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reporting to the study drug

The BTTC Coordinating Center will forward all SAE reports to the NCI IRB via the Lead PI, FDA (when applicable), and Novartis and Bayer Pharmaceuticals. The Lead Principal Investigator will report any SAEs, study drug exposure during pregnancy, and reports of misuse or abuse of study drug, including initial and follow up reports, to Novartis on a MedWatch form (including coversheet and Novartis Study Code found in M-CRADA) within 1 business day of becoming aware of such information. The Lead Principal Investigator will forward to Novartis any findings that might alter the current benefit-risk profile of the study drug or that would be sufficient to consider changes in the study drug administration or in the overall conduct of the study within five calendar days of becoming aware of such information.  
| Bayer HealthCare Pharmaceuticals Inc. FAX: (973) 709-2185  Telephone: 1-888-842-2937  Email: DrugSafety.GPV.US@bayer.com Novartis Pharmaceuticals Corporation   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Novartis Pharmaceutical U.S. DS&E Department FAX: 877-778-9739 If above Fax \# is non-functional, send to: clinicalsafetyop.phuseh@novartis.com SAEs will be forwarded to Bayer/Onyx via the BTTC Coordinating Center in accordance with the following:
All serious adverse events should be reported to Bayer/Onyx within 24 hours. In the event of an SAE, the investigator should refer to the Pharmacovigilance section of the contract for reporting procedures. In brief:
The Lead PI may report serious adverse **drug reactions (SADRs) using either:**
An ADEERS form (Adverse Event Expedited Reporting System) available at http://ctep.cancer.gov/reporting/adeers.html OR A MedWatch form available at http://www.fda.gov/medwatch/ All reports shall be sent electronically to:
Electronic Mailbox: DrugSafety.GPV.US@bayer.com Facsimile: (973) 709-2185 Address: Global Pharmacovigilance - USA Mail only Bayer HealthCare Pharmaceuticals Inc.  
P.O. Box 1000 Montville, NJ 07045-1000 Address: 340 Changebridge Road FDX or UPS only Pine Brook, NJ 07058 Reports for all Bayer products can also be phoned in via our Clinical Communications Dept: Phone: 1-888-842-2937 Occasionally BTTC may contact the reporter for additional information, clarification, or current status of the subject for whom an adverse event was reported.  
Novartis Safety Information The Lead PI shall report any other relevant/ important safety information to Novartis in the final study report and at such other periods as Novartis may request. The Sponsor Principal Investigator shall ensure that at a minimum the form contains:
(a) Information on the person who contacted Sponsor (i.e., the initial reporter);  
(b) Information about the patient or clinical trial subject; (c) Details of the suspected Study Drug (d) Details on the safety events experienced by the patient
The Lead PI shall cooperate with all reasonable requests by Novartis to ensure that individual safety reports are sufficiently investigated, including requests to seek additional information relating to an individual safety reports or other relevant safety information. The Lead PIshall perform SAE reconciliation between the Sponsor's Study database and an output of the Novartis Safety Database at the following time points:
- One year after First Patient First Visit and yearly thereafter  
- At Last Patient Last Visit
The Lead PI will confirm that, for the period being reconciled, all information in the Sponsor's Study database that needed to be transferred to Novartis as per Novartis Annex, are contained in the output from the Novartis Safety Database. Where discrepancies are identified the Lead PI shall send/resend the information to Novartis DS&E as per the contact information in and using the supplied Novartis cover sheet.
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novartis u.s. drug safety and

- All reports of SAEs, drug exposure during pregnancy, study drug abuse or misuse Any Adverse Drug Reactions to Novartis products should be sent to U.S. DS&E at fax\#: 877-778-9739
- The Novartis Coversheets must be attached to all SAE submissions
- SAE Submissions must reference the Novartis Study Code. - Should the designated SAE Fax\# be non-functional please send SAEs to the designated SAE mailbox: clinicalsafetyop.phuseh@novartis.com)
The Lead PI shall provide the Novartis Medical contact listed in Novartis Annex with a written confirmation that the reconciliation was performed, the outcome of the reconciliation and documentation that, where discrepancies were identified, Novartis DS&E was informed (e.g. delivery confirmations).
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guidelines & procedures for reporting

Neither the FDA nor the ICH GCP guidelines define the terms "protocol violation" or "protocol deviation." The definition is often left to the Lead Institution IRB. Accordingly, since NCI, Center for Cancer Research is the Coordinating Center and the Lead PI must adhere to those policies set by the NCI IRB, the definitions for unanticipated problem and protocol deviation as described by the NCI IRB will be applied for reporting purposes for all institutions participating in the NCI
Center for Cancer Research Multi-center Project. Definitions are listed in section 6.1.  
Protocol Deviations or Unanticipated problems occurring at a participating institution will be submitted to that institution's own IRB in accordance with local policies and procedures. However, the participating institution must submit a report to the BTTC Coordinating Center even in instances where the local IRB does not require a report. Deviations or Unanticipated Problems must be submitted to the BTTC Coordinating Center within 5 business calendar days after becoming aware of the event (if not reportable to the local IRB. When Deviations or Unanticipated Problems are reported to BTTC, but, the local IRB does not require a report, the report that is submitted to the BTTC Coordinating Center must be accompanied by a formal memo explaining the local policy and the rationale for not reporting the event to the local IRB. Deviation or Unanticipated Problem Reports and any accompanying documentation (to include the local IRB acknowledgement of the event when applicable) are to be submitted to the BTTC Coordinating Center's Research Nurse, via fax 301-451-4432, or email using the problem report form in Appendix **13.6**
NCI Center for Cancer Research Coordinating Center: Upon receipt of the deviation/unanticipated problem report from the participating institution, the BTTC Coordinating Center will submit the report to the Lead Principal Investigator for review. Subsequently, the participating institution's IRB deviation/unanticipated problem report will be submitted to the NCI IRB for review.
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data and safety monitoring plan

The clinical research team will have a teleconference every other week 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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bttc coordinating center monitoring plan

As the CCR is the coordinating center for this multi-site study, the CCR to maintain a monitoring program. The CCR's program allows for confirmation of: study data, specifically data that could affect the interpretation of primary study endpoints; adherence to the protocol, regulations, and SOPs; and human subjects protection. This is done through independent verification of study data with source documentation focusing on:
- Informed consent process
- Eligibility confirmation
- Drug administration and accountability
- Adverse events monitoring
- Response assessment.  
The monitoring program also extends to multi-site research when the CCR is the coordinating center. This trial will be monitored by personnel employed by an NCI contractor. Monitors are qualified by training and experience to monitor the progress of clinical trials. Personnel monitoring this study will not be affiliated in any way with the trial conduct.
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safety monitoring committee (smc)

This protocol will require oversight from the Safety Monitoring Committee (SMC). Initial review will occur as soon as possible after the annual NCI-IRB continuing review date. Subsequently, each protocol will be reviewed as close to annually as the quarterly meeting schedule permits or more frequently as may be required by the SMC. For initial and subsequent reviews, protocols will not be reviewed if there is no accrual within the review period. Written outcome letters will be generated in response to the monitoring activities and submitted to the Principal investigator and Clinical Director or Deputy Clinical Director, CCR, NCI.
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7.0 statistical considerations phase i

A Phase I design will be used where up to 6 patients will be treated at each dose combination. For each dose combination, three patients will be treated. If none show a DLT as defined in section 3.1.3, then the dose will be escalated for the next cohort of patients. If 2 or 3 have a DLT, then the previous dose (as defined in the cohort sequence above) is the maximum tolerated dose (MTD). If 1 of 3 patients has a DLT, then an additional 3 patients will be added to this dose. If 1 of 6 has a DLT, then the dose will be escalated. If 2 or more of 6 have a DLT, then the previous dose will be the MTD given that 6 patients have been treated in that dose. This 3+3 design has a 91% chance (70%, 17%) of dose escalating when the true toxicity rate for that dose is 10% (30%, 50%). It is expected that up to 6 dose combination will be observed, so that the expected sample size will range from 6 (if unacceptable toxicities are seen at the lowest doses) to 36 (if 6 patients per cohort are required for all 6 cohorts).
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phase ii component

Time to progression and overall survival will be evaluated using the Kaplan-Meier product-limit survival curve methodology. Six-month Progression Free Survival (PFS) will be estimated using Kaplan-Meier estimates and associated two-sided 95% confidence intervals.  
Group A: Recurrent glioblastoma with no **prior exposure to bevacizumab cohort:**
A maximum of 34 patients will be observed in a two-stage Simon optimum design. In the first stage, 9 patients will be accrued. If two or more patients are progression-free at 6 months (PFS6), an additional 25 patients will be accrued. We halt registering patients after 9 patients until we have at least 2 patients are progression free at six months. If 9 or more out of 34 have PFS6, then the study will be declared promising. This study has a 5% chance of declaring promise if the PFS6 rate is at most 15%. It has an 80% chance of declaring promise if the PFS rate is at least 35%.  
**Group B: Recurrent glioblastoma with prior exposure to bevacizumab cohort:** In the group that failed bevacizumab, a maximum of 32 patients will be observed in a twostage Simon optimum design. In the first stage, 14 patients will be accrued. If one or more patients is progression-free at 3 months (PFS3), an additional 18 patients will be accrued. We will halt registration after 14 patients until at least 1 patient is progression free at 3-months. If 2 or more out of 32 have PFS3, then the study will be declared promising. This study has a 5% chance of declaring promise if the PFS3 rate is at most 1%. It has an 80% chance of declaring promise if the PFS rate is at least 12%.  
**Group C:** A third cohort consisting of 16 patients with **anaplastic glioma** (as defined in section **2.1.1.1**) will enroll independently but will not be included in the primary endpoint assessment.
The Phase II Multicenter component of the trial will be monitored by the Study Chair, Jeffrey Raizer, MD, and the study statistician, Yuan Ying PhD, as described below. At phase II, we will monitor the toxicity based on the combined data from the above three cohorts with a total sample size of 82. All grade 3 or greater toxicities attributable to the study treatment in the first 28-day cycle will be counted. Accrual will be temporarily suspended for analysis after each of the following interim accrual goals. We will monitor the toxicity when the accrual is 5, 10, 20, 35, 50 and 65 based on using the following stopping rule: if the posterior probability of toxicity greater than 0.3 is greater than 0.95 (i.e., Pr(toxicity>0.3|data) >0.95), we terminate the study for toxicity. Assuming the beta prior Beta(0.6, 1.4) for the toxicity, we have the following operating characteristics.  
| True toxicity probability          | 0.2   | 0.3   | 0.4   | 0.5   |
|------------------------------------|-------|-------|-------|-------|
| Stopping Probability               | 1.4%  | 14.1% | 64.6% | 97.2% |
| Average number of patients treated | 82    | 74.9  | 49.9  | 24.9  |  
Operating characteristics of the proposed stopping rule We obtain the following stopping boundary: the study will be terminated if we observe >= 4/5, 6/10, 10/20, 16/35, 21/50, 26/65 (\# of patients experienced DLTs/\# of patients treated). Note that our safety monitoring starts with a small cohort size of 5, and then gradually increases to 15. Therefore, if the treatment agents are overly toxic, the trial will stop before exposing many patients to toxicities.  
Patient-reported outcomes: The sample size for this trial was based on the primary end point of the study. Received MDASI-BT forms will be checked versus the timing schedule and considered as valid if they fall within ten days of the scheduled assessment. Compliance rates will be calculated as the number of received valid forms over the number of expected forms. Differences between groups in compliance will be tested by use of Fisher's exact test at every time point. We will use descriptive statistics to describe how patients rate symptom severity and interference with function at each time point. Error bar graphs for each of the symptoms will be constructed at each time point. The proportion of patients rating their symptoms to be 7 or greater (on a 0-10 scale) will also be reported. We will construct individual patient profiles for each of the selected symptoms to describe the individual patients' patterns of change over time. We will calculate the mean core symptom severity, mean severity of the MDASI-BT and mean symptom interference at the time of clinical evaluation. Estimates of differences in the mean symptom severity and mean symptom interference between responders and non-responders will be estimated in the intent to treat population. All patients with at least one valid questionnaire will be included in the analyses. Questionnaires completed at study registration will be considered baseline. All questionnaire data received after randomization will be used in the primary analyses. Differences of at least 2 points will be classified as the minimum clinically meaningful change in the symptom severity and symptom interference measures. For example, an increase of 2 points or more would mean a moderate improvement, whereas a decrease of 2 points or more would be interpreted as moderate worsening. For individual symptoms, a rise in a symptom score means deterioration, whereas a reduced score means improvement of the specific symptom.
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8.0 collaborative agreements agreement type

