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6 dosing delays/dose modification

6.1 **Notification of the Study Chair** The study chair or co-chair must be notified of any dosage modifications, prior to the implementation of the dose modification.
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6.2 hematologic and non-hematologic adverse

Each patient is allowed a maximum of two dose reductions as outlined in section 6.2.2, 6.2.3 and 6.2.4. Updated Date: September 26, 2018 If toxicity does not resolve to meet eligibility parameters within 14 days of drug discontinuation, the patient must be removed from protocol therapy. If a dose-limiting toxicity occurs in a patient who has resumed treatment at a reduced dose, the patients may have a second dose reduction to a lower dose level if available.  
If a dose-limiting toxicity occurs in a patient who has had two dose reductions, or for whom there is no lower dose level available (i.e. At dose level -1), the patient must be removed from protocol therapy. A dose-dependent drug-drug interaction (DDI) was observed between ribociclib and everolimus based on clinical PK analyses in a separate dose escalation trial among adults, where everolimus exposure increased 2- to 4-fold in the presence of ribociclib. If a dose adjustment of both ribociclib and everolimus are required, a dose reduction in ribociclib is considered as a method to reduce exposure to both drugs since everolimus exposure is increased with increased ribociclib doses through a DDI. However, if attribution is clearly due to everolimus, everolimus will be initially decreased. First dose reduction will occur with ribociclib. However, if the attribution is clearly due to everolimus only, the everolimus dose will be reduced. The second dose reduction will occur for everolimus if the first dose reduction was ribociclib or will occur for ribociclib if the first dose reduction was everolimus. For patients enrolled in dose level 2, two dose level reductions are allowed. 6.2.1 Ribociclib specific dose reduction guidelines For patients requiring a dose reduction enrolled on Dose Levels 2 and 3 (both at 170 mg/ m2/ day ribociclib) with BSA between 0.45 m2 **and 0.73m**2, the ribociclib dose will be reduced to 120 mg/ m2/
day (first reduction) then to 75 mg/ m2/ day (second reduction) if needed. Ribociclib dose reduction will be based on the **actual calculated dose** and will not use the monograms in Appendix 15.5. The calculated dose will be rounded to the nearest 0.1 mL (or 3 mg).  
For example: A patient with a BSA **0.5 m**2 enrolled at dose level 2 (170 mg/ m2/ day). The first dose reduction will be 120 mg/ m2/ day. The patient calculated dose reduction will be **60 mg** (120 x 0.5) or 2 mL Ribociclib solution (30 mg/mL). If second dose reduction is needed, the second reduced dose will be 37.5 mg (or 1.2 mL) Ribociclib solution (30 mg/mL).  
Patients enrolled on dose levels 2 or 3 with a BSA of at least 0.74m2 or higher, will follow the nomograms in appendix 15.5 for dose reductions. 6.2.2 Dose modifications for non-hematologic toxicities Protocol therapy will be discontinued if a non-hematologic dose limiting toxicity occurs after two dose modifications. If a patient experiences a dose-limiting non-hematological toxicity, as defined in Section 5.3, study drug should be withheld. Unless otherwise stated below, if the toxicity resolves to meet on study parameters within 14 days of drug discontinuation, the patient may resume treatment at the next lower dose level. For patients enrolled at Dose Level 1, the dose should be reduced to Dose Level 0 or -0.5 pending attributions. Patients already receiving Dose Level -1 at the time of dose limiting toxicity must be removed from study. Doses reduced for toxicity will not be re-escalated, even if there is minimal or no toxicity with the reduced dose. Updated Date: September 26, 2018 6.2.3 Dose modifications for hematologic toxicities ≥ Grade 3 thrombocytopenia: Platelet transfusion is permissible and strongly encouraged for patients with dose-modifying thrombocytopenia to minimize risk of intra-tumoral hemorrhage. Ribociclib and everolimus should not be restarted until platelet count has recovered to ≥ 100 x 109cells/ L (transfusion independent for 7 days). Patients with grade 4 neutropenia (during any time throughout the course) may receive filgrastim (G-CSF) support (Investigator's discretion) only for documented Grade 3 or greater infection and/or sepsis.  
Ribociclib and everolimus should not be restarted until the ANC is ≥ 1.0 x 109cells/ L and for at least 48 hours without G-CSF support. Patients should start the subsequent course at one lower dose level without G-CSF support. In the event of hematological DLT, complete blood counts should be repeated twice weekly for any hematological toxicity described above until counts recover to meet criteria for starting subsequent course of maintenance therapy. Missed doses will not be made up if drug was held for a DLT. A patient who experiences any DLT at dose level -1 will be removed from study. If a patient experiences myelosuppression (i.e. thrombocytopenia or neutropenia) that causes a delay of >14 days between treatment cycles, counts should be checked every 3-4 days for thrombocytopenia and for neutropenia during this period. Once neutropenia or thrombocytopenia has resolved to eligibility criteria, the patient may resume treatment at the next lower dose level for ribociclib and everolimus dose will remain the same. For patients on dose level -1, the patient must be removed from protocol therapy. Doses reduced for toxicity will not be re-escalated. If a dose-limiting toxicity occurs in a patient who has had two dose reductions, or for whom there is no lower dose level available ( i.e. if already at dose level -1), the patient must be removed from protocol therapy. 6.2.4 Dose modifications for specific toxicities  
| Table 9: Guidance for dose modifications for hepatic toxicities                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Total bilirubin OR ALT/AST increased above baseline value Grade 3 Dose interruption of ribociclib and everolimus  - If resolved to ≤ grade 1 in ≤14 days, lower 1 dose level of ribociclib and  maintain everolimus dose Repeat liver enzymes and bilirubin tests twice  weekly for 2 weeks after dose resumption Grade 4 (>20.0 x ULN) Discontinue ribociclib and everolimus Confounding factors and/or alternative causes for increase of total bilirubin should be excluded before dose  interruption/reduction. AST or ALT and concurrent Bilirubin For patients with normal ALT or AST or total  bilirubin at baseline: AST or ALT ≥ grade 2  combined with total bilirubin >1.5-3 x ULN  without evidence of cholestasis Discontinue ribociclib and everolimus |  
Additional Follow-up for Hepatic *Toxicities* Increase in transaminases combined with total bilirubin (TBIL) increase may be indicative of druginduced liver injury (DILI), and should be considered as clinically important events.  
The threshold for potential DILI may depend on the patient's baseline AST/ALT and TBIL value; patients meeting any of the following criteria will require further follow-up as outlined below:
- For patients with normal ALT or AST or TBIL value at baseline: AST or ALT Grade 3 combined with TBIL Grade 3.  
- For patients with elevated AST or ALT or TBIL value at baseline: (AST or ALT > 2 x baseline AND > Grade 3) OR (AST or ALT Grade 3), whichever is lower, combined with (TBIL > 2 x baseline AND Grade 2).  
In the absence of cholestasis, these patients should be immediately discontinued from study drug treatment, and repeat Liver Function Tests (LFTs) as soon as possible, preferably within 48 hours from the awareness of the abnormal results. The evaluation should include laboratory tests, detailed history, physical assessment and the possibility of obstructions/compressions, etc. Hepatic toxicity monitoring includes the following LFTs: albumin, ALT, AST, total bilirubin, direct and indirect bilirubin, alkaline phosphatase (fractionated if alkaline phosphatase is grade 2 or higher), creatine kinase, prothrombin time (PT/INR) and GGT. For patients with Gilbert Syndrome: total and direct bilirubin must be monitored, intensified monitoring applies to changes in direct bilirubin only. Close observation is recommended in case of AST, ALT, and/or bilirubin increase requiring dose interruption, which involves:
- Repeating liver enzyme and serum bilirubin tests two or three times weekly. Frequency of retesting can decrease to once a week or less if abnormalities stabilize or return to normal values.  
- Obtaining a more detailed history of prior and/or concurrent diseases, including history of any pre-existing liver conditions or risk factors.  
- Obtaining a history of concomitant drug use (including non-prescription medications, herbal and dietary supplements), alcohol use, recreational drug use, and special diets.  
- Ruling out acute viral hepatitis types A, B, C, D, and E; hepatotropic virus infections (CMV,
EBV or HSV); autoimmune or alcoholic hepatitis; Nonalcoholic steatohepatitis (NASH); hypoxic/ischemic hepatopathy; and biliary tract disease.  
- Obtaining a history of exposure to environmental chemical agents.  
- Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, direct bilirubin).  
- Considering gastroenterology or hepatology consultations.  
- Assessing cardiovascular dysfunction or impaired liver oxygenation, including hypotension or right heart failure as possible etiologies for liver dysfunction.  
Liver biopsy as clinically indicated to assess pathological change and degree of potential liver injury. All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no other alternative cause for LFT abnormalities identified, should be considered as "medically significant", thus met the definition of SAE (section 7.4.2) and reported as an SAE with a comment using the term "potential drug-induced liver injury". All events should be followed up with the outcome clearly documented. Updated Date: September 26, 2018  
| Table 10: Guidance for Dose modifications for QT prolongation                                                                                                   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |                                                                      |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------|
| Grade                                                                                                                                                           | Dose Modification                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                      |
| All Grades                                                                                                                                                      | 1.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Check the quality of the ECG and the QT value and repeat if  needed. |
| 2.                                                                                                                                                              | Perform analysis of serum electrolytes (K+, Ca++, Phos, Mg++).  If outside of the normal range, interrupt ribociclib administration,  correct with supplements or appropriate therapy as soon as  possible, and repeat electrolytes until documented as normal.                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |                                                                      |
| 3.                                                                                                                                                              | Review concomitant medication usage for the potential to inhibit  CYP3A4 and/or to prolong the QT interval.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                                      |
| 4.                                                                                                                                                              | Check compliance with correct dose and administration of  ribociclib.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                      |
| 1 (QTc 450- 480 ms)                                                                                                                                             | Perform Steps 1-4 as directed in "For All Grades".  No dose adjustment required.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                      |
| 2 (QTc 481-500 ms)                                                                                                                                              | Interrupt ribociclib and everolimus.  Perform steps 1-4 as directed in "For All Grades." Perform a repeat ECG within one hour after the first QTc of ≥481 ms - If QTc <481 ms, restart ribociclib by 1 dose level. Refer to Table 8 for dosing schedule..  - If QTc remains ≥481 ms, repeat ECG within 14 days until the QTc returns to <481 ms. Hold ribociclib and everolimus. Restart  ribociclib reduced by 1 dose level and everolimus at the same dose  level.  - If QTc ≥481 ms recurs, ribociclib should be reduced again by 1  dose level and everolimus at same dose - Repeat ECGs 7 days and 14 days after dose resumption (then as  clinically indicated) for any patient who has therapy interrupted  due to QTc ≥481 ms |                                                                      |
| 3 (QTc ≥ 501 ms on at least                                                                                                                                     | Interrupt ribociclib and everolimus                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                      |
| two separate ECGs)                                                                                                                                              | - Perform a repeat ECG within one hour of the first QTc of ≥501 ms.  - If QTc remains ≥501 ms, consult with a cardiologist (or qualified  specialist) and repeat cardiac monitoring as indicated until the QTc  returns to <481 ms.  - If QTc returns to <481 ms within 14 days, ribociclib should be  reduced by 1 dose level and maintain everolimus dose.  - If QTc remains ≥ 481ms after performing steps 1-2 as directed in  "for all grade," discontinue Ribociclib and everolimus. - Repeat ECGs 7 days and 14 days after dose resumption for any  patient who has therapy interrupted due to QTc ≥501 ms  - If QTc of ≥501 ms recurs, discontinue ribociclib and everolimus                                                   |                                                                      |
| 4 (QT/QTc ≥ 501 or > 60 ms  change from baseline)  and (Torsades de pointes or  polymorphic ventricular  tachycardia, or signs/symptoms of serious  arrhythmia) | Discontinue Ribociclib and everolimus and removal from study                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |                                                                      |  
Updated Date: September 26, 2018  
| Table 11: Guidance for dose modification and management for cardiac dysfunction               |                                                                                                                                                                                                                                |                                                 |
|-----------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------|
| Adverse drug reaction                                                                         | Severity                                                                                                                                                                                                                       | Dose adjustment and management  recommendations |
| Asymptomatic, resting ejection fraction 40- 50%; or 10-20% drop from baseline                 | Maintain dose level, and continue  ribociclib and everolimus with  caution. Repeat LVEF within 4 weeks or as  clinically appropriate.                                                                                          |                                                 |
| Symptomatic, responsive to intervention,  ejection fraction 20-39% or >20% drop from baseline |                                                                                                                                                                                                                                |                                                 |
| Cardiac - Left  Ventricular Systolic  Dysfunction                                             | Hold ribociclib and everolimus until  resolved, then reduce ribociclib by  one dose level; LVEF measurement to be repeated, if  not resolved within 28 days  permanently discontinue ribociclib  and everolimus if applicable. |                                                 |  
6.2.5 Dose Modifications for Everolimus related toxicities  
| Table 12: Dose modification and management for Mucositis                                            |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |                                                                                                                                              |
|-----------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------|
| Adverse drug                                                                                        | Severity                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Dose adjustment and management                                                                                                               |
| reaction                                                                                            | recommendations                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |                                                                                                                                              |
| Mucositis characterized  by ulceration  or  inflammation  of the oral  mucosa                       | Grade 1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | No dose adjustment required. Manage with non-alcoholic steroid mouthwash and salt  water (0.9%) mouthwash four times a day (section  5.4.7). |
| Asymptomatic or mild  symptoms; intervention not  indicated                                         | Interrupt everolimus and ribociclib until recovery to  grade 1 within 14 days. - Re-initiate study treatment at the same dose. - If stomatitis recurs, interrupt ribociclib and  everolimus until recovery to grade 1. - Re-initiate everolimus at a one dose lower.                                                                                                                                                                                                                                                           |                                                                                                                                              |
| Grade 2 Moderate pain or ulcer that  does not interfere with oral  intake; modified diet  indicated | Manage with topical analgesic mouth treatments (e.g.  benzocaine,butyl minobenzoate, tetracaine  hydrochloride, menthol or phenol) with or without  topical corticosteroids (i.e. triamcinolone oral paste). Interrupt everolimus and ribociclib until recovery to  grade ≤1. - Re-initiate everolimus at a reduced dose level  and maintain ribociclib dosing - If reoccurs, interrupt ribociclib and everolimus  until recovery to grade ≤1. - Re-initiate ribociclib at reduced dose level and  maintain everolimus dosing. |                                                                                                                                              |
| Grade 3 Severe pain; interfering  with oral intake                                                  |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |                                                                                                                                              |  
Updated Date: September 26, 2018  
| Adverse drug                                                           | Severity   | Dose adjustment and management   |
|------------------------------------------------------------------------|------------|----------------------------------|
| reaction                                                               | recommendations Manage with topical analgesic mouth treatments (i.e.  benzocaine, butyl aminobenzoate, tetracaine  hydrochloride, menthol or phenol) with or without  topical corticosteroids (i.e. triamcinolone oral paste). Hold ribociclib and everolimus and provide appropriate  medical therapy.  - If recovered to ≤grade 1 within 14 days, Reinitiate everolimus at a reduced dose.  - If reoccurs, interrupt ribociclib and everolimus  until recovery to grade ≤1.  - Re-initiate ribociclib at reduced dose level and  maintain everolimus reduced dosing            |                                  |
| Grade 4 Life-threatening  consequences; urgent  intervention indicated |            |                                  |  
Table 13: Dose modification and management for Hypertension Hypertension is to be reported as 'Vascular disorders-Other, Pediatric Hypertension" and graded as defined in Table 13.  
| Adverse drug reaction                                                                                                                                                                                    | Dose Adjustment and management recommendations                                                                                                                                                                                                                                                          |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade 1 Children 1-13y: Elevated BP: ≥90th percentile to <95th  percentile or 120/80 mm Hg to <95th  percentile (whichever is lower)                                                                     | No dose modifications                                                                                                                                                                                                                                                                                   |
| Children ≥13y Elevated BP: 120/<80 to 129/<80 mmHg Grade 2 Children 1-13y Stage 1 Hypertension (HTN): ≥95th  percentile to <95th percentile + 12 mm  Hg, or 130/80 to 139/89 mm Hg  (whichever is lower) | No dose modifications                                                                                                                                                                                                                                                                                   |
| Children ≥13y Stage 1 HTN: 130/80 to 139/89 mm Hg Grade 3 Children 1-13y Stage 2 HTN ≥95th percentile + 12 mm  Hg or ≥140/90 mm Hg (whichever is  lower)                                                 | Hold ribociclib and everolimus and follow up blood  pressure if the toxicity resolves to meet on study  parameters within 14 days of drug discontinuation, the  patient may resume treatment at the next lower dose level.                                                                              |
| Children ≥13y Stage 2 HTN: ≥140/90 mm Hg                                                                                                                                                                 | If Grade 3 hypertension reoccurs, hold ribociclib and  everolimus and follow up blood pressure if the toxicity  resolves to meet on study parameters within 14 days of  drug discontinuation, the patient may resume treatment at  the next lower dose level (2 dose levels lower than  starting dose). |  
| If Grade 3 hypertension reoccurs after 2 dose level  reductions, ribociclib and everolimus will be  discontinued.   |                                        |
|---------------------------------------------------------------------------------------------------------------------|----------------------------------------|
| Grade 4 - All Ages Life-threatening consequences; urgent  intervention indicated                                    | Discontinue ribociclib and everolimus. |
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7 adverse events list and

Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The following list of AEs (Section 7.1 and 7.2) and the characteristics of an observed AE (Section 7.3) will determine whether the event requires expedited reporting via the CTEP Adverse Event Reporting System (CTEPAERS) **in addition** to routine reporting. The coding of attribution in the Rave database pertains to adverse events related to ribociclib and everolimus.  
- *Baseline Abnormalities* Any baseline (pretreatment) abnormalities observed during the initial physical examination should be recorded in the Rave database.  
- *Treatment or within 30 days of treatment* Only record adverse events grades 1 and 2 if the attribution is at least possibly related to ribociclib and everolimus. Record all adverse events grades 3 through 4 and deaths), regardless of attribution on the electronic case report forms.
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7.1 adverse event list(s) for

Adverse events considered to be *expected* with ribociclib (3 weeks on 1 week off dosing regimen) for reporting purposes. May also refer to the most current version of the Ribociclib Investigator Brochure (available on the PBTC-050 webpage) for additional expected adverse events.  
| Event                                                  | Frequency category*   | Frequency    | category*    |
|--------------------------------------------------------|-----------------------|--------------|--------------|
| all grades                                             | grade 3/4             |              |              |
| MedDRA system organ  class Blood and lymphatic         | Anemia                | Very common  | common       |
| system disorders                                       | Febrile neutropenia   | common       | common       |
| Eye Disorders                                          | Dry eye               | Common       | Not reported |
| Watering eyes                                          | Common                | Not reported |              |
| Gastrointestinal disorders                             | Abdominal pain        | Very common  | common       |
| Constipation                                           | Very common           | common       |              |
| Diarrhea                                               | Very common           | common       |              |
| Dyspepsia                                              | Common                | Not reported |              |
| Mucositis oral                                         | Very common           | Uncommon     |              |
| Nausea                                                 | Very common           | common       |              |
| Vomiting                                               | Very common           | common       |              |
| General disorders and  administration site  conditions | Fatigue               | Very common  | Common       |
| Edema limbs                                            | Very common           | Not reported |              |
| Fever                                                  | Very common           | Uncommon     |              |
| Hepatobiliary disorders                                | Hepatic Failure       | Uncommon     | Uncommon     |  
Updated Date: September 26, 2018  
| Infections                                                                                                                                                                                 | Urinary tract infection        | Very common   | Uncommon   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------|---------------|------------|
| Investigations                                                                                                                                                                             | Electrocardiogram QT corrected | common        | Uncommon   |
| interval prolonged Alanine aminotransferase                                                                                                                                                | Very common                    | Common        |            |
| increased Aspartate aminotransferase                                                                                                                                                       | Very common                    | Common        |            |
| increased Alkaline phosphatase increased                                                                                                                                                   | Very common                    | Common        |            |
| Blood creatinine increased                                                                                                                                                                 | Common                         | Uncommon      |            |
| White blood cells decreased                                                                                                                                                                | Very Common                    | Very Common   |            |
| Neutrophil count decreased                                                                                                                                                                 | Very common                    | Very Common   |            |
| Lymphocyte count decreased                                                                                                                                                                 | Very Common                    | Very Common   |            |
| Platelet count decreased                                                                                                                                                                   | Common                         | Uncommon      |            |
| Weight decreased                                                                                                                                                                           | Common                         | Uncommon      |            |
| Metabolism and nutrition  disorders                                                                                                                                                        | Hypokalemia                    | Common        | common     |
| Hypophosphatemia                                                                                                                                                                           | Common                         | common        |            |
| Hypocalcemia                                                                                                                                                                               | Common                         | Common        |            |
| Anorexia                                                                                                                                                                                   | Very common                    | Common        |            |
| Musculoskeletal and  connective tissue  disorders                                                                                                                                          | Back pain                      | Very common   | common     |
| Nervous System                                                                                                                                                                             | Headache                       | Very common   | Uncommon   |
| Disorders                                                                                                                                                                                  | Syncope                        | Common        | Common     |
| Dysgeusia                                                                                                                                                                                  | Common                         | Uncommon      |            |
| Psychiatric disorder                                                                                                                                                                       | Insomnia                       | Very Common   | Uncommon   |
| Respiratory, thoracic and  mediastinal disorders                                                                                                                                           | Dyspnea                        | Very common   | common     |
| Epistaxis                                                                                                                                                                                  | Common                         | Not reported  |            |
| Skin and subcutaneous                                                                                                                                                                      | Rash maculo-papular            | Very common   | Uncommon   |
| tissue disorders                                                                                                                                                                           | Pruritus                       | Very common   | uncommon   |
| Erythema                                                                                                                                                                                   | Common                         | Not reported  |            |
| Alopecia                                                                                                                                                                                   | Very common                    | Not reported  |            |
| *Frequency category for each adverse drug reaction is based on the following:  Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); |                                |               |            |  
The adverse drug reactions frequencies are determined from the data from study CLEE011A2301 (a double-blinded randomized placebos controlled trial) and where reasonable evidence of a possible causal relationship with ribociclib was proven. Note: Ribociclib in combination with other agents could cause an exacerbation of any adverse event currently known to be caused by the other agent, or the combination may result in events never previously associated with either agent. 7.2 **Adverse Event List(s) for everolimus (RAD-001, NSC 733504)** Adverse Events considered to be *expected* with everolimus for Reporting Purposes. Refer to most current version of **everolimus** Investigator Brochure located on the PBTC-050 webpage for additional expected adverse events. Updated Date: September 26, 2018  
| Blood and lymphatic system disorders            | Anemia                 | Very common   |
|-------------------------------------------------|------------------------|---------------|
| Gastrointestinal disorders                      | Abdominal pain         | Common        |
| Dry mouth                                       | Common                 |               |
| Oral pain                                       | Common                 |               |
| Dysphagia                                       | Common                 |               |
| Constipation                                    | Common                 |               |
| Diarrhea                                        | Very common            |               |
| Mucositis oral                                  | Very common            |               |
| Nausea                                          | Very common            |               |
| Vomiting                                        | Very common            |               |
| Dyspepsia                                       | Common                 |               |
| General disorders and administration site       | Fatigue                | Very common   |
| conditions                                      | Edema limbs            | Very common   |
| Fever                                           | Common                 |               |
| Non-cardiac chest pain                          | Uncommon               |               |
| Immune System Disorders                         | Allergic reaction      | Uncommon      |
| Anaphylaxis                                     | Uncommon               |               |
| Infections and Infestations                     | Infections1            | Very common   |
| Injury, poisoning and procedural complications  | Wound complication2    | Uncommon      |
| Investigations                                  | Weight loss            | Very common   |
| Alanine aminotransferase increased              | Common                 |               |
| Aspartate aminotransferase increased            | Common                 |               |
| Alkaline phosphatase increased                  | Common                 |               |
| Hypercholesterolemia                            | Very Common            |               |
| Blood creatinine increased                      | Common                 |               |
| White blood cell decreased                      | Common                 |               |
| Lymphocyte count decreased                      | Common                 |               |
| Neutrophil count decreased                      | Common                 |               |
| Platelet count decreased                        | Common                 |               |
| Metabolism and nutrition disorders              | Hypertriglyceridemia   | Common        |
| Anorexia                                        | Very common            |               |
| Hyperglycemia                                   | Very common            |               |
| Hypophosphatemia                                | Common                 |               |
| Diabetes mellitus                               | Common                 |               |
| Hyperlipidemia                                  | Common                 |               |
| Hypokalemia                                     | Common                 |               |
| Dehydration                                     | Common                 |               |
| Musculoskeletal and connective tissue           | Arthralgia             | Common        |
| disorders                                       | Pain in extremity      | Common        |
| Back pain                                       | Common                 |               |
| Nervous System Disorders                        | Headache               | Very common   |
| Dysgeusia                                       | Very common            |               |
| Psychiatric disorders                           | Insomnia               | Common        |
| Respiratory, thoracic and mediastinal disorders | Pneumonitis3           | Very common   |
| Epistaxis                                       | Very common            |               |
| Cough                                           | Very common            |               |
| Dyspnea                                         | common                 |               |
| Renal and Urinary disorders                     | Proteinuria            | Common        |
| Renal Failure                                   | Common                 |               |
| Acute kidney injury                             | Uncommon               |               |
| Urinary frequency (daytime)                     | Uncommon               |               |
| Reproductive system and breast disorders        | Irregular menstruation | Common        |
| Amenorrhea                                      | Uncommon               |               |
| Skin and subcutaneous tissue disorders          | Rash maculo-papular    | Very common   |
| Pruritus                                        | Very common            |               |
| Dry Skin                                        | Common                 |               |
| Nail Disorder                                   | Common                 |               |
| Acne                                            | Common                 |               |
| Angioedema                                      | Rare                   |               |  
| Erythema                                                                                                                                                                                                          | Common       |        |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------|--------|
| Hand-foot syndrome4                                                                                                                                                                                               | Common       |        |
| Vascular disorders                                                                                                                                                                                                | Hypertension | Common |
| Deep vein thrombosis                                                                                                                                                                                              | Uncommon     |        |
| Thromboembolic event - Pulmonary                                                                                                                                                                                  | Uncommon     |        |
| embolism Acute Respiratory Distress Syndrome                                                                                                                                                                      | Rare         |        |
| Bleeding                                                                                                                                                                                                          | Hemorrhage5  | Common |
| *Frequency category for each adverse drug reaction is based on the following:  Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). |              |        |  
Bleeding Hemorrhage5 Common
*Frequency category for each adverse drug reaction is based on the following: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).  
1Infection includes all reactions within the 'infections and infestations' system organ class including common: pneumonia, urinary tract infection; uncommon: bronchitis, herpes zoster, sepsis, abscess and isolated cases of opportunistic infections (e.g. aspergillosis, candidiasis, and hepatitis B) and rare: viral myocarditis.  
2 Everolimus delays wound healing and increases the occurrence of wound-related complications like wound dehiscence, wound infection, incisional hernia, lymphocele, and seroma.  
3Includes common: pneumonitis, interstitial lung disease, lung infiltration, and rare: alveolitis, pulmonary alveolar hemorrhage and pulmonary toxicity.  
4 Reported as palmar-plantar erythrodysesthesia syndrome 5 Includes different bleeding events from different sites not listed individually
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7.3 adverse event characteristics 7.3.1

