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4.1.2.5 renal failure events

Cases of renal failure (including acute renal failure), some with fatal outcome, occurred in patients treated with everolimus. Renal function of patients should be monitored particularly where patients have additional risk factors that may further impair renal function.  
Elevations of serum creatinine, usually mild, and proteinuria have been reported in patients taking everolimus. Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein, or serum creatinine, is recommended prior to the start of everolimus therapy and periodically thereafter. 4.1.2.6 Management of stomatitis / oral mucositis / mouth ulcers  
| Adverse Drug Reaction                                                                                                                             | Severity                                                                                                                                                                                                                                                                                                                                                                                                                                           | Everolimus Dose Adjustment and Management  Recommendations                                                    |
|---------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------|
| Stomatitis                                                                                                                                        | Grade 1  (Minimal  symptoms,  normal diet)                                                                                                                                                                                                                                                                                                                                                                                                         | No dose adjustment required.  Manage with non-alcoholic or salt water (0.9%)  mouth wash several times a day. |
| Grade 2  (Symptomatic  but can eat  and swallow  modified diet)                                                                                   | Temporary dose interruption until recovery to grade  ≤1.  Re-initiate everolimus at the same dose.  If stomatitis recurs at grade 2, interrupt dose until  recovery to grade ≤1. Re-initiate everolimus at one  dose level lower.  Manage with topical analgesic mouth treatments (e.g.  benzocaine, butyl aminobenzoate, tetracaine  hydrochloride, menthol or phenol) with or without  topical corticosteroids (i.e. triamcinolone oral paste)*. |                                                                                                               |
| Grade 3  (Symptomatic  and unable to  adequately eat  or hydrate  orally)                                                                         | Temporary dose interruption until recovery to grade  ≤1.  Re-initiate everolimus at one dose level lower.  Manage with topical analgesic mouth treatments (i.e.  benzocaine, butyl aminobenzoate, tetracaine  hydrochloride, menthol or phenol) with or without  topical corticosteroids (i.e. triamcinolone oral paste)*                                                                                                                          |                                                                                                               |
| Grade 4  (Symptoms  associated  with lifethreatening  consequences)                                                                                                                                                   | Discontinue everolimus and treat with appropriate  medical therapy.                                                                                                                                                                                                                                                                                                                                                                                |                                                                                                               |
| * using agents containing alcohol, hydrogen peroxide, iodine, and thyme derivatives in management of stomatitis as  they may worsen mouth ulcers. |                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                                                                                                               |  
Patients with a clinical history of stomatitis/mucositis/mouth ulcers and those with gastrointestinal morbidity associated with mouth/dental infections, irritation of esophageal mucosa e.g. gastroesophageal reflux disease (GERD) and pre-existing stomatitis/mucositis must be monitored even more closely. Patients should be instructed to report the first onset of buccal mucosa irritation/reddening to their study physician immediately. Stomatitis/oral mucositis/mouth ulcers due to everolimus should be treated using local supportive care. Please note that investigators in earlier trials have described the oral toxicities associated with everolimus as mouth ulcers, rather than mucositis or stomatitis. If your examination reveals mouth ulcers rather than a more general inflammation of the mouth, please classify the adverse event as such. The suggested paradigm for treatment of stomatitis/oral mucositis/mouth ulcers is as follows:  
1. For mild toxicity (grade 1), no dose adjustment required. Manage with non-alcoholic mouth wash or salt water (0.9%) mouth wash several times a day until resolution.  
2. For more severe toxicity (grade 2 in which case patients have pain but are able to maintain adequate oral alimentation, or grade 3 in which case patients cannot maintain adequate oral  
alimentation), the suggested treatments are topical analgesic mouth treatments (i.e., local anesthetics such as, benzocaine, butyl aminobenzoate, tetracaine hydrochloride, menthol, or phenol) with or without topical corticosteroids, such as triamcinolone oral paste 0.1%
(Kenalog in Orabase®).  
3. Agents containing alcohol, hydrogen peroxide, iodine, and thyme derivatives may tend to worsen mouth ulcers. These agents should be avoided.  
4. Antifungal agents should be avoided unless a fungal infection is diagnosed. In particular, systemic imidazole antifungal agents (ketoconazole, fluconazole, itraconazole, etc.) should be avoided in all patients due to their strong inhibition of everolimus metabolism, therefore leading to higher everolimus exposures. Therefore, topical antifungal agents are preferred if an infection is diagnosed.
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4.1.2.7 management of diarrhea

Appearance of grade 1-2 diarrhea attributed to study drug toxicity may be treated with supportive care such as loperamide, initiated at the earliest onset (for example 4 mg orally followed by 2 mg orally every 2 hours until resolution of diarrhea).  
| 4.1.2.8                                              | Management of hyperlipidemia and hyperglycemia                                                                                      |                                                                                 |
|------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------|
| Adverse Drug Reaction                                | Severity                                                                                                                            | Everolimus Dose Adjustment and Management  Recommendations                      |
| Metabolic events  (e.g. hyperglycemia, dyslipidemia) | Grade 1                                                                                                                             | No dose adjustment required.  Initiate appropriate medical therapy and monitor. |
| Grade 2                                              | No dose adjustment required.  Manage with appropriate medical therapy and monitor.                                                  |                                                                                 |
| Grade 3                                              | Temporary dose interruption.  Re-initiate everolimus at one dose level lower.  Manage with appropriate medical therapy and monitor. |                                                                                 |
| Grade 4                                              | Discontinue everolimus and treat with appropriate  medical therapy.                                                                 |                                                                                 |  
Treatment of hyperlipidemia should take into account the pre-treatment status and dietary habits of the patient. Grade 2 or higher hypercholesterolemia (>300 mg/dL or 7.75 mmol/L) or grade 2 hypertriglyceridemia or higher (>2.5x upper normal limit) should be treated with a 3-hydroxy-3methyl-glutaryl (HMG)-CoA reductase inhibitor (e.g. atorvastatin, pravastatin, fluvastatin) or appropriate triglyceride-lowering medication, in addition to diet. Note: Concomitant therapy with fibrates and an HMG-CoA reductase inhibitor is associated with an increased risk of a rare but serious skeletal muscle toxicity manifested by rhabdomyolysis, markedly elevated creatine phosphokinase (CPK) levels and myoglobinuria, acute renal failure and sometimes death. The risk versus benefit of using this therapy should be determined for individual patients based on their risk of cardiovascular complications of hyperlipidemia. Dyslipidemia (including hypercholesterolemia and hypertriglyceridemia) has been reported in patients taking everolimus. Monitoring of blood cholesterol and triglycerides prior to the start of everolimus therapy and periodically thereafter as well as management with appropriate medical therapy is recommended.  
Hyperglycemia has been reported in patients taking everolimus. Monitoring of fasting serum glucose is recommended prior to the start of everolimus and periodically thereafter. More frequent monitoring is recommended when everolimus is co-administered with other drugs that may induce hyperglycemia. Optimal glycemic control should be achieved before starting a patient on everolimus. 4.1.2.9 Management of non-infectious pneumonitis Non-infectious pneumonitis is a class effect of rapamycin derivatives. Cases of non-infectious pneumonitis (including interstitial lung disease) have also been described in patients taking everolimus. Some of these have been severe and on rare occasions, a fatal outcome was observed.  
x A diagnosis of non-infectious pneumonitis should be considered in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough or dyspnea, and in whom infectious, neoplastic and other non-medicinal causes have been excluded by means of appropriate investigations. Opportunistic infections such as PJP should be ruled out in the differential diagnosis of non-infectious pneumonitis. Patients should be advised to report promptly any new or worsening respiratory symptoms.
Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue everolimus therapy without dose alteration. If symptoms are moderate (grade 2), consideration should be given to interruption of therapy until symptoms improve. The use of corticosteroids may be indicated. Everolimus may be reintroduced at a daily dose approximately 50% lower than the dose previously administered. For cases of grade 3 non-infectious pneumonitis, interrupt everolimus until resolution to less than or equal to grade 1. Everolimus may be re-initiated at a daily dose approximately 50% lower than the dose previously administered depending on the individual clinical circumstances. If toxicity recurs at grade 3, consider discontinuation of everolimus. For cases of grade 4 noninfectious pneumonitis, everolimus therapy should be discontinued. Corticosteroids may be indicated until clinical symptoms resolve. For patients who require use of corticosteroids for treatment of non-infectious pneumonitis, prophylaxis for pneumocystis jirovecii pneumonia (PJP) may be considered. The two compounds studied most extensively for prophylaxis against PJP have been trimethoprim-sulfamethoxazole, given orally, and pentamidine, given as an aerosol. If non-infectious pneumonitis develops, the guidelines should be followed. Consultation with a pulmonologist is recommended for any case of pneumonitis that develops during the study. Management of non-infectious pneumonitis  
| Version Date: 01/15/2019 Worst grade  Suggested investigations                                                                                                                                                                                                                                     | Management of                                                                                                                                                                                                                                                                                                                          | Everolimus dose adjustment                                                                                    |                                                                                                                                                                                                                       |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| pneumonitis                                                                                                                                                                                                                                                                                        | pneumonitis                                                                                                                                                                                                                                                                                                                            |                                                                                                               |                                                                                                                                                                                                                       |
| Grade 1  (Asymptoma tic,  radiographic  findings  only)                                                                                                                                                                                                                                            | CT scans with lung windows.                                                                                                                                                                                                                                                                                                            | No specific  therapy is  required                                                                             | No dose adjustment required.  Initiate appropriate monitoring.                                                                                                                                                        |
| Grade 2  (Symptomati c, not  interfering  with  Activities of  Daily  Living)                                                                                                                                                                                                                      | CT scan with lung windows.  Consider pulmonary function  testing includes: spirometry,  DLCO, and room air O2 saturation at rest. Consider a  bronchoscopy with biopsy  and/or BAL. Monitoring at each  visit until return to ≤ grade 1.  Return to initial monitoring  frequency if no recurrence.                                    | Symptomatic  only. Consider  corticosteroids  and/or other supportive  therapy if  symptoms are  troublesome. | Rule out infection and consider  interruption of everolimus until  symptoms improve to Grade ≤  1. Re-initiate everolimus at one  dose level lower.  Discontinue everolimus if  failure to recover within ≤ 28  days. |
| Grade 3  (Symptomati c, Interfering  with  Activities of  Daily Living.  O2 indicated                                                                                                                                                                                                              | Rule out infection and interrupt  everolimus until symptoms  improve to Grade ≤ 1. Consider re-initiating  everolimus at one dose level  lower.  Discontinue everolimus if  failure to recover within ≤ 28  days. If toxicity recurs at Grade  3, consider discontinuation                                                             |                                                                                                               |                                                                                                                                                                                                                       |
| CT scan with lung windows and  pulmonary function testing  includes: spirometry, DLCO,  and room air O2 saturation at  rest. Monitoring at each visit  until return to ≤ grade 1. Return  to initial monitoring frequency if  no recurrence. Bronchoscopy  with biopsy and/or BAL is  recommended. | Consider  corticosteroids if  infective origin  is ruled out.  Taper as  medically  indicated.                                                                                                                                                                                                                                         |                                                                                                               |                                                                                                                                                                                                                       |
| Grade 4  (Lifethreatening,  ventilatory  support  indicated)                                                                                                                                                                                                                                                                                                    | CT scan with lung windows and  required pulmonary function  testing, if possible, includes:  spirometry, DLCO, and room air  O2 saturation at rest. Monitoring  at each visit until return to ≤  grade 1. Return to initial  monitoring frequency if no  recurrence. Bronchoscopy with  biopsy and/or BAL is  recommended if possible. | Consider  corticosteroids if  infective origin  is ruled out.  Taper as  medically  indicated.                | Rule out infection and  discontinue everolimus.                                                                                                                                                                       |
| 4.1.2.10 Management of hepatitis reactivation / flare                                                                                                                                                                                                                                              |                                                                                                                                                                                                                                                                                                                                        |                                                                                                               |                                                                                                                                                                                                                       |  
Reactivation of Hepatitis B (HBV) has been observed in patients with cancer receiving chemotherapy[98]. Sporadic cases of Hepatitis B reactivation have also been seen in this setting with everolimus. Use of antivirals during anti-cancer therapy has been shown to reduce the risk of Hepatitis B virus reactivation and associated morbidity and mortality[99]. A detailed assessment of Hepatitis B/C medical history and risk factors must be done for all patients at baseline, with testing performed prior to the first dose of study drug.
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monitoring and prophylactic treatment for