There is a BTTC consortium agreement in place between all of the participating institutions listed on the title page of this study. There is a CDA in place (CDA \#13471-17). In addition, there is an executed CRADA agreement with Novartis (\#03235) and an executed CRADA with Bayer (\#03195) who support this study.
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9.0 human subjects protections rationale

This study was designed to include women and minorities, but was not designed to measure differences of intervention effects. Males and females will be recruited with no preference to gender. No exclusion to this study will be based on race. Minorities will actively be recruited to participate. High grade gliomas occur in patients of all races and although there is a slight predominance in men, this is a disease that is also common in women. The molecular targets of the everolimus and sorafenib within the tumor are not known to be different among patients based on gender or race; hence this study will be open to all adults.
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participation of children

Individuals under the age of 18 will not be eligible to participate in this study because they are unlikely to have glioblastoma, and because of unknown toxicities of the study agents in the pediatric patient. Furthermore, the targets of the everolimus and sorafenib are not as prevalent in pediatric malignant gliomas and therefore, the efficacy of this regimen will be initially determined in the adult population before consideration of its use in pediatrics.
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participation of subjects unable to

For adults who are or may be unable to consent: All research protocols should state whether adults who are unable to provide initial informed consent are excluded or are eligible to enroll, and the conditions, if any, under which adults who lose the ability to provide on-going consent subsequent to giving initial consent, may continue to participate. 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 **9.6.3**), all subjects ≥ age 18 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 MAS Policy 87-4 f and NIH HRPP SOP 14E or 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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participation of subjects unable to

Each institution will follow their own procedure for re-consenting subjects unable to re-consent and will notify the Coordinating Center at time of continuing review of these occurrences. At time of Amendment C, Version 10-04-2017, subjects enrolled at non-NCI sites are off treatment.
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evaluation of benefits and risks/discomforts

The primary risk to patients participating in this research study is from the toxicity of sorafenib, everolimus, or both drugs. Both are investigational agents in the treatment of gliomas, although bevacizumab is an FDA-approved drug for the treatment of colorectal carcinoma. The protocol provides for detailed and careful monitoring of all patients to assess for toxicity. Toxicity data from the current dose level will be collected and reviewed to ensure that there were no severe toxicities that would preclude further patient enrollment. Patients will be treated with therapeutic intent and response to the therapy will be closely monitored.
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risks/benefits analysis benefits

The potential benefit to a patient on this study is a reduction in the bulk of their tumor and improvement in cancer lesions, which may or may not have favorable impact on symptoms and/or survival.
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risks

Risks include the possible occurrence of any of a range of side effects which are listed in the Consent Document or this protocol document. Frequent monitoring for adverse effects will help to minimize the risks associated with administration of the study agents.
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risks/benefits analysis

The potential benefits from this therapy are disease stabilization or shrinkage and a reduction in symptoms caused by the brain tumor such as neurological deficits and headache. Given the efforts to minimize risk with the administration of this combination, this protocol involves greater than minimal risk, but presents the potential for direct benefit to individual subjects.
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consent and assent process and

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. Separate consents will be obtained for any surgical procedures performed. 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. If new safety information results in significant changes in the risk/ benefit assessment, the consent form will be reviewed and updated as necessary. All subjects (including those already being treated) will be informed of the new information, be given a copy of the revised form, and be asked give their consent to continue in the study.
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reconsent via phone (at nci)

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. A witness to the subject's signature will sign and date the 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.  
Informed Consent of non-English speaking subjects (at NCI)
If there is an unexpected enrollment of a research participant for whom there is no translated extant IRB approved consent document, the principal investigator and/or those authorized to obtain informed consent will use the Short Form Oral Consent Process as described in MAS Policy M772, OHSRP SOP 12, and 45 CFR 46.117 (b) (2). The summary that will be used is the English version of the extant IRB approved consent document. Signed copies of both the English version of the consent and the translated short form will be given to the subject or their legally authorized representative and the signed original will be filed in the medical record. Unless the PI is fluent in the prospective subject's language, an interpreter will be present to facilitate the conversation (using either the long translated form or the short form). Preferably someone who is independent of the subject (i.e., not a family member) will assist in presenting information and obtaining consent. Whenever possible, interpreters will be provided copies of the relevant consent documents well before the consent conversation with the subject (24 to 48 hours if possible). We request prospective IRB approval of the use of the short form process for non-English speaking subjects and will notify the IRB at the time of continuing review of the frequency of the use of the Short Form.
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10.0 pharmaceutical information there will

This study meets the criteria for exemption for an IND as this investigation is not intended to support a new indication for use or any other significant change to the labeling; the drugs are already approved and marketed and the investigation is not intended to support a significant change in advertising; and the investigation does not involve a route of administration or dosage level in use in a patient population or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product.
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sorafenib

Drug Name:
Sorafenib tosylate Chemical Name:
4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2carboxamide-4methylbenzenesulfonate Molecular Formula:
C21H16ClF3N4O3 X C7H8O3S
Molecular Weight:
637.0 Appearance:
White to yellowish or brownish solid.  
How supplied:
Sorafenib tablets are supplied as round, biconvex, red film-coated tablets, debossed with the "Bayer cross" on one side and "200" on the other side, each containing sorafenib tosylate equivalent to 200 mg of sorafenib. Bottles of 120 tablets NDC 50419-488-58.
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formulation

Red, round, biconvex, film coated tablet. Each tablet contains 274 mg sorafenib tosylate equivalent to 200 mg sorafenib and the inactive ingredients cellulose microcrystalline, croscarmellose sodium, hypromelose, magnesium stearate, and sodium lauryl sulfate. The coating material consists of hypromellose, macrogol (synthetic polyethylene glycol), titanium dioxide, and ferric oxide-red.  
Storage and Stability:
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Store in a dry place.  
Mechanism of Action:
Sorafenib is a kinase inhibitor that decreases tumor cell proliferation in vitro. Sorafenib was shown to inhibit multiple intracellular (CRAF, BRAF and mutant BRAF) and cell surface kinases (KIT, FLT-3, RET, VEGFR-1, VEGFR-2, VEGFR-3, and PDGFR-ß). Several of these kinases are thought to be involved in tumor cell signaling, angiogenesis, and apoptosis. Sorafenib inhibited tumor growth and angiogenesis of human hepatocellular carcinoma and renal cell carcinoma, and several other human tumor xenografts in immunocompromised mice.
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pharmacology

After administration of sorafenib-containing tablets, the drug's mean elimination half-life is between 25 and 48 h. Sorafenib reaches peak plasma levels f3 h after oral administration. With a high-fat meal, sorafenib bioavailability was reduced 29% compared with fasting bioavailability. In vitro binding of sorafenib to human plasma proteins is 99.5%. Sorafenib is metabolized primarily in the liver; oxidative metabolism is mediated by CYP3A4, and glucuronidation is mediated by UGT1A9. Sorafenib accounts for 70% to 85% of the circulating analytes in plasma at steady state. Following oral administration of a 100 mg sorafenib dose in a solution formulation, 77% of the dose was excreted in feces, and 19% was excreted in urine as glucuronidated metabolites. Unchanged sorafenib, which accounted for 51% of the dose, was found in feces but not in urine. Analyses of demographic data suggest that no dose adjustments are necessary based on patient age or gender. No pharmacokinetic data exist for pediatric patients. In patients with mild (Child-Pugh A, n = 14 patients) or moderate (Child-Pugh B, n = 8) hepatic impairment, drug exposure values were within the range observed in patients with no hepatic impairment. Sorafenib's pharmacokinetics has not been studied in patients with severe (Child-Pugh C) hepatic impairment. In four phase 1 clinical trials, sorafenib was evaluated in patients with normal renal function, mild renal impairment (creatinine clearance >50-80 mL/min, n = 24), and moderate renal impairment (creatinine clearance = 30-50 mL/min, n = 4). No relationship was observed between renal function and steady-state sorafenib area under the curve at doses of 400 mg twice daily. The drug's pharmacokinetics has not been studied in patients with severe renal impairment (creatinine clearance <30 mL/min) or in patients undergoing dialysis. Steady-state dosing of ketoconazole (400 mg), a potent inhibitor of cytochrome P450 3A4 (CYP3A4) did not alter the mean area under the curve of an oral dose of sorafenib. Administration of sorafenib tablets did not alter the exposure of concomitantly given midazolam (CYP3A4 substrate), dextromethorphan (CYP2D6 substrate), or omeprazole (CYP2C19 substrate). The possible effect of sorafenib on the CYP2C9 substrate warfarin was assessed indirectly by measuring the PT-INR. Mean changes from baseline in PT-INR were not higher in patients administered sorafenib tablets compared with patients given a placebo. Although not studied clinically, inducers of CYP3A4 activity are expected to increase metabolism of sorafenib and thus decrease sorafenib concentrations. Sorafenib tablets have been given with the antineoplastic agent's gemcitabine, oxaliplatin, doxorubicin, and irinotecan. Concomitant treatment with sorafenib resulted in a 21% increase in the area under the curve of doxorubicin. When given with irinotecan, whose active metabolite SN-38 is further metabolized by the UGT1A1 pathway, sorafenib produced a 67% to 120% increase in the area under the curve of SN-38 and a 26% to 42% increase in the area under the curve of irinotecan. Because sorafenib inhibits CYP2B6 and CYP2C8 in vitro, systemic exposure to substrates of CYP2B6 and CYP2C8 might be expected to increase when coadministered with sorafenib. Similarly, although not studied clinically, sorafenib inhibits glucuronidation by the UGT1A1 and UGT1A9 pathways, and systemic exposure to substrates of UGT1A1 and UGT1A9 may increase when co-administered with sorafenib. CYP1A2 and CYP3A4 activities were not altered after treatment of cultured human hepatocytes with sorafenib, indicating that sorafenib is unlikely to be an inducer of CYP1A2 and CYP3A4 in vivo.  
Pre-clinical Toxicology:
Repeat-dose animal toxicology was generally predictive of the toxicities observed in humans as indicated by the clinical adverse events. In the repeat-dose toxicology studies, findings included cirrhotic changes, glomerulopathy and renal tubular dilation, gastrointestinal hemorrhage, adrenal necrosis and hemorrhage, hypothyroidism, pancreatitis, and changes in serum a-amylase. Osteodystrophy of the jaw was noted in rats. Young animals showed incomplete epiphyseal closure, thickening of growth plates, and dentin alteration. Potential cardiotoxicity was evidenced by positive findings in the in vitro hERG and action potential assays and inflammation/congestion/hemorrhage in the heart and increased creatine kinase in the chronic dog toxicity study. Changes in coagulation values were inconclusive. Sorafenib can cross the bloodbrain barrier. Based on a safety pharmacology study, sorafenib may cause sensory neuropathy.  
Sorafenib is teratogenic. Embryo-fetal toxicities, observed in rats and rabbits, occurred at subtherapeutic exposures and included increased post-implantation loss, fetal malformations, and necrotic placentas. Although fertility and early developmental studies were not conducted, adverse findings in the reproductive organs in the repeat dose toxicity studies suggest that sorafenib has the potential to impair reproductive function and fertility in males and females. Pharmacokinetic studies in rats with radiolabeled sorafenib indicated that sorafenib is excreted into the milk.  
Human Toxicity:
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likely (occurring in more than