The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting with the exception of grading for Hypertension . Hypertension will be reported as "Vascular disorders - Other, pediatric hypertension", and is to be graded according to the definitions outlined in Table 14. All appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. In 2017, Flynn JT et al reported new clinical practice guidelines for high blood pressure in children and adolescents. 78 Definitions of blood pressure categories and stages have been redefined as noted in Table 14. These definitions are not aligned with CTCAE version 5.0 as the 99th percentile for pediatric pressure no longer exists in the definition of hypertension in children. Stage 2 hypertension is defined as the 95th percentile + 12mmHg. Per CTCAE version 5, the definition of Grade 3 hypertension in pediatrics is systolic and/or diastolic > 5mmHg above the 99th percentile.  
| Table 14: Updated Definitions of BP Categories and Stages   |                                                                                                                                                             |                                      |     |         |    |
|-------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------|-----|---------|----|
| Grade                                                       | For Children Aged 1-13 years                                                                                                                                | For Children Aged ≥13 years          |     |         |    |
| Normal                                                      | Normal BP: <90th percentile                                                                                                                                 | Normal BP: <120/<80 mm Hg            |     |         |    |
| 1                                                           | Elevated BP: ≥90th percentile to <95th percentile or 120/80                                                                                                 | Elevated                             | BP: | 120/<80 | to |
| mm Hg to <95th percentile (whichever is lower)              | 129/<80 mm Hg                                                                                                                                               |                                      |     |         |    |
| 2                                                           | Stage 1 Hypertension (HTN): ≥95th percentile to <95th  percentile + 12 mm Hg, or 130/80 to 139/89 mm Hg  (whichever is lower)                               | Stage 1 HTN: 130/80 to 139/89  mm Hg |     |         |    |
| 3                                                           | Stage 2 HTN ≥95th percentile + 12 mm Hg or ≥140/90 mm                                                                                                       | Stage 2 HTN: ≥140/90 mm Hg           |     |         |    |
| Hg (whichever is lower)                                     |                                                                                                                                                             |                                      |     |         |    |
| 4                                                           | Life threatening consequences (e.g. malignant hypertension, transient or permanent  neurologic deficit, hypertensive crisis); urgent intervention indicated |                                      |     |         |    |  
7.3.2 Attribution of the AE:
- Definite - The AE *is clearly related* to the study treatment.  
- Probable - The AE *is likely related* to the study treatment.  
- Possible - The AE *may be related* to the study treatment.  
- Unlikely - The AE *is doubtfully related* to the study treatment.  
- Unrelated - The AE *is clearly NOT related* to the study treatment.
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7.4 expedited adverse event reporting

Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event Reporting System), accessed via the CTEP Web site (https://eapps-ctep.nci.nih.gov/ctepaers). The reporting procedures to be followed are presented in the "NCI Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs" which can be downloaded from the CTEP Web site http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm. These requirements are briefly outlined in the tables below (Section 7.4.2). In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be made to the PBTC operation office by telephone at 901-595-7793. Once Internet connectivity is restored, the 24-hour notification phoned in must be entered electronically into CTEP-AERS by the original submitter at the site. 7.4.1 Distribution of Adverse Event Reports CTEP-AERS is programmed for automatic electronic distribution of reports to the following individuals: Principal Investigator and the responsible Protocol Coordinator at the PBTC, the local treating physician, and the Reporter and Submitter. CTEP-AERS provides a copy feature for other e-mail recipients.  
The following must be copied on expedited reports (24-hour notification and the complete report) submitted via CTEP-AERS:  
  
Study Chair **and IND Holder:**  
  
Mariko DeWire-Schottmiller, MD  
  
Updated Date: September 26, 2018 The OBDMC will email and/or fax the SAE /CTEP-AERS report, within 24 hours of their awareness of the event to Novartis (fax\#: 1- 877- 778- 9739). The IND holder, shall notify the FDA of any event that is both a serious suspected adverse reaction and unexpected in accordance with FDA rules and regulations (21 CFR 312.32). Follow-up information to a safety report will be submitted, as requested. The IND Sponsor or designee will submit a report of the unexpected, suspected adverse event to the FDA using the FDA's reporting form (FDA 3500A MedWatch Form) and guidelines. The report should describe the event as fully as possible. Supporting documentation (lab reports, summary notes, and autopsy report) should accompany the report. A fatal or immediately life-threatening suspected adverse event will be reported to the FDA within 7 calendar days of the receipt of the initial report by the IND sponsor. A non-fatal, non-life threatening unexpected, suspected, serious adverse event will be reported to the FDA within 15 calendar days of receipt of the initial report by the IND Sponsor. The PBTC OBDMC will post all IND Safety Letters on the PBTC-050 webpage. Sites will be notified via email of the receipt of the IND Safety Letter(s) and instructed to submit these to their local IRB in accordance with the institution's requirements. A copy of the Annual Progress Reports is submitted by the IND holder as required by FDA, by the sponsor-investigator. This submission will be cross referenced according to local regulations to the Novartis product number at the time of submission. Any SAEs experienced after this 30 days period should only be reported to Novartis if the investigator suspects a causal relationship to the study treatment. Recurrent episodes, complications, or progression of the initial SAE must be reported as follow-up to the original episode within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a different time interval outside the 30-day period post last dose and related to therapy should be reported separately as a new event. 7.4.2 Expedited Reporting Guidelines Use the NCI protocol number and the protocol-specific patient ID assigned during trial registration on all reports.  
Note: A death on study requires both routine and expedited reporting, regardless of causality.  
Attribution to treatment or other cause must be provided.  
Death due to progressive disease should be reported as **Grade 5 "Disease progression"** in the system organ class (SOC) "General disorders and administration site conditions". Evidence that the death was a manifestation of underlying disease (*e.g.*, radiological changes suggesting tumor growth or progression: clinical deterioration associated with a disease process) should be submitted. Phase 1 and Early Phase 2 Studies: Expedited Reporting Requirements for Adverse Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the Investigational Agent/Intervention **1, 2**
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312)
NOTE: Investigators **MUST** immediately report to the sponsor /NCI **ANY** Serious Adverse Events, whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64)
An adverse event is considered serious if it results in ANY of the following outcomes:  
1) Death  
  
  
  
  3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 6) Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6).  
| ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic  submission within the timeframes detailed in the table below. Hospitalization Grade 1 and Grade 2 Timeframes Grade 3-5 Timeframes Resulting in  Hospitalization  10 Calendar Days ≥ 24 hrs 24-Hour 5 Calendar  Days Not resulting in  Hospitalization  Not required ≥ 24 hrs Expedited AE reporting timelines are defined as: o "24-Hour; 5 Calendar Days" - The AE must initially be submitted electronically within 24 hours of learning  of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. o "10 Calendar Days" - A complete expedited report on the AE must be submitted electronically within 10   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
  
  
  
Expedited 10 calendar day reports for:
- Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, rounded UP to the nearest whole day, after the agent/intervention was last administered. Footnote "1" above applies after this   
7.4.3 Additional Protocol Specific Expedited Adverse Event Reporting Exclusions For this protocol only, the AEs/grades listed below do not require expedited reporting via CTEP-AERS. However, they still must be reported through the routine reporting mechanism (Section 7.4):  
| CTCAE      | Adverse       | Grade                            | Hospitalization/   |          |                        |
|------------|---------------|----------------------------------|--------------------|----------|------------------------|
| SOC        | Event         | Prolongation of  Hospitalization | Attribution        | Comments |                        |
| Blood/Bone | Lymphopenia   | ≤4                               | Regardless         | Any      | Expedited reporting is |
| Marrow     | not required. |                                  |                    |          |                        |  
7.4.4 Routine Adverse Event Reporting All Adverse Events **must** be reported in routine study data submissions. AEs reported expeditiously through CTEP-AERS must also be reported in routine study data submissions. Adverse event data collection and reporting, which are required as part of every clinical trial, are done to ensure the safety of patients enrolled in the studies as well as those who will enroll in future studies using similar agents. AEs are reported in a routine manner at scheduled times during the trial using Medidata Rave. For this trial the Adverse Event CRF is used for routine AE reporting in Rave. 7.4.5 Pregnancy Although not an adverse event in and of itself, pregnancy as well as its outcome must be documented via CTEP-AERS. In addition, the *Pregnancy Information Form* included within the NCI Guidelines for Adverse Event Reporting Requirements must be completed and submitted to CTEP. Any pregnancy occurring in a patient or patient's partner from the time of consent to 90 days after the last dose of study drug must be reported and then followed for outcome. Newborn infants should be followed until 30 days old. Please see the "NCI Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD
(CTEP and CIP) and DCP INDs and IDEs" (at http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm) for more details on how to report pregnancy and its outcome to CTEP. 7.4.6 Secondary Malignancy A *secondary malignancy* is a cancer caused by treatment for a previous malignancy (*e.g.*, treatment with investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is not considered a metastasis of the initial neoplasm. CTEP requires all secondary malignancies that occur following treatment with an agent under an NCI IND/IDE be reported expeditiously via CTEP-AERS. Three options are available to describe the event:
- Leukemia secondary to oncology chemotherapy such as acute myelocytic leukemia (AML)
- Myelodysplastic syndrome (MDS)
- Treatment-related secondary malignancy Any malignancy possibly related to cancer treatment (including AML/MDS) should also be reported via the routine reporting mechanisms outlined in each protocol. 7.4.7 Second Malignancy A second malignancy is one unrelated to the treatment of a prior malignancy (and is **NOT** a metastasis from the initial malignancy). Second malignancies require **ONLY** routine AE reporting unless otherwise specified.
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8 agent information

A list of the adverse events and potential risks associated with the investigational and commercial agents administered in this study can be found in Section 7.1 and 7.2.
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8.1 everolimus (rad001)

Chemical Name: (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy12-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl]-19,30- Updated Date: September 26, 2018 dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta16,24, 26,28-tetraene-2,3,10,14,20-pentaone Other Names: RAD001, Afinitor Classification: mTOR inhibitor CAS Registry Number: 159351-69-6 Molecular Formula: C53H83NO14 **M.W.:** 958.2 Mode of Action: Everolimus is an inhibitor of selective mammalian target of rapamycin (mTOR), the effects of which specifically target the mTOR-raptor signal transduction complex 1 (mTORC1). Inhibition of mTORC1, an essential regulator of global protein synthesis downstream on the PI3K/AKT/mTOR pathway, reduces tumor cell proliferation, glycolysis and angiogenesis. The PI3K/AKT/mTOR pathway is dysregulated in the majority of human cancers and is the object of many targeted agents.  
Description: White to faintly yellow powder How Supplied: Everolimus will be supplied by Novartis or its designee as dispersible tablets (also referred to as 'tablets for oral suspension') and is available as a 2 mg dosage forms. Each box of 28 tablets contains 4 blister cards of 7 tablets each. Extent of absorption of everolimus through topical exposure is not known. Caregivers are advised to avoid contact with suspensions of everolimus. Wash hands thoroughly before and after preparation of the suspension. All dosages prescribed and dispensed to the patient and all dose changes during the study must be recorded. Dispersible tablets contain butylhydroxytoluene/butylated hydroxytoluene (BHT), cellulose microcrystalline/microcrystalline cellulose, crospovidone, hypromellose/hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, mannitol/D-mannitol, silica colloidal anhydrous/colloidal silicon dioxide.  
Everolimus will be packaged in bottles. They will include storage conditions for the drug but no information about the patient. The study drug will be labeled and packaged under the responsibility of the Novartis drug supply management department. The medication will be supplied as open label supply to the site in a way that allows the patient to take medication at home.  
Storage: Store at 25°C (77°F). Excursions permitted between 15 to 30°C (59 to 85°F).  
If a storage temperature excursion is identified, promptly return everolimus to controlled room temperature and quarantine the supplies. Provide a detailed report of the excursion (including documentation of temperature monitoring and duration of the excursion) to Novartis for determination of suitability.  
Storage of the prepared oral suspension: The suspension should be discarded if not administered within 60 minutes of preparation.  
Stability: Refer to the clinical labels for current shelf life, in-use, expiration date and proper storage condition. Store tablets in the original container and protect from light and moisture.  
Stability or BUD (beyond-use date) **of the prepared oral suspension**: The oral suspension of everolimus prepared in an oral syringe or in a small drinking glass should be administered immediately after preparation. The oral syringe or glass should be rinsed with the same volume of water and the rinse should be completely swallowed to ensure that the entire dose is administered and there is no drug residue remaining in the oral syringe or glass.  
Route and Method **of Administration:** Oral administration. The dispersible tablet is prepared as a suspension of undissolved medicine that is mixed with water, and then taken by mouth. The suspension can be prepared in an oral syringe or small drinking glass. Everolimus dispersible tablet is an *ad-hoc* drug compounding. Patient and/or guardian will be taught how to prepare the oral suspension by research nursing staff. A patient/caretaker educational template is available on the PBTC-050 webpage for stepby-step ad-hoc drug preparation and administration guidance for Everolimus dispersible tablet in the home settings and included in the protocol as Appendices 15.7 and 15.8. They can be taken with or without food, but should be taken consistently the same time every day. If a dose is missed, it can still be taken up to 6 hours after the usual time of administration. Missed doses more than 6 hours late should be skipped for that day.
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potential drug interactions

Everolimus is a substrate of CYP3A4 and P-glycoprotein (PgP). Concomitant treatment with strong inhibitors or inducers of CYP3A4 or PgP should be avoided. Use caution when everolimus is given concomitantly with moderate inhibitors or inducers of CYP3A4 and PgP. Consult the protocol document or study investigator prior to making any dose adjustments related to potential drug-drug interactions. In vitro, everolimus is a competitive inhibitor of CYP3A4, a mixed inhibitor of CYP2D6, an inhibitor of transport proteins, OATP1B1 and OATP1B3 and a moderate inhibitor of P-gp. Exercise caution when everolimus is taken in combination with orally administered substrates of these enzymes and transporters, in particular, CYP3A4 and 2D6 substrates with a narrow therapeutic index. Everolimus does not appear to affect CYP 2C8 or 2C9 activity according to *in vitro* studies using reference substrates. Co-administration with angiotensin-converting enzyme (ACE) inhibitors may increase the risk for angioedema.  
Patient Care Implications: Patients taking everolimus should avoid the use of live vaccines and close contact with those who have received live vaccines. Examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.
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8.2 ribociclib