Table 11 provides detail of monitoring and prophylactic therapy according to the baseline results of viral load and serologic markers testing.  
| Table 11                                        | Action to be taken based on screening hepatitis B results                              |                |                                   |        |                                     |
|-------------------------------------------------|----------------------------------------------------------------------------------------|----------------|-----------------------------------|--------|-------------------------------------|
| Test                                            | Result                                                                                 | Result         | Result                            | Result | Result                              |
| HBV-DNA                                         | +                                                                                      | + or -         | -                                 | -      | -                                   |
| HBsAg                                           | + or -                                                                                 | +              | -                                 | -      | -                                   |
| HBsAb                                           | + or -                                                                                 | + or -         | +  and no prior  HBV  vaccination | + or - | -  or + with prior  HBV vaccination |
| HBcAb                                           | + or -                                                                                 | + or -         | + or -                            | +      | -                                   |
| Recommendation                                  | Prophylaxis treatment  should be started 1-2 weeks  prior to first dose of  everolimus | No prophylaxis | No specific  action               |        |                                     |
| Monitor HBV-DNA  approximately every 3-4 weeks  |                                                                                        |                |                                   |        |                                     |
| Monitor HBV-DNA  approximately every 4-8  weeks |                                                                                        |                |                                   |        |                                     |  
Antiviral prophylaxis therapy should continue for at least 4 weeks after last dose of everolimus. For HBV reactivation definition and management guidelines, see **Table 12**.  
| Table 12   | Guidelines for the management of hepatitis B reactivation   |
|------------|-------------------------------------------------------------|
| HBV reactivation (with or without clinical signs and symptoms)* For patients with baseline  results:  Positive HBV-DNA  OR positive HBsAg ---------------------------------- ---- reactivation is defined as: [Increase of 1 log in HBVDNA relative to baseline  HBV-DNA value OR new  appearance of measurable  HBV-DNA]  Treat: Start a second antiviral medication  AND Interrupt everolimus administration until resolution:  x ≤ baseline HBV-DNA levels  If resolution occurs within ≤ 28 days, everolimus should be re-started  at one dose lower, if available. (see Table 7 for dose levels available) If  the patient is already receiving the lowest dose of everolimus according  to the protocol, the patient should restart at the same dose after  resolution. Both antiviral therapies should continue at least 4 weeks  after last dose of everolimus.  If resolution occurs > 28 days Patients should discontinue everolimus  but continue both antiviral therapies at least 4 weeks after last dose of  everolimus.  For patients with baseline  results: Negative HBV-DNA and HBsAg AND [Positive HBsAb (with no  prior history of vaccination  against HBV), OR positive  HBcAb] ---------------------------------- --- Reactivation is defined as:  New appearance of  measurable HBV-DNA  Treat: Start first antiviral medication  AND Interrupt everolimus administration until resolution:  x ≤ undetectable (negative) HBV-DNA levels  If resolution occurs within ≤ 28 days, everolimus should be re-started  at one dose lower, if available (see Table 7 for dose levels available).  If the patient is already receiving the lowest dose of everolimus  according to the protocol, the patient should restart at the same dose  after resolution. Antiviral therapy should continue at least 4 weeks after  last dose of everolimus.  If resolution occurs > 28 days Patients should discontinue everolimus  but continue antiviral therapy at least 4 weeks after last dose of  everolimus.  * All reactivations of HBV are to be recorded as grade 3 (e.g. CTCAE Version 4.0 -  Investigations/Other: Viral Reactivation), unless considered life threatening by the investigator, in            |                                                             |  
* All reactivations of HBV are to be recorded as grade 3 (e.g. CTCAE Version 4.0 -  
Investigations/Other: Viral Reactivation), unless considered life threatening by the investigator, in  
which case they should be recorded as grade 4. Date of viral reactivation is the date on which the rise or reappearance of HBV-DNA was recorded.
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monitoring for hepatitis c flare

The following two categories of patients should be monitored every 4–8 weeks for HCV flare:  
x Patients with detectable HCV RNA-PCR test at screening.  
x Patients known to have a history of HCV infection, despite a negative viral load test at screening (including those that were treated and are considered 'cured')
For definitions of HCV flare and actions to be taken in the event of a flare, please refer to Table 13.  
| Table 13                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Guidelines for the management of hepatitis C flare                                                            |                        |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------|------------------------|
| Baseline results                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | HCV flare definition*                                                                                         | HCV flare  management  |
| Detectable HCV-RNA                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | > 2 log10 IU/mL increase in HCV-RNA  AND ALT elevation > 5 x ULN or 3 x baseline  level, whichever is higher. | Discontinue everolimus |
| Knowledge of past hepatitis C  infection with no detectable  HCV-RNA                                                                                                                                                                                                                                                                                                                                                                                                                          | New appearance of detectable HCVRNA AND ALT elevation > 5 x ULN or 3 x baseline  level, whichever is higher.                                                                                                               | Discontinue everolimus |
| * All flares of HCV are to be recorded as grade 3 (e.g. CTCAE Version 4.0 - Investigations - Other:  Viral Flare), unless considered life threatening by the investigator; in which case, they should be  recorded as grade 4. Date of viral flare is the date on which both the clinical criteria described above  were met. (e.g., for a patient whose HCV-RNA increased by 2 logs on 01 JAN 2011 and whose ALT  reached > 5 x ULN on 22 JAN 2011, the date of viral flare is 22 JAN 2011). |                                                                                                               |                        |
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4.2 concurrent medications 4.2.1 general

Patients must be instructed not to take any medications (over-the-counter or other products) during the protocol treatment period without prior consultation with the investigator. The investigator should instruct the patient to notify the study site about any new medications he/she takes after the start of study drug. All medications (other than study drug) and significant nondrug therapies (including physical therapy and blood transfusions) taken within 28 days of starting study treatment through the 30-day safety follow up visit should be reported on the CRF. 4.2.2 Cytochrome P450 and P-glycoprotein inhibitors/inducers/substrates Co-administration of everolimus or sunitinib with strong inhibitors of CYP3A4 or PgP should be avoided; and may cause increased drug concentrations. For a current table of Substrates, Inhibitors and Inducers please access the following website: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio nsLabeling/ucm093664.htm Everolimus is metabolized by CYP3A4 in the liver and to some extent in the intestinal wall.  
Therefore, the following are recommended:
x Co-administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir) or P-glycoprotein (PgP) inhibitor should be avoided.  
x Co-administration of either study drug with moderate CYP3A4 inhibitors (e.g.,
erythromycin, fluconazole) or PgP inhibitors should be used with caution. If a patient requires co-administration of moderate CYP3A4 inhibitors or PgP inhibitors, reduce the dose of everolimus by approximately 50%. Additional dose reductions to every other day may be required to manage toxicities. If the inhibitor is discontinued, the everolimus dose should be returned to the dose used prior to initiation of the moderate CYP3A4/PgP inhibitor after a washout period of 2 to 3 days.
x Grapefruit, Seville oranges, and starfruit affect P450 and PgP activity. Concomitant use should be avoided.  
x If patients require co-administration of a strong CYP3A4 inducer with everolimus, consider doubling the daily dose of everolimus (based on pharmacokinetic data), using increments of 5 mg or less. This dose of everolimus is predicted to adjust the AUC to the range observed without inducers. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers. If the strong inducer is discontinued, consider a washout period of at least 3 to 5 days (reasonable time for significant enzyme de-induction), before the everolimus dose is returned to the dose used prior to initiation of the strong CYP3A4 inducer.  
x This dose adjustment of everolimus is intended to achieve similar AUC to the range observed without inducers. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers. If the strong inducer is discontinued the everolimus dose should be returned to the dose used prior to initiation of the strong CYP3A4/PgP inducer.  
Please refer to **Table 14** listing relevant inducers and inhibitors of CYP3A and **Table 15** for a list of relevant substrates, inducers, and inhibitors of PgP.
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4.2.2.1 everolimus and drugs influencing

Everolimus is a substrate of CYP3A4, and a substrate and moderate inhibitor of the multidrug efflux pump, PgP (PgP, MDR1, and ABCB1). Therefore, extent of absorption and subsequent elimination of systemically absorbed everolimus may be influenced by products that are substrates, inhibitors, or inducers of CYP3A4 and/or PgP. Concurrent treatment with strong CYP3A4-inhibitors should be avoided. Inhibitors of PgP may decrease the efflux of everolimus from brain or tumor and therefore increase everolimus concentrations in these tissues. In vitro studies showed that everolimus is a competitive inhibitor of CYP3A4 and of CYP2D6, potentially increasing the concentrations of products eliminated by these enzymes. Thus, caution should be exercised when co-administering everolimus with CYP3A4 and CYP2D6 substrates with a narrow therapeutic index. Clinical studies have been conducted in healthy subjects to assess pharmacokinetic drug interactions between everolimus and potential CYP3A modifiers (ketoconazole, verapamil, erythromycin, rifampin, midazolam, and HMGCoA reductase inhibitors (statins).
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table 14 clinically relevant drug

