded as AEs. If there is any indication that the event may be related to study 
participation or the test article, the event should be recorded as an adverse event. 
Adverse events separate from the progression of malignancy (example, deep vein thrombosis at 
the time of progression or hemoptysis concurrent with finding of disease progression) will be 
reported as per usual guidelines used for such events with proper attribution regarding relatedness 
to the drug. 
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8.1.2 Laboratory test abnormalities 
Definitions and reporting 
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in ribociclib and/or everolimus treatment), should be recorded. Whenever possible, a 
diagnosis, rather than a symptom should be provided (e.g. anemia instead of low hemoglobin). 
Laboratory abnormalities that meet the criteria for Adverse Events should be followed until they 
have returned to normal or an adequate explanation of the abnormality is found. When an abnormal 
laboratory or test result corresponds to a sign/symptom of an already reported adverse event, it is 
not necessary to separately record the lab/test result as an additional event. 
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 
investigator’s discretion. A dose hold or medication for the lab abnormality may be required by 
the protocol in which case the lab abnormality would still, by definition, be an adverse event and 
must be reported as such. 
8.1.3 Adverse events of special interest (AESI) 
Based upon the currently available information from the pre-clinical studies, mechanism of action, 
pharmacological class effect, and clinical data for ribociclib and everolimus, defined AESIs to date 
are: Hepatotoxicity, QT prolongation and Interstitial Lung Disease, and Pneumonitis. 
8.2 Serious adverse events 
8.2.1 Definitions 
Serious adverse event (SAE) is defined as one of the following: 
•
Is fatal or life-threatening
•
Results in persistent or significant disability/incapacity
•
Constitutes a congenital anomaly/birth defect
•
Is medically significant, i.e., defined as an event that jeopardizes the patient or may require
medical or surgical intervention to prevent one of the outcomes listed above
•
Requires inpatient hospitalization or prolongation of existing hospitalization,
•
Note that hospitalizations for the following reasons should not be reported as serious adverse
events:
•
Routine treatment or monitoring of the studied indication, not associated with any
deterioration in condition
•
Elective or pre-planned treatment for a pre-existing condition that is unrelated to the
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•
Social reasons and respite care in the absence of any deterioration in the patient’s general
condition
•
Hospitalization due solely to progression of the underlying cancer
•
Events that are clearly consistent with the expected pattern of progression of the
underlying disease should not be recorded as AEs.
•
Events that are clearly related to surgical complications experienced as a result of the
craniotomy and not related to study participation or the test article(s) should not be
recorded as AEs. If there is any indication that the event may be related to study
participation or the test article, the event should be recorded as an adverse event.
•
Note that treatment on an emergency outpatient basis that does not result in hospital admission
and involves an event not fulfilling any of the definitions of a SAE given above is not a serious
adverse event
8.2.2 Reporting 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the first 
study drug administration and until at least 30 days after the patient has stopped treatment must be 
reported to Ivy Brain Tumor Center (IBTC) within 24 hours of learning of its occurrence. 
Any SAE experienced after this 30 days period should only be reported if the investigator suspects 
a causal relationship to the treatment. Recurrent episodes, complications, or progression of the 
initial SAE must be reported as follow-up to the original episode within 24 hours of the investigator 
receiving the follow-up information. An SAE occurring at a different time interval or otherwise 
considered completely unrelated to a previously reported one should be reported separately as a 
new event. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report Form; 
all applicable sections of the form must be completed in order to provide a clinically thorough 
report. The investigator must assess and record the relationship of each SAE to each specific study 
treatment (if there is more than one study treatment), complete the SAE Report Form, and send 
the completed, signed form safety@ivybraintumorcenter.org within 24 hours of learning of its 
occurrence. 
The original copy of the SAE Report Form must be kept at the study site. 
Follow-up information is sent to the same contact(s) to whom the original SAE Report Form was 
sent, using a new SAE Report Form stating that this is a follow-up to the previously reported SAE 
and giving the date of the original report. Each re-occurrence, complication, or progression of the 
original event should be reported as a follow-up to that event regardless of when it occurs. The 
follow-up information should describe whether the event has resolved or continues, if and how it 
was treated, and whether the patient continued or withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the treatment, IBTC may need to report the event in a 
MedWatch report to the FDA. 