Fatigue, rash/desquamation, hand/foot reaction, alopecia, diarrhea, nausea, anorexia, abdominal pain. Laboratory abnormalities include hypophosphatemia, elevated lipase, elevated amylase, and lymphopenia.  
*Information obtained from sorafenib package insert
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common (occurring in 3 -

Hypertension, weight loss, pruritis, dry skin, vomiting, constipation, hemorrhage (all sites, including gastrointestinal tract and respiratory tract), sensory neuropathy, joint pain, headache, dyspnea, mucositis, stomatitis (including dry mouth and glossodynia), myalgia, depression, renal failure, erectile dysfunction, hoarseness. Laboratory abnormalities include neutropenia, thrombocytopenia, and transaminase elevation.
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rare but serious (occurring in

Hypertensive crisis, myocardial ischemia and/or infarction, congestive heart failure, keratoacanthomas/squamous cell cancer of skin, pancreatitis, gastrointestinal perforation, cerebral hemorrhage, hypersensitivity reactions (including skin reactions and urticaria, and reversible posterior encephalopathy. The overall safety profile of sorafenib is based on 1286 cancer patients, who received sorafenib as single agent. This table will be used to determine the "expectedness" of ADRs used for reporting of adverse events to Regulatory Agencies from clinical studies. It is not a complete list of adverse events reported in clinical trials.  
| Adverse Drug Reactions in patients in multiple clinical trials (MedDRA coded) System Organ  Very Common Common Uncommon Class > 10% > 1% to < 10% > 0.1% to < 1% Infections and  Folliculitis infection infestations Blood and  lymphatic  system  disorders Lymphopenia Leucopenia Neutropenia  Anemia Thrombocytopenia Immune  system  disorders  Hypersensitivity  reactions (including  skin reactions and  urticaria) Endocrine  Hypothyroidism disorders Metabolism  and nutrition  disorders Hypophosphatemia Anorexia Hyponatremia Dehydration Psychiatric  Depression disorders Nervous  system  disorders Peripheral sensory  Reversible posterior  neuropathy  leukoencephalopath y* Ear and  labyrinth  disorders Tinnitus Cardiac  Myocardial ischemia  disorders  and infarction*  Congestive heart  failure*   |
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| Vascular                                                 | Hemorrhage                                                                                      |                                                                                         |                                                                                                 |
| disorders                                                | (including  gastrointestinal* and  respiratory tract* and  cerebral  hemorrhage*)  Hypertension | Hypertensive crisis*                                                                    |                                                                                                 |
| Respiratory,  thoracic and  mediastinal  disorders       | Hoarseness                                                                                      | Rhinorrhea                                                                              |                                                                                                 |
| Gastrointestina                                          | Diarrhea                                                                                        |                                                                                         |                                                                                                 |
| l disorders                                              | Nausea Vomiting                                                                                 | Gastro esophageal  reflux disease Pancreatitis Gastritis Gastrointestinal  perforation* |                                                                                                 |
| Hepato-biliary                                           | Increase in bilirubin                                                                           |                                                                                         |                                                                                                 |
| disorders                                                | and jaundice                                                                                    |                                                                                         |                                                                                                 |
| Skin and  subcutaneous  tissue disorders                 | Constipation Stomatis (including dry  mouth and  glossodynea)  Dyspepsia Dysphagia              |                                                                                         |                                                                                                 |
| Rash Alopecia Hand-foot reaction**  Pruritis Erythema    | Dry skin Dermatitis exfoliative Acne Skin desquamation                                          | Eczema Erythema  multiforme minor                                                       |                                                                                                 |
| Musculoskelet al, connective  tissue and bone  disorders | Arthralgia Myalgia                                                                              |                                                                                         |                                                                                                 |
| Reproductive  system and  breast  disorders              | Erectile                                                                                        | Gynaecomastia                                                                           |                                                                                                 |
| dysfunction                                              |                                                                                                 |                                                                                         |                                                                                                 |
| General  disorders and  administration  site conditions  | Fatigue Pain (inc. mouth,  abdominal, bone  pain, headache and  tumor pain)                     | Asthenia Fever Influenza-like illness                                                   | Transient increase in  blood alkaline  phosphatase, INR  abnormal,  prothrombin level  abnormal |
|                                                          | Investigations                                                                                  | Increased amylase                                                                       | Weight decreased                                                                                |
| Increased lipase                                         | Transient increase in  transaminases                                                            |                                                                                         |                                                                                                 |  
* Events may have a life-threatening or fatal outcome. Such events are uncommon. ** Palmar plantar erythrodysaethesia syndrome in MedDRA In combination with cytotoxic agents, myelosuppression leading to febrile neutropenia has also been observed. Such events may have a life-threatening or fatal outcome.  
10.1.12.1 Laboratory Abnormalities The following laboratory abnormalities were observed in the phase III advanced RCC (TARGETS) trial: Elevated lipase and amylase: Elevated lipase and amylase levels were very commonly reported. CTCAE Grade 3 or 4 lipase elevations occurred in 12% of patients in the sorafenib group compared to 7% of patients in the placebo group. CTCAE Grade 3 or 4 amylase elevations were reported in 1% of patients in the sorafenib group compared to 3% of patients in the placebo group. Clinical pancreatitis was reported in 2 of 451 sorafenib treated patients (CTCAE Grade 4) and 1 of 451 patients (CTCAE Grade 2) in the placebo group. Hypophosphatemia: Hypophosphataemia was a common laboratory finding, observed in 45% of sorafenib treated patients compared to 12% of placebo patients. CTCAE Grade 3 hypophosphataemia (1–2 mg/dl) occurred in 13% on sorafenib treated patients and 3% of patients in the placebo group. There were no cases of CTCAE Grade 4 hypophosphataemia (< 1 mg/dl) reported in either sorafenib or placebo patients. The etiology of hypophosphataemia associated with sorafenib is not known. Lymphopenia: CTCAE Grade 3 or 4 were reported for lymphopenia in 13% of sorafenib treated patients and 7% of placebo patients, for neutropenia in 5% of sorafenib treated patients and 2% of placebo patients, for anemia in 2% of sorafenib treated patients and 4% of placebo patients and for thrombocytopenia in 1% of sorafenib treated patients and 0% of placebo. Anemia: Observed in 44% of sorafenib-treated patients and 49% of placebo patients. CTCAE Grade 3 or 4 anemia was reported in 2% of sorafenib-treated patients and 4% of placebo patients. Thrombocytopenia: Observed in 12% of sorafenib-treated patients and 5% of placebo patients. CTCAE Grade 3 or 4 thrombocytopenia was reported in 1% of sorafenib-treated patients and 0% of placebo patients.
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special warnings and precautions for