Inducers Strong inducers:
avasimibe, carbamazepine, mitotane, phenobarbital, phenytoin, rifabutin, rifampin (rifampicin), St.  
John's wort (hypericum perforatum) Moderate inducers:
bosentan, efavirenz, etravirine, genistein, modafinil, nafcillin, ritonavir, [talviraline], thioridazine, tipranavir Weak inducers: amprenavir, aprepitant, armodafinil (R-modafinil), bexarotene, clobazam, danshen, dexamethasone, Echinacea, garlic (allium sativum), gingko (ginkgo biloba), glycyrrhizin, methylprednisolone, nevirapine, oxcarbazepine, pioglitazone, prednisone, [pleconaril], primidone, raltegravir, rufinamide, sorafenib, telaprevir, terbinafine, topiramate, [troglitazone] , vinblastine Inhibitors
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strong inhibitors

boceprevir, clarithromycin, cobicistat, conivaptan, elvitegravir, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, nefazodone, nelfinavir, posaconazole[100], ritonavir, saquinavir, telaprevir, telithromycin, tipranavir, troleandamycin, voriconazole Moderate inhibitors:
Amprenavir, aprepitant, atazanavir, casopitant, cimetidine, ciprofloxacin, cyclosporine, darunavir, diltiazem, dronedarone, erythromycin, fluconazole, fosamprenavir, grapefruit juice (citrus parasidi fruit juice), imatinib, schisandra sphenanthera, tofisopam, verapamil
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rifampin st john's wort pgp

amiodarone, azithromycin, captopril, carvedilol, clarithromycin, conivaptan, diltiazem, dronedarone, elacridar, erythromycin, felodipine, fexofenadine, fluvoxamine, ginkgo (ginkgo biloba), indinavir, itraconazole, lopinavir, mibefradil, milk thistle (silybum marianum), nelfinavir, nifedipine, nitrendipine, paroxetine, quercetin, quinidine, ranolazine, rifampin, ritonavir, saquinavir, Schisandra chinensis, St John's wort (hypericum perforatum), talinolol, Telaprevir, telmisartan, ticagrelor, tipranavir, tolvaptan, valspodar, verapamil Reference: Internal Clinical Pharmacology Drug-drug interaction (DDI) memo, updated Oct. 2, 2011,29-Oct-2012 which summarizes DDI data from three sources including the FDA's "Guidance for Industry, Drug Interaction Studies", the University of Washington's Drug Interaction Database, and Indiana University School of Medicine's Drug Interaction Table.
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4.2.3 vaccinations

Immunosuppressants may affect the response to vaccination and vaccination during treatment with everolimus may therefore be less effective. The use of live vaccines should be avoided during treatment with everolimus. For pediatric patients with SEGA that do not require immediate treatment, complete the recommended childhood series of live virus vaccinations prior to the start of therapy according to local treatment guidelines. Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.
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5 biospecimen collection 5.1 sample

Within 4 weeks prior to initiation of treatment with the respective study agent (everolimus or sunitinib), patients who meet eligibility criteria, will undergo biopsy of the primary tumor or any metastatic site for molecular analyses. Patients will undergo a percutaneous core needle (16 or 18 gauge) biopsy of the tumor under local anesthesia if there are no paraffin blocks available of tumor sample previously removed or biopsied. These percutaneous biopsies will be performed by interventional radiology (CT scan or ultrasound guidance). If needed, patients will be offered conscious sedation for the biopsy procedure. Sample collection will be performed according to standard operating procedures. Four core needle biopsies will be obtained, three samples will be formalin fixed and sent to the Laboratory of Pathology in the NCI for histological study. The official pathology report and samples will then be taken to Dr. Paul Meltzer's laboratory:
Paul Meltzer, Email: paulmeltzer@mail.nih.gov
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cancer genetics branch

Bldg. 37/Room 6183, Bethesda, MD 20892, Phone: 240-760-6136 The remaining sample will be immediately placed in cryovials, snap frozen on liquid nitrogen or dry ice and transported to Dr. Naris Nilubol's laboratory. Fresh tissue samples should be collected into empty, unused cryovials (Nunc catalog \#50010012, 5001-1020 or equivalent) on dry ice or liquid nitrogen. Samples may be obtained by FNA or core biopsy. The interval between sample acquisition and freezing on dry ice must not exceed 30 minutes. Frozen, vialed samples should be transferred from dry ice to -80°C (minimum) or liquid nitrogen frozen storage within 2 hours. Samples will be recorded in LabMatrix and reviewed by the Laboratory of Pathology to confirm the diagnosis. The remaining sample will be transported to Dr. Paul Meltzer's laboratory [Paul Meltzer, M.D., Bldg. 37/Room 6138, Bethesda, MD 20892, Phone: 240-760-6136, Email: pmeltzer@mail.nih.gov] for tumor genotyping along the saliva DNA.
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5.1.2 saliva collection and peripheral

Saliva specimen (2-13 ml) will be obtained for targeted sequencing and comparison to tumor sequencing results and mutation calls before treatment. The saliva samples will be collected by a saliva collecting kit with complete and detailed instructions for collection available in the kit and on manufacturer's website at http://www.dnagenotek.com/ROW/products/OG500.html (an alternative saliva collecting kit can be used if needed). The saliva will be processed by and stored in the laboratory of Dr. Paul Meltzer and will be used as an autologous control for future genomic studies. 3 mL of saliva will be collected using the Oragene saliva collection kit (DNA Genotek). The sample may be collected at any time after informed consent has been obtained, but collection is preferred at baseline. Ideally, the patient should be advised not to eat or drink anything 30 minutes prior to collection. Once the sample is obtained, the top of the device is closed, releasing a preservative, the top is removed, and a cap is placed on the tube. The date and exact time of the collection should be recorded on the sample. Samples will be recorded in LabMatrix. DNA will be extracted from the saliva samples and the DNA sample (along with the coded, linked tumor sample) will be transported to Dr. Paul Meltzer's laboratory. Dr. Meltzer will not have access to the sample code key. Peripheral blood (30 mL) may be obtained for targeted sequencing and comparison to tumor sequencing results and mutation calls after enrollment and before treatment. The blood will be processed by and stored in the laboratory of Dr. Paul Meltzer and will be used as an autologous control for future genomic studies.  
| Test/assay                                 | Volume         | Type of                 | Collection point       | Location of            |
|--------------------------------------------|----------------|-------------------------|------------------------|------------------------|
| (approx.)                                  | tube           | specimen analysis       |                        |                        |
| Molecular Analysis                         | 4 Core Tumor   | Screening               | Dr. Paul Meltzer's lab |                        |
| Biopsies                                   |                |                         |                        |                        |
| Targeted  Sequencing & Autologous  Control | 2-13 ml Saliva | Saliva  Collecting  Kit | Baseline               | Dr. Paul Meltzer's lab |
| Targeted                                   | 30 ml Serum    | Baseline                | Dr. Paul Meltzer's lab |                        |
| Sequencing                                 |                |                         |                        |                        |
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5.2 sample storage tracking and

5.2.1 Procedures for Storage of Specimens in the Laboratory of Dr. Naris Nilubol  
x In patients who undergo biopsy, the samples will be immediately snap frozen in liquid nitrogen and transported to the Dr. Naris Nilubol Lab by calling 240-760-6155. Samples will be labeled with the date and time of acquisition, the type of tissue and patient study ID. Upon receipt in the lab, samples will be bar coded and logged in to the tissue
database, LabMatrix. Samples will be stored in -20°C or -80°C freezers until molecular analysis. All freezers are monitored and are on separate emergency generator lines.  
x Saliva and serum samples for correlative studies may also be obtained and will be stored and tracked in the same manner as tissue samples.  
x At the completion of the protocol, the investigator will dispose of all specimens in accordance with the environmental protection laws, regulations and guidelines of the Federal Government and the State of Maryland.  
x Samples at NIH will be ordered in CRIS and tracked through a Clinical Trial Data Management system. Should a CRIS screen not be available, the CRIS downtime procedures will be followed. Samples will not be sent outside NIH without IRB notification and an executed MTA.  
x All specimens obtained in the protocol are used as defined in the protocol. Any specimens that are remaining at the completion of the protocol will be stored in the conditions described below. The study will remain open so long as sample or data analysis continues. Samples from consenting subjects will be stored until they are no longer of scientific value or if a subject withdraws consent for their continued use, at which time they will be destroyed. The PI will report any loss or destruction of samples to the NIH IRB as soon as he is made aware of such loss x If the patient withdraws consent the participant's data will be excluded from future distributions, but data that have already been distributed for approved research use will not be able to be retrieved.  
x The PI will report destroyed samples to the IRB if samples become unsalvageable because of environmental factors (ex. broken freezer or lack of dry ice in a shipping container) or if a patient withdraws consent. Samples will also be reported as lost if they are lost in transit between facilities or misplaced by a researcher. Freezer problems, lost samples or other problems associated with samples will also be reported to the IRB, the NCI Clinical Director, and the office of the CCR, NCI.  
5.2.2 Procedures for Storage of Tissue Specimens in the Laboratory of Pathology Tissues designated for clinical diagnostics are transported to the Laboratory of Pathology (LP) where they are examined grossly, and relevant portions are fixed, embedded in paraffin and sectioned and stained for diagnostic interpretation. Unutilized excess tissues are stored for up to three months, in accordance with College of American Pathologists/Joint Commission on Accreditation of Healthcare Organizations (CAP/JCAHO) guidelines, and then discarded. Following completion of the diagnostic workup, the slides and tissue blocks are stored indefinitely in the LP's clinical archives. All specimens are catalogued and retrieved utilizing the clinical laboratory information systems, in accordance with CAP/JCAHO regulations. The use of any stored specimens for research purposes is only allowed when the appropriate IRB approval has been obtained. In some cases, this approval has been obtained via the original protocol on which the patient was enrolled
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5.3 samples for genetic/genomic analysis

5.3.1 Description of the scope of genetic/genomic analysis  
o Tumor genotyping: Somatic mutation analysis of tumor biopsy specimens will be performed by sequencing 197 driver genes (**Appendix C**) in a CLIA certified genetic laboratory.  
o Germline sequencing for 197 driver genes (**Appendix C**) will be performed on saliva samples or peripheral blood samples in a CLIA certified genetic laboratory o Histology: Tissues may be examined by standard histology, immunohistochemistry and or in situ hybridization in the Laboratory of Pathology, NCI.
5.3.2 Privacy and Confidentiality of medical information/biological specimens Fresh tumor and blood samples will be stored in a minus 80-degree freezer. The samples of each patient will be assigned a study ID number, and that number will be used in all laboratory studies. At no time will patient's names be used on the blood and tissue samples. The molecular studies will be done in the CLIA certified genetic laboratory of Paul Meltzer, MD. Sometimes, because a group collaboration or journal policy requires it, a subject's genetic data may be deposited in a database such as dbGaP. Although there is controlled access to such a database, such a submission carries theoretical risks of revealing the identity of the subject. This is discussed in the consent. 5.3.3 A Certificate of Confidentiality will be obtained for the study as described in Section 10.3.1.5.
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5.3.4 management of results

The results of molecular studies will be communicated to the patient. Other than initial determination of the presence of particular genetic alteration(s) outlined in **Appendix C** and Appendix D, the results of subsequent molecular studies are for research purposes only and will not be communicated to the patient. The exceptions to this are potential incidental findings that are deemed medically significant and actionable. Subjects, treated in NCI will be contacted if a clinically actionable gene variant is discovered. Clinically actionable findings for the purpose of this study are defined as disorders appearing in the American College of Medical Genetics and Genomics recommendations for the return of incidental findings that is current at the time of primary analysis. (A list of current guidelines is maintained on the CCR intranet: https://ccrod.cancer.gov/confluence/display/CCRCRO/Incidental+Findings+Lists). Subjects who still remain on the study will be contacted at this time with a request to provide a blood sample to be sent to a CLIA certified laboratory.
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5.3.4.1 genetic counseling in nci

If the research findings are verified in the CLIA certified lab, the subject will be offered the opportunity to come to NIH (at our expense) to have genetic education and counseling with the NCI Genetics Branch to explain this result. If the subject does not want to come to NIH, a referral to a local genetic healthcare provider will be provided (at their expense). This is the only time during the course of the study that incidental findings will be returned. No interrogations regarding clinically actionable findings will be made after the primary analysis
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6 data collection and evaluation