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review, the DSMB will provide recommendations regarding study modification, continuation or 
termination.  
8.6.1 Dose Escalations 
At the time of dose escalation, a written report will be submitted to the DSMB Chair (or qualified 
alternate) describing the cohorts, dose levels, adverse events, safety reports and any DLTs 
observed. The DSMC Chair will review the report and provide a written authorization to proceed 
or request more information within 2 business days. Approval for the dose escalation must be 
obtained prior to implementation. 
9 Data collection and management 
9.1 Site monitoring 
The Ivy Brain Tumor Center (IBTC) will be the monitoring entity for this study. A monitor from 
IBTC will audit study-related activities to ensure the study is conducted in accordance with the 
protocol, local standard operating procedures, FDA regulations and Good Clinical Practice (GCP). 
9.2 Data confidentiality, collection, management, and quality control 
All databases will be kept on a password-protected, HIPAA-compliant computer system, REDCap 
Cloud. REDCap is a secure web application with authentication and data logging. Only authorized 
study personnel will have access to the study data.  Individually-identifiable health information 
will be protected by assignment of patient identifiers and password-protection of the key.  Only 
the Investigators and the Research will have access to this database. All biological specimens will 
be de-identified and assigned the corresponding patient code from which they are derived. 
9.3 Analysis sets 
9.3.1 Full Analysis Set 
The statistical analysis of the data obtained from this study will be the responsibility of the Clinical 
Biostatistics division of the Ivy Brain Tumor Center (IBTC). 
9.4 Patient demographics/other baseline characteristics 
The comparability of the treatment groups for each relevant characteristic will be assessed by the 
use of tables and/or graphs. No statistical hypothesis tests will be performed on these 
characteristics.  The number and percentage of patients screened, randomized, the primary reasons 
for screening failure, and the primary reason for discontinuation will be displayed.  Demographic 
variables (such as age) and baseline characteristics will be summarized by treatment either by 
descriptive statistics or categorical tables.  The reasons for exclusion from the Full Analysis Set 
(if any) will be summarized. 
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9.5 Primary objective 
Objective 
Endpoint 
Primary 
• To determine the dose-
limiting toxicity (DLT) 
and maximum tolerated 
dose (MTD) for study 
drug when administered 
in combination. 
• To identify recurrent
high-grade glioma
patients with positive
PK and PD effects.
• MTD: highest dose of drug that did not
cause a DLT in > 17% of participants 
• PK: total and unbound ribociclib and
everolimus drug concentrations in non-
enhancing and contrast-enhancing tumor
tissue samples
• PD: pRB-positive cells and pS6-positive
cells
9.6 Secondary and exploratory objectives 
Objective 
Endpoint 
Secondary 
• To explore safety and
efficacy in recurrent
high-grade glioma
patients with
demonstrated PK and
PD effects and
determine RP2D
• To describe PK for
Phase 2 patients
• Progression-free survival (PFS): rate
measured from time of surgery to date of
recurrence
• Overall survival (OS): Median Overall
Survival (OS) from time of surgery to
date of death from any cause
• Drug-related toxicity
• RP2D
• Systemic PK profiles of ribociclib and
everolimus when combined.
Exploratory 
• To explore evidence for
CDK4/6 and mTOR
pathway activity in
tumor tissue (as
compared to archival
tissue) and mechanisms
of resistance
• Pharmacometabolomics:
To explore the plasma
metabolomic signature
of the exposure of
ribociclib and
everolimus
• Quantification of total and
phosphorylated forms of Rb, FoxM1, S6,
4EBP, as well as cleaved Caspase-3 and
MIB1. Expression of Cyclin D1, Cyclin
E1, PI3K/mTOR signaling components
• Plasma metabolomic profiles (i.e., levels
of ~250 metabolites) at the pretreatment
and at predefined time points after the
combination therapy.
• Pharmacogenomics studies using RNA-
seq and Whole Exome Sequencing to
identify alterations in gene expression
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• To identify resistance
mechanism and
alternate pathways
treatment and post-treatment tissues and 
plasma. 