Sorafenib (Nexavar®) is approved for treatment of patients with advanced renal cancer and unresectable hepatocellular cancer. Because this is a novel agent, current knowledge of the adverse events associated with this compound is limited. As with any new chemical entity, there is always potential for unexpected adverse events.  
Pregnancy: Women should avoid becoming pregnant while on therapy.  
Women of childbearing potential must be apprised of the potential hazard to the fetus, which includes severe malformation (teratogenicity), failure to thrive and fetal death (embryotoxicity). Sorafenib should not be used during pregnancy. Prescribers may only consider it to be used, if the potential benefits justify the potential risks to the fetus. Based on the proposed mechanism of multikinase inhibition and multiple adverse effects seen in animals at exposure levels significantly below the clinical dose, sorafenib should be assumed to cause fetal harm when administered to a pregnant woman. Breastfeeding should be discontinued during sorafenib therapy.  
Dermatological Toxicities: Hand-foot skin reaction (palmar-plantar erythrodysaesthesia) and rash represent the most common adverse drug reactions with sorafenib. Rash and hand-foot skin reaction are usually CTCAE Grade 1 and 2 and generally appear during the first six weeks of treatment with sorafenib. Management of dermatologic toxicities may include topical therapies for symptomatic relief, temporary treatment interruption and/or dose modification of sorafenib, or in severe or persistent cases, permanent discontinuation of sorafenib. Patients who take sorafenib should be suggested to avoid long exposure to hot water such as washing dishes, long showers, or tub bath, and to avoid the activities to cause excessive pressure and friction on the soles of the feet or palms of hands such as jogging, aerobics, power walking, jumping, and/or using garden and household tools. Hand-foot syndrome may be treated with topical emollients (such as Aquaphor), topical/systemic steroids, and/or antihistamine agents. Vitamin B6 (pyridoxine; 5001250 mg orally each day) may also be used.  
Hypertension: An increased incidence of hypertension was observed in sorafenib-treated patients.  
Hypertension was usually mild to moderate, occurred early in the course of treatment, and was amenable to management with standard antihypertensive therapy. Blood pressure should be monitored regularly and treated, if required, in accordance with standard medical practice. In cases of severe or persistent hypertension, or hypertensive crisis despite adequate antihypertensive therapy, permanent discontinuation of sorafenib should be considered.  
Hemorrhage: An increase in the risk of bleeding may occur following sorafenib administration.  
The incidence of severe bleeding events is uncommon. If any bleeding event necessitates medical intervention, it is recommended that permanent discontinuation of sorafenib should be considered.  
Wound healing complications: No formal studies of the effect of sorafenib on wound healing have been conducted. In patients undergoing major surgical procedures, temporary interruption of sorafenib therapy is recommended for precautionary reasons. There is limited clinical experience regarding the timing of reinitiation of therapy following major surgical intervention. Therefore, the decision to resume sorafenib therapy following a major surgical intervention should be based on clinical judgment of adequate wound healing.  
Cardiac Ischemia and/or Infarction: In the Phase 3 Advanced RCC study (TARGETS), the incidence of treatment-emergent cardiac ischemia/infarction events was higher in the sorafenib group (2.9%) compared with the placebo group (0.4%). Patients with unstable coronary artery disease or recent myocardial infarction were excluded from this study. Temporary or permanent discontinuation of sorafenib should be considered in patients who develop cardiac ischemia and/or infarction.  
Gastrointestinal perforation: Gastrointestinal perforation is an uncommon event and has been reported in less than 1% of patients taking sorafenib. In some cases this was not associated with apparent intra-abdominal tumor. Sorafenib therapy should be discontinued in patients with GI perforation.  
Effects on ability to drive and use machines: No studies on the effects of sorafenib on the ability to drive or use machines have been performed. There is no evidence that sorafenib affects the ability to drive or operate machinery.  
Patients with Hepatic Impairment: *In vitro* and *in vivo* data indicate that sorafenib is primarily metabolized by the liver. Systemic exposure and safety data were comparable in patients with Child-Pugh A and B hepatic impairment. Sorafenib has not been studied in patients with ChildPugh C hepatic impairment. No dose adjustment is necessary when administering sorafenib to patients with Child-Pugh A and B hepatic impairment.  
Patients with Renal Impairment: Sorafenib has not been studied in patients with severe renal impairment (CrCl <30 mL/min) or in patients undergoing dialysis.  
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies have not been performed with sorafenib. Sorafenib was clastogenic when tested in an *in vitro* mammalian cell assay (Chinese Hamster Ovary) in the presence of metabolic activation. Sorafenib was not mutagenic in the *in vitro* Ames bacterial cell assay or clastogenic in an *in vivo* mouse micronucleus assay. One intermediate in the manufacturing process, which is also present in the final drug substance (<0.15%), was positive for mutagenesis in an *in vitro* bacterial cell assay (Ames test) when tested independently. No specific studies with sorafenib have been conducted in animals to evaluate the effect on fertility. However, results from the repeat-dose toxicity studies suggest there is a potential for sorafenib to impair reproductive performance and fertility. Multiple adverse effects were observed in male and female reproductive organs, with the rat being more susceptible than mice or dogs. Typical changes in rats consisted of testicular atrophy or degeneration, degeneration of epididymis, prostate, and seminal vesicles, central necrosis of the corpora lutea and arrested follicular development. Sorafenib-related effects on the reproductive organs of rats were manifested at daily oral doses ≥30 mg/m2 (approximately 0.5 times the AUC in cancer patients at the recommended human dose). Dogs showed tubular degeneration in the testes at 600 mg/m2/day (approximately 0.3 times the AUC at the recommended human dose) and oligospermia at 1200 mg/m2/day of sorafenib. Adequate contraception should be used during therapy and for at least 2 weeks after completing therapy.  
Pediatric Use: The safety and effectiveness of sorafenib in pediatric patients have not been studied. Repeat dosing of sorafenib to young and growing dogs resulted in irregular thickening of the femoral growth plate at daily sorafenib doses ≥600 mg/m2 (approximately 0.3 times the AUC
at the recommended human dose), hypocellularity of the bone marrow adjoining the growth plate at 200 mg/m2/day (approximately 0.1 times the AUC at the recommended human dose), and alterations of the dentin composition at 600 mg/m2/day. Similar effects were not observed in adult dogs when dosed for 4 weeks or less.  
Geriatric Use: In total, 32% of RCC patients treated with sorafenib were age 65 years or older, and 4% were 75 and older. No differences in safety or efficacy were observed between older and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 10.1.12.2 Interaction with Other Medications Drug-Drug Interactions: Caution is recommended when administering sorafenib together with compounds that are metabolized/ eliminated predominantly by the UGT1A1 pathway (e.g. irinotecan).  
.  
- **CYP3A4 inducers:** There is no clinical information on the effect of CYP3A4 inducers on the pharmacokinetics of sorafenib. Inducers of CYP3A4 activity (e.g. rifampicin, Hypericum perforatum also known as St. John's wort, phenytoin, carbamazepine, phenobarbital, and dexamethasone) may increase metabolism of sorafenib and thus decrease sorafenib plasma concentrations.  
- **CYP3A4 inhibitors:** Ketoconazole, a potent inhibitor of CYP3A4, administered once daily for 7 days to healthy male volunteers did not alter the mean AUC of a single 50 mg dose of sorafenib. Therefore, clinical pharmacokinetic interactions of sorafenib with CYP3A4 inhibitors are unlikely.  
- **CYP2C9 substrates:** The possible effect of sorafenib on the metabolism of the CYP2C9 substrate warfarin was assessed indirectly by measuring PTINR. The mean changes from baseline in PT-INR were not higher in sorafenib patients compared to placebo patients, suggesting that sorafenib did not inhibit warfarin metabolism *in vivo*. However, patients taking warfarin should have their INR checked regularly.  
- **CYP isoform-selective substrates:** Concomitant administration of midazolam, dextromethorphan and omeprazole, which are substrates of cytochromes CYP3A4, CYP2D6 and CYP2C19, respectively, following 4 weeks of sorafenib administration did not significantly alter the exposure of these agents. This indicates that sorafenib is neither an inhibitor nor a clinically meaningful inducer of these cytochrome P450 isoenzymes.  
- **Combination with other anti-neoplastic agents:** In clinical studies, sorafenib has been administered together with a variety of other antineoplastic agents at their commonly used dosing regimens, including gemcitabine, oxaliplatin, doxorubicin, and irinotecan. Sorafenib had no effect on the pharmacokinetics of gemcitabine or oxaliplatin. Concomitant treatment with sorafenib resulted in a 21% increase in the AUC of doxorubicin. When administered with irinotecan, whose active metabolite SN-38 is further metabolized by the UGT1A1 pathway, there was a 67-120% increase in the AUC of SN38 and a 26-42% increase in the AUC of irinotecan. The clinical significance of these findings is unknown. However, caution is recommended when administering sorafenib with doxorubicin and with compounds that are metabolized/eliminated predominantly by the UGT1A1 pathway (e.g. irinotecan).  
- **Warfarin:** Infrequent bleeding events or elevations in the International Normalized Ratio
(INR) have been reported in some patients taking warfarin while on sorafenib therapy. Patients taking warfarin concomitantly should be monitored regularly for changes in prothrombin time, INR and for clinical bleeding episodes.  
10.1.12.3 Pregnancy and Lactation Pregnancy: Women should avoid becoming pregnant while on therapy. Women of childbearing potential must be apprised of the potential hazard to the fetus, which includes severe malformation (teratogenicity), failure to thrive and fetal death (embryotoxicity). Sorafenib should not be used during pregnancy. Prescribers may only consider it to be used, if the potential benefits justify the potential risks to the fetus.  
- There are no adequate and well-controlled studies in pregnant women using sorafenib.  
Studies in animals have shown reproductive toxicity including malformations. In rats, sorafenib and its metabolites were demonstrated to cross the placenta and sorafenib is anticipated to inhibit angiogenesis in the fetus.  
- Women should avoid becoming pregnant while on therapy. Women of childbearing potential must be apprised of the potential hazard to the fetus, which includes severe malformation (teratogenicity), failure to thrive and fetal death (embryotoxicity).  
- Sorafenib should not be used during pregnancy. Prescribers may only consider it to be used, if the potential benefits justify the potential risks to the fetus.  
- In animals, sorafenib has been shown to be teratogenic and embryotoxic. Adequate contraception should be used during therapy and for at least 2 weeks after completion of therapy.
Breastfeeding should be discontinued during sorafenib therapy.  
- It is not known whether sorafenib is excreted in human milk. In animals, sorafenib and/or its metabolites were excreted in milk. Because many drugs are excreted in human milk and because the effects of sorafenib on infants have not been studied, woman should discontinue breastfeeding during sorafenib treatment.  
Effects on fertility: Results from animal studies indicate that sorafenib can impair male and female fertility.  
Clinical Pharmacokinetic Properties:
After administration of sorafenib tablets, the mean relative bioavailability is 38-49% when compared to an oral solution. The mean elimination half-life of sorafenib is approximately 25-48 hours. Multiple dosing of sorafenib for 7 days resulted in a 2.5-to 7-fold accumulation compared to single dose administration. Steady-state plasma sorafenib concentrations are achieved within 7 days, with a peak-to-trough ratio of mean concentrations of less than 2. 10.1.13.1 Absorption and Distribution Following oral administration, sorafenib reaches peak plasma levels in approximately 3 hours. When given with a moderate-fat meal (30% fat; 700 calories), bioavailability was similar to that in the fasted state. With a high-fat meal (50% fat; 900 calories), sorafenib bioavailability was reduced by 29% compared to administration in the fasted state. It is recommended that sorafenib be administered without food. Mean Cmax and AUC increased less than proportionally beyond doses of 400 mg administered orally twice daily. In vitro binding of sorafenib to human plasma proteins is 99.5%.
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10.1.13.2 metabolism and elimination

Sorafenib is metabolized primarily in the liver, undergoing oxidative metabolism, mediated by CYP3A4, as well as glucuronidation mediated by UGT1A9. Sorafenib accounts for approximately 70-85% of the circulating analytes in plasma at steady-state. Eight metabolites of sorafenib have been identified, of which five have been detected in plasma. The main circulating metabolite of sorafenib in plasma, the pyridine N-oxide, shows in vitro potency similar to that of sorafenib. This metabolite comprises approximately 9-16% of circulating analytes at steady-state. Following oral administration of a 100 mg dose of a solution formulation of sorafenib, 96% of the dose was recovered within 14 days, with 77% of the dose excreted in feces, and 19% of the dose excreted in urine as glucuronidated metabolites. Unchanged sorafenib, accounting for 51% of the dose, was found in feces but not in urine. 10.1.13.3 Special Populations Age: Analyses of demographic data suggest that no dose adjustments are necessary for age. Gender: Analyses of demographic data suggest that no dose adjustments are necessary for gender. Race: A study of the pharmacokinetics of sorafenib indicated that the mean AUC of sorafenib in Asians (N=78) was 30% lower than in Caucasians (N=40).  
Pediatric: There are no pharmacokinetic data in pediatric patients.  
Hepatic Impairment: Sorafenib is cleared primarily by the liver. Comparison of data across studies suggests that in HCC patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, 400 mg doses of sorafenib appear to be associated with AUC values that were 23 to 65% lower than those of other subjects without hepatic impairment. The AUC of sorafenib is similar between HCC patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment. The pharmacokinetics of sorafenib have not been studied in patients with severe (Child-Pugh C) hepatic impairment.  
Renal Impairment: In a study of drug disposition after a single oral dose of radiolabeled sorafenib to healthy subjects, 19% of the administered dose of sorafenib was excreted in urine. In a clinical pharmacology study, the pharmacokinetics of sorafenib were evaluated following administration of a single 400 mg dose to subjects with normal renal function, and in subjects with mild (CrCl > 50-80 ml/min), moderate (CrCl 30-50 ml/min), or severe (CrCl <30 ml/min) renal impairment, not undergoing dialysis. There was no relationship observed between sorafenib exposure and renal function. No dosage adjustment is necessary based on mild, moderate or severe renal impairment not undergoing dialysis. Monitoring of fluid balance and electrolytes in patients at risk of renal dysfunction is advised.
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administration