The PI will be responsible for overseeing entry of data into a password protected electronic system (NCI C3D) and ensuring data accuracy, consistency and timeliness. Clinical data will be entered into the NCI C3D electronic database at least once every two weeks when patients are enrolled on the trial. Protocol-specific eCRFs will be developed for this trial in C3D. The principal investigator, associate investigators/research nurses and/or a contracted data manager will assist with the data management efforts. All data obtained during the conduct of the protocol will be kept in secure network drives or in approved alternative sites that comply with NIH security standards. Primary and final analyzed data will have identifiers so that research data can be attributed to an individual human subject participant. The NCI investigators will be responsible for the collection, maintenance, and quality control of the study data. Labmatrix will be used for sample data collection. Data in this system will be entered by the NCI staff. All adverse events, including clinically significant abnormal findings on laboratory evaluations, regardless of severity, will be followed until return to baseline or stabilization of event. Patients will be followed for adverse events for at least 30 days after removal from study treatment or until off-study, whichever comes first. An abnormal laboratory value will be recorded in the database as an AE **only** if the laboratory abnormality is characterized by any of the following:
x Results in discontinuation from the study  
x Is associated with clinical signs or symptoms x Requires treatment or any other therapeutic intervention
x Is associated with death or another serious adverse event, including hospitalization.  
x Is judged by the Investigator to be of significant clinical impact x If any abnormal laboratory result is considered clinically significant, the investigator will provide details about the action taken with respect to the test drug and about the patient's outcome.
End of study procedures: Data will be stored according to HHS, FDA regulations and NIH Intramural Records Retention Schedule as applicable. Loss or destruction of data: Should we become aware that a major breach in our plan to protect subject confidentiality and trial data has occurred, the IRB will be notified. 6.1.1 Source Documents The PI will permit trial-related monitoring, audits, IRB review, and regulatory inspection(s), providing direct access to source documents.
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6.1.2 case report forms

Data may be entered from the source documents directly into eCRFs in C3D for each patient enrolled in this study. The principal investigator or research nurse will review the eCRFs for completeness and accuracy. Site personnel may also conduct independent audits to ensure completeness and accuracy of data in C3D.  
Only the following adverse events will be recorded on the Case Report Form:
- Grade 2 unexpected events that are possibly, probably or definitely related to the study drugs;
- Grade 3 and 4 events that are possibly, probably or definitely related to the study drugs;
- Grade 5 events regardless of attribution; - Serious Events regardless of attribution.
Patients who meet the standard of care criteria for resection of their disease will undergo a major operative procedure and may receive extensive care in the ICU. The principal investigator or designee will closely monitor and document the clinical care and treatment of each patient as per standard of care at the NIH Clinical Center. As per NIH Clinical Center standards of practice, the Occurrence Reporting System will be used to report any clinical events meeting these reporting criteria.
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6.1.3 data quality assurance

The research team will monitor each patient's dataset throughout the study. Source document review will be made against entries on the eCRF and a quality assurance check will be performed to ensure that the investigator is complying with the protocol and regulations. In addition, after the research team (data managers) completes the CRFs a research nurse or physician at the NCI will review and verify the data.
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6.2 data sharing plans 6.2.1

I will share human data generated in this research for future research as follows:  
x Coded, linked data in an NIH-funded or approved public repository.  
x Coded, linked data in BTRIS (automatic for activities in the Clinical Center)
How and where will the data be shared? Data will be shared through:
x An NIH-funded or approved public repository. Clinicaltrials.gov.  
x BTRIS
x Publication and/or public presentations.  
When will the data be shared?  
x Before publication.  
x At the time of publication or shortly thereafter.
6.2.2 Genomic Data Sharing Plan Unlinked genomic data will be deposited in public genomic databases such as dbGaP in compliance with the NIH Genomic Data Sharing Policy.
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6.3 response criteria

For the purposes of this study, patients should be re-evaluated for response every 12 weeks. Response and progression will be evaluated in this study using the international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria.
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6.3.1 definitions

Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first treatment with sunitinib or everolimus. Evaluable for objective response: Only those patients who according to RECIST guideline (version 1.1) have measurable disease present at baseline, have been started on therapy with everolimus or sunitinib, 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 end of cycle 1 will also be considered evaluable.) Evaluable Non-Target Disease Response: Patients who have lesions present at baseline that are evaluable but do not meet the definitions of measurable disease, have been started on therapy with everolimus or sunitinib, and have had their disease re-evaluated will be considered evaluable for non-target disease. The response assessment is based on the presence, absence, or unequivocal progression of the lesions. 6.3.2 Disease Parameters Measurable disease: Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as:
x By chest x-ray: >20 mm;  
x By CT scan:
o Scan slice thickness 5 mm or under as >10 mm with CT scan o Scan slice thickness >5 mm: double the slice thickness x With calipers on clinical exam: >10 mm.
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). Metastatic lymph nodes. To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or MRI), are considered as non-measurable. Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be considered as malignant lesions (neither measurable nor non-measurable) since they are, by definition, simple cysts. 'Cystic lesions' thought to represent cystic metastases can be considered as measurable lesions, if they meet the definition of measurability described above. However, if non-cystic lesions are present in the same patient, these are preferred for selection as target lesions. Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs, should be identified as target lesions and recorded and measured at baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter), be representative of all involved organs, but in addition should be those that lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does not lend itself to reproducible measurement in which circumstance the next largest lesion which can be measured reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the short axis is added into the sum. The baseline sum diameters will be used as reference to further characterize any objective tumor regression in the measurable dimension of the disease. Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over and above the 5 target lesions should be identified as non-target lesions and should also be recorded at baseline. Measurements of these lesions are not required, but the presence, absence, or in rare cases unequivocal progression of each should be noted throughout follow-up. 6.3.3 Methods for Evaluation of Measurable Disease All measurements will be taken and recorded in metric notation using a ruler or calipers. All baseline evaluations will be performed as closely as possible to the beginning of treatment and never more than 4 weeks before the beginning of the treatment. The same method of assessment and the same technique will be used to characterize each identified and reported lesion at baseline and during follow-up. Conventional CT: This guideline has defined measurability of lesions on CT scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. Ideally, the same type of scanner should be used and the image acquisition protocol should be followed as closely as possible to prior scans. Body scans should be performed with breath-hold scanning techniques, if possible. Tumor markers: Chromogranin A levels, which represents a constitutive neuroendocrine secretory protein, is the most widely accepted biomarker. Chromogranin A was compared to a panel of biomarkers and proved to be the most accurate, with a specificity of 85.7% and sensitivity of 67.9%[101]. Chromogranin A is elevated in 60- 80% of patients with neuroendocrine tumors. The National Cancer Institute (NCI) recommends that serial  
measurements of CgA be incorporated into prospective clinical trials[49]. Chromogranin A level will be checked within 2 weeks prior to treatment, and every 3 months after treatment initiation. 68-Gallium DOTATATE: We and others have demonstrated that 68-Gallium DOTATATE is more sensitive for detecting sites of metastatic disease than anatomic imaging studies [102]. Therefore, we will also use 68-Gallium DOTATATE imaging results that show new lesions within 18 months follow up time to define progression of disease. All patients must have a target lesion as identified by conventional CT or MRI, however, to be eligible for enrollment in the study to evaluate response by RECIST criteria. 6.3.4 Response Criteria 6.3.4.1 Evaluation of Target Lesions Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes
(whether target or non-target) must have reduction in short axis to <10 mm.  
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study. 6.3.4.2 Evaluation of Non-Target Lesions Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). Note: If tumor markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete clinical response. Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. Although a clear progression of "non-target" lesions only is exceptional, the opinion of the treating physician should prevail in such circumstances, and the progression status should be confirmed at a later time by the review panel (or Principal Investigator). 6.3.4.3 Evaluation of Best Overall Response The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria.  
| For Patients with Measurable Disease (i.e., Target Disease)  Target  Non-Target  New  Overall  Best Overall Response when  Lesions  Lesions  Lesions  Response  Confirmation is Required*  CR CR No CR >4 wks. Confirmation**  CR NonCR/Non-PD  No PR  CR Not  No PR  evaluated  >4 wks. Confirmation**  PR NonCR/NonPD/not  evaluated  No PR  SD NonCR/NonPD/not  evaluated  No SD  Documented at least once >4  wks. from baseline** PD Any Yes or  PD  No  Any PD*** Yes or no prior SD, PR or CR PD  No  Any Any Yes PD  * See RECIST 1.1 manuscript for further details on what is evidence of a  new lesion.  ** Only for non-randomized trials with response as primary endpoint.  *** In exceptional circumstances, unequivocal progression in non-target  lesions may be accepted as disease progression.  Note: Patients with a global deterioration of health status requiring  discontinuation of treatment without objective evidence of disease  progression at that time should be reported as "symptomatic  deterioration." Every effort should be made to document the objective  progression even after discontinuation of treatment.   |
|---|  
For Patients with Non-Measurable Disease (i.e., Non-Target Disease)  
| Non-Target Lesions                                                                                                                                                                                                                             | New Lesions   | Overall Response   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------|--------------------|
| CR                                                                                                                                                                                                                                             | No            | CR                 |
| Non-CR/non-PD                                                                                                                                                                                                                                  | No            | Non-CR/non-PD*     |
| Not all evaluated                                                                                                                                                                                                                              | No            | not evaluated      |
| Unequivocal PD                                                                                                                                                                                                                                 | Yes or No     | PD                 |
| Any                                                                                                                                                                                                                                            | Yes           | PD                 |
| * 'Non-CR/non-PD' is preferred over 'stable disease' for non-target disease since  SD is increasingly used as an endpoint for assessment of efficacy in some trials  so to assign this category when no lesions can be measured is not advised |               |                    |  
6.3.5 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. 6.3.6 Progression-Free Survival PFS is defined as the duration of time from start of each treatment to time of progression or death, whichever occurs first. 6.3.7 Response Review Simultaneous review of the patients' files and radiological images for all responses will be reviewed by an expert(s) independent of the study at the study's completion.
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6.4 toxicity criteria

The following adverse event management guidelines are intended to ensure the safety of each patient while on the study. The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm\#ctc_40).
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7 safety reporting requirements/data and

Any untoward medical occurrence in a human subject, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the subject's participation in research, whether or not considered related to the subject's participation in the research. 7.1.2 Suspected adverse reaction Suspected adverse reaction means any adverse event for which there is a reasonable possibility that the drug caused the adverse event. For the purposes of IND safety reporting, 'reasonable possibility' means there is evidence to suggest a causal relationship between the drug and the adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means any adverse event caused by a drug.
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7.1.3 unexpected adverse reaction

An adverse event or suspected adverse reaction is considered "unexpected" if it is not listed in the investigator brochure or is not listed at the specificity or severity that has been observed; or, if an investigator brochure is not required or available, is not consistent with the risk information described in the general investigational plan or elsewhere in the current application. "Unexpected" also refers to adverse events or suspected adverse reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug but are not specifically mentioned as occurring with the particular drug under investigation.
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7.1.4 serious

An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious Adverse Event or if it compromises the safety, welfare or rights of subjects or others. 7.1.5 Serious Adverse Event An adverse event or suspected adverse reaction is considered serious if in the view of the investigator or the sponsor, it results in any of the following:
x Death,  
x A life-threatening adverse drug experience
x Inpatient hospitalization or prolongation of existing hospitalization  
x Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions x A congenital anomaly/birth defect.  
x Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse drug experience when, based upon appropriate 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.
7.1.6 Disability A substantial disruption of a person's ability to conduct normal life functions.
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7.1.7 life-threatening adverse drug experience