9.6.1 Statistical hypothesis, model, and method of analysis 
If, after the study has begun, changes are made to primary and/or key secondary hypotheses, or 
the statistical methods related to those hypotheses, then the protocol will be amended.  Changes to 
exploratory or other non-confirmatory analyses made after the protocol has been finalized, along 
with an explanation as to when and why they occurred, will be listed in results for the study.  Post 
hoc exploratory analyses will be clearly identified.  No separate Statistical Analysis Plan (SAP) 
will be issued for this study. 
9.6.2 Safety objectives 
Safety measurements are described in 7.2.2. 
9.6.3 Adverse Events (AEs) 
Adverse events (AEs) are described in 8.1. 
9.7 Statistical Methods 
All continuous variables (e.g., drug concentrations in plasma and high-grade glioma tissue, and 
any continuous PD biomarkers, and their pre/post treatment change) will be summarized with 
standard descriptive statistics (N, median, mean, standard deviation, minimum, maximum, and the 
80% confidence interval [CI] for the mean). The 80% confidence level is appropriate for a Phase 
0 study with small sample sizes. 
These continuous variables will be summarized by time interval and overall. Statistical graphics 
(e.g., boxplots and scatterplots) will be used as appropriate. The pre/post treatment changes (as % 
change variables) will also be displayed as waterfall plots. All categorical variables (e.g., PD 
parameters such as scoring of Rb phosphorylation staining intensity: 0, 1, 2, or 3) will be 
summarized as frequency distributions. If dichotomized (e.g., score 2 or higher), those proportions 
will be described by point estimates and 80% CIs using the Wilson’s method. These categorical 
variables will be summarized by time interval, and overall. The pre/post treatment changes in 
categorical variables (whether dichotomized or not) will be displayed as 2-way frequency 
distributions (i.e., contingency tables). 
9.7.1 Objectives, endpoints, analysis, and sample size justification 
The primary objective of Phase 0 dose escalation and expansion studies is to determine the MTD 
and to identify patients with positive PK and PD effects and the key secondary objective is to 
explore the clinical effect of everolimus plus ribociclib in recurrent GBM patients.  The 
exploratory objectives are to explore pharmacometabolomics (PM) markers, mechanisms of 
resistance, and to examine evidence for CDK4/6 and mTOR pathway activity described in the 
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10 Ethical considerations and administrative procedures 
10.1 Regulatory and ethical compliance 
This clinical study was designed, shall be implemented and reported in accordance with the ICH 
Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local regulations 
(including US Code of Federal Regulations Title 21), and with the ethical principles laid down in 
the Declaration of Helsinki. 
10.2 Informed consent procedures 
The initial informed consent form and any subsequent revised written informed consent form, and 
written information must receive the IRB/IEC’s approval/favorable opinion in advance of use. 
The patient or his/her legally acceptable representative should be informed in a timely manner if 
new information becomes available that may be relevant to the patient’s willingness to continue 
participation in the trial.  The communication of this information should be documented. 
10.3 Discontinuation of the study 
Subjects/patients may withdraw at any time or be dropped from the study at the discretion of the 
investigator should any untoward effects occur. In addition, a subject/patient may be withdrawn 
by the investigator if he/she violates the study plan or for administrative and/or other safety 
reasons. When a subject/ patient discontinues/withdraws prior to study completion, all applicable 
activities scheduled for the final study visit should be performed at the time of discontinuation. 
Any adverse experiences which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in section  
Subjects/patients who discontinue from the study for reasons unrelated to the study (e.g., personal 
reasons) will be replaced as required for the study to meet its objectives.  The decision to remove 
a subject/patient and to replace dropouts will be made by the investigator and study statistician.  
The replacement will generally receive the same treatment or treatment sequence (as appropriate) 
as the allocation number replaced.  Both the replacement and originally allocated number will be 
unique numbers. 
10.4 Publication of the study and results 
10.4.1 Communication and Publication of Clinical Trial Results 
Communication and publication of study results will be coordinated by Ivy Brain Tumor Center 
(IBTC). 