400 mg (2 tablets) orally twice daily without food (at least 1 hour before or 2 hours after a meal).  
Supplier:
Bayer Pharmaceuticals Unused or defective agent:
Refer to the detailed instructions described in Section **10.2.18** Unused or defective drug will be destroyed. Bayer Pharmaceuticals should be notified of this action.
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everolimus

Drug Name:
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-aza-tricyclo[30.3.1.04,9]hexatriaconta-16,24, 26,28-tetraene-2,3,10,14,20-pentaone.  
Molecular Formula:
C53H83NO14 Molecular Weight:
958.2 Appearance:  
2.5 mg tablet White to slightly yellow, elongated tablets with a beveled edge and no score, engraved with "LCL" on one side and "NVR" on the other.
5 mg tablet - White to slightly yellow, elongated tablets with a beveled edge and no score, engraved with "5" on one side and "NVR" on the other.  
7.5 mg tablet White to slightly yellow, elongated tablets with a beveled edge and engraved with "7P5" on one side and "NVR" on the other.  
10 mg tablet - White to slightly yellow, elongated tablets with a beveled edge and no score, engraved with "UHE" on one side and "NVR" on the other.  
How supplied:
Each carton contains 4 blister cards of 7 tablets per card, total 28 tablets per carton. Store everolimus tablets at 25° C (77°F); excursions permitted between 15°–30°C (59°–86°F). [See USP Controlled Room Temperature.] Store in the original container, protect from light and moisture. Keep this and all drugs out of the reach of children. Procedures for proper handling and disposal of anticancer drugs should be considered. Everolimus tablets should not be crushed. Direct contact of crushed tablets with the skin or mucous membranes should be avoided. If such contact occurs, wash thoroughly. Personnel should avoid exposure to crushed tablets.
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formulation

Everolimus is supplied as tablets for oral administration containing everolimus together with butylated hydroxytoluene, magnesium stearate, lactose monohydrate, hypromellose, crospovidone and lactose anhydrous as inactive ingredients.
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storage and stability

Current stability data permits a shelf-life of 36 months at storage conditions below 30°C and maintenance in the original packs.
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mechanism of action

Everolimus is an inhibitor of mTOR (mammalian target of rapamycin), a serine-threonine kinase, downstream of the PI3K/AKT pathway. The mTOR pathway is dysregulated in several human cancers. Everolimus binds to an intracellular protein, FKBP-12, resulting in an inhibitory complex formation and inhibition of mTOR kinase activity. Everolimus reduced the activity of S6 ribosomal protein kinase (S6K1) and eukaryotic elongation factor 4E-binding protein (4E-BP), downstream effectors of mTOR, involved in protein synthesis. In addition, everolimus inhibited the expression of hypoxia-inducible factor (e.g., HIF-1) and reduced the expression of vascular endothelial growth factor (VEGF). Inhibition of mTOR by everolimus has been shown to reduce cell proliferation, angiogenesis, and glucose uptake in in vitro and/or in vivo studies.
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pharmacology

10.2.10.1 Drug Interactions Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug efflux pump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6.  
10.2.10.1.1 Agents that may Increase Everolimus Blood Concentrations CYP3A4 Inhibitors and PgP Inhibitors: In healthy subjects, compared to everolimus treatment alone there were significant increases in everolimus exposure when everolimus was coadministered with:  
- ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and 15.0-fold, respectively.  
- erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC
increased by 2.0- and 4.4-fold, respectively.  
- verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3-and 3.5-fold, respectively.
Concomitant strong or moderate inhibitors of CYP3A4 and PgP inhibitors should not be used.  
10.2.10.1.2 Agents that may Decrease Everolimus Blood Concentrations CYP3A4 Inducers: In healthy subjects, co-administration of everolimus with rifampin, a strong inducer of CYP3A4, decreased everolimus AUC and Cmax by 64% and 58% respectively, compared to everolimus treatment alone. Consider a dose increase of everolimus when coadministered with strong inducers of CYP3A4 or PgP if alternative treatment cannot be administered. Agents whose Plasma Concentrations may be Altered by Everolimus Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions between everolimus and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (a nonCYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of everolimus. Patients will be instructed not to take any additional medications (including over-the-counter products) during the course of the study without prior consultation with the investigator. At each visit, the investigator will ask the patient about any new medications he/she is or has taken after the start of the study drug. All Concomitant medications/Significant non-drug therapies taken ≤ 30 days prior to start and after start of study drug, including physical therapy and blood transfusions, should be recorded.  
- Growth factors (e.g. G-CSF, GM-CSF, erythropoietin, platelets growth factors etc.) are not to be administered prophylactically but may be prescribed by the investigator for rescue from severe hematologic events, if this is thought to be appropriate.  
- Concurrent administration of everolimus and strong CYP3A4 inhibitors (such as ketoconazole, itraconazole, ritonavir) and inducers (such as rifampin, rifabutin) should be
avoided. Provided there is no alternative treatment available, patients should be closely monitored for potential toxicities.  
- Concurrent administration of everolimus and moderate CYP3A4 inhibitors (such as erythromycin, fluconazole, calcium channel blockers, benzodiazepines) and moderate CYP3A4 inducers (e.g. carbamazepine, phenobarbital) should also be avoided if possible, or used subject to caution (e.g. increased frequency of safety monitoring, temporary interruption of everolimus).  
- Competitive inhibition could occur when everolimus is combined with drugs which are also CYP3A4 substrates. Therefore caution should be exercised in such cases.  
- Co-administration with substrates, inducers, or inhibitors of P-glycoprotein should be avoided, if possible, or used subject to caution (e.g. increased frequency of safety monitoring, temporary interruption of everolimus).  
- Grapefruit and grapefruit juice affect cytochrome P450 and P-glycoprotein activity and should therefore be avoided.
- In addition, patients should avoid Seville oranges and star fruit, as well as the juice of these fruits, which are potent CYP3A4-inhibitors.  
- No chronic treatment with immunosuppressive agents. Topical or inhaled corticosteroids are allowed.  
- Everolimus may affect the response to vaccinations making the response to the vaccination less effective. Live vaccines should be avoided while a patient is treated with everolimus.  
Oral anticoagulants such as warfarin are CYP2C9 substrates and, as such, no interaction with everolimus is expected. However, drug-drug interaction studies between macrolide antibiotics and warfarin have produced mixed outcomes and the disparity in these findings has led to the conclusion that multiple factors may alter the clearance of warfarin. The co-administration of everolimus and oral anticoagulants is possible but should be subject to verification of coagulation (INR) once steady state is reached (after one week's treatment).  
Examples are provided in **Table 3-3**. A comprehensive list of cytochrome P450 isoenzymes and CYP3A4 inhibitors, inducers, and substrates can be found at http://medicine.iupui.edu/flockhart. This website is continually revised and should be checked frequently for updates.
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pre-clinical toxicology

In safety pharmacology studies, Everolimus was devoid of relevant effects on vital functions including the cardiovascular, respiratory and nervous systems. Everolimus had no influence on QT interval prolongation. Furthermore, everolimus showed no antigenic potential. Although everolimus passes the blood-brain barrier, there was no indication of relevant changes in the behavior of rodents, even after single oral doses up to 2000mg/kg or after repeated administration at up to 40 mg/kg/day. Based on these findings, the potential of everolimus to affect vital functions in patients is considered to be low. Everolimus is considered to have no genotoxicity or carcinogenicity potential. All significant adverse events observed in preclinical toxicology studies with everolimus in mice, rats, monkeys and minipigs were consistent with its anticipated pharmacologic action as an antiproliferative and immunosuppressant and at least in part reversible after a 2- or 4-week recovery period with the exception of the changes in male reproductive organs, most notably testes. Ocular effects (lenticular disorders) observed in rats were not observed in any other species and are considered to be a species-specific disorder.
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human toxicity

Hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients.  
Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus and other rapamycin derivatives.
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warnings and precautions 10.2.12.1 non-infectious

Non-infectious pneumonitis is a class effect of rapamycin derivatives, including everolimus. In the randomized study, non-infectious pneumonitis was reported in 14% of patients treated with everolimus. The incidence of CTCAE grade 3 and 4 non-infectious pneumonitis was 4% and 0%, respectively. Fatal outcomes have been observed. Consider a diagnosis of non-infectious pneumonitis 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 causes have been excluded by means of appropriate investigations. Advise patients 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, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated. Everolimus may be reintroduced at 5 mg daily. For cases where symptoms of non-infectious pneumonitis are severe, discontinue everolimus therapy and the use of corticosteroids may be indicated until clinical symptoms resolve. Therapy with everolimus may be re-initiated at a reduced dose of 5 mg daily depending on the individual clinical circumstances.
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10.2.12.2 infections

Everolimus has immunosuppressive properties and may predispose patients to infections, especially infections with opportunistic pathogens. Localized and systemic infections, including pneumonia, other bacterial infections and invasive fungal infections, such as aspergillosis or candidiasis, have occurred in patients taking everolimus. Some of these infections have been severe (e.g., leading to respiratory failure) or fatal. Physicians and patients should be aware of the increased risk of infection with everolimus, be vigilant for signs and symptoms of infection and institute appropriate treatment promptly. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with everolimus. If a diagnosis of invasive systemic fungal infection is made, discontinue everolimus and treat with appropriate antifungal therapy. Reactivation of Hepatitis B (HBV) has been observed in patients with cancer receiving chemotherapy. 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. A detailed assessment of Hepatitis B/C medical history and risk factors must be done for all patients at screening, with testing performed prior to the first dose of everolimus.
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10.2.12.3 oral ulceration

Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with everolimus. In the randomized study, approximately 44% of everolimus treated patients developed mouth ulcers, stomatitis, or oral mucositis, which were mostly CTCAE grade 1 and 2. In such cases, topical treatments are recommended, but alcohol- or peroxide-containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed.
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10.2.12.4 renal function

Elevations of serum creatinine, usually mild, have been reported in clinical trials. Monitoring of renal function, including measurement of blood urea nitrogen (BUN) or serum creatinine, is recommended prior to the start of everolimus therapy and periodically thereafter.
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10.2.12.5 blood glucose and lipids

Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in clinical trials. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of everolimus therapy and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on everolimus. 10.2.12.6 Hematological Parameters Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials. Monitoring of complete blood count is recommended prior to the start of everolimus therapy and periodically thereafter.
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10.2.12.7 cyp3a4 interactions