Chemical Name: 7-Cyclopentyl-N, N-dimethyl-2-[[5-(piperazin-1-yl) pyridin-2-yl]amino]-
7Hpyrrolo[2,3-d]pyrimidine-6-carboxamide succinate (1:1) Updated Date: September 26, 2018 Other Names: LEE011, KISQALI Classification: cyclin-dependent kinase (CDK) inhibitor CAS Registry Number: 1211441-98-3 (free base)
Molecular Formula: C23H30N8O.C4H6O4 **M.W.:** 434.55 Mode of Action: An orally available cyclin-dependent kinase (CDK) inhibitor targeting cyclin D1/CDK4 and cyclin D3/CDK6 cell cycle pathway, with potential antineoplastic activity. Ribociclib specifically inhibits CDK4 and 6, thereby inhibiting retinoblastoma (Rb) protein phosphorylation. Inhibition of Rb phosphorylation prevents CDK-mediated G1-S phase transition, thereby arresting the cell cycle in the G1 phase, suppressing DNA synthesis and inhibiting cancer cell growth. Overexpression of CDK4/6, as seen in certain types of cancer, causes cell cycle deregulation.  
Description: Light tan to yellow powder How supplied: Ribociclib will be supplied by Novartis or its designee. The available formulations are 50 mg (capsules) and 200 mg (capsules or film-coated tablets) and a 30mg/mL in 100 mL placed in a 180 ml glass bottle (oral solution) provided as an individual patient supply packaged in bottles. All dosages prescribed and dispensed to the patient and all dose changes during the study must be recorded. Ribociclib capsules/tablets and the liquid form will be packaged in bottles. They will include storage conditions for the drug but no information about the patient. The study drug will be labeled and packaged under the responsibility of the Novartis drug supply management department. The medication will be supplied as open label supply to the site in a way that allows the patient to take medication at home. Ribociclib may be administered orally in different ways based upon available formulations and capsule or tablet sizes:
- Capsule: swallow whole or open capsule and pour contents onto semi-solid food or dissolve contents of opened capsule in water or Ora-Sweet (or equivalent) and administer orally or via feeding tube (e.g. nasogastric or gastric)
- Liquid formulation: Since ribociclib did not show pH-dependent solubility in biorelevant media, the exposure/bioavailability is not expected to be limited by its dissolution rate due to different dosage form of administration. Liquid may be administered via feeding tube (e.g. nasogastric (NG)/nasojejunal (NJ)/gastric).  
Storage: The shelf life of the drug product is established based on ongoing stability studies and may be extended during the clinical study. The capsules are stored in HDPE bottles. Storage for the capsules is "Do not store above 25 °C, protect from moisture". The oral solution is stored in brown glass bottles. Storage for the oral solution is "store at 2-8 degrees C, do not freeze". Refer to the clinical labels for current shelf-life, in-use and storage conditions for the capsules, film-coated tablets and oral solution.  
Stability: Stable for at least 2 years after receipt when stored at -20°C
Route **and Method of Administration:** Ribociclib can be taken by mouth or NG/NJ/G-tube at the approximate same time daily for 3 weeks followed by one week off without regard to meals.
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8.3 agent ordering and agent

8.3.1 Agent Ordering Ribociclib and Everolimus may be requested by the Principal Investigator (or their authorized designee) at each participating institution. All regulatory documents, as required by the PBTC, must be current and up to date prior to requesting the study drugs. Drug request form can be found on the PBTC-050 protocol and resources webpage. The form can be emailed to Novartis. In general, sites may order initial agent supplies when a subject is being screened for enrollment onto the study. 8.3.2 Agent Inventory Records The investigator, or a responsible party designated by the investigator, must maintain a careful record of the receipt, dispensing, use and disposal of ribociclib and everolimus received from Novartis using the appropriate NCI Investigational Agent (Drug) Accountability Record (DARF) available on the CTEP forms page. Store and maintain separate the Investigational Agent Accountability Records for each agent, strength, formulation and ordering investigator on this protocol. Any unused/used/expired study drug and containers may be destroyed according to the institutional standard operating procedure. The method and the record of destruction must be documented and maintained at the site. 8.3.3 Useful Links and Contacts
- CTEP Forms, Templates, Documents: https://ctep.cancer.gov/forms/ - NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov
- CTEP Identity and Access Management (IAM) account: https://ctepcore.nci.nih.gov/iam/ - CTEP IAM account help email: ctepreghelp@ctep.nci.nih.gov.
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9 biomarker correlative and special

This section contains the collection, shipping and handling information for all planned biomarker and exploratory correlative studies, neuropathology review and research imaging. The table below identifies the tests, sample type and amount, analyzing laboratory and whether it is required or optional. For additional details, please review the associated section below.  
Tissue Requirements: Tissue for CLIA-certified Rb1 expression assessment for screening will be required for patients to enroll with the exception of DIPG patients. Prior testing for Rb1 IHC in a CLIAcertified laboratory will be accepted in lieu of tissue submission. For the Phase I study, tissue for exploratory correlative studies will be strongly recommended but not required.
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phase i

| Test Name                 | Sample Type and Amount                       | Analyzing   | Required or   | Section   |
|---------------------------|----------------------------------------------|-------------|---------------|-----------|
| Laboratory                | Optional                                     | ID          |               |           |
| Screening:  Assessment of | Rb1                                          |             |               |           |
| expression                | (FFPE) tumor tissue - 2 unstained slides + 1 | Christine   |               |           |
| H&E stained slide         | Fuller, MD CCHMC                             | Required*   | 9.1.1         |           |  
| Pharmacokinetics                                                                                                 | Plasma - 1 mL per sample                | Stewart                                  | Required    | 9.2.2    |       |
|------------------------------------------------------------------------------------------------------------------|-----------------------------------------|------------------------------------------|-------------|----------|-------|
| Laboratory                                                                                                       |                                         |                                          |             |          |       |
| Pharmacokinetics                                                                                                 | Serial or single CSF - 2 mL             | Stewart                                  | Optional    | 9.2.3    |       |
| Laboratory                                                                                                       |                                         |                                          |             |          |       |
| Genomics- Wholeexome sequencing  and RNA  sequencing                                                                                                                  | Frozen tumor tissue or FFPE and PBMCs** | Will                                     | Parsons,    |          |       |
| MD Texas  Children's  Hospital                                                                                   | Optional                                | 9.2.5                                    |             |          |       |
| PBTC                                                                                                             | CRB                                     | 20 unstained slides and blood for future | PBTC CRB at | Optional | 9.2.1 |
| Repository Samples                                                                                               | research                                | CHLA                                     |             |          |       |
| *Required for HGG, medulloblastoma, CNS embryonal tumor (NOS), Ependymoma, ATRT or with atypical presentation of |                                         |                                          |             |          |       |  
*Required for HGG, medulloblastoma, CNS embryonal tumor (NOS), Ependymoma, ATRT or with atypical presentation of DIPG. Patients with typical DIPG appearance who have biopsied may also submit tissue if available. If there is known Rb1 status, screening will not be required. **In all cases, frozen tissue is preferable to FFPE, but either will be accepted.
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surgical study

Rb1 testing will be completed on diagnostic tissue PRIOR to enrollment for the surgical study. The PK sample collection requirements for patients enrolled on the surgical study are noted below. Surgical study patients should still be invited to participate in the optional genomics studies and submission of repository samples as noted in the Phase I table.  
| Test Name                                                                                                      | Sample Type and Amount                                                                                                     | Analyzing                   | Required or   | Section   |
|----------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------|-----------------------------|---------------|-----------|
| Laboratory                                                                                                     | Optional                                                                                                                   | ID                          |               |           |
| Screening:  Assessment of Rb1  expression                                                                      | (FFPE) tumor tissue - 2 unstained slides + 1                                                                               | Christine                   |               |           |
| H&E stained slide                                                                                              | Fuller, MD CCHMC                                                                                                           | Required*                   | 9.1.1         |           |
| Intratumoral                                                                                                   | Tumor tissue (collected during surgery)***                                                                                 | Stewart                     | Required      | 9.2.2     |
| Pharmacokinetics                                                                                               | Laboratory                                                                                                                 |                             |               |           |
| Pharmacokinetics                                                                                               | Plasma - 1 mL per sample                                                                                                   | Stewart                     | Required      | 9.2.2     |
| Laboratory                                                                                                     |                                                                                                                            |                             |               |           |
| Pharmacokinetics                                                                                               | CSF - 2 mL                                                                                                                 | Stewart                     | Optional      | 9.2.3     |
| Laboratory                                                                                                     |                                                                                                                            |                             |               |           |
| Pharmacodynamics                                                                                               | FFPE - 2 unstained slides FFPE (1 FFPE each  from pre-treatment tumor and post-treatment  tumor***) + 1 H&E OR tumor block | Christine  Fuller, MD CCHMC | Optional      | 9.2.4     |
| *Required for HGG, medulloblastoma, CNS embryonal tumor (NOS), Ependymoma, ATRT. If there is known Rb1 status, |                                                                                                                            |                             |               |           |  
*Required for HGG, medulloblastoma, CNS embryonal tumor (NOS), Ependymoma, ATRT. If there is known Rb1 status, screening will not be required.  
*** For patients who consent to participate in the PD study, post-surgery tissue should be split between intra-tumoral PK and PD studies. Site should ensure sufficient tissue is sent per protocol requirement to each lab.
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9.1 integral laboratory studies

9.1.1 Assessment of Retinoblastoma (Rb1) expression All diagnostic tumor samples will be evaluated for Rb protein by immunohistochemistry (IHC) in a CLIA certified lab - either at ) or local Lab. Tumor samples will be sent to CCHMC if the tissue has not been previously tested locally. Additionally, left over tumor samples will be stored after required studies are completed for future research with participant consent. Formalin fixed paraffin embedded (FFPE) tumor tissue will be collected from all patients prior to enrollment (except for those with DIPG who have not undergone previous biopsy). Unstained slides and Updated Date: September 26, 2018 a corresponding H & E stained slide will be prepared from the original and/or recurrent surgery by sites and sent to CCHMC for Rb immunohistochemistry and interpretation. Unstained sections should be cut to 5µm in thickness on (+) slides from a section containing at least 50% tumor cells. The turn-around time for this test is approximately 7-10 days. Tumor RB protein status will be denoted as "positive" if ≥ 20% of tumor cells have positive nuclear staining. Rb+ endothelial cells will serve as an internal positive control. All slides will be centrally reviewed by the Neuro-pathologist at CCHMC.
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9.1.1.1 assay method

Immunohistochemistry for Rb will be performed as previously described79 using a mouse monoclonal anti-RB antibody (G3-245; BD Biosciences, San Jose, CA) and an automated IHC staining process (Benchmark XT; Ventana Medical Systems, Inc, Tucson, AZ). Briefly, antigen retrieval will be performed in Tris, pH 8.0 at 95C for 1 hour, followed by incubation in 3% H2O2 for 16 minutes and primary antibody at 1: 100 at room temperature for 60 minutes. Immunohistochemistry will be scored as follows: 0, denotes expression in less than 20% of tumor cells; 1, denotes expression ins 20% to 50% of tumor cells; and 2, indicate positive expression in more than 50% of tumor cells. At least three 20x-fields will be evaluated per case. The assay is performed and interpreted in a laboratory that is CLIA certified (CCHMC) to perform high complexity testing. 9.1.1.2 *Collection and shipping of Specimen(s)* Two unstained slides for FFPE material will be collected along with one H & E stained slide prepared from the same block will be submitted to CCHMC. Slides must be shipped to CCHMC within 3 days of reservation. Sites will be notified of the results of the Rb1 testing within 2 weeks. All screened patients who are eligible for participating in the PBTC-050 study must be enrolled via OPEN within 10 days of the site notification of a patient's Rb1 status. Slides must be labeled with the PBTC enrollment tracking number (OPEN tracking \#) and protocol number. Samples should be shipped Monday through Thursday using the PBTC-050 FedEx account. Weekend deliveries are not permitted. The sample shipping date must be documented in the eCRF by the sites. All specimens should be shipped at room temperature. Send the following to CCHMC:  
  