10.5 Study documentation, record keeping and retention of documents 
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
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regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents. 
10.6 Confidentiality of study documents and patient records 
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to IBTC. Signed informed consent forms and patient enrollment log 
must be kept strictly confidential to enable patient identification at the site. 
10.7 Audits and inspections 
Source data/documents must be available to inspections by IBTC or designee or Health 
Authorities. 
10.8 Financial disclosures 
N/A 
11 Protocol adherence 
11.1 Amendments to the protocol 
All protocol amendments will be reviewed and approved by the IBTC, as well as each investigative 
site’s IRB.  
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12 References 
Bachelot, Thomas, et al. "Randomized phase II trial of everolimus in combination with tamoxifen 
in patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative 
metastatic breast cancer with prior exposure to aromatase inhibitors: A GINECO study." Journal 
of Clinical Oncology 30.22 (2012): 2718-2724. 
Bao, X., Wu, J., Kim, S., LoRusso, P., Li, J. “Pharmacometabolomics Reveals Irinotecan 
Mechanism of Action in Cancer Patients.” The J of Clinical Pharmacology. (2019). 59(1): 20-34 
Bao, X., Wu, J., Sanai, N., Li, J. “Determination of total and unbound ribociclib in human 
plasma and brain tumor tissues using liquid chromatography coupled with tandem mass 
spectrometry.” J Pharm Biomed Anal. (2019), 166:194-201 
Bardia, A., Modi S, Chavez-MacGregor M, Kittaneh M, Marino AJ, Matano A, Bhansali S, 
Hewes B, Cortes J. Phase Ib/II study of LEE011, everolimus, and exemestane in postmenopausal 
women with ER+/HER2-metastatic breast cancer. J Clin Oncol. 2014;32:5s(Suppl) Abstract 535. 
Baselga, J., Campone, M., Piccart, M., Burris III, H. A., Rugo, H. S., Sahmoud, T., ... & Beck, J. 
T. (2012). Everolimus in postmenopausal hormone-receptor–positive advanced breast cancer.
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Baselga, José, et al. "Phase II randomized study of neoadjuvant everolimus plus letrozole 
compared with placebo plus letrozole in patients with estrogen receptor–positive breast cancer." 
Journal of Clinical Oncology 27.16 (2009): 2630-2637. 
CHMP Type II Variation Assessment Report for Afinitor . European Medicines Agency. 
(2012).file:///G:/Protocols/Articles%20for%20Ribo-Eve%20Protocol/Report%20RD-2011 
50492%20Article.pdf 
Chukwueke, P., Wen, P.Y. Use of the Response Assessment in Neuro-Oncology (RANO) 
criteria in clinical trials and clinical practice. CNS Oncology (2019) 8(1): CNS28 
Crowe, A. and Lemaire, M. Pharm Res. (1998). In Vitro and In Situ Absorption of SDZ-RAD 
Using a Human Intestinal Cell Line (Caco-2) and a Single Pass Perfusion Model in Rats: 
Comparison with Rapamycin. 15:1666. doi: 10.1023/A:1011940108365 
Ellis R. E.  (1961) The Distribution of Active Bone Marrow in the Adult, Phy. Med. Biol. 5,255-
258 
Grunberg SM, Espersen BT, et al (2010) Evaluation of new antiemetic agents and definition of 
antineoplastic agent emetogenicity--state of the art. Support Care Cancer.;19 Suppl 1:S43-7. 
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Guba M, von Breitenbuch P, Steinbauer M, Koehl G, Flegel S, Hornung M, et al. (2002). 
Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of 
vascular endothelial growth factor. Nat Med. 8:128–35. doi: 10.1038/nm0202-128 
Infante, J, Shapiro G, Witteveen, P, Gerecitano, J, Ribrag, V, Chugh, R, Issa, I, Chakraborty, A, 
Matano, A, Zhao, X, Parasuraman, S, Cassier, P. Journal of Clinical Oncology. 2014 
32:15_suppl, 2528-2528 
Kovarik JM, Hartmann S, Figueiredo J, Rordorf C, Golor G, Lison A, Budde K, Neumayer HH. 