Due to significant increases in exposure of everolimus, co-administration with strong or moderate inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, amprenavir, indinavir, nelfinavir, delavirdine, fosamprenavir, voriconazole, aprepitant, erythromycin, fluconazole, grapefruit juice, verapamil or diltazem) or Pglycoprotein (PgP) should be avoided.  
Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug efflux pump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6.  
10.2.12.7.1 Agents that may Increase Everolimus Blood Concentrations CYP3A4 Inhibitors and PgP Inhibitors:
In healthy subjects, compared to everolimus treatment alone there were significant increases in everolimus exposure when everolimus was coadministered with:
- ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and 15.0-fold, respectively.  
- erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC
increased by 2.0- and 4.4-fold, respectively.  
- verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3-and 3.5-fold, respectively.
Concomitant strong or moderate inhibitors of CYP3A4 and PgP inhibitors should not be used.  
10.2.12.7.2 Agents that may Decrease Everolimus Blood Concentrations CYP3A4 Inducers:
In healthy subjects, co-administration of everolimus with rifampin, a strong inducer of CYP3A4, decreased everolimus AUC and Cmax by 64% and 58% respectively, compared to everolimus treatment alone. Consider a dose increase of everolimus when co-administered with strong inducers of CYP3A4 or PgP if alternative treatment cannot be administered.  
10.2.12.7.3 Agents whose Plasma Concentrations may be Altered by Everolimus Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions between everolimus and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (a non-CYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of everolimus. 10.2.12.8 Adverse Reactions Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice. The data described below reflect exposure to everolimus (n=274) and placebo (n=137) in a randomized, controlled trial in patients with metastatic renal cell carcinoma who received prior treatment with sunitinib and/or sorafenib. The median age of patients was 61 years (range 27-85), 88% were Caucasian, and 78% were male. The median duration of blinded study treatment was 141 days (range 19-451) for patients receiving everolimus and 60 days (range 21-295) for those receiving placebo. The most common adverse reactions (incidence ≥30%) were stomatitis, infections, asthenia, fatigue, cough, and diarrhea. The most common grade 3/4 adverse reactions (incidence ≥3%) were infections, dyspnea, fatigue, stomatitis, dehydration, pneumonitis, abdominal pain, and asthenia. The most common laboratory abnormalities (incidence ≥50%) were anemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and increased creatinine. The most common grade 3/4 laboratory abnormalities (incidence ≥3%) were lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hypercholesterolemia. Deaths due to acute respiratory failure (0.7%), infection (0.7%) and acute renal failure (0.4%) were observed on the everolimus arm but none on the placebo arm. The rates of treatment-emergent adverse events (irrespective of causality) resulting in permanent discontinuation were 14% and 3% for the everolimus and placebo treatment groups, respectively. The most common adverse reactions (irrespective of causality) leading to treatment discontinuation were pneumonitis and dyspnea. Infections, stomatitis, and pneumonitis were the most common reasons for treatment delay or dose reduction. The most common medical interventions required during everolimus treatment were for infections, anemia, and stomatitis.
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likely (occurring in more than

Adverse events most frequently observed with everolimus are rash, stomatitis/oral mucositis, fatigue, anorexia, nausea, diarrhea, peripheral edema, asthenia, cough, dyspnea, ocular toxicity and infections. Infections include nasopharyngitis (6%), pneumonia (6%), urinary tract infection (5%), bronchitis (4%), sinusitis (3%), aspergillosis (<1%), candidiasis (<1%), and sepsis (<1%). Laboratory abnormalities include anemia, neutropenia, thrombocytopenia, lymphopenia, hypercholesterolemia, and/or hypertriglyceridemia, hyperglycemia, hypophosphatemia, aspartate and alanine transaminase elevation. The majority of these AEs have been of mild to moderate severity (CTCAE grade 1-2).
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common (occurring in 3 -

Adverse events occurring in 3-20% of patients include vomiting, pyrexia, mucosal inflammation, epistaxis, pneumonitis (includes pneumonitis, interstitial lung disease, lung infiltration,, pulmonary alveolar hemorrhage, pulmonary toxicity, and alveolitis), pruritus, dry skin, headache, dysgeusia, pain in extremity, abdominal pain, dry mouth, hemorrhoids, dysphagia, chest pain, chills, pleural effusion, pharyngolaryngeal pain, rhinorrhea, hand-foot syndrome, nail disorder, erythema, onychoclasis, skin lesion, acneiform dermatitis, insomnia, dizziness, paresthesia, eyelid edema, hypertension, renal failure, tachycardia, jaw pain, and hemorrhage. Laboratory abnormalities include increased bilirubin (<1% grade 3 or 4).
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rare but serious (occurring in

Acute respiratory failure and acute renal failure. 10.2.12.9 Pregnancy and Breast Feeding There are no adequate and well-controlled studies of everolimus in pregnant women. However, based on mechanism of action, everolimus may cause fetal harm when administered to a pregnant woman. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures at the recommended dose of 10 mg daily. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use highly effective methods of contraception while receiving everolimus and for up to 8 weeks after ending treatment. In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, preimplantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g.,
sternal cleft) and retarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities occurred at approximately 4% the exposure (AUC0-24h) in patients receiving the recommended dose of 10 mg daily. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose approximately 1.6 times the recommended human dose on a body surface area basis. The effect in rabbits occurred in the presence of maternal toxicities. In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At approximately 10% of the recommended human dose based on body surface area, there were no adverse effects on delivery and lactation and there were no signs of maternal toxicity. However, there was reduced body weight (up to 9% reduction from the control) and slight reduction in survival in offspring (~5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring. Doses that resulted in embryo-fetal toxicities in rats and rabbits were ≥0.1 mg/kg (0.6 mg/m2) and 0.8 mg/kg (9.6 mg/m2), respectively. The dose in the pre- and post-natal development study in rats that caused reduction in body weights and survival of offspring was 0.1 mg/kg (0.6 mg/m2).
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10.2.12.10 nursing mothers

It is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Therefore, women who are taking everolimus should not breastfeed during treatment and for 2 weeks after the last dose.
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clinical pharmacokinetic properties absorption

In patients with advanced solid tumors, peak everolimus concentrations are reached 1 to 2 hours after administration of oral doses ranging from 5 mg to 70 mg. Following single doses, Cmax is dose-proportional between 5 mg and 10 mg. At doses of 20 mg and higher, the increase in Cmax is less than dose-proportional, however AUC shows dose-proportionality over the 5 mg to 70 mg dose range. Steady-state was achieved within two weeks following once-daily dosing. Food effect: Based on data in healthy subjects taking 10 mg everolimus tablets, a high-fat meal reduced Cmax and AUC by 54% and 22%, respectively.
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distribution

The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 to 5000 ng/mL, is 17% to 73%. The amount of everolimus confined to the plasma is approximately 20% at blood concentrations observed in cancer patients given everolimus 10 mg/day. Plasma protein binding is approximately 74% both in healthy subjects and in patients with moderate hepatic impairment.
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metabolism

Everolimus is a substrate of CYP3A4 and PgP. Following oral administration, everolimus is the main circulating component in human blood. Six main metabolites of everolimus have been detected in human blood, including three monohydroxylated metabolites, two hydrolytic ringopened products, and a phosphatidylcholine conjugate of everolimus. These metabolites were also identified in animal species used in toxicity studies, and showed approximately 100-times less activity than everolimus itself. In vitro, everolimus competitively inhibited the metabolism of CYP3A4 and was a mixed inhibitor of the CYP2D6 substrate dextromethorphan. The mean steady state Cmax following an oral dose of 10 mg daily is more than 12-fold below the Ki-values of the in vitro inhibition. Therefore, an effect of everolimus on the metabolism of CYP3A4 and CYP2D6 substrates is unlikely.
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excretion

No specific excretion studies have been undertaken in cancer patients. Following the administration of a 3 mg single dose of radiolabelled everolimus in patients who were receiving cyclosporine, 80% of the radioactivity was recovered from the feces, while 5% was excreted in the urine. The parent substance was not detected in urine or feces. The mean elimination half-life of everolimus is approximately 30 hours. Patients with Renal Impairment Approximately 5% of total radioactivity was excreted in the urine following a 3 mg dose of [14C]- labeled everolimus. In a population pharmacokinetic analysis which included 170 patients with advanced cancer, no significant influence of creatinine clearance (25 - 178 mL/min) was detected on oral clearance (CL/F) of everolimus.
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patients with hepatic impairment

The average AUC of everolimus in eight subjects with moderate hepatic impairment (Child-Pugh class B) was twice that found in eight subjects with normal hepatic function. AUC was positively correlated with serum bilirubin concentration and with prolongation of prothrombin time and negatively correlated with serum albumin concentration. A dose reduction for patients with ChildPugh class B hepatic impairment is recommended. Everolimus should not be used in patients with severe (Child-Pugh class C) hepatic impairment as the impact of severe hepatic impairment on everolimus exposure has not been assessed.
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effects of age and gender

In a population pharmacokinetic evaluation in cancer patients, no relationship was apparent between oral clearance and patient age or gender.
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ethnicity

Based on a cross-study comparison, Japanese patients (n = 6) had on average exposures that were higher than non-Japanese patients receiving the same dose. Based on analysis of population pharmacokinetics, oral clearance (CL/F) is on average 20% higher in Black patients than in Caucasians. The significance of these differences on the safety and efficacy of everolimus in Japanese or Black patients has not been established.
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administration

Everolimus should be taken whole by mouth with a full glass of water as instructed by the investigator. Everolimus should be taken by the patient in a fasting state or with no more than a light fat-free meal. Patients should take their tablets at the same time of the day and at the same time in relation to meals. Patients should avoid eating grapefruit and/or grapefruit juice for the entire duration of the study. All patients should be instructed to contact the investigator if he/she is unable to take the study drug as prescribed for any reason.
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supplier novartis

Unused or defective agent: Refer to the detailed instructions described in Section 10.2.18.2 below.
Agent Storage and Accountability The investigator is responsible for the proper and secure physical storage and record keeping of investigational agents received for BTTC protocols. Specifically, the investigator must:  
- Maintain a careful record of the receipt, use and final disposition of all investigational agents received, using the NCI Agent Accountability Record Form (DARF), http://ctep.cancer.gov/forms/index.html.  
- Store the agent in a secure location, accessible to only authorized personnel, preferably in the pharmacy.  
- Maintain appropriate storage of the investigational agent to ensure the stability and integrity of the agent.  
- Return any unused investigational agents at the completion of the study or upon notification that an agent is being withdrawn.
The intent of the agent accountability procedures described in this section is to assist the investigator in making certain that agents received from BTTC are used only for patients entered onto an approved protocol. The record keeping described in this section is required under FDA regulation. 10.2.17.1 BTTC Procedures for Agent Accountability and Storage  
- Each investigational agent should be stored separately by protocol. If an agent is used for more than one protocol, there should be separate physical storage for each protocol. Remember that agents are provided and accounted for on a protocol-by-protocol basis.  
- Each agent should be accounted for separately by protocol. If an agent is used for more than one protocol, there should be a separate Drug Accountability Record Form (DARF) for each protocol, http://ctep.cancer.gov/forms/index.html. There should be a separate DARF for each agent in a multi-agent protocol.  
- Separate accountability forms should be maintained for each different strength or dosage form of a particular agent (e.g., an agent with a 1-mg vial and a 5-mg vial would require a different DARF for the 1-mg vial than for the 5-mg vial).  
- The DARF has been designed for use at each location where agents are stored, e.g., main pharmacy, satellite pharmacy, physician's office, or other dispensing areas.  
- The DARF is also designed to accommodate both dispensing records and other agent transaction documentation (e.g., receipt of agent, returns, broken vials, etc.). A copy of the DARF may be found at http://ctep.cancer.gov/forms/index.html.  
- Unauthorized inter-institutional transfer of BTTC investigational agents from one participating institution to another is not permitted. For some protocols the **lead**
institution may enter into contractual agreements to forward agents to participating institutions (see BTTC Operations Manual).
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verification of compliance