Any adverse event or suspected adverse reaction that places the patient or subject, in the view of the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction that had it occurred in a more severe form, might have caused death. 7.1.8 Protocol Deviation (NIH Definition) Any change, divergence, or departure from the IRB-approved research protocol. 7.1.9 Non-compliance (NIH Definition) The failure to comply with applicable NIH Human Research Protections Program (HRPP) policies, IRB requirements, or regulatory requirements for the protection of human research subjects. 7.1.10 Unanticipated Problem Any incident, experience, or outcome that:
x Is unexpected in terms of nature, severity, or frequency in relation to
(a) the research risks that are described in the IRB-approved research protocol and informed consent document; Investigator's Brochure or other study documents, and (b) the characteristics of the subject population being studied; AND
x Is related or possibly related to participation in the research; AND  
x Suggests that the research places subjects or others at a *greater risk of harm* (including physical, psychological, economic, or social harm) than was previously known or recognized.
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7.2 nih intramural irb and

7.2.1 NIH Intramural IRB and NCI CD Expedited Reporting of Unanticipated Problems and Deaths
The Protocol PI will report in the NIH Problem Form to the NIH Intramural IRB and NCI Clinical Director:
x All deaths, except deaths due to progressive disease x All Protocol Deviations x All Unanticipated Problems x All non-compliance Reports must be received within 7 days of PI awareness via iRIS. 7.2.2 NIH Intramural IRB Requirements for PI Reporting at Continuing Review The protocol PI will report to the NIH Intramural IRB:  
1. A summary of all protocol deviations in a tabular format to include the date the deviation occurred, a brief description of the deviation and any corrective action.  
2. A summary of any instances of non-compliance 3. A tabular summary of the following adverse events:
x All Grade 2 **unexpected** events that are possibly, probably or definitely related to the research; x All Grade 3 and 4 events that are possibly, probably or definitely related to the research; x All Grade 5 events regardless of attribution; x All Serious Events regardless of attribution.
NOTE: Grade 1 events are not required to be reported.  
7.2.3 NIH Intramural IRB Reporting of IND Safety Reports Only IND Safety Reports that meet the definition of an unanticipated problem will need to be reported to the NIH Intramural IRB.
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7.3 safety reporting criteria to

The Principal Investigator will notify Novartis of each Serious Adverse Event (SAE) as defined under 21 CFR 310.305 encountered in the Clinical Trial within 24 hours of becoming aware of it. This applies to SAEs which occur after the patient takes the first dose of study drug and continues until at least 30 days after the patient has stopped study treatment or until the patient is taken off-study, whichever comes first. Information about all SAEs is collected and recorded on the Novartis Serious Adverse Event Report Form; all applicable sections of the form must be completed in order to provide a clinically thorough report. The PI must assess and record the relationship of each SAE to each specific study treatment, complete the SAE Report Form and send the completed, signed form along with the Novartis provided fax cover sheet to the Novartis Oncology Drug Safety and Epidemiology (DS&E) department by fax (877-778-9739) or email (clinicalsafetyop.phuseh@novartis.com) within 24 hours of PI's awareness.To ensure patient safety, each pregnancy occurring while the patient is on study treatment must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be followed up to determine outcome, including spontaneous or voluntary termination, details of the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal and/or newborn complications. Pregnancy should be reported by the investigator to the oncology Novartis Drug Safety and Epidemiology Department (DS&E) by fax (877-778-9739) or email (clinicalsafetyop.phuseh@novartis.com). Pregnancy follow-up should include an assessment of the possible relationship to the investigational/study treatment and any pregnancy outcome. Any SAE experienced during pregnancy must be reported on the SAE Report Form. Pregnancy outcomes must be collected for the female partners of any males who took study treatment in this study. Consent to report information regarding these pregnancy outcomes should be obtained from the mother.
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7.3.2 pfizer

The Principal Investigator will notify Pfizer of each Serious Adverse Event (SAE) encountered in the Clinical Trial within 24 hours of becoming aware of it, even if complete information is not yet available. This applies to SAEs which occur after the patient takes the first dose of study drug and continues until at least 30 days after the patient has stopped study treatment or is taken offstudy, whichever comes first. Additionally, the Principal Investigator will notify Pfizer of any SAE the PI suspects has a causal relationship between the Pfizer Product and the SAE at any time after the patient's last study treatment. Information about all SAEs is collected and recorded on the Pfizer-provided Investigator-Initiated Research Serious Adverse Event Form; all applicable sections of the form must be completed in order to provide a clinically thorough report. The PI must assess and record the relationship of each SAE to each specific study treatment, complete the SAE Report Form and send the completed, signed form along with the Pfizer Reportable Event Fax Cover Sheet to the Pfizer US Drug Safety Unit fax number 866997-8322 within 24 hours of PI's awareness. To ensure patient safety, the Principal Investigator will also report each pregnancy, drug exposure during lactation, occupational exposure, and reportable instances of lack of effect as SAEs to Pfizer.
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7.4 data and safety monitoring

The clinical research team will meet on a weekly basis when patients are being actively treated on the trial to discuss each patient. Decisions about dose level enrollment and dose escalation if applicable will be made based on the toxicity data from prior patients. All data will be collected in a timely manner and reviewed by the principal investigator or a lead associate investigator. Adverse events will be reported as required above. Any safety concerns, new information that might affect either the ethical and or scientific conduct of the trial, or protocol deviations will be immediately reported to the IRB using iRIS. The principal investigator will review adverse event and response data on each patient to ensure safety and data accuracy. The principal investigator will personally conduct or supervise the investigation and provide appropriate delegation of responsibilities to other members of the research staff.
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8 statistical considerations

The primary objective of this trial is to determine PFS of patients with low- or intermediate grade NET who receive first-line targeted therapy. This will provide preliminary data to explore whether the PFS on first-line therapy in patients treated with sunitinib or everolimus based on tumor genotyping may represent a potential improvement over published results with regular treatment with everolimus/sunitinib. Secondary objectives include evaluation of response and OS as well as safety and exploring the association between tumor genotype and PFS, and response to treatment. If the findings suggest improved PFS from targeted treatment, a larger randomized trial to confirm the findings will be developed. Following tumor genotyping, eligible patients will be treated with everolimus (Arm 2) or sunitinib (Arm 1). Based on results of the genotyping, enrolled patients will then receive targeted treatment with sunitinib (for mutations in MEN1/PDGFR/KIT/*FTL3* or everolimus (for mutations in NF1/*PTEN/ PI3K/AKT/mTOR/VHL*). Patients with other different mutations or multiple types of mutations will be assigned to receive sunitinib since almost all of these tumors have elevated levels of VEGF/VEGFR expression. Results from previously published trials[53, 55] both demonstrated approximately 11 months PFS in patients similar to the ones to be treated on this protocol. Those patients had not received cytoreductive surgery, and also were not assigned to receive treatment on the basis of any tumor genotype information. In the context of this trial, the study will be designed to determine if meaningful improvement in PFS may be obtained using this focused strategy. For purposes of sample size determination, patients will be primarily evaluated based on the treatment received. Thus, within each treatment arm, using the method of Brookmeyer and Crowley, with 44 patients accrued during a 48-month period (88 total patients for the two arms), and followed for up to an additional 12 months (60 months total from entry of the first patient), there would be 80% power to test whether the median PFS is consistent with 18 months, and greater than 11 months, with a 0.10 alpha level one-sided significance test. In practice, a Kaplan-Meier curve of PFS will be constructed for each arm and will have the median as well as key time points such as 12 and 18 months estimated, along with appropriate 80% and 95% confidence intervals to explore whether the present results exceed those from prior studies. In addition, the Kaplan-Meier curves for all patients who received either sunitinib and everolimus as their treatments may be combined into one pooled Kaplan-Meier curve if the two curves for these treatments are sufficiently similar to one another (p>0.30 by a two-tailed logrank test). This combined curve will then be evaluated relative to the published median of 11 months PFS for each arm to provide a more powerful comparison relative to the historically expected results. In addition, Kaplan-Meier curves limited to the patients who received targeted therapy based solely on mutation status may be constructed for exploratory and descriptive purposes. Response and overall survival will also be evaluated as secondary endpoints, based on the patients treated with sunitinib or everolimus, using all patients receiving treatment. These results will be descriptive and may consist of fractions of responses as well as Kaplan-Meier curves for survival. The association between genotype and PFS will be explored by evaluating the results within a treatment based on the major genotype categories identified. Safety will be evaluated by tabulating and reporting the distribution of the worst grade of each type of toxicity found, per patient, separately by arm. Should any particular type of toxicity result in 5 or more patients with grade 3-4 toxicity, a comparison of the distributions of toxicity between the two arms may be performed using a Cochran-Armitage test for trend. Because the patients may not end up being assigned in equal proportions to the two arms, and because the goal is to have 44 evaluable patients who have received each treatment, additional patients beyond the 44 described above may be enrolled on the arm with faster accrual. As such, the study will have an accrual ceiling of 120 patients, with accrual ending when there are 44 evaluable patients on the arm with fewer patients. An amendment may also be needed if a lower proportion of patients than expected receive study drug therapy or if a high portion of treated patients are not evaluable for response. It is anticipated that 20-30 patients per year may enroll onto this trial; thus, accrual may be completed in 4-5 years.
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9 collaborative agreements 9.1 cooperative

The everolimus used in this trial in NCI will be obtained under a CRADA (02975) with Novartis, the manufacturer of the agent.
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9.2 clinical trials agreement (cta)

The sunitinib used in this trial in NCI will be obtained under CTA with Pfizer (00963-14), the manufacturer of the agent.
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10 human subjects protections 10.1

Subjects from both gender groups and all racial/ethnic groups are eligible for this study if they meet the eligibility criteria. Efforts will be made to extend accrual to a representative population.
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10.2 participation of children

Patients age 18 and older will be eligible for this study. The incidence and prevalence of metastatic pancreatic and gastrointestinal neuroendocrine tumors in the pediatric patient population is exceedingly rare and this is the rationale for not including this patient population.
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10.3 participation of subjects unable

Adults unable to give consent are excluded from enrolling in the protocol. However re-consent may be necessary and there is a possibility, though unlikely, that subjects could become decisionally impaired. For this reason and because there is a prospect of direct benefit from research participation (Section **10.5**), all subjects will be offered the opportunity to fill in their wishes for research and care, and assign a substitute decision maker on the "NIH Advance Directive for Health Care and Medical Research Participation" form so that another person can make decisions about their medical care in the event that they become incapacitated or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH Ability to Consent Assessment Team (ACAT) for evaluation as needed for the following: an independent assessment of whether an individual has the capacity to provide consent; assistance in identifying and assessing an appropriate surrogate when indicated; and/or an assessment of the capacity to appoint a surrogate. For those subjects that become incapacitated and do not have pre-determined substitute decision maker, the procedures described in NIHMEC Policy 87-4 and NIH HRPP SOP 14E for appointing a surrogate decision maker for adult subjects who are (a) decisionally impaired, and (b) who do not have a legal guardian or durable power of attorney, will be followed.
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10.4 evaluation of benefits and