Effect of food on everolimus absorption: quantification in healthy subjects and a confirmatory 
screening in patients with renal transplants. Pharmacotherapy. 2002;22:154–159 
Kovarik, J. M., Beyer, D., Bizot, M. N., Jiang, Q., Shenouda, M., & Schmouder, R. L. (2005). 
Effect of multiple-dose erythromycin on everolimus pharmacokinetics. European journal of 
clinical pharmacology, 61(1), 35-38. 
Kuhn B, Jacobsen W, Christians U, Benet L, and Kollman P. (2001). Metabolism of Sirolimus 
and Its Derivative Everolimus by Cytochrome P450 3A4:  Insights from Docking, Molecular 
Dynamics, and Quantum Chemical Calculations. Journal of Medicinal Chemistry 2001 44 (12), 
2027-2034 . doi: 10.1021/jm010079y 
Laplante, A., Demeule, M., Murphy, G. F., & Beliveau, R. (2002). Interaction of 
immunosuppressive agents rapamycin and its analogue SDZ-RAD with endothelial P-gp. In 
Transplantation proceedings (Vol. 8, No. 34, pp. 3393-3395). 
Lane H, Wood JM, McSheehy P.M, Allegrini P.R, Boulay A, Brueggen J, Littlewood-Evans A, 
Maira S-M, Martiny-Baron G, Schnell C.R, Sini, P and O'Reilly, T.(2009). mTOR Inhibitor 
RAD001 (Everolimus) Has Antiangiogenic/Vascular Properties Distinct from a VEGFR 
Tyrosine Kinase Inhibitor. Clin Cancer Res. (15) (5) 1612-1622. doi: 10.1158/1078-0432.CCR-
08-2057
Lange, C. A., & Yee, D. (2011). Killing the second messenger: targeting loss of cell cycle 
control in endocrine-resistant breast cancer. Endocrine-related cancer, 18(4), C19-24. 
doi:10.1530/ERC-11-0112 
Leijen S, Beijnen JH, Schellens JH. Abrogation of the G2 checkpoint by inhibition of Wee-1 
kinase results in sensitization of p53-deficient tumor cells to DNA-damaging agents. Curr Clin 
Pharmacol. 2010 Aug;5(3):186-91. Review. PMID: 20406171.  
Mabuchi, Seiji & A Altomare, Deborah & C Connolly, Denise & Klein-Szanto, Andrés & 
Litwin, Samuel & K Hoelzle, Matthew & Hensley, Harvey & Hamilton, Thomas & Testa, 
Joseph. (2007). RAD001 (Everolimus) Delays Tumor Onset and Progression in a Transgenic 
Mouse Model of Ovarian Cancer. Cancer research. 67. 2408-13. doi: 10.1158/0008-5472.CAN-
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Marangoni, E., Vincent-Salomon, A., Auger, N., Degeorges, A., Assayag, F., de Cremoux, P., ... 
& Rebucci, M. (2007). A new model of patient tumor-derived breast cancer xenografts for 
preclinical assays. Clinical cancer research, 13(13), 3989-3998. 
Roila F, van der Wetering M, et al (2016) 2016 MASCC and ESMO guideline update for the 
prevention of chemotherapy- and radiotherapy-induced nausea and vomiting and of nausea and 
vomiting in advanced cancer patients. Ann Oncol. 27(suppl 5):v119-v133. 
Tsutsumi, Norifumi & Yonemitsu, Yoshikazu & Shikada, Yasunori & Onimaru, Mitsuho & 
Tanii, Mitsugu & Okano, Shinji & Kaneko, Kazuhiro & Hasegawa, Mamoru & Uemura, 
Munenori & Maehara, Yoshihiko & Sueishi, Katsuo. (2004). Essential Role of PDGFRα-
p70S6K Signaling in Mesenchymal Cells During Therapeutic and Tumor Angiogenesis In Vivo 
Role of PDGFRα During Angiogenesis. Circulation research. 94. 1186-94. doi: 
10.1161/01.RES.0000126925.66005.39. 