Investigators are reminded that compliance with procedures to ensure proper agent usage will be reviewed during site visits conducted under the monitoring program. Specifically, site visitors will check that the agent accountability system is being maintained, and will spot-check the agent accountability records by comparing them with the patients' medical records to verify that the agents were administered to a patient entered in the recorded protocol Returning or destroying unused and/or defective Agent:
Investigators/Designees should make every effort to minimize the amount of agent ordered and returned unused, (e.g. limit inventories to an 8 week supply or less). Investigators/Designees must return unused supplied agent as directed in the protocol when:
- The agent is no longer required because the study is completed.  
- Agent is outdated. Investigators/designees should only return outdated agents with a firm expiration date or if they have received written notification that an agent has expired and should be returned.  
- The agent is damaged or unfit for use. Investigators/designees should contact the supplier prior to returning investigational agents because of stability concerns, (e.g. loss of refrigeration or exposure to elevated temperatures). Do **NOT** return broken vials. Broken vials should be destroyed at the clinical site. Follow the appropriate agent accountability guidelines.
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general guidelines

- Regulations require that all agents received be returned to the supplier for accountability and disposition.  
- Return only unused vials/bottles. Do **NOT** return opened or partially used vials/bottles unless specifically requested otherwise in the protocol.  
- Return only supplied agents. Do **NOT** ship agents received from other sources to the supplier.
10.2.18.1 Sorafenib Return Procedure All unused and returned sorafenib may be destroyed on site. The site must follow their local drug destruction policy and procedure. A copy of the drug destruction record must be submitted to Bayer Pharmaceuticals using the Bayer form provided (attached as a separate form).
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contact amanda rozner

Bayer Healthcare, US Medical Affairs Investigator Sponsored Studies & Medical Education 100 Bayer Boulevard, P.O. Box 915 Bldg 200, 4th Floor Whippany, NJ 07981-0915 Phone: 1-862-404-5842 Email: amanda.rozner@bayer.com 10.2.18.2 Everolimus Return Procedure All unused and returned everolimus may be destroyed on site. The site must follow their local drug destruction policy and procedure. A copy of the drug destruction record must be submitted to Novartis.  
Contact: **Krystal Saintil**
Novartis Pharmaceuticals Corporation USEH One Health Plaza Building 345 East Hanover, NJ 07936-1080 USA  
Phone: +1 862778 7169 Email: krystal.saintil@novartis.com 10.2.18.3 Handling of study medication: Pharmacists should use appropriate precautions in handling and disposal of hazardous agents.
10.2.18.4 Notice of Defect or Non-Conformity: The Sponsor (NCI) shall ensure that any notice of defect or non-conformity is sent to Novartis within ten (10) days from receipt of Study Drug. The failure to provide such notice shall be deemed an acceptance of Study Drug by the Sponsor or its Subcontractors. Latent defects which are detected later shall be immediately reported to Novartis for further processing within Novartis.
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11.0 multicenter procedures general procedures

The BTTC Operations Manual and Data Submission Forms, on file at all BTTC institutions, document the data management and quality assurance programs for this collaboration. BTTC institutions will follow the guidelines as addressed below and throughout this protocol.
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principal investigators

The principal investigator(s) will be responsible for the conduct of the study and monitoring its progress. The responsibility for all reports and forms required by BTTC will be that of the principal investigator(s).
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procedures for site registration

Before an institution may begin participating in a BTTC protocol, they must complete the following steps:  
- Submit all required regulatory documents to the BTTC Coordinating Center as outlined in the BTTC Operations Manual
- Participate in a site initiation visit, webcast, or conference call
- Receive training regarding study specific CRF's and/or databases After these requirements have been fulfilled, the participating institution will receive by fax, email, or hard copy memo a Site Activation Notification. Once the Site Activation Notification has been received, the participating institution may begin to register patients to the protocol.
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institutional review

Each cooperating center will submit the protocol to its own IRB. Documentation of the IRB approval will be forwarded to the BTTC Coordinating Center before a patient from that institution can be registered on protocol. No changes in the protocol will be allowed unless approved by the principal investigator and BTTC.
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protocol revisions and closure

Non life-threatening revisions: BTTC investigators will receive written notification of protocol revisions regarding non life-threatening events. Page 82 Life-threatening revisions: BTTC investigators will receive telephone notification of lifethreatening revisions with follow-up by fax and/or e-mail. Life-threatening protocol revisions will be implemented immediately.  
Protocol closures and temporary holds: BTTC investigators will receive email notification of protocol closures and holds. Closures and holds will be effective immediately. Centers will be updated on an ongoing basis about protocol accrual data so that they will be aware of imminent protocol closures.
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12.0 references

1. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al.  
Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. The New England journal of medicine. 2005;352(10):987-96. 2. Lamborn KR, Yung WK, Chang SM, Wen PY, Cloughesy TF, DeAngelis LM, et al. Progression-free survival: an important end point in evaluating therapy for recurrent high-grade gliomas. Neuro-oncology. 2008;10(2):162-70.  
3. Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, et al. Phase II trial of singleagent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2009;27(5):740-5. 4. Vredenburgh JJ, Desjardins A, Herndon JE, 2nd, Marcello J, Reardon DA, Quinn JA, et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2007;25(30):4722-9. 5. CBTRUS. CBTUS. Statistical Report: Primary Brain Tumors in the United States, 19982002. In: Published by the Central Brain Tumor Registry of the United States. 2005. 6. Sathornsumetee S, Reardon DA, Desjardins A, Quinn JA, Vredenburgh JJ, Rich JN. Molecularly targeted therapy for malignant glioma. Cancer. 2007;110(1):13-24. 7. Duda DG, Jain RK, Willett CG. Antiangiogenics: the potential role of integrating this novel treatment modality with chemoradiation for solid cancers. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2007;25(26):4033-42. 8. Vredenburgh JJ, Desjardins A, Herndon JE, 2nd, Dowell JM, Reardon DA, Quinn JA, et al. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clinical cancer research : an official journal of the American Association for Cancer Research. 2007;13(4):12539. 9. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer research. 2004;64(19):7099-109. 10. Hilger RA, Scheulen ME, Strumberg D. The Ras-Raf-MEK-ERK pathway in the treatment of cancer. Onkologie. 2002;25(6):511-8. 11. Chang YS, Henderson A, Xue D, Chen C, McNabola A, Wilkie D, et al. BAY 43-9006 (Sorafenib) inhibits ectopic (s.c.) and orthotopic growth of a murine model of renal adenocarcinoma (Renca) predominantly through inhibition of tumor angiogenesis. Cancer research. 2005;65(9 Supplement):1372. 12. Awada A, Hendlisz A, Gil T, Bartholomeus S, Mano M, de Valeriola D, et al. Phase I safety and pharmacokinetics of BAY 43-9006 administered for 21 days on/7 days off in patients with advanced, refractory solid tumours. British journal of cancer. 2005;92(10):1855-61. 13. Clark JW, Eder JP, Ryan D, Lathia C, Lenz HJ. Safety and pharmacokinetics of the dual action Raf kinase and vascular endothelial growth factor receptor inhibitor, BAY 43-9006, in patients with advanced, refractory solid tumors. Clinical cancer research : an official journal of the American Association for Cancer Research. 2005;11(15):5472-80. 14. Moore M, Hirte HW, Siu L, Oza A, Hotte SJ, Petrenciuc O, et al. Phase I study to determine the safety and pharmacokinetics of the novel Raf kinase and VEGFR inhibitor BAY 43-9006, administered for 28 days on/7 days off in patients with advanced, refractory solid tumors. Annals of oncology : official journal of the European Society for Medical Oncology. 2005;16(10):1688-94. 15. Strumberg D, Richly H, Hilger RA, Schleucher N, Korfee S, Tewes M, et al. Phase I clinical and pharmacokinetic study of the Novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2005;23(5):965-72. 16. Richly H, Henning BF, Kupsch P, Passarge K, Grubert M, Hilger RA, et al. Results of a Phase I trial of sorafenib (BAY 43-9006) in combination with doxorubicin in patients with refractory solid tumors. Annals of oncology : official journal of the European Society for Medical Oncology. 2006;17(5):866-73. 17. Siu LL, Awada A, Takimoto CH, Piccart M, Schwartz B, Giannaris T, et al. Phase I trial of sorafenib and gemcitabine in advanced solid tumors with an expanded cohort in advanced pancreatic cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2006;12(1):144-51. 18. Escudier B, Szczylik C, Eisen T, Stadler WM, Schwartz B, Shan M, et al. Randomized phase III trial of the Raf kinase and VEGFR inhibitor sorafenib (BAY 43–9006) in patients with advanced renal cell carcinoma (RCC). Journal of Clinical Oncology. 2005;23(16_suppl):LBA4510-LBA. 19. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006;124(3):471-84. 20. Bjornsti MA, Houghton PJ. The TOR pathway: a target for cancer therapy. Nature reviews Cancer. 2004;4(5):335-48. 21. Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007;129(7):1261-74. 22. Fan QW, Specht KM, Zhang C, Goldenberg DD, Shokat KM, Weiss WA. Combinatorial efficacy achieved through two-point blockade within a signaling pathway-a chemical genetic approach. Cancer research. 2003;63(24):8930-8. 23. Carmichael J, Fink U, Russell RC, Spittle MF, Harris AL, Spiessi G, et al. Phase II study of gemcitabine in patients with advanced pancreatic cancer. Br J Cancer. 1996;73(1):101-5. 24. Armstrong TS, Mendoza TR, Gring I, Coco C, Cohen MZ, Ericksen L, et al. Validation of the M. D. Anderson Symptom Inventory Brain Tumor Module (MDASI-BT). J Neurooncol.  
2006;In press. 25. Armstrong C, Mollman, J., Corn, B.W., Alavi, J., Grossman, M. Effects of radiation therapy on adult brain behavior: evidence for a rebound phenomenon in a Phase I trial. Neurology. 1993;43(1961-1965).
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13.0 appendices