- 2 unstained slides - 1 H&E stained slide - Completed PBTC-050 specimen transmittal form Attn: Christine Fuller, MD 9.2 **Pathology and Exploratory Correlative Studies** The Biorepository (CRB)'s function is to collect, distribute and store specimens for planned correlative studies which support the laboratory objectives of this protocol. The CRB will also serve as a central repository for specimens collected for future research and left over specimens (tumor tissue, blood, urine or CSF) returned to the repository following the planned analysis from patients who consent to long term storage of unused specimen. These samples will be stored in the repository for undefined future studies which support the mission of the PBTC. If the patient does not consent to participation in the repository, correlative study samples should be submitted following the guidelines in the appropriate correlative study section below. If the patient does not consent to long term storage, remaining correlative study samples will be destroyed once the PBTC-050 analysis is complete. 9.2.1 PBTC CRB Submission Guidelines If the patient consents to provide slides for submission to the repository at the time of participation in a PBTC trial the following should be submitted:
- Tumor material Slides from the original and/or recurrent surgery should be prepared for storage. The site should provide up to twenty (20) unstained sections cut at 4µm in thickness on (+) slides from the most representative section. For patients who have consented to other correlative studies (e.g. genomics, pharmacodynamics studies) on this protocol that require slides, these submitted slides will be used for the conduct of studies outlined in the corresponding sections below (9.2.4, 9.2.5). Fewer unstained sections may be submitted based on size and availability of tissue. Preference is for tissue that has not previously been frozen. The corresponding pathology report (s) including immunohistochemical, special stains, and molecular/genetic results is to be uploaded to the PBTC using the secure File Upload system. These reports will be made available to the pathologist via a link in the ProtoLab. Suitability of sections would be established by preparing one (1) H&E to ensure that the sections meet the following criteria:
o histologically representative of the reported lesion o contain at least 60% viable tumor o no more than 40% necrosis Slides submitted by patients who have consented to the PBTC CRB will undergo neuro-pathology review.  
Central pathology review is **not** required for this study. Pathologist review for this study will include the following elements:
o Examination of H&E stained slides. For each subject one (1) H&E stained slide per one representative block from the brain tumor, removed either at initial diagnosis or relapse, should be submitted for review.  
o Review of the corresponding pathology report(s) of the immunohistochemical, special stains, and molecular/genetic results from current and/or original primary tumor o If necessary, review of immunohistochemical or special stained slides.  
Slides submitted to the PBTC CRB will be digitized to 40X. H&E stained sections will be retained and filed at the CRB. Original immunohistochemical or special stain slides will be returned to the submitting institution.  
- Peripheral Blood Mononuclear Cells PBMC may be collected by processing a 2-5mL whole blood specimen with Ficoll or collecting the specimen in a BD Vacutainer™ CPT™ Cell Preparation Tube with Sodium Citrate as noted below. Once separated, all pellets must be snap frozen and stored at least at -20oC prior to dry ice shipment Specimen Collection and Processing by Ficoll tube
- Collect 2 - 5mL of fresh blood into an EDTA tube. - Transfer blood into a sterile 50-mL tube and add double the amount of PBS. MIX GENTLY.  
- Set up another tube containing half of its total volume of Ficoll. For example, if there is 15 mL of blood + PBS, then use 7.5 mL of Ficoll (2:1 ratio).  
At very slow pace (approx. 2 mL/minute), layer the blood + PBS mixture onto the Ficoll so that the solutions DO NOT MIX. Spin the blood/Ficoll at 750 g in slow mode for 30 minutes @ 25ºC. After spin you will see four distinct layers: plasma (top layer), white fluffy ring (2nd layer), Ficoll (3rd layer), and blood (bottom layer).  
- Remove plasma layer down to about 1 mL above the white fluffy ring and discard.  
- Collect the entire white fluffy ring. If ring is hard to see, also take extra liquid above. Then discard everything else.  
- Place this fraction of white blood cells into a fresh 50 mL sterile tube with 20 mL of PBS. Spin down for 10 minutes @ 25ºC, 750 g in fast mode. Remove the supernatant. Add back to pellet 1 mL of PBS and spin for 5 min. at 4°C at 10000rpm. Remove supernatant.  
- Freeze the pellet of WBCs and store at -80ºC until shipment.  
- Ensure that all tubes are clearly labeled with the PBTC patient accession number. Please ensure that the labeling system used is designed to withstand temperatures down to -80oC. Samples should be stored at -80ºC until shipment. For short term storage (2-3 weeks) -20ºC is acceptable. NOTE 4ºC IS NOT ACCEPTABLE STORAGE.  
If it is not possible to collect the PBMC by Ficoll gradient then separation of PBMC can be conducted using CPT tube separation as an alternative. However the PBMC pellet MUST BE frozen immediately and stored at -80oC.  
Collection and Processing by CPT tube
- Peripheral blood should be collected in a BD Vacutainer CPT™ Cell Preparation Tube with Sodium Citrate or similar tube which is available locally. 8 mL and 4 mL CPT tubes can be obtained from Fisher Scientific (Cat\# 02-685-125, 02-688-81) or Becton-Dickinson (BD No.362761, 362760). The 8 mL tubes have a 6 mL minimum draw and the 4 mL tubes have a 3 mL minimum draw.  
- Centrifuge the CPT™ tube at 1500 x g for 30 minutes at room temperature (20o C to 25o C). DO
NOT APPLY THE BREAK ON THE CENTRIFUGE. Use acceleration 5, brake 0 ("slow mode").  
- It may be necessary to spin the tube longer to ensure that all of the red blood cell components have been separated from the plasma layer through the polyester gel barrier.  
- The tube should be removed immediately from the centrifuge. The mononuclear layer and plasma lie above the polyester gel plug.  
- Using a sterile pipette, remove as much of the plasma component (upper half of the CPT tube)
without disturbing the mononuclear layer if possible and discard.  
- Transfer mononuclear cell layer (and some residual plasma layer) to a labeled 15- mL conical centrifuge tube and add 5 mL sterile room temperature magnesium or calcium-free phosphate buffered saline (PBS) to fill the conical tube and recap.  
- Centrifuge at 450 x g for 10 minutes at room temperature (20o C to 25o C). Use acceleration 9, brake ("fast mode").  
- Remove supernatant, being careful not to aspirate the cellular pellet at the bottom of the tube. - Add 1 mL of sterile PBS to the pellet and gently re-suspend by pipetting up and down. Transfer the entire suspended pellet to the labeled cryovial.  
- Centrifuge the cryovial at 450 x g for 5 minutes (or spin down the microcentrifuge tube at 1300 x g for 5 minutes) at room temperature. Discard the supernatant. Store the cell pellet cryovial frozen at -80ºC. For short term storage (2-3 weeks) -20o C is acceptable.  
If the patient consents to other secondary correlative studies as outlined in sections 9.2.4, 9.2.5), the following specimens may also be submitted to the CRB for distribution and storage.  
- Fresh-frozen tissue: approximately 100 micrograms = pea-sized portion of tumor, frozen in foil in liquid nitrogen and stored at -70°C until time of shipping
- Peripheral blood mononuclear cells: quantity and schedule of collection as outlined in section 9.2.1.  
9.2.1.1 *Handling of Specimens*
- Slides are to be labeled with the study ID and the patient PBTC Accession \# and these slides should be designated as PBTCR \# (where the \# assigned from 1 to 20, or the highest number of unstained sections prepared, sequentially) or PBTCR H&E for the H&E stained section.  
- Frozen tumor tissue or Formalin Fixed, Paraffin Embedded (FFPE) tumor materials are to be labeled with the PBTC Accession \# and the PBTC study for which the sample is provided. When fresh frozen tumor (FFT) sample is available, we would additionally request a minimum amount of 20 mg. In the event that genomic DNA (gDNA) has already been extracted from tumor material, this can be submitted in lieu of FFT sample and we would request a minimum of 250 ng of gDNA.  
9.2.1.2 *Shipment of Specimens* Samples collected for the repository should be sent to the PBTC CRB overnight via FedEx by completing the Internet form at http://www.fedex.com/us/ and requesting FedEx to e-mail at researchsupportbiorepository@chla.usc.edu. FedEx user ID and password for pathology shipping can be found at PBTC-050 protocol webpage. Weekend deliveries are not permitted. Receipt and processing of biological materials will be recorded in ProtoLab, as appropriate, by staff at the PBTC CRB. The sites sending the materials must document sample collection and shipping dates in the eCRF. Samples should be shipped in the appropriate environment as described below:
- Fresh frozen tumor sample should be shipped in a separate box on dry ice.  
- FFPE tumor material should be shipped at room temperature.  
- Blood samples should be shipped in a separate box with cold pack (1-10 degrees C), unless otherwise specified.
Samples are to be shipped to:
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phase i study

Pharmacokinetic studies for ribociclib and everolimus will be performed on all patients enrolled on the Phase I component of the trial (including surgical patients who are eligible to initiate Phase I treatment). The pharmacokinetics of these agents alone and in combination are unknown in the setting of pediatric CNS neoplasia, and because various agents commonly used in patients with brain tumors (e.g., corticosteroids) can alter the disposition of these agents, this information will be useful for evaluating toxicity and disease response and for refining dosing in future clinical trials. Moreover, since both these agents are metabolized by CYP3A4 and studies in adults have suggested that the disposition of at least one of the agents is altered, it will be important to know if either of these agents alter the systemic disposition of the other in the setting of pediatric brain tumor therapy. Thus, patients will begin ribociclib therapy two days earlier than the everolimus so that we can perform ribociclib pharmacokinetic studies to gain a baseline of the ribociclib disposition, and then during Course 2 to hold the ribociclib dose on day 1 so that we can perform everolimus pharmacokinetic studies to gain a baseline of the everolimus disposition. 9.2.2.1 *Sampling Strategy for Phase I Pharmacokinetic Study* Mandatory plasma pharmacokinetic studies will be obtained from all patients enrolled on this study on days 1, 2, 3, and 17 and 18 of Course 1, and days 1 and 2 of Course 2 to evaluate the pharmacokinetics of ribociclib and everolimus alone and the pharmacokinetics of the combination. A single dose of ribociclib will be administered on Day 1 of Course 1 to obtain a baseline ribociclib pharmacokinetic study with which to compare the effect of everolimus on ribociclib when they are administered in combination (i.e., Course 1 day 17/18). Moreover, the effect of ribociclib on everolimus will be evaluated by comparing the Course 2 day 1 (and 2) everolimus (without ribociclib) baseline when they are administered in combination (i.e., C1 day 17/18).
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- ribociclib serial sampling strategy

Beginning on day 1 of Course 1, serial whole blood samples for ribociclib pharmacokinetic studies will be collected in a labeled lavender-top K2-EDTA Vacutainer tube at the following times: pre-dose and at, 1, 2, 4, 8 (±1), 24 (±4), 32 (±4), and 48 (±4) hours after the oral dose (8 mL total). **The ribociclib dose**
on day 2 should be held during course 1 and resumed on day 3 after the 48 hour time point pharmacokinetic sample has been obtained. It is crucial that the 48-hour time point be obtained prior to administration of either drug (ribociclib or everolimus) on Day 3.
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- ribociclib and everolimus serial

On day 17 (± 2 days) of Course 1: On day 17 ± 2 days, serial whole blood samples for ribociclib and everolimus pharmacokinetic studies will be collected at the following times: pre-dose and at, 1, 2, 4, 8 (±1), and 24 (±4) (immediately prior to the next dose) hours after the dose (12 mL total). Because these samples will be used for both ribociclib and everolimus, 2 mL of whole blood will be collected in a labeled lavender-top K2-EDTA Vacutainer tube at each time point. The sample will be split and 1 mL of blood will be processed to plasma for ribociclib, and 1 mL of whole blood will be used for the everolimus studies.
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- everolimus serial sampling strategy

Whole blood samples for everolimus pharmacokinetic studies will be collected into a labeled lavendertop K2EDTA Vacutainer tube at the following times: pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 (±1), and 24 (±4)
(immediately prior to the next dose) hours after the oral dose (9 mL total). The ribociclib dose on day 1 should be held and day 2 should be delayed **until the last everolimus sample is collected**.
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surgical study

9.2.2.2 *Sampling Strategy for Ribociclib Neurosurgical Study* Mandatory plasma and fresh frozen tumor tissue will be obtained from all patients enrolled on this aspect of the clinical trial after continuous ribociclib therapy of 7-10 days to determine the ribociclib plasma and brain tumor concentrations.
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- ribociclib plasma and brain

After 7 - 10 days of continuous ribociclib dosing, a 1 mL whole blood sample will be collected into a labeled lavender-top K2-EDTA vacutainer tube at the following times:.  
- Prior to starting ribociclib (Day -7 or Day -10)
- Prior to dose on Day -5 (±1 day) - Prior to dose on Day -2 (±1 day)
- On the day of surgery (Day 0)
- During surgery at time tumor tissue is collected
Record the exact time of day the sample is acquired and the time of the last dose of ribociclib on the Pharmacokinetic Data Collection Form. During the neurosurgical procedure, brain tumor tissue will be acquired at the time of tumor resection. Record the time and day of sample acquisition, the anatomical location from which the tumor sample was acquired, and the condition of the sample at the time of acquisition (e.g., viable tumor material, necrotic tumor material). Each separate piece of tumor tissue should be placed into an appropriately labeled tube. 9.2.2.3 *Collection and Handling of Specimens*
- Ribociclib Plasma Sample Collection and Processing Instructions: Updated Date: September 26, 2018 Collect the ribociclib blood samples according to institutional policies and procedures, ensuring that where applicable, sterile discard volume is returned to the patient after the blood sample is obtained. At times specified, 1 mL of whole blood should be drawn into an appropriately labeled lavender-top EDTA vacutainer tube. The samples should be inverted several times to mix, immediately aliquoted to microcentrifuge tubes, and centrifuged at 10,000 rpm for 2 minutes. For participating facilities equipped with lower speed centrifuges, samples may be centrifuged at 1,000 - 1,300 x g for 10 minutes (see vendor specific rotor instructions for rpm to rcf conversion). The plasma supernatant should then be transferred to an appropriately labeled, screw-capped polypropylene tube and stored at -80°. (Record the exact time that the sample is drawn along with the exact time that the drug is administered on the Pharmacokinetic Data Collection Form. Refer to the Pharmacokinetics Laboratory section with the Clinical Operations Manual for detailed instructions for the collection, handling, and processing of pharmacokinetic samples.)
- Everolimus Whole Blood Sample Collection and Processing Instructions:
At each time point, the designated amount of blood (see the amounts of blood collected in Section 9.2.2.1 and Correlative lab studies calendar 10.3) will be collected into appropriately labeled amber tubes containing K2-EDTA. One (1) mL of blood is needed for bioanalysis. The Pharmacokinetic Data Collection Form should be completed with the exact time that the sample is drawn as well as the exact time that the drug is administered. The Pharmacokinetic Data Collection Form is located on the PBTC050 webpage. The samples should be labeled with the PBTC Accession number and the Course, Day and Time information for each sample.  
- Tumor Sample Collection and Processing Instructions for surgical study Approximately 50 to 100 mg of fresh flash-frozen tumor material will be collected into an appropriately labeled 15-mL conical tube. All samples (i.e., plasma and tumor) should be shipped on dry ice. 9.2.2.4 *Shipping of Specimens* At the start of the study, each participating institution will receive a Pharmacokinetics (PK) kit from Dr. Clinton Stewart for the collection of samples. Samples should be shipped for delivery Monday through Thursday with a generous amount of dry ice enclosed to safeguard against shipping delays. Weekend and holiday deliveries should be avoided. Sites should contact the Stewart Laboratory to request a Pharmacokinetics Kit for each patient enrolled on the study.  
Samples should be shipped within 30 days of the last sample being taken. The site should use the PBTC050 PK FedEx account details, located on the PBTC member website. Ship all pharmacokinetic samples on dry ice, along with a completed Pharmacokinetics Sample Transmittal Form located on the PBTC-050 webpage to: Stewart Laboratory  
  