Urva, S. , Bouillaud, E. , Delaney, R. , Jappe, A. and Cheung, W. (2013), A Phase I Study 
Evaluating the Effect of Everolimus on the Pharmacokinetics of Midazolam in Healthy Subjects. 
J Clin Pharmacol, 53: 444-450. doi:10.1002/jcph.7 
Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub 
T, Mesirov JP, Alexe G, Lawrence M, O’Kelly M, Tamayo P, Weir BA, Gabriel S, Winckler W, 
Gupta S, Jakkula L, Feiler HS, Hodgson JG, James CD, Sarkaria JN, Brennan C, Kahn A, Spellman 
PT,Wilson RK, Speed TP, Gray JW, Meyerson M, Getz G, Perou CM,  Hayes DN, Cancer Genome 
Atlas Research Network. Integrated genomic analysis identifies clinically relevant subtypes of 
glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 
2010; 17: 98–110 
Yu, Y. (1999), MAP kinases, phosphatidylinositol 3‐kinase, and p70 S6 kinase mediate the 
mitogenic response of human endothelial cells to vascular endothelial growth factor. J. Cell. 
Physiol., 178: 235-246. doi:10.1002/(SICI)1097-4652(199902)178:2<235::AID-
JCP13>3.0.CO;2-S   
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13 Appendices 
Appendix 1: ECOG Performance Status Scale 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity, but ambulatory and able to 
carry out work of a light or sedentary nature (e.g., light housework, office 
work) 
2 
Ambulatory and capable of all self-care, but unable to carry out any work 
activities 
Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours 
4 
Completely disabled 
Cannot carry on any self-care 
Totally confined to bed or chair 
5 
Dead 


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Appendix 2: List of prohibited concomitant medications and concomitant 
medications requiring caution 
Table 16 Prohibited medications that are strong inducers or inhibitors of CYP3A, or CYP3A substrates with 
narrow therapeutic index 
Category 
Drug Name 
Strong CYP3A4/5 
inhibitors 
Atazanavir/ritonavir, boceprevir, clarithromycin, cobicistat, conivaptan, 
danoprevir/ritonavir, darunavir/ritonavir, elvitegravir/ritonavir, grapefruit juice, 
idelalisib, indinavir, indinavir/ritonavir, itraconazole, ketoconazole, lopinavir/ritonavir, 
mibefradil, nefazodone, nelfinavir,ombitasvir/paritaprevir/dasabuvir/ritonavir (VIEKIRA
PAK), posaconazole, ritonavir,  saquinavir/ritonavir, telaprevir, telithromycin, 
tipranavir/ritonavir, troleandomycinvoriconazole 
Strong CYP3A4/5 
inducers 
Apalutamide, carbamazepine3, enzalutamide, lumacaftor, mitotane, phenobarbital, 
phenytoin3, rifabutin, rifampin (rifampicin)3, St. John's wort (hypericum perforatum)2,3 
CYP3A4/5 substrates 
with NTI1 
Alfentanil, astemizole, cisapride, cyclosporine, diergotamine (dihydroergotamine), 
ergotamine, fentanyl, lomitapide5, lovastatin, nicardipine, nisoldipine, pimozide, 
quinidine, simvastatin, sirolimus, tacrolimus 
Medications with a 
known risk for QT 
prolongation4 
Amiodarone, anagrelide, arsenic trioxide, astemizole, azithromycin,bepridil 
chloroquine, cocaine chlorpromazine, cilostazol, ciprofloxacin, cisapride, citalopram, 
clarithromycin, disopyramide, dofetilide, domperidone, donepezil, dronedarone, 
droperidol, erythromycin, escitalopram, flecainide, fluconazole, gatifloxacin, 
grepafloxacin, halofantrine, haloperidol, ibutilide, levofloxacin, levomepromazine, 
levosulpiride, levomethadyl, mesoridazine methadone, moxifloxacin, ondansetron, 
oxaliplatin, papaverine HCl (intra-coronary), pentamidine, pimozide, probucol, 
procainamide, propofol, quinidine, roxithromycin, sevoflurane, sotalol, sparfloxacin, 
sulpiride, sultopride, terlipressin, terodiline, terfenadine, thioridazine, vandetanib 
Herbal preparations/ 
medications or dietary 
supplements 
Herbal preparations/medications or dietary supplements known as strong inducers or 
inhibitors of CYP3A4/5 or those with a known risk of QT prolongation are prohibited 
throughout the study. These herbal medications include, but are not limited to: St. 