The risks and benefits of participation for adults who become unable to consent, are no different than those described for patients who are less vulnerable.
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10.4.1.1 risks 10.4.1.1.1 study drug

The risks of participation in this study are primarily associated with the toxicities of the study agents as discussed in Section 11. Both study agents have been approved by the FDA for the treatment of progressive, locally advanced or metastatic pancreatic NETs and have been available for clinical use since 2011. Patients will be monitored routinely in order to minimize the risk of complications.
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10.4.1.1.2 specimen collection risks

Risks also include those associated with specimen collection include pain, bleeding and the possibility of infection at the sampling site. Risk of baseline biopsy: All care will be taken to minimize risks that may be incurred by tumor sampling. However, there are procedure-related risks (such as bleeding, infection and visceral injury) that will be explained fully during informed consent. If patients suffer any physical injury as a result of the biopsy, immediate medical treatment is available at the enrolling center. Although no compensation is available, any injury will be fully evaluated and treated in keeping with the benefits or care to which patients are entitled under applicable regulations.
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10.4.1.1.3 risk of radiation

This research study involves exposure to radiation from one CT guided biopsy. This radiation exposure is not required for medical care and is for research purposes only. The amount of radiation received in this study is 0.80 rem which is below the guideline of 5 rem per year allowed for research subjects by the NIH Radiation Safety Committee. The average person in the United States receives a radiation exposure of 0.3 rem per year from natural sources, such as the sun, outer space, and the earth's air and soil. More information about radiation is available in the pamphlet, An Introduction to Radiation for NIH Research Subjects. 10.4.1.1.4 Non-Physical Risks of Genetic Research x Risk of receiving unwanted information Anxiety and stress may arise as a result of the anticipation that unwanted information regarding disease related DNA sequencing or disease tendencies, or misattributed paternity. Patients will be clearly informed that the data related to DNA sequencing and genetic analysis is coded, investigational and will not be shared with patients, family members or health care providers.  
x Risk related to possibility that information may be released This includes the risk that data related to genotype, DNA sequencing or risk for disease tendency or trait can be released to members of the public, insurers, employers, or law enforcement agencies. Although there are no plans to release results to the patients, family members or health care providers, this risk will be included in the informed consent document.  
x Risk to family or relatives Family members or relatives may or may not want to be aware of familial tendencies or genetic risks of disease which may cause anxiety about possible future health problems. As previously noted, patients will be given the option in the consent document to be notified of any medically significant and actionable incidental findings.
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10.4.1.1.5 certificate of confidentiality

As part of study efforts to provide confidentiality of subject information, this study will obtain a Certificate of Confidentiality which helps to prevent forced disclosure of personally identifiable research information. The Certificate of Confidentiality allows investigators on this trial to refuse to disclose identifying information related to the research participants, should such disclosure have adverse consequences for subjects or damage their financial standing, employability, insurability or reputation. The informed consent includes the appropriate coverage and restrictions of the Certificate of Confidentiality.
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10.4.1.2 benefits

Subjects participating in the study may benefit from the study drugs, both of which are indicated in the use of the diseases. Additional possible benefits are tumor shrinkage and reduced morbidity.
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10.5 consent process and documentation

All patients who are being considered for this trial will undergo informed consent prior to being enrolled on the trial. The PI or associate investigator will perform the consenting process. Patients and family members when applicable will be asked to read the consent and will be encouraged to ask questions. It will be stated clearly that participation in the research study is voluntary and that participants can withdraw from the study without losing benefits they would otherwise be entitled to. Patients will be enrolled after the consent document has been signed. The informed consent process will be documented in the patient's medical record and on the  
informed consent document. This process will be performed by the local Principal Investigator or designee. 10.5.1 Procedure for Consent via Telephone The informed consent document will be sent to the subject. An explanation of the study will be provided over the telephone after the subject has had the opportunity to read the consent form. The subject will sign and date the informed consent. The original informed consent document will be sent back to the consenting investigator who will sign and date the consent form with the date the consent was obtained via telephone. A fully executed copy will be returned via mail for the subject's records. The informed consent process will be documented on a progress note by the consenting investigator.
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11 pharmaceutical information 11.1 sunitinib

Sunitinib is manufactured by Pfizer and will be provided to the NIH CC Pharmacy under a CRADA. 11.1.2 Toxicity (Please see package insert for a complete list of toxicities) In over 10,000 subjects with solid malignant tumors diarrhea (52.4%), fatigue (49.0%), nausea (42.7%), decreased appetite (38.5%), vomiting (33.9%), palmar-plantar erythrodysaesthesia syndrome (28.7%), hypertension (27.6%), stomatitis (26.0%), dysgeusia (25.9%), and mucosal inflammation (25.7%) were the most commonly reported treatment emergent adverse events. Overall, 60.3% experienced treatment-related AEs of Grade 3, 4, or 5 severity; Grade 3 in 46.9% of subjects, Grade 4 and grade 5 in 11.9% and1.6% of subjects respectively. The most commonly reported were neutropenia (13.5%), fatigue (9.2%), thrombocytopenia (8.6%), palmar-plantar erythrodysaesthesia syndrome (7.4%), diarrhea (6.3%), hypertension (5.5%), and asthenia (5.0%). Neutropenia (0.3%), fatigue (8.8%), palmar-plantar erythrodysaesthesia syndrome (7.4%), thrombocytopenia (6.8%), diarrhea (6.1%); and hypertension (5.4%) were the most commonly reported treatment-related AEs of Grade 3 severity. Neutropenia (3.2%), thrombocytopenia (1.8%), and anemia (0.9%) were the most commonly reported treatment-related AEs of Grade 4 severity. Pulmonary embolism, cardiac failure, death, cerebral hemorrhage, renal failure, myocardial infarction, hepatic failure, gastrointestinal hemorrhage, multi-organ failure, respiratory failure, pneumonia, septic shock, cardiac arrest, sepsis, sudden death, tumor hemorrhage, and hemorrhage, were among the Grade 5 treatment-related AEs reported in at least 3 subjects.
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boxed warning

SUTENT has been associated with hepatotoxicity, which may result in liver failure or death. Liver failure has been observed in clinical trials (7/2281 [0.3%]) and post-marketing experience.  
Liver failure signs include jaundice, elevated transaminases and/or hyperbilirubinemia in conjunction with encephalopathy, coagulopathy, and/or renal failure. Monitor liver function tests (ALT, AST, bilirubin) before initiation of treatment, during each cycle of treatment, and as clinically indicated. SUTENT should be interrupted for Grade 3 or 4 drug-related hepatic adverse events and discontinued if there is no resolution. Do not restart SUTENT if patients subsequently experience severe changes in liver function tests or have other signs and symptoms of liver failure. Safety in patients with ALT or AST >2.5 × ULN or, if due to liver metastases, >5.0 × ULN has not been established. 11.1.3 Formulation and preparation Sunitinib malate capsules consist of hard gelatin capsules containing sunitinib malate equivalent to 12.5, 25 and 50 mg sunitinib together with mannitol, croscarmellose sodium, povidone, and magnesium stearate.
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11.1.4 stability and storage

Sunitinib - will be stored in a closed container at room temperature (15 to 30°C), away from heat, moisture, and direct light. 11.1.5 Administration procedures Please see Section **3.2.1** 11.1.6 Incompatibilities Co-administration of sunitinib with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase sunitinib concentrations. Grapefruit may also increase plasma concentrations of sunitinib. A dose reduction for sunitinib should be considered when it must be co-administered with strong CYP3A4 inhibitors.
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11.2 everolimus

| Chemical name   | (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)- 1,18-dihydroxy-12-{(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3- methoxycyclohexyl]-1-methylethyl}-19,30-dimethoxy15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24, 26,28-tetraene-2,3,10,14,20- pentaone            |
|-----------------|------------|
| International nonproprietary name                 | Everolimus |  
11.2.2 Chemical structure
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11.2.3 source

Everolimus will be manufactured and provided to the NIH CC Pharmacy by Novartis under a Clinical Trials Agreement.
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11.2.4 toxicity

(Please see package insert for a complete list of toxicities) Toxicity information is based on pooled safety data in cancer patients receiving everolimus
(N=2470) in clinical studies including randomized, double-blind, placebo- or active comparatorcontrolled phase-III trials and phase-II studies related to the approved indications in oncology.  
The most common ADRs (incidence ≥1/10 and suspected to be related to treatment by the investigator) from the pooled safety data were (in decreasing order): stomatitis, rash, fatigue, diarrhea, infections, nausea, decreased appetite, anemia, dysgeusia, pneumonitis, hyperglycemia, weight decreased, pruritus, asthenia, peripheral edema, hypercholesterolemia, epistaxis, and headache.  
The most common grade 3/4 adverse drug reactions (incidence ≥1/100 to <1/10 and suspected to be related to treatment by the investigator) were stomatitis, anemia, hyperglycemia, fatigue, infections, pneumonitis, diarrhea, asthenia, thrombocytopenia, neutropenia, dyspnea, lymphopenia, proteinuria, hemorrhage, hypophosphatemia, rash, hypertension, aspartate aminotransferase (AST) increased, alanine aminotransferase (ALT) increased and pneumonia. The most common adverse events were stomatitis (in 64% of the patients in the everolimus group vs. 17% in the placebo group), rash (49% vs.10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), and infections (23% vs. 6%). The most common grade 3 or 4 drug-related adverse events were anemia, hyperglycemia, stomatitis, thrombocytopenia, diarrhea, hypophosphatemia, and neutropenia[55]. 11.2.5 Formulation and preparation  
| mg, and 10 mg formulations   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                                                                                                                                                                                      |
|------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| x                            | Dispersible tablets (also referred to as  'tablets for oral suspension'): 2 mg, 3  mg and 5 mg. 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.                                                                                                                                                                                                                           |                                                                                                                                                                                                                                      |
| Composition/excipients:      | x                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Tablets: Everolimus drug substance,  butylhydroxytoluene/butylated  hydroxytoluene (BHT), magnesium  stearate, lactose anhydrous/Anhydrous  lactose, lactose monohydrate,  hypromellose/hydroxypropyl  methylcellulose, crospovidone |
| x                            | Dispersible tablets: Everolimus drug  substance,  butylhydroxytoluene/butylated  hydroxytoluene (BHT), magnesium  stearate, lactose monohydrate,  hypromellose/hydroxypropyl  methylcellulose, crospovidone, silica  colloidal anhydrous /colloidal silicon  dioxide, mannitol/D-mannitol, cellulose  microcrystalline/microcrystalline  cellulose The excipients comply with the  requirements of the applicable  compendial monographs European  Pharmacopeia (Ph. Eur.), Unites States  Pharmacopeia / National Formulary  (USP/NF). |                                                                                                                                                                                                                                      |
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11.2.6 stability and storage

Everolimus tablets and everolimus tablets for oral suspension are stored at 25°C (77°F); with excursions permitted between 15°–30°C (59°–86°F). Store everolimus in the original container, and protect from light and moisture. 11.2.7 Administration procedures See Section **3.2.2** 11.2.8 Hazards and precautions The extent of absorption of everolimus through topical exposure is not known. Therefore, caregivers are advised to avoid contact with suspensions of everolimus tablets or dispersible tablets. Wash hands thoroughly before and after preparation of either suspension.
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11.2.9 incompatibilities