  
Samples must be shipped from the site to the respective laboratory within 30 days of last sample collection in order to receive cost reimbursement. The sample collection and shipping dates must be documented in the eCRF. 9.2.2.5 *Site Performing Correlative Study* Stewart Laboratory 9.2.3 Cerebrospinal Fluid (CSF) Pharmacokinetic Studies
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phase i

Pharmacokinetic studies for ribociclib, everolimus, or the combination of the two drugs will also be performed in all research participants with access to CSF who agree to participate. 9.2.3.1 *Serial CSF Studies*
- Ventricular CSF (0.5 mL) should be obtained in a screw-top tube pre-dose and at 1, 4, and 8 hours after drug administration on Course 1, Day 1 (C1D1); Course 1, Day 17 (C1D17) and Course 2, Day 1 (C2D1).  
- The exact time that the CSF sample is obtained should be recorded along with the exact time that the drug is administered on the Pharmacokinetic Data Collection Form.  
9.2.3.2 *Single CSF Studies*
- A single CSF sample may be available for collection where CSF is collected as part of the best clinical practice at any time during treatment (e.g., those requiring CSF diversion or VP shunt revision during therapy, or research participants requiring shunt externalization for infection), therapy should be preferentially continued without interruption, and all attempts should be made to obtain a sample of CSF for pharmacokinetic studies.  
- A simultaneous plasma sample should be obtained at the time of all CSF sample collection(s).
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surgical study

If a CSF sample is obtained during a surgical procedure from a patient receiving ribociclib, the ribociclib concentration in that sample will be determined. 9.2.3.3 *Collection and Handling of Specimen(s)* Phase I Collect 0.5 milliliters of CSF in a screw-top tube along with concomitant plasma sample. Record the exact time that the CSF and plasma samples were obtained along with the exact time of drug administration on the CSF Pharmacokinetic Data Collection Form located on the PBTC-050 webpage in the "Protocol Specific Instructions/Forms" section. Samples should be labeled with the PBTC Accession number and the Course, Day information for each sample. Samples should be stored at -80°C until shipped.  
Updated Date: September 26, 2018 CSF will be obtained (2 mL in a screw-top tube) at the time of surgery after 7-10 days of daily administration of ribociclib (at steady state). Samples should be labeled with the PBTC Accession number and the Course, Day information for each sample. Samples should be stored at -80°C until shipped. 9.2.3.4 *Shipping of Specimen(s)* The sample collection and shipping dates must be documented in the eCRF. All samples should be forwarded via FedEx, Monday through Thursday, by completing the internet form at http://www.fedex.com/us/ and requesting FedEx to email the laboratory. Fed Ex account information for the shipment of samples can be obtained on the PBTC -050 website. Weekend deliveries are not permitted. In no instance should any CSF sample remain at a participating site for more than 30 days after its acquisition unless prior approval is obtained by Dr. Clinton Stewart or his designee. All CSF samples should be shipped on dry ice, along with a completed CSF PK Transmittal Form located on the PBTC050 webpage to:  
  
9.2.3.5 *Site Performing Correlative Study* Stewart Laboratory 9.2.4 Pharmacodynamics (Only applicable for surgical study) The rationale for this test is to look at change in Ki67 by comparing pre-treatment (prior to ribociclib) and post-treatment (after 7-10 days of ribociclib) tissue. Surrogate pharmacodynamics studies for a drug that targets the cell cycle can be performed on pre-treatment tumor and post-treatment tumor. Ki67 is a marker of cellular proliferation. In the adult clinical studies with Ribociclib, pharmacodynamics markers were tested in skin and tumor biopsies by IHC assessment of p-Rb and Ki67. A ≥ 50% reduction was observed a doses of 400 mg and higher. The study currently continues in the expansion phase for further assessment of toxicity and efficacy.  
48 For the Surgical Study, Ki67 will be evaluated in pre-treatment tumor (diagnostic) and post-treatment tumor (recurrent) tissue in consenting patients. 9.2.4.1 *Collection of Specimen(s)* The following will be collected from representative (diagnostic and recurrent) tumor tissue:
- 2 (Two) unstained FFPE slides [1 each from pre-treatment tumor (diagnostic) and post-treatment tumor (recurrent) tissue] + 1 H&E
- OR tissue block from tumor material 9.2.4.2 *Handling of Specimens(s)* The samples should be labeled with the PBTC Accession number and the Course, Day information for each sample. 9.2.4.3 *Shipping of Specimen(s)* The sample collection and shipping dates must be documented in the eCRF. All samples should be forwarded via FedEx, Monday through Thursday, by completing the internet form at http://www.fedex.com/us/ and requesting FedEx to email the laboratory. Fed Ex account information for the shipment of samples can be obtained on the PBTC website. Weekend deliveries are not permitted. Specimens should be shipped in the room temperature, along with a completed PD Specimen Transmittal Form located on the PBTC-050 webpage to:  
  
9.2.4.4 *Site Performing Correlative Study*  
 Christine Fuller, MD 9.2.5 Genomic Studies As an ancillary/exploratory study in consenting patients, tumor tissue in the form of formalin fixed, paraffin embedded tumor material (FFPE) or frozen tumor, if available, from any previous surgical excision/biopsy of the primary tumor or recurrent tumor(s), and any additional resected tumor if surgery is performed while the subject is on study, will be analyzed as described above in 9.1.1, and 9.2.4. For all tissue specimens submitted for genomics analysis, an additional 5 mL of blood should be collected prior to treatment, as a normal control for sequencing studies. This blood study is mandatory for those subjects who also consent to the tumor tissue genomics studies and have tissue available. The blood sample should be collected and processed as described in Section 9.2.1 Peripheral Blood Mononuclear cells. After analysis, left over material will be stored at the PBTC specimen repository. Assays performed on FFPE and PBMCs will be undertaken in combination with the Biology and Pathology Committee and CRB on material that may include:
- Survey methylome analysis using Illumina 450k methylation array profiling of tumor tissue to confirm histological diagnosis, ascertain intra-diagnosis molecular subgroup, and evaluate copy number gains/losses, including those in genes involved in cell cycle regulation, PI3K/mTOR signaling, or related cancer pathways (see Exploratory Objective in section 1.3)
- Targeted DNA/RNA panel analysis and/or whole exome sequencing of matched tumor and normal
(blood) tissue to identify genetic alterations targeting cancer genes, including those in genes involved in cell cycle regulation, PI3K/mTOR signaling, or related cancer pathways that are known to be mutated in cancer and in pediatric brain tumors in particular.  
- Other genomic tests including targeted deep sequencing, transcriptome (RNA) sequencing, or whole genome sequencing in order to identify cancer gene mutations, copy number alterations, structural rearrangements, and other types of genetic alterations.  
9.2.5.1 *Shipping of Specimen(s)*
- Fresh frozen tissue tumor material should be rapidly transferred (without thawing) from long term storage to a Styrofoam box filled with dry ice.  
- FFPE slides/blocks should be shipped at ambient temperature. - PBMCs - Once separated, all pellets must be snap frozen and stored at least at -20°C until shipped.  
Samples should be shipped overnight in a separate box with a 2-day supply of dry ice.  
The sample collection and shipping dates must be documented in the eCRF. All samples should be forwarded via FedEx, Monday through Thursday, by completing the internet form at http://www.fedex.com/us/ and requesting FedEx to email at researchsupportbiorepository@chla.usc.edu. Fed Ex account information for the shipment of samples can be obtained on the PBTC-050 website. Weekend deliveries are not permitted. Genomic specimens should be shipped as described in Section 9.2.5.1, along with a completed Genomics Specimen Transmittal Form located on the PBTC-050 webpage to:  
  
9.2.5.2 *Site(s) Performing Correlative Study* Will Parsons, MD, PhD 9.3 **Neuroimaging Studies** Patients will have MRI Brain with and without contrast performed prior to therapy, after courses 2, 4, 6 then every 12 weeks thereafter until time of progression or completion of treatment. MRI Spine should be performed prior to therapy and at the same time points as standard MRI Brain, if clinically indicated. Standard MR imaging will include Sagittal T1 MPRAGE, axial FLAIR, axial T2, post gadolinium sagittal T1 MPRAGE (with reconstructions) and axial T2 images. Standard MR Spine imaging protocol is Sagittal T1 images after gadolinium (slice thickness 3mm skip 0). Axial T1 images are after gadolinium (slice thickness 3mm skip 0). Axial T2 images are optional. Standard MR Spine imaging protocol is Sagittal T1 images after gadolinium (slice thickness 3mm skip 0). Axial T1 images are after gadolinium (slice thickness 3mm skip 0). Axial T2 images are optional. The standard MR parameters are listed on the PBTC
NIC web page located at http://www.childrenshospital.org/research-and-innovation/researchlabs/pediatric-brain-tumor-consortium-neuroimaging-center under Neuroimaging Studies/ Specific MR
Imaging Sequences- Open PBTC Protocols. There is also a link to the same PBTC-NIC webpage from the PBTC-050 protocol study page. Volumetric analyses will be done at the Neuroimaging Center (NIC, Children's Hospital Boston) via the Vitrea (Vitrea™) workstation, from the axial FLAIR and T1-weighted post-contrast brain images. 9.3.1 Neuroimaging Review All patient specific data are stripped from the images and replaced with PBTC Accession numbers prior to transmitting the images to the NIC. All image data transfer is accomplished using PGP (pretty-goodprivacy) 128-bit encryption which meets industry standard for secure communication.  
Only scans showing a response, the confirmation scan obtained approximately 8 weeks later if available and the corresponding baseline scan will be electronically transferred to the PBTC Neuroimaging Center (NIC) for central review scan for confirmation. Local review of MR imaging studies at each site and central review of the MR imaging studies will be conducted through the PBTC Neuroimaging Center (NIC). NIC review will include assessment of response to therapy (as feasible). The director and one neuroradiologist of NIC will review the imaging studies at study completion. If the local and central review are not in agreement the NIC neuroradiologist will confer with the participating site to determine why there is a discrepancy via conference call.
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10 study calendar

Data is to be submitted according to the Data submission timelines located on the PBTC-050 webpage.
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10.1 surgical study

| Screening                                                                                                      | Pre- Enroll  - Enrollment   | Presurgery         | Surgery   | Postsurgery        | Switch to Phase  I (see 10.2)   |            |
|----------------------------------------------------------------------------------------------------------------|-----------------------------|---------|-----------|--------|---------------------------------|------------|
| Visit Window                                                                                                   | Week -5                     | Week -3 | Week -2   | Week 0 | Week 2 -                        | > Week 2-4 |
| week 4                                                                                                         |                             |         |           |        |                                 |            |
| OPEN registration system                                                                                       | X                           | X       |           |        |                                 |            |
| Screening consent                                                                                              | X                           |         |           |        |                                 |            |
| Informed consent                                                                                               | XA                          | XB      |           |        |                                 |            |
| Confirmation of intact Rb1 required for  HGG, medulloblastoma, CNS embryonal  tumor (NOS), Ependymoma, or ATRT | X                           |         |           |        |                                 |            |
| Ribociclib administration C                                                                                    | X                           |         |           |        |                                 |            |  
Updated Date: September 26, 2018  
| Updated Date: September 26, 2018                                                                                                                                                                                           | Screening   | Pre- Enroll  - Enrollment   | Presurgery    | Surgery   | Postsurgery   | Switch to Phase  I (see 10.2)   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------|-----------------------------|----|-----------|---|---------------------------------|
| Physical Assessments Medical history                                                                                                                                                                                       | X           | X                           |    |           |   |                                 |
| Physical exam /height/weight                                                                                                                                                                                               | X           | X                           |    |           |   |                                 |
| Vital signs                                                                                                                                                                                                                | X           | X                           |    |           |   |                                 |
| Performance status                                                                                                                                                                                                         | X           | X                           |    |           |   |                                 |
| Neurologic exam                                                                                                                                                                                                            | X           | X                           |    |           |   |                                 |
| Review of eligibility assessments,                                                                                                                                                                                         | AE,         |                             |    |           |   |                                 |
| concomitant meditations, prior therapy  assessment                                                                                                                                                                         | X           | X                           |    |           |   |                                 |
| Laboratory Evaluations CBC                                                                                                                                                                                                 | X           | X                           |    |           |   |                                 |
| WBC, HgB, Hct, Platelets, ANC, ALC  Serum Chemistry Sodium, Potassium, Bicarbonate,  Chloride, Calcium, BUN, Creatinine,  Glucose, Phosphorous, Magnesium,  Albumin, Total Protein, SGPT(ALT),  SGOT(AST), Total Bilirubin | X           | X                           |    |           |   |                                 |
| Lipid profile (fasting) Triglycerides, total cholesterol,                                                                                                                                                                  | HDL,        |                             |    |           |   |                                 |
| LDL                                                                                                                                                                                                                        | X           |                             |    |           |   |                                 |
| Serum or Urine pregnancy test (for  females of childbearing potential)                                                                                                                                                     | X           | XD                          | XD |           |   |                                 |
| CSF cytology (if clinically indicated)                                                                                                                                                                                     | X           |                             |    |           |   |                                 |
| Other assessments 12-lead EKG                                                                                                                                                                                              | X           |                             |    |           |   |                                 |
| ECHO                                                                                                                                                                                                                       | X           |                             |    |           |   |                                 |
| Imaging Assessments Brain MRI (standard) with diffusion                                                                                                                                                                    | X           | XE                          | XE |           |   |                                 |
| Spinal MRI (if clinically indicated)                                                                                                                                                                                       | X           |                             |    |           |   |                                 |
| Correlatives PK Blood                                                                                                                                                                                                      | XF          | XF                          |    |           |   |                                 |
| PK Tumor tissue                                                                                                                                                                                                            | XG          |                             |    |           |   |                                 |
| CSF PK (if consented)                                                                                                                                                                                                      | XH          |                             |    |           |   |                                 |
| PD (if consented)                                                                                                                                                                                                          | X           |                             |    |           |   |                                 |  
Updated Date: September 26, 2018  
| Screening   | Pre- Enroll  - Enrollment                                                                                                                        | Presurgery   | Surgery   | Postsurgery   | Switch to Phase  I (see 10.2)   |
|-------------|--------------------------------------------------------------------------------------------------------------------------------------------------|---|-----------|---|---------------------------------|
| A.          | Informed consent for surgical study                                                                                                              |   |           |   |                                 |
| B.          | Informed consent for Phase I                                                                                                                     |   |           |   |                                 |
| C.          | Ribociclib will be administered 7 - 10 days prior to surgery.                                                                                    |   |           |   |                                 |
| D.          | Within 72 hours prior to starting study drug(s)                                                                                                  |   |           |   |                                 |
| E.          | Intraoperative OR post- operative (<96 hours) MRI                                                                                                |   |           |   |                                 |
| F.          | PK blood - obtain 1 mL each prior to dose on day -7 or day -10, day -5, Day -2, on the day of surgery, and during  surgery. See section 9.2.2.2. |   |           |   |                                 |
| G.          | 50 to 100 mg of fresh flash-frozen tumor will be collected at the time of surgery. See section 9.2.2.3.                                          |   |           |   |                                 |
| H.          | CSF PK - obtain 2 mL at the time of surgery                                                                                                      |   |           |   |                                 |  
Updated Date: September 26, 2018
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10.2 phase i