John’s wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone 
(DHEA), yohimbe, saw palmetto, black cohosh, and ginseng. Patients should stop 
using these herbal medications or dietary supplements 7 days prior to first dose of 
study drug. 
Other investigational and 
antineoplastic therapies 
Other investigational therapies must not be used while the patient is on the study. 
Anticancer therapy (chemotherapy, hormonal therapy, including but not limited to all 
SERMS [including raloxifene], biologic or radiation therapy [except for palliative 
radiotherapy as outlined in the protocol], and surgery) other than the study treatments 
must not be given while the patient is on the study medication. If such agents are 
required, then the patient must discontinue the study drug. 


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Category 
Drug Name 
1 NTI = narrow therapeutic index drugs whose exposure-response indicates that increases in their exposure levels 
by the concomitant use of potent inhibitors may lead to serious safety concerns (e.g., Torsades de Pointes) or 
drugs which have <2-fold difference in the minimum toxic concentrations and minimum effective concentrations in 
the blood. 
2 Herbal product 
3 P-gp inducer 
4 The list provided is as of December 2019.Check https www.crediblemeds.org/healthcare-providers/drug-list for 
the most updated list.  
5  Drug has warning for risk of hepatotoxicity.As far as possible, avoid co-administration of QT prolonging drugs or 
any other drugs with the potential to increase the risk of drug-related QT prolongation (e.g., via a potential DDI 
that increases the exposure of ribociclib or the exposure of the QT prolonging drug). A definitive list of drugs with 
a known risk, possible risk, or conditional risk of QT prolongation and/or Torsades de Pointes (TdP) is available 
online at qtdrugs.org. 
Source: Novartis PK Sciences Memorandum: Drug-Drug Interactions (DDI) and Co-medication Considerations for 
Novartis Clinical Trials (January 2018), which is compiled from Indiana University “Clinically Relevant” Flockhart 
Table™, University of Washington Drug Interaction Database, and FDA Drug Development and Drug Interactions: 
Table of Substrates, Inhibitors and Inducers. 


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Table 17 List of medications to be used with caution during study drug treatment 


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Category 
Drug Name 
Moderate CYP3A4/5 
inhibitors 
Aprepitant, amprenavir, asafoetida resin (Ferula asafoetida) cimetidine, crizotinib, 
diltiazem, faldaprevir,  imatinib,  isavuconazole, netupitant, nilotinib, tofisopam, 
Schisandra sphenanthera (nan wu wei zi), verapamil 
Moderate CYP3A4/5 
inducers 
Bosentan, dabrafenib, efavirenz, etravirine, genistein,lopinavir5, modafinil, 
nafcillin, telotristat 
Sensitive CYP3A4/5 
substrates1 
Alpha-dihydroergocryptine,  aprepitant,  atorvastatin, avanafil, 
bosutinib,brotizolam, budesonide, buspirone, cannabinoids6, cannabidiol6, 
cobimetinib,   darifenacin, dasatininb, ebastine, eletriptan, eplerenone, 
everolimus, felodipine, fluticasone, grazoprevir, ibrutnib, isavuconazole, 
ivabradine, ivacaftor, , levomethadyl (LAAM), lomitapide, lovastatin, lumefantrine, 
lurasidone, maraviroc, midazolam, midostaurin, naloxegol, neratinib, nisoldipine, 
perospirone, quetiapine, ridaforolimus, sildenafil, simeprevir, simvastatin, 
ticagrelor, tilidine,  tolvaptan, triazolam, ulipristal, vardenafil, venetoclax, vicriviroc, 
voclosporin 
BSEP inhibitors 