Co-administration of everolimus with strong CYP3A4-inhibitors (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, boceprevir, telaprevir) and strong CYP3A4 inducers (e.g., rifampin, rifabutin) is not recommended without close monitoring of everolimus whole blood trough concentrations. Grapefruit and grapefruit juice inhibit cytochrome P450 3A4 and P-gp activity and should therefore be avoided with concomitant use of everolimus. Please refer to Section 4.2.2
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74. Cohen, H.T. and F.J. McGovern, *Renal-cell carcinoma.* N Engl J Med, 2005. 353(23): p.  
2477-90.  
75. Tanaka, C., et al., *Identifying optimal biologic doses of everolimus (RAD001) in patients* with cancer based on the modeling of preclinical and clinical pharmacokinetic and pharmacodynamic data. J Clin Oncol, 2008. 26(10): p. 1596-602.  
76. Yao, J.C., et al., *Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to* intermediate-grade neuroendocrine tumors: results of a phase II study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2008. 26(26): p. 4311-4318.  
77. Yao, J.C., et al., Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2010. 28(1): p. 69-76.  
78. Mendel, D.B., et al., *In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor* targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res, 2003. 9(1): p. 327-37.  
79. O'Farrell, A.M., et al., SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood, 2003. 101(9): p. 3597-605.  
80. Gan, H.K., B. Seruga, and J.J. Knox, *Sunitinib in solid tumors.* Expert Opin Investig Drugs, 2009. 18(6): p. 821-34.  
81. Chow, L.Q. and S.G. Eckhardt, *Sunitinib: from rational design to clinical efficacy.* J Clin Oncol, 2007. 25(7): p. 884-96.  
82. Abrams, T.J., et al., SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther, 2003. 2(5): p. 4718.  
83. Abrams, T.J., et al., *Preclinical evaluation of the tyrosine kinase inhibitor SU11248 as a* single agent and in combination with "standard of care" therapeutic agents for the treatment of breast cancer. Mol Cancer Ther, 2003. 2(10): p. 1011-21.  
84. Rosen, L., M. Mulay, and J. Long, *Phase I trial of SU011248, a novel tyrosine kinase* inhibitor in advanced solid tumors. . J Clin Oncol, 2008. 21(23s): p. suppl; abst 284.  
85. Faivre, S., et al., *Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral* multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol, 2006. 24(1): p.  
25-35.  
86. Fiedler, W., et al., A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease. Blood, 2005. 105(3): p. 986-93.  
87. Sweeney, C.J., et al., *A phase I study of sunitinib plus capecitabine in patients with* advanced solid tumors. J Clin Oncol, 2010. 28(29): p. 4513-20.  
88. Chow, L., D.L. Yonker, and S.A. Laurie, *Sunitinib (SU) in combination with pemetrexed (P)*
in patients (pts) with advanced solid malignancies: a phase I dose escalation study. J Clin Oncol, 2008. 26(15s): p. suppl; abstr 3560.  
89. Traynor, A.M. and J.H. Schiller, Phase I dose-escalation and pharmacokinetic (PK) study of sunitinib (SU) plus docetaxel (D) in patients (pts) with advanced solid tumors (STs). J Clin Oncol, 2008. 26(15s): p. suppl; abstr 3564.  
90. Brell, J.M., et al., *Phase I study of sunitinib malate continuously dosed and standardinfusion gemcitabine in solid tumors. .* J Clin Oncol, 2008. 26(15s): p. suppl; abst 13533.  
91. Heath, E.I. and J.R. Cohen, *Phase I study of sunitinib in combination with carboplatin (C)*
plus paclitaxel (P) in patients (pts) with advanced solid tumors (STs). J Clin Oncol, 2008. 26(15s): p. suppl; abstr 3565.  
92. Chien, A.J., et al., Phase I/II study of sunitinib (SU) in combination with metronomic dosing of cyclophosphamide (C) and methotrexate (M) in patients (pts) with metastatic breast cancer (MBC). J Clin Oncol, 2010. 28(15s): p. suppl; abstr 1067.  
93. Stadler, W.M., *New targets, therapies, and toxicities: Lessons to be learned.* J Clin Oncol, 2006. 24(1): p. 4-5.  
94. Robert, C., et al., *Cutaneous side-effects of kinase inhibitors and blocking antibodies.* Lancet Oncology, 2005. 6(7): p. 491-500.  
95. Suwattee, P., et al., *Sunitinib: a cause of bullous palmoplantar erythrodysesthesia,*
periungual erythema, and mucositis. Arch Dermatol, 2008. 144(1): p. 123-5.  
96. Rosenbaum, S.E., et al., Dermatological reactions to the multitargeted tyrosine kinase inhibitor sunitinib. Support Care Cancer, 2008. 16(6): p. 557-66.  
97. Akerstrom, G. and P. Hellman, *Surgery on neuroendocrine tumours.* Best practice &
research.Clinical endocrinology & metabolism, 2007. 21(1): p. 87-109.  
98. Yeo, W., et al., Hepatitis B reactivation in patients with hepatocellular carcinoma undergoing systemic chemotherapy. Ann Oncol, 2004. 15(11): p. 1661-6.  
99. Loomba, R., et al., Systematic review: the effect of preventive lamivudine on hepatitis B
reactivation during chemotherapy. Ann Intern Med, 2008. 148(7): p. 519-28.  
100. Krishna, G., et al., Effects of oral posaconazole on the pharmacokinetic properties of oral and intravenous midazolam: a phase I, randomized, open-label, crossover study in healthy volunteers. Clin Ther, 2009. 31(2): p. 286-98.  
101. Bajetta, E., et al., Chromogranin A, neuron specific enolase, carcinoembryonic antigen, and hydroxyindole acetic acid evaluation in patients with neuroendocrine tumors. Cancer, 1999. 86(5): p. 858-865.  
102. Sadowski, S.M., et al., *Prospective Study of 68Ga-DOTATATE Positron Emission* Tomography/Computed Tomography for Detecting Gastro-Entero-Pancreatic Neuroendocrine Tumors and Unknown Primary Sites. J Clin Oncol, 2016. 34(6): p. 588-96.
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13 appendices

| ECOG Performance Status Scale       |                                                                                                                                                                                                                                                           |
|-------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade                               | Descriptions                                                                                                                                                                                                                                              |
| Normal activity. Fully active, able |                                                                                                                                                                                                                                                           |
| 0                                   | to carry on all pre-disease  performance without restriction.  Symptoms, but ambulatory.  Restricted in physically strenuous  activity, but ambulatory and able  to carry out work of a light or  sedentary nature (e.g., light  housework, office work). |
| 1                                   | In bed <50% of the time.  Ambulatory and capable of all  self-care, but unable to carry out  any work activities. Up and about  more than 50% of waking hours.                                                                                            |
| 2                                   | In bed >50% of the time. Capable  of only limited self-care, confined  to bed or chair more than 50% of  waking hours.                                                                                                                                    |
| 3                                   | 100% bedridden. Completely  disabled. Cannot carry on any  self-care. Totally confined to bed  or chair.                                                                                                                                                  |
| 5                                   | Dead.                                                                                                                                                                                                                                                     |
| 4                                   |                                                                                                                                                                                                                                                           |
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13.2 appendix b pregnancy and

There are no adequate data from the use of everolimus in pregnant women. Studies in animals have shown reproductive toxicity effects including embryo-toxicity and feto-toxicity. The potential risk for humans is unknown. Everolimus should not be given to pregnant women unless the potential benefit outweighs the potential risk to the fetus. If a pregnancy occurs while on study treatment, the newborn will be followed for at least 12 months. It is not known whether everolimus is excreted in breast milk. However, in animal studies everolimus and/or its metabolites readily passed into the milk of lactating rats. Women taking everolimus should therefore not breast-feed.
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women of childbearing potential

Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must use highly effective contraception during the study and for 8 weeks after stopping treatment. Highly effective contraception is defined as either:
x Total abstinence: When this is in line with the preferred and usual lifestyle of the subject.  
[Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception]
x Sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment x Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). [For female subjects on the study, the vasectomised male partner should be the sole partner for that subject].  
x Use of a combination of any two of the following (a+b or a+c or b+c):
a. Use of oral, injected, implanted or other hormonal methods of contraception b. Placement of an intrauterine device (IUD) or intrauterine system (IUS) c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository x In case of use of oral contraception, women should have been stable on the oral agent before taking study treatment.
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male contraception

Sexually active males must use a condom during intercourse while taking the drug and for 8 weeks after stopping treatment and should not father a child in this period. A condom is required to be used also by vasectomised men in order to prevent delivery of the drug via seminal fluid. Female partners of male patients must also be advised to use one of the following contraception methods: Use of (1) oral, injected, implanted or other hormonal methods of contraception, or (2) intrauterine device (IUD) or intrauterine system (IUS), or (3) prior male/female sterilization.
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fertility