| Pre                                                                                                                                                                                                                               |          |                              |           |             |    |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------|------------------------------|-----------|-------------|----|
| therapy                                                                                                                                                                                                                       | Course 1 | Courses 2-                   | Courses   | Completion/ |    |
| Course 13                                                                                                                                                                                                                     | 14-26    | Discontinuation Of Treatment |           |             |    |
| Study drugs administration                                                                                                                                                                                                    | X        | X                            | X         |             |    |
| (ribociclib + everolimus) Medical history                                                                                                                                                                                     | X        | Weekly                       | X         | X           | X  |
| Physical exam /height/weight                                                                                                                                                                                                  | X        | Weekly                       | X         | X           | X  |
| Vital signs                                                                                                                                                                                                                   | X        | Weekly                       | X         | X           | X  |
| Performance status                                                                                                                                                                                                            | X        | Weekly                       | X         | X           | X  |
| Neurologic exam                                                                                                                                                                                                               | X        | Weekly                       | X         | X           | X  |
| CBC                                                                                                                                                                                                                           | X        | WeeklyA                      | WeeklyA,B | XB          | X  |
| WBC, HgB, Hct, Platelets, ANC, ALC A,B Serum Chemistry Sodium, Potassium, Bicarbonate, Chloride,  Calcium, BUN, Creatinine, Glucose,  Phosphorous, Magnesium, Albumin, Total  Protein, SGPT(ALT), SGOT(AST), Total  Bilirubin | X        | XB                           | XB        | XB          | X  |
| Lipid profile (fasting)                                                                                                                                                                                                       | X        | XC                           | XC        | X           |    |
| Triglycerides, total cholesterol, HDL, LDL C Serum or Urine pregnancy test (for females of                                                                                                                                    | X        | XB                           | XB        | XB          | X  |
| childbearing potential) B CSF cytology (if clinically indicated)                                                                                                                                                              | X        |                              |           |             |    |
| 12-lead EKG D                                                                                                                                                                                                                 | X        | XD                           | XD        | XD          | X  |
| ECHO                                                                                                                                                                                                                          | X        | XE                           | XE        | XE          |    |
| Imaging Assessments Brain MRI (standard) with diffusion F                                                                                                                                                                     | X        | XF                           | XF        | XF          |    |
| Spinal MRIF (if clinically indicated) G                                                                                                                                                                                       | X        | XG                           | XG        | X           |    |  
Updated Date: September 26, 2018  
| Pre           |          |                              |         |             |
|-----------|----------|------------------------------|---------|-------------|
| therapy   | Course 1 | Courses 2-                   | Courses | Completion/ |
| Course 13 | 14-26    | Discontinuation Of Treatment |         |             |  
A. CBC with differential at baseline and q weekly during each cycle for the first 3 cycles; consideration can be given to increase interval to q 2 weeks from course 4 onwards if the patient did not DLT in the previous cycle. If patient develops Grade 4 neutropenia or thrombocytopenia, then CBCs should be checked every 3-4 days until recovery to Grade 3.  
B. Within 72 hours prior to starting the next course C. Lipid profile is to be obtained every other course (prior to course 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26)
D. 12-lead EKG at baseline, days 15 of cycle 1 and prior to cycles 2 and 3. Thereafter, EKG should be done prior to the start of every 3rd cycle (prior to 6, 9, 12, 15, 18, 21, 24 and end of treatment). For patients with QTc  481 ms at any time, interrupt study treatment and follow the procedures described in Table 10**Error! Reference source not found.**
EKG must be completed within 7 days prior to starting next course of ribociclib and everolimus.  
E. ECHO must be obtained within 7 days prior to anticipated start of therapy of course 3. Additional studies may be done as clinically indicated at the investigator's discretion.  
F. Standard imaging with diffusion is to be done every 8 weeks (after courses 2, 4, 6, and then every 12 weeks thereafter through the 26 courses of treatment or progression). All required imaging dates are to be entered in the database. However, only scans showing a partial response or complete response, and the corresponding baseline scan, will be uploaded.  
G. MRI Spine should be done at the indicated time and when clinically indicated.
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10.3 correlative lab studies calendar

| Correlative Laboratory  Studies                                                      | Screening                                                                                         | Pre          |
|--------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------|----------|
| therapy                                                                              | Course 1                                                                                          | Course 2 |
| Rb1 expression (required)                                                            | X A                                                                                               |          |
| Pharmacokinetics blood: Ribociclib serial samples  (required)                        | D1 of C1                                                                                          |          |
| -                                                                                    | pre-dose, and 1, 2, 4, 8  (±1), 24 (±4), 32 (±4), and  48 (±4) hours after dose.B                 |          |
| - 1 mL each ( 8 mL total)                                                            |                                                                                                   |          |
| Pharmacokinetics blood:  Everolimus serial samples  (required)                       | D1 of C2                                                                                          |          |
| -                                                                                    | pre-dose, 0.5, 1, 1.5,  2, 4, 6, 8 (±1), and 24 (±4) hr after dose. C  - 1 mL each ( 9 mL  total) |          |
| Pharmacokinetics blood: Both  ribociclib and everolimus serial  samples (required)   | D17 of C1 (+/- 2 days)                                                                            |          |
| - pre-dose, 1, 2, 4, 8 (±1),  and 24 (±4) hrs after dose - 2 mL each (12   mL total) |                                                                                                   |          |
| PK - serial CSF (if consented)                                                       | XD                                                                                                |          |
| PK - single CSF (if consented)                                                       | XE                                                                                                |          |
| Pre-trial tumor materials and  PBMCs for Genomics (if  consented)                    | X                                                                                                 |          |
| Tumor Tissue and blood for                                                           | X                                                                                                 |          |
| Biorepository (if consented)                                                         |                                                                                                   |          |  
Updated Date: September 26, 2018  
A. Required for patients with HGG, medulloblastoma, CNS embryonal tumor (NOS), Ependymoma, or ATRT or with atypical presentation of DIPG. Tissue may be submitted if available for patients with typical presentation of DIPG
who have undergone previous biopsy but not mandated.  
B. 48-hour time point will be obtained prior to administration of either drug (ribociclib or everolimus) on Day 3 C. The ribociclib dose on day 1 should be held and day 2 should be delayed until the last everolimus sample is collected on day 2.  
D. See section 9.2.3 for details. E. Anytime during treatment. See section 9.2.3 for details.
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11 measurement of effect

Although the clinical benefit of ribociclib/everolimus drug(s) has not yet been established, the intent of offering this treatment is to provide a possible therapeutic benefit, and thus the patient will be carefully monitored for tumor response and symptom relief in addition to safety and tolerability. Patients with measurable disease will be assessed by standard criteria. For the purposes of this study, patients should be re-evaluated every 8 weeks for the first 3 courses (Courses 2, 4, 6), then every 12 weeks (Courses 9, 12, and Course 15, 18, 21, 24, 26 during extended therapy period) thereafter until time of progression or completion of treatment. In addition to a baseline scan, confirmatory scans will also be obtained 8 weeks following initial documentation of an objective response.
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11.1 antitumor effect 11.1.1 definitions

- Evaluable for Toxicity Patients who receive at least 1 dose of ribociclib or everolimus and are removed from treatment for toxicity during the dose-finding period (first 4 weeks of treatment) are evaluable for estimating the MTD. Patients who receive approximately 85% (≥18/21 doses of ribociclib and ≥22/26 doses of everolimus) of prescribed therapy during the dose-finding period but who progress prior to completing the course may be considered evaluable for estimating the MTD, as long as no additional anti-cancer therapy or supportive care that would confound the interpretation of any observed toxicity or side effect is given. Patients must have completed all of the clinical and laboratory monitoring requirements specified by the protocol up to the time of disease progression for them to be considered evaluable for MTD. Patients who have completed all therapy during the dose-finding period but who failed to comply with all the specified clinical and laboratory monitoring requirements for the first course may be considered inevaluable for estimating the MTD and replaced. Patients who receive less than 85% (<18/21 doses of ribociclib and <22/26 doses of everolimus) doses of the protocol specified therapy and who go off treatment for reasons other than toxicity (e.g. progressive disease, withdrawal of consent etc.) during the dose finding period will be considered inevaluable for estimating the MTD and will be replaced.  
- Evaluable for Objective Response Only those patients who have measurable disease present at initiation of phase I treatment, have received at least one dose of therapy, and have had their disease re-evaluated will be considered evaluable for response. These patients will have their response classified according to the definitions stated below. (Note: Patients who exhibit objective disease progression prior to the next scheduled MRI will also be considered evaluable.)
- Evaluable for PK intra-tumoral PK on the surgical study Patients with adequate tumor tissue (amount and quality) to be analyzable for the PK objective will be considered evaluable for the surgical study. Please note patients who may not be evaluable for the PK study may still be evaluable for the Phase I trial should they proceed to that component of the study.
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11.2 disease parameters

Sites should report tumor measurements in 3 dimensions in the database. In order to completely document the assessment of response, the measurements of the longest tumor dimension, and its perpendicular, of all target lesions upon which the assessments of tumor response are based should be explicitly noted in the radiology report for the baseline and all subsequent follow-up exams. Reports for the follow-up exams should reiterate the measurements obtained at baseline for each target lesion. Non-target lesions or newly occurring lesions should also be enumerated in these reports, and changes in non-target lesions should be described. The same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline and during follow-up. Tumor response criteria are determined by changes in size using the longest tumor dimension, and its perpendicular. FLAIR, T2 or post contrast T1 weighted images may be used - whichever gives the best estimate of tumor size. Since many tumors contain nonenhancing components (or, in some cases, the tumor may not enhance at all), both the enhancing and the non-enhancing components must be evaluated - on post contrast T1 weighted images and on FLAIR/T2 weighted images respectively. Increase in enhancement on T1 weighted images without accompanying increase in disease bulk on T2 or FLAIR images is not considered tumor progression. In return, enlarging areas of nonenhancing tumor (defined as mass effect/tissue thickening) are evidence of tumor progression. Conversely, decrease in enhancing tumor component without decrease in overall FLAIR/T2 extent may represent change in tumor permeability (commonly observed with antiangiogenic therapies) rather than represent tumor response.
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11.2.1 method

The following section describes the methodology. (See Figure 9 below for illustration.)
- For MRI imaging (preferred), the longest measurement of the tumor (or width, W) should be determined. It can be measured from the axial plane or the plane in which the tumor is best seen or measured, provided the same plane is used in follow ups. .  
- The transverse measurement should be the longest length perpendicular to the selected W. These dimensions will serve as the comparator for subsequent disease response assessments. NOTE: A measurable lesion should have a minimal transverse measurement that is at least twice the combined thickness of the image slice and the interslice gap. For example, with a 4 mm slice and a 0.4 mm gap, minimal measurable lesion diameter is 8.8 mm. Smaller lesions would not be measurable for study purpose.  
- Leptomeningeal tumor spread is usually not a target lesion, and usually cannot be measured accurately. Presence and location of leptomeningeal tumor spread should be noted, and change in extent/thickness assessed on follow up studies.  
- Follow-up examinations should assess the same 2 largest dimensions assessed at baseline.  
  