Alectinib, atorvastatin,  bromocriptine, candesartan, clobetasol, clofaziminie, 
dabigatran, dipyridamole, glyburide, grazoprevir, ledipasvir, 
mifepristone,pioglitazone, reserpine,rifamycin, simeprevir, telmisartan,timcodar, 
troglitazone, velpatasvir 
Medications that carry a 
possible risk for QT 
prolongation2 
Alfuzosin, apomorphine, aripiprazole, artenimol+piperaquine , asenapine, 
, atomoxetine,  bedaquiline, bendamustine, bortezomib, bosutinib, buprenorphine, 
cabozantinib, capecitabine, ceritinib, clomipramine, crizotinib,clozapine, 
cyamemazine (cyamepromazine), dabrafenib, dasatinib, degarilix, delamanid, 
desipramine, dexmedetomidine, dolasetron, efavirenz, eliglustat, epirubicin, 
eribulin mesylate, ezogabine(retigabine), famotidine, felbamate, fingolimod, 
flupentixol,  gemifloxacin, granisetron, hydrocodone-ER, iloperidone, imipramine 
(melipramine), isradipine, ketanserin, lapatinib, lenvatinib, leuprolide, lithium, 
melperone, midostaurin, mifepristone, mirabegron, mirtazapine, moexipril/HCTZ, 
necitumumab, nicardipine, nilotinib, norfloxacin, nortriptyline, nusinersen, 
ofloxacin, osimertinib,  oxytocin, paliperidone, palonosetron,  panabinostat, 
pasireotide, pazopanib, perflutren lipid microspheres, perphenazine, pilsicainide, 
pimavanserin, pipamperone, promethazine, prothipendyl,  rilpivirine, risperidone, 
romidepsin, sertindole, sorafenib, sunitinib, tamoxifen, tipiracil/trifluridine, 
tizanidine, tolterodine, toremifene,trimipramine, tropisetron, vardenafil, 
vemurafenib, venlafaxine, vorinostat, ziprasidone 
MATE1/2 substrates3 
Acyclovir, cephalexin, cimetidine, fexofenadine, ganciclovir, glycopyrronium, 
metformin, pindolol, plisicainide, ranitidine, topotecan, varenicline 
OCT1/2 substrates4 
 Amantadine, carboplatin, cisplatin, cephalexin, cephradine, ipratropium,  
lamivudine, linagliptin, metformin,  oxyplatin, oxybutynin, phenformin, picoplatin, 
pilsicainide, pindolol, ranitidine, sorafenib,  tropisetron, trospium, umeclidinium,, 
and zidovudine 
BCRP substrates 
Daunorubicin, dolutegravir, doxorubicin, hematoporphyrin, imatinib, methotrexate, 
mitoxantrone, pitavastatin, rosuvastatin, irinotecan, ethinyl estradiol, simvastatin, 
sulfasalazine, sofosbuvir, tenofovir, topotecan, venetoclax 
1 Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold or higher when co-
administered with a potent inhibitor. 
2  The list provided is as of January 2018. Check https www crediblemeds.org/healthcare-providers/drug-list for 
the most updated list. 
3 MATE1 and MATE2 share considerable substrate specificity.  
4 OCT1 and OCT2 share considerable substrate specificity. 
5 Lopinavir and atazanavir is prohibited when combined with ritonavir (see Table 17) 
6 Based data that, exposure of cannabidiol (CBD), tetrahydrocannabinol (THC), 11-hydroxy THC, increased by 
~2-3 folds when co-administered with ketoconazole (CYP3A4 inhibitor); Stott et al, Springerplus. 2013; 2: 236 
Source: Novartis PK Sciences Memorandum: Drug-Drug Interactions (DDI) and Co-medication Considerations for 
Novartis Clinical Trials (January 2018), which is compiled from Indiana University “Clinically Relevant” Flockhart 
Table™, University of Washington Drug Interaction Database, and FDA Drug Development and Drug Interactions: 
Table of Substrates, Inhibitors and Inducers. 


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Confidential 
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Protocol No. IVY 2018-01 
Initial Version date: 10/16/2018 
Revision date: 03/11/2019, 5/07/2019, 09/26/2019, 03/17/2020, 08/26/2024