APPENDIX: KARNOFSKY **PERFORMANCE STATUS AND NEUROLOGICAL FUNCTION**
Patient's performance status and Neurologic Functions will be graded according to the following scales:
Karnofsky Performance Status KPS 100 Normal; no complaints; no evidence of disease  
| KPS 90   | Able to carry on normal activity; minor signs or symptoms of disease        |
|----------|-----------------------------------------------------------------------------|
| KPS 80   | Normal activity with effort; some sign or symptoms of disease               |
| KPS 70   | Cares for self; unable to carry on normal activity or do active work        |
| KPS 60   | Requires occasional assistance, but is able to care for most personal needs |
| KPS 50   | Requires considerable assistance and frequent medical care                  |
| KPS 40   | Disabled; requires special care and assistance                              |
| KPS 30   | Severely disabled; hospitalization is indicated, although death no imminent |
| KPS 20   | Very sick; hospitalization necessary; active support treatment is necessary |
| KPS 10   | Moribund; fatal processes progressing rapidly                               |  
KPS 0 Dead  
Neurologic Function
+2 Definitely Better  
| +1   | Possibly Better   |
|------|-------------------|
| 0    | Unchanged         |
| -1   | Possibly Worse    |
| -2   | Definitely Worse  |
| B    | Baseline          |  
  
APPENDIX: EIAEDS AND NON-EIAEDS
EIAED  
| Carbamazipine            | (Tegretol, Tegretol XR, Carbatrol)   |
|--------------------------|--------------------------------------|
| Oxcarbazepine            | (Trileptal)                          |
| Phenytoin                | (Dilantin, Phenytek)                 |
| Fosphenytoin             | (Cerebyx)                            |
| Phenobarbital  Primidone | (Mysoline)                           |
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non-eiaeds

| Valproic acid   | (Depakote, Depakene)   |
|-----------------|------------------------|
| Gabapentin      | (Neurontin)            |
| Lamotrigine     | (Lamictil)             |
| Topriamate      | (Topamax)              |
| Tiagabine       | (Gabatril)             |
| Zonisamide      | (Zonegran)             |
| Levatriacetam   | (Keppra)               |
| Clonazepam      | (Klonopin)             |
| Clonozam        | (Frisium)              |  
| APPENDIX: DRUGS KNOWN TO BE METABOLIZED BY CYP450 ISOENZYMES 2D6 AND 3A4 CYP3A3/4 Substrates Acetaminophen Aifentanil Alosetron  Alprazolam Amiodarone  Amitriptyline (minor) Amlodipine  Anastrozole  Androsterone  Antipyrine Astemizole Atorvastatin Benzphetamine  Bepridil  Bexarotene Bromazepam Bromocriptine  Budesonide  Bupropion (minor)  Buspirone  Busutfan  Caffeine Cannabinoids  Carbamazepine Cevimeline Cerivastatin Digitoxin Diltiazem Disopyramide Docetaxel Dolasetron Donepezil  Doxorubicin  Doxycycline Dronabinol  Enalapril Erythromycin Estradiol  Ethinyl estradiol Ethosuximide  Etoposide  Exemestene Dofetilide (minor) Chlorpromazine Cimetidine Cisapride  Citałopram Clarithromycin Clindamycin Clomipramine Clonazepam Clozapine  Cocaine Codeine (demethylation)  Cortisol  Cortisone  Cyclobenzaprine (demethylation) Cyclophosphamide  Cyclosporine  Dapsone  Dehydroepiandrostendione  Delavirdine  Desmethyldiazepam Dexamethasone Dextromethorphan (minor, Ndemethylation)  Diazepam (minor; hydroxylation, Ndemethylation) Nefazodone  Nelfinavir Nevirapine  Nicardipine  Nifedipine  Niludipine  Nimodipine  Nisoldipine  Nitrendipine  Omeprazole (sulfonation)  Ondansetron  Oral contraceptives Orphenadrine  Paclitaxel Pantoprazole  Pimozide Pioglitazone Pravastatin   |
|---|  
| Felodipine Fentanyl Fexotenadine  Finaxteride Fluoxetine  Flutamide Glyburide  Granisetron Halofantrine  Hydrocortixone  Hydroxyarginine  lfosfamide lmipramine lndinavir  lsradipine  ltraconazole Ketoconazole  Lansoprazole (minor)  Letrozole  Levobupivicaine  Lidocaine  Loratadine  Losartan Lovastatin Methadone  Mibefradil Miconazole  Midazolam Mifepristone  Mirtazapine (N-demethylation) Montelukast  Navelbine  Toremifene Trazodone  Tretinoin Triazolam Troglitazone  Troleandomycin  Venlafaxine (N-demethylation) Verapamil Vinblastine   | Prednisone Progesterone  Proguanil  Propafenone  Quercetin Quetiapine  Quinidine  Quinine  Repaglinide  Retinoic acid Rifampin Risperidone  Ritonavir  Salmeterol Saquinavir  Sertindole  Sertraline Sibutramine Sildenafil citrate Simvastatin Sirolimus Sufentanil  Tacrolimus Tamoxifen Temazepam Teniposide  Terfenadine Testosterone  Tetrahydrocannabinol  Theophylline  Tiagabine  Tolterodine  Vincristine Warfarin (R-warfarin) Yohimbine  Zaleplon (minor pathway)  Zatoestron Zileuton Ziprasidone  Zolpidem  Zonisamide   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Inducers Carbamazepine Dexamethasone Ethosuximide                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Phenytoin Primidone  Progesterone                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |  
| Glucocorticoids Griseofulvin  Nafcillin Nelfinavir Nevirapine  Oxcarbazepine Phenobarbital  Phenylbutazone                                                                                                                                                                                                                                                                       | Rifabutin Rifampin Rofecoxib (mild)  St John's wort Sulfadimidine Sulfinpyrazone  Troglitazone                                                                                                                                                                                                                                                                                          |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Inhibitors Amiodarone Anastrozole  Azithromycin Cannabinoids  Cimetidine Clarithromycin Clotrimazole Cyclosporine  Danazol Delavirdine  Dexamethasone Diethyldithiocarbamate Diltiazem Dirithromycin Disulfiram Entacapone (high dose)  Erythromycin Ethinyl estradiol Fluconazole (weak) Fluoxetine  Fluvoxamine  Gestodene  Grapefruit juice lndinavir  lsoniazid ltraconazole | Ketoconazole Metronidazole  Mibefradil Miconazole (moderate) Nefazodone  Nelfinavir Nevirapine  Norfloxacin Norfluoxetine  Omeprazole (weak) Oxiconazole  Paroxetine (weak) Propoxyphene  Quinidine  Quinine  Quinupristin and dalfopristin  Ranitidine Ritonavir  Saquinavir  Sertindole  Sertraline Troglitazone  Troleandomycin  Valproic acid (weak) Verapamil Zafirlukast Zileuton |
| (Adapted from Cytochrome P-450 Enzymes and Drug metabolism. In : Lacy CF,  Armstrong LL, Goldman MP, Lance LL eds. Drug Information Handbook 8th ed. Hudson,                                                                                                                                                                                                                     |                                                                                                                                                                                                                                                                                                                                                                                         |  
Table 13-1: Examples of clinically relevant drug interaction: substrates, inducers and inhibitors of isoenzyme CYP3A.  
| Substrates   | (competitive   |
|--------------|----------------|
| inhibition)  |                |  
| Version Date: 06/15/18                                                                                                                                                                                                                                                                                                                                                                                            | Page 90 of 99                                                                                                                     |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------|
| Calcium Channel Blockers:   amlodipine  diltiazem  felodipine   nifedipine   nisoldipine   nitrendipine  verapamil HMG CoA Reductase Inhibitors2 :  atorvastatin cerivastatin lovastatin simvastatin Miscellaneous: aprepitant  buspirone   haloperidol   methadone   pimozide   quinine  sildenafil tamoxifen  trazodone  vincristine                                                                            |                                                                                                                                   |
| Inducers Carbamazepine Phenobarbital  Phenytoin*  Rifabutin* Antibiotics1 :  clarithromycin* erythromycin  telithromycin* Anti-arrhythmics:  quinidine  Benzodiazepines:  alprazolam diazepam midazolam triazolam Immune Modulators:   cyclosporine   tacrolimus (FK506)  HIV Protease Inhibitors:   indinavir*   ritonavir*   saquinavir*  Prokinetic:  cisapride Antihistamines: astemizole  chlorpheniramine90 | Rifampin* St John's wort Troglitazone                                                                                             |
| Inhibitors Amiodarone  Cimetidine Clarithromycin Delaviridine Diltiazem Erythromycin Fluvoxamine*  Grapefruit juice Sevilla orange                                                                                                                                                                                                                                                                                | Indinavir  Itraconazole* Ketoconazole* Voriconazole*  Posaconazole* Mibefradil Nefazodone*  Nelfinavir* Troleandomycin  Verapamil |  
Based on: Ingelman-Sundberg M, Human drug metabolising cytochrome P450 enzymes: properties and polymorphisms, Naunyn Schmiedebergs Arch Pharmacol. 2004 Jan;369(1):89-104. and [http://www.medicine.iupui.edu/flockhart/clinlist.htm as of July 13, 2006]
* asterisk denotes strong inhibition/ induction Please note:
- strong inhibitor implies that it can cause ≥5-fold increase in AUC or ≥80%
decrease in clearance of sensitive CYP substrates
- moderate inhibitor implies that it can cause 2 to 5-fold increase in AUC values or 50-80% decrease in clearance of sensitive CYP substrates. (Distinction is not always categorical as interaction can vary according to conditions).  
1. Macrolide antibiotics: Azithromycin is not a CYP3A substrate. It may therefore be employed where antibiotherapy with a macrolide is desirable in a patient being treated with everolimus 2. Statins: Atorvastatin and pravastatin may be associated with everolimus, since a PK
interaction study has shown that there is no relevant PK interaction.  
  
Date:
untitled h1
13.4 appendix m.d. a nderson

| 6   | 7   | 8   |
|-----|-----|-----|
| o   | o   | o   |
| o   | o   | o   |
| o   | o   | o   |
| o   | o   | o   |
| o   | o   | o   |
| o   | o   | o   |
| o   | o   | o   |
| o   | o   | o   |
| o   | o   | o   |
| o   |     |     |
| o   | o   |     |
| o   | o   | o   |
| o   | o   | o   |
| o   | o   | o   |
| o   | o   | o   |
| o   | o   | o   |
| o   | o   | o   |  
| 2   | 3   | 4   |
|-----|-----|-----|
| o   | o   | o   |
| o   | o   | o   |
| o   | o   | o   |
| o   | o   | o   |
| o   | o   | o   |
| o   | o   | o   |
| o   | o   | o   |
| o   | o   | o   |
| o   | o   | o   |
| o   | o   |     |
| o   |     |     |
| o   | o   | o   |
| o   | o   | o   |
| o   |     |     |
| o   | o   |     |
| o   | o   | o   |
| o   | o   | o   |
| o   | o   | o   |  
| Not     |    |
|---------|----|
| Present |    |
| 0       | 1  |
| o       | o  |
| o       | o  |
| o       | o  |
| o       | o  |
| o       |    |
| o       |    |
| o       | o  |
| o       | o  |
| o       | o  |
| o       | o  |
| o       | o  |
| o       | o  |
| o       | o  |
| O       | o  |
| o       | o  |
| o       | o  |
| o       | o  |  
| As Bad As You   |    |
|-----------------|----|
| Can Imagine     |    |
| 9               | 10 |
| o               | o  |
| o               | o  |
| o               | o  |
| o               | o  |