  
Figure 9: Tumor size measurement based on cross-sectional imaging 11.2.2 Overall Response Assessment The overall response assessment takes into account response in both target and non-target lesion, and the appearance of new lesions, where applicable, according to the criteria described in the table below. The overall response assessment is shown in the last column, and depends on the assessments of target, nontarget, and new lesions in the preceding columns.  
| Overall Response Assessment                                                                                                                                                                                             |              |                  |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------|------------------|
| Target Lesions                                                                                                                                                                                                          | New Lesions* | Overall Response |
| CR                                                                                                                                                                                                                      | No           | CR               |
| PR                                                                                                                                                                                                                      | No           | PR               |
| SD                                                                                                                                                                                                                      | No           | SD               |
| PD                                                                                                                                                                                                                      | Yes or No    | PD               |
| Any                                                                                                                                                                                                                     | Yes          | PD               |
| CR - Complete Response; PD - Progressive Disease;  PR - Partial Response; IR - Incomplete Response; SD - Stable Disease *If CSF cytology becomes positive, it will be considered a new lesion and  progressive disease. |              |                  |  
11.2.3 Selection of Target and Non-target Lesions
- For most CNS tumors, only one lesion/mass is present and therefore is considered a "target" for measurement/follow up to assess for tumor progression/response.  
- If multiple measurable lesions are present, a minimum of the 2 largest lesions should be measured; a maximum of 5 should be selected as "target" lesions. Target lesions should be selected on the basis of size and suitability for accurate repeated measurements. All other lesions will be followed as non-target lesions.  
- The lower size limit of the target lesion(s) should be at least twice the thickness of the slices showing the tumor to decrease the partial volume effect (e.g., 8 mm lesion for a 4 mm slice).
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11.3 tumor response criteria 11.3.1

Complete disappearance on MR of all evaluable tumor and mass effect, on a stable or decreasing dose of corticosteroids (or receiving only adrenal replacement doses), accompanied by a stable or improving neurologic examination, and maintained for at least 8 weeks. If CSF was positive, it must be negative.
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11.3.2 partial response (pr)

Greater than or equal to 50% reduction in tumor size by bi-dimensional measurement, as compared with the baseline measurements, on a stable or decreasing dose of corticosteroids, accompanied by a stable or improving neurologic examination, and maintained for at least 8 weeks.
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11.3.3 stable disease (sd)

Neurologic exam is at least stable and maintenance corticosteroid dose not increased, and MR/CT imaging meets neither the criteria for PR nor the criteria for Progressive Disease.
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11.3.4 progressive disease (pd)

Progressive Disease (PD): Progressive neurologic abnormalities or worsening neurologic status not explained by causes unrelated to tumor progression (e.g., anticonvulsant or corticosteroid toxicity wean, electrolyte disturbances, sepsis, hyperglycemia, etc.), OR a greater than 25% increase in the bidimensional measurement, taking as a reference the smallest disease measurement recorded since the start of protocol therapy, OR the appearance of a new tumor lesion. Increasing doses of corticosteroids required to maintain stable neurological status should be strongly considered as a sign of clinical progression unless in the context of recent wean or transient neurologic change due to treatment effect.
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11.3.5 progression-free survival

Interval of time between date of initiation of protocol treatment and minimum date of documentation of PD, second malignancy, death due to any cause, or date of last follow-up.
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11.3.5 duration of response

- Duration of overall response: The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that progressive disease is objectively documented.  
- Duration of stable disease: Stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started, including the baseline measurements.
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12 study oversight and data

Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7 (Adverse Events: List and Reporting Requirements).
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12.1 study oversight

This protocol is monitored at several levels, as described in this section. The Protocol Principal Investigator is responsible for monitoring the conduct and progress of the clinical trial, including the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and serious adverse events; reporting of expedited adverse events; and accumulation of reported adverse events from other trials testing the same drug(s). The Protocol Principal Investigator and statistician have access to the data at all times through Medidata Rave.  
All Study Investigators at participating sites who register/enroll patients on a given protocol are responsible for timely submission of data via Medidata Rave and timely reporting of adverse events for that particular study. This includes timely review of data collected on the electronic CRFs submitted via Medidata Rave. All studies are also reviewed in accordance with the Pediatric Brain Tumor Consortium's (PBTC) data safety monitoring plan.
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12.2 data reporting

Data collection for this study will be done exclusively through the Medidata Rave clinical data management system. Access to the trial in Rave is granted through the iMedidata application to all persons with the appropriate roles assigned in Regulatory Support System (RSS). To access Rave via iMedidata, the site user must have an active CTEP-IAM account (check at https://ctepcore.nci.nih.gov/iam/) and the appropriate Rave role (Rave CRA, Read-Only, CRA (Lab Admin), SLA or Site Investigator) on either the LPO or participating organization roster at the enrolling site. To the hold Rave CRA role or CRA Lab Admin role, the user must hold a minimum of an AP registration type. To hold the Rave Site Investigator role, the individual must be registered as an NPIVR or IVR. Associates can hold read-only roles in Rave. If the study has a DTL, individuals requiring write access to Rave must also be assigned the appropriate Rave tasks on the DTL. Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned on the appropriate roster will be sent a study invitation e-mail from iMedidata. To accept the invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) using their CTEP-IAM user name and password, and click on the "accept" link in the upper right-corner of the iMedidata page. Please note, site users will not be able to access the study in Rave until all required Medidata and study specific trainings are completed. Trainings will be in the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in the upper right pane of the iMedidata screen. Users that have not previously activated their iMedidata/Rave account at the time of initial site registration approval for the study in RSS will also receive a separate invitation from iMedidata to activate their account. Account activation instructions are located on the CTSU website, Rave tab under the Rave Updated Date: September 26, 2018 resource materials (Medidata Account Activation and Study Invitation Acceptance). Additional information on iMedidata/Rave is available on the CTSU members' website under the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com. Users may also contact OBDMC to get help with study specific issues including clinical forms, data entry, data query, data sign-offs and/or uploading of regulatory and other required documents. For complete OBDMC contact details, click on the OBDMC Contact Information link that is available in the Members' Area of the PBTC website (http://www.pbtc.org/).
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12.2.1 method

This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0. A protocol and subject-specific CDUS "Abbreviated" data set will be submitted electronically to CTEP on a quarterly basis via CDUS OPEN (Oncology Patient Enrollment Network). Reports are due January 31, April 30, July 31, and October 31. Instructions for submitting data using the CDUS can be found on the CTEP website (http://ctep.cancer.gov/reporting/cdus.html). 12.2.2 Responsibility for Data Submission The OBDMC for the PBTC is responsible for compiling and submitting CDUS data to CTEP for all participants and for providing the data to the Principal Investigator for review.
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12.3 ctep multicenter guidelines n/a

Participant confidentiality is strictly held in trust by the participating investigators, their staff and the sponsor(s) and their agents. This confidentiality is extended to cover testing of biological samples and genetic tests in addition to the clinical information relating to participants. Therefore, the study protocol, documentation, data and all other information generated will be held in strict confidence. No information concerning the study and the data will be released to an unauthorized third party without the prior written approval of the Pediatric Brain Tumor Consortium (PBTC). The PBTC protocol coordinators, other authorized representatives of the sponsor, regulatory representatives, PBTC auditors, representatives of the IRB or the pharmaceutical collaborator supplying study product may inspect all documents and records required to be maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical study site will permit access to such records. Source documents which are the original records of clinical findings, observations or activities in a clinical trial are to be maintained at each participating site. Sites must upload all source documentation which supports the eligibility of the participant to the PBTC via the RAVE database. In the event the patient experiences unexpected events, additional source documentation may be requested to complete the event Updated Date: September 26, 2018 review. These documents may include but are not limited to, hospital records, clinical and office charts, laboratory notes, memoranda and radiographic images. Study participant study related data, which is for purposes of statistical analysis and scientific reporting will be transmitted to the Pediatric Brain Tumor Consortium electronically via the RAVE database. This will not include the participant's contact or identifying information. Rather, research participants and their research data will be identified by a unique study identification number assigned at the time of screening or registration. The study participant's contact information will be securely stored at each clinical site for internal use during the study. At the end of the study, all records will continue to be kept in a secure location for as long a period as dictated by local IRB and institutional regulations. The study data entry and study management systems used by clinical sites and by the PBTC will be secured and password protected. At the end of the study, all study data is maintained on a secure server. After the study is completed, the data collected will be maintained on a server and may be used by other investigators, including those outside the study. With the participant's approval and as approved by local IRBs, biological samples labeled only with the participant's protocol specific identification number will be stored at the PBTC Central Review and Biorepository and could be made available to other investigators for future unspecified research. Investigators conducting future studies will not have access to the key for stored data collected while the participant is on study. Clinical data will be de-identified before it is shared with other investigators. If the participant agrees to submit a repository sample, those samples contain genetic information that may be used for research related to brain tumors and their treatment. They may also be used to develop tests/assays to improve diagnosis and treatment of these diseases in the future. Genetic research may consist of the analysis of one or more genes or the analysis of genetic markers throughout the genome.
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13 statistical considerations 13.1 study

Phase I Study A "Rolling-6" Phase I design will be used to estimate the maximum tolerated dose (MTD), where dose escalations are planned in cohorts of two-six patients. No intra-patient escalation will be allowed.  
Skolnik et al80 introduced the Rolling-6 design, motivated by the observation that most pediatric Phase I
trials in oncology have not produced excessive toxicities. A possible explanation for this could be that pediatric studies are often preceded by adult trials and the knowledge gained in the latter is utilized towards ensuring safety in the former. The Rolling-6 design aims to shorten the duration of pediatric Phase I trials by minimizing the time the trial would be closed to accrual for toxicity monitoring. This is achieved by enrolling anywhere from 2 to 6 patients at a dose level without requiring that the DLT status of the patients already assigned to the same dose level are known; hence reducing the number of patients who would be turned away due to unavailability of open slots. The simulations in Skolnik et al. as well as Onar-Thomas and Xiong81 indicate that this approach decreases the duration of a Phase I trial compared to the traditional Updated Date: September 26, 2018 method and that the toxicity associated with the Rolling-6 design is not higher than the toxicity associated with the traditional method.
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13.2 dose escalation/de-escalation rules

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

Surgical patients will be counted towards the accrual of the Phase I trial when they initiate the combination treatment post-surgical recovery. Since we expect a delay of 4-6 weeks from enrollment of a surgical patient on the surgical study to his/her enrollment on the Phase I trial, it would be infeasible to reserve a slot on a given dose level for that long. Given the rarity of these patients we also do not want to miss enrolling a surgical patient due to unavailability of slots on the Phase 1 trial. Thus we propose the following contingencies for the surgical patients: - As long as accrual to the Phase I trial remains open, accrual to the surgical study will continue. - Surgical patients who meet treatment initiation criteria for the Phase 1 component post-surgical recovery will be enrolled on the current dose level where non-surgical patients are being enrolled (see section 5 for details).  
o If a slot is available at the time a surgical patient presents for Phase I enrollment, then the patient will count towards the maximum accrual of 6 patients at that dose level.  
o If a slot is not available at the current dose level i.e. 6 patients have been enrolled and accrual is temporarily on hold for DLT assessment, we will nonetheless enroll the surgical patient(s) at that dose level bringing the total to 7 (or more) patients. In this case, if the observed DLT rate is <0.33 (i.e. 2 or fewer DLTs in 7 or 8 patients) then we will allow escalation. Otherwise the dose will be declared too toxic and de-escalation will occur.  
o Given the rarity of these patients we do not anticipate that we will enroll any more than 8 patients at a dose level but in the unlikely event that we do we will use 0.33 as the threshold for escalation/de-escalation decisions.  
Based on the above-outlined escalation rules, if the lowest proposed dose level is found to be too toxic, then the trial will be closed to accrual and the merits of amending or closing the trial permanently will be reconsidered. On the other hand, if the maximum dose level proposed for the study is deemed to be safe, then the MTD will be considered to be beyond the highest dose level and consideration may be given to investigate higher dose levels. Alternatively, the highest dose level may be recommended as the Phase II dose. Once the MTD has been estimated or the recommended Phase II dose has been determined, 6 additional patients will be treated at that dose level to better describe the toxicity profile of the agent. If the number of toxicities observed in the expansion cohort suggests that the initial estimate of the MTD is too toxic then we will consider de-escalating to a lower dose level and treating additional patients at that level including an expansion cohort in an effort to estimate the phase II recommended dose.
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contingencies

If all the dose levels are investigated with acceptable toxicity, consideration may be given to investigating higher dose levels. A deliberate decision will be made by the study committee and the sponsor. If a decision is made to not study higher doses, then the highest dose level may be recommended for further study in Phase II trials. In the event of a single fatal toxicity, the OBDMC will suspend enrollment, pending discussion with the study chair, IDB and others as necessary.
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13.3 sample size/accrual rate

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

We will summarize toxicities observed on the study by dose level and by attribution in a table format. Similarly data from correlative studies will be reported descriptively. Tumor PK concentrations will be compared to plasma PK and described descriptively as there are no data on CNS distribution of Ribociclib in humans and the expected sample size for the surgical trial is small. Paired tests may also be used to capture any significant changes in these markers pre and post treatment. 13.4.1 Statistical Analysis of Pharmacokinetics Plasma drug concentrations and pharmacokinetic parameters will be presented in tabular and graphical form. Pharmacokinetic parameters of interest, such as apparent volume of the central compartment (Vc/F), elimination rate constant (Ke), half-life (t1/2), apparent oral clearance (CL/F), and area under the plasma concentration time curve (AUC) will be estimated using compartmental methods. Dose proportionality in pharmacokinetic parameters will be investigated by performing one-way analysis of variance (ANOVA) on dose-normalized parameters.
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13.5 analysis of secondary endpoints

Any objective responses (CR+PR) which may be observed in this trial will be described by dose and by histology. Prolonged stable diseases will also be reported in a descriptive fashion. Target inhibition will be descriptively defined by changes in phospho-RB1 and ki-67 via plots and summary statistics. We will also descriptively summarize any associations between molecular subgroup designations and other biology correlates with observed response to ribociclib and everolimus if there are any. Prevention of stomatitis with dexamethasone-based mouthwash during course 1 and 2 will be descriptively defined by reporting the number of events of stomatitis and grade. In addition to estimating individual pharmacokinetic parameters, we will also estimate the population parameters using nonlinear mixed effects modeling methods (NONMEM). This method estimates the population parameters and both the inter- and intra-subject variability. Once the population parameters and corresponding covariance matrix are estimated, individual estimates can be obtained using post hoc analysis.