The potential for everolimus to cause infertility in male and female patients is unknown. However, menstrual irregularities, secondary amenorrhea and associated luteinizing hormone (LH)/follicle stimulating hormone (FSH) imbalance has been observed. Based on non-clinical findings, male and female fertility may be compromised by treatment with everolimus. 13.3 APPENDIX C: **PANEL OF 197 GENES TESTED FOR IN CLINICAL MOLECULAR PROFILING**
CORE (CLIA-COMPLIANT). **GENES IMPLICATED IN NETS ARE IN BOLD.**  
| Genes   |         |        |         |
|---------|---------|--------|---------|
| ABL1    | DMBT1   | KRAS   | RNF2    |
| ACN9    | DNMT3A  | KRT20  | RPS15   |
| ACVR1B  | DPYD    | MAGI1  | RUNX1   |
| AKT1    | EGF     | MAP2K4 | SCLC1   |
| ALK     | EGFR    | MEN1   | SDHA    |
| APC     | EGR3    | MET    | SDHAF1  |
| ARHGEF2 | EIF4G2  | MGMT   | SDHAF2  |
| ARID1A  | EML4    | MIB1   | SDHB    |
| ASXL1   | ENO1    | MKI67  | SDHC    |
| ATM     | ENO2    | MLH1   | SDHD    |
| ATRX    | ERBB2   | MPL    | SELT    |
| BAG3    | ERBB3   | MSH2   | SETD2   |
| BAI3    | ERBB4   | MSH6   | SLC38A1 |
| BAP1    | ERG     | MUC1   | SLC6A2  |
| BCAN    | EZH2    | MUC17  | SLTM    |
| BCL2    | F10     | MUC2   | SMAD4   |
| BRAF    | FAM123B | MUC3A  | SMARCA4 |
| BRCA1   | FBXW7   | MUTYH  | SMARCB1 |
| BRCA2   | FGFR1   | MVP    | SMO     |
| CA12    | FGFR2   | MYC    | SMOX    |
| CA9     | FGFR3   | MYD88  | SMUG1   |
| CALU    | FH      | NAT1   | SOCS1   |
| CARD11  | FHIT    | NAT2   | SRC     |
| CBL     | FLCN    | NES    | SST     |
| CCND1   | FLT3    | NF1    | STC1    |
| CD34    | FOXL2   | NF2    | STK11   |
| CDC73   | FZR1    | NOTCH1 | SUFU    |
| CDH1    | GATA1   | NOTCH2 | SYP     |
| CDK4    | GATA2   | NPM1   | TCF7L2  |
| CDKN2A  | GATA3   | NRAS   | TET2    |
| CDX2    | GFAP    | PBRM1  | TFE3    |
| CEACAM7 | GNA11   | PCNA   | TFEB    |
| CEBPA   | GNAQ    | PDGFRA | TMEM97  |
| CES3    | GNAS    | PDZD4  | TNFAIP3 |
| CHDM    | GRP     | PGR    | TNFSF13 |
| CRLF2   | GSTM1   | PHOX2B | TP53    |  
| CSF1R   | HIVEP3    | PIK3CA   | TPD52L2   |
|---------|-----------|----------|-----------|
| CSF3    | HNF1A     | PMS2     | TPM4      |
| CTNNA1  | HRAS      | PPP2R1A  | TSC1      |
| CTNNB1  | IDH1      | PRCC     | TSC2      |
| CUL2    | IDH2      | PRKAR1A  | TSHR      |
| CYLD    | IFNA1     | PTCH1    | TYK2      |
| CYP1A1  | IGKV1D-43 | PTEN     | VHL       |
| DAXX    | IL2       | PTGS2    | VIM       |
| DCC     | ITGB5     | PTPN11   | WT1       |
| DES     | JAK1      | RB1      | WTS       |
| DIRAS1  | JAK2      | REEP5    | XRCC1     |
| DIRC2   | JAK3      | RET      | ZNF135    |
| DKK3    | KDR       | RNF139   |           |
| DLD     | KIT       |          |           |  
13.4 APPENDIX D: PATHWAY ANALYSIS OF 193 MAPPED GENES USING INGENUITY PATHWAY  
ANALYSIS*  
| ANALYSIS*                                  |                                                                                         |
|--------------------------------------------|-----------------------------------------------------------------------------------------|
| Ingenuity  Canonical  Pathways             | Molecules                                                                               |
| AMPK Signaling                             | SRC,TSC1,PIK3CA,PPP2R1A,GNAS,AKT1,STK11,TSC2,SMARCA4,ATM,PRKAR1A                        |
| Angiopoietin  Signaling                    | PIK3CA,AKT1,NRAS,PTPN11,HRAS,KRAS,ATM                                                   |
| EGF Signaling                              | MAP2K4,SRC,PIK3CA,JAK1,AKT1,EGF,HRAS,ATM,EGFR                                           |
| Endothelin-1  Signaling                    | BRAF,MYC,SRC,PIK3CA,GNAS,NRAS,GNA11,GNAQ,HRAS,KRAS,PTGS2,ATM                            |
| Ephrin A Signaling                         | PIK3CA,PTPN11,ATM                                                                       |
| Ephrin B Signaling                         | GNAS,CBL,GNA11,GNAQ,HRAS,CTNNB1                                                         |
| Ephrin Receptor  Signaling                 | SRC,GNAS,AKT1,NRAS,PTPN11,GNA11,ABL1,GNAQ,EGF,HRAS,KRAS,JAK2                            |
| ErbB Signaling                             | MAP2K4,PIK3CA,AKT1,NRAS,ERBB4,EGF,HRAS,KRAS,ERBB3,ERBB2,ATM,EGFR                        |
| ErbB2-ErbB3                                | PIK3CA,NRAS,TYK2,HRAS,KRAS,ERBB3,CCND1,PTEN,MYC,AKT1,ERBB2,JAK3,A                       |
| Signaling                                  | TM                                                                                      |
| ErbB4 Signaling                            | PIK3CA,AKT1,NRAS,ERBB4,HRAS,KRAS,ATM                                                    |
| ERK/MAPK  Signaling                        | BRAF,MYC,SRC,PIK3CA,PPP2R1A,NRAS,HRAS,KRAS,ATM,PRKAR1A                                  |
| ERK5 Signaling                             | MYC,SRC,AKT1,NRAS,PTPN11,GNAQ,EGF,HRAS,KRAS,EGFR                                        |
| Erythropoietin  Signaling                  | SOCS1,SRC,PIK3CA,AKT1,NRAS,CBL,HRAS,KRAS,JAK2,ATM                                       |
| Inhibition of  Angiogenesis by  TSP1       | MAP2K4,TP53,AKT1,KDR                                                                    |
| Insulin Receptor                           | TSC1,PIK3CA,JAK1,NRAS,HRAS,KRAS,JAK2,PTEN,AKT1,CBL,PTPN11,TSC2,PRKA                     |
| Signaling                                  | R1A,ATM                                                                                 |
| mTOR Signaling                             | TSC1,PIK3CA,PPP2R1A,AKT1,NRAS,EIF4G2,STK11,TSC2,RPS15,HRAS,KRAS,ATM                     |
| p38 MAPK  Signaling                        | MAP2K4,TP53,MYC,DAXX  MYC,MAP2K4,SRC,PIK3CA,NRAS,JAK1,TYK2,PDGFRA,ABL1,HRAS,KRAS,JAK2,J |
| PDGF Signaling                             | AK3,ATM                                                                                 |
| PI3K/AKT                                   | TP53,TSC1,PIK3CA,JAK1,NRAS,TYK2,HRAS,KRAS,JAK2,CCND1,PTEN,BCL2,PPP2                     |
| Signaling                                  | R1A,AKT1,TSC2,PTGS2,JAK3,CTNNB1                                                         |
| Protein Kinase A                           | GNAS,PTCH1,GNAQ,HNF1A,PTEN,BRAF,PTPN11,DCC,SMO,SMAD4,PTGS2,CTNN                         |
| Signaling                                  | B1,TCF7L2,PRKAR1A  PIK3CA,NRAS,FGFR1,HRAS,FGFR2,KRAS,CCND1,PTEN,BCL2,FGFR3,MAGI1,CBL,   |
| PTEN Signaling                             | AKT1,PDGFRA,KDR,EGFR                                                                    |
| Role of Tissue                             | TP53,SRC,PIK3CA,NRAS,GNA11,GNAQ,HRAS,KRAS,JAK2,PTEN,F10,AKT1,PTPN1                      |
| Factor in Cancer                           | 1,ITGB5,EGFR,ATM                                                                        |
| VEGF Family  Ligand-Receptor  Interactions | PIK3CA,AKT1,NRAS,HRAS,KRAS,KDR,ATM                                                      |
| VEGF Signaling                             | SRC,PIK3CA,AKT1,NRAS,PTPN11,HRAS,KRAS,KDR,ATM,BCL2                                      |
| Wnt/β-catenin                              | TP53,CDKN2A,SRC,GNAQ,CCND1,HNF1A,APC,ACVR1B,MYC,CDH1,PPP2R1A,AK                         |
| Signaling                                  | T1,DKK3,SMO,CTNNB1,TCF7L2                                                               |
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13.5 appendix e collection/recording of

1.0 General Guidelines 1.1 Frequency of monitoring. Blood pressure (BP) should be monitored at baseline, and then at every clinic visit, as well as at home during weeks when there is no clinic visit.  
1.2 Data recording. All required data should be recorded in the appropriate CRF or on the patient's blood pressure monitoring diary, as appropriate. The following data are required at baseline and at each subsequent assessment:
x Assessment date and time x Pulse x Systolic and diastolic BP
1.3 Risk factors for hypertension (assess and record data in baseline history/physical CRF)
x Diabetes (type 1 or type 2) x Renal disease (specify on CRF) x Endocrine condition associated with HTN (specify on CRF)
x Use of steroids or NSAIDs (specify all concomitant meds)
x Underlying cardiovascular condition - specify (i.e., ischemic heart disease)
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2.0 baseline data collection (at

x Current BP x Proteinuria, if present 2.2 Patients with preexisting hypertension (*i.e.*, those for whom "hypertension" is entered as a concomitant condition at study entry, or those who are currently receiving therapy with antihypertensive medication) - also record:
x Date of HTN diagnosis (original) x Type HTN (essential or secondary)
x CTCAE grade of HTN (at time of study entry)
x Trade name, drug class*, dose, dose frequency, start/stop dates/ongoing of the following: - Antihypertensive agents taken at study entry - Antihypertensive agents taken in past (e.g., discontinued for toxicity, lack of efficacy)
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3.0 follow up bp data

3.1 All patients (at each clinic visit)
x Current BP x Proteinuria, if present 3.2 Patients with treatment-emergent hypertension [defined as BP increase of >20 mmHg
(diastolic) OR systolic BP >139 OR diastolic BP > 90 (if previously normal or grade 1 per CTCAE v4) - record at time of hypertension diagnosis and at all subsequent clinic visits:
x BP changes from baseline (or from previous assessment) (specify CTCAE
grade changes)
x Hypertension-related symptoms as reported by patient (e.g., headache) x Other relevant changes associated with development of hypertension (e.g.,
ECG abnormalities)
x Trade name, drug class*, dose, dose frequency, start/stop dates/ongoing of currently prescribed antihypertensive agents 3.3 Patients with pre-existing hypertension at study entry - record at each clinic visit x BP changes from previous clinic visit (specify CTCAE grade changes)
x Hypertension-related symptoms reported by patient (e.g., headache) x Other relevant changes associated with development of hypertension (e.g.,
ECG abnormalities)
x Changes in antihypertensive medications since last assessment (*e.g.*, dose change, add/discontinue drug)
*Classes of antihypertensive drugs include ACE inhibitors, calcium channel blockers, alpha blockers, beta blockers, diuretics, angiotension II receptor antagonists.
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13.6 appendix f patient drug

13.6.1 Sunitinib Patient Name _________________________________ Study ID __________________
Please complete this form and return to the research nurse or doctor every cycle You will take: Sunitinib **Dose**: _____ mg each morning with or without food. Be advised to drink plenty of water while you are on sunitinib.  
You will only need to take your blood pressure once per week. Please be sure you are seated when you take the measurement.  
| take the measurement. DAY DATE TIME TAKEN Blood Pressure                                      | COMMENTS (side effects or  missed doses)   |
|-----------------------------------------------------------------------------------------------|--------------------------------------------|
| 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26 |                                            |  
| 27  28   |
|----------|  
13.6.2 Everolimus  
Patient Name _________________________________ Study ID __________________ Please complete this form and return to the research nurse or doctor every cycle You will take: E**verolimus** Dose: *________.*  
| You will take: Everolimus                                                                             | Dose: ________.                                    |
|-------------------------------------------------------------------------------------------------------|----------------------------------------------------|
| DAY DATE                                                                                              | TIME TAKEN COMMENTS (side effects or missed doses) |
| 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28 |                                                    |  
Patient Signature:____________________________________  
| Parameter                   | 1 point                        | 2 points         | 3 points           |
|-----------------------------|--------------------------------|------------------|--------------------|
| Total bilirubin (mg/dl)     | <2                             | 2-3              | >3                 |
| Serum albumin, (g/dl)       | >3.5                           | 2.8-3.5          | <2.8               |
| PT INR                      | <1.7                           | 1.71-2.30        | > 2.30             |
| Ascites                     | None                           | Mild             | Moderate to Severe |
| Hepatic encephalopathy None | Grade I-II (or suppressed with | Grade III-IV (or |                    |
| medication)                 | refractory)                    |                  |                    |  
Points are assigned based on the above parameters and totaled. Based on totals the following categories are assigned.  
| Points   | Child Pugh Class   |
|----------|--------------------|
| 5-6      | A                  |
| 7-9      | B                  |
| 10-15    | C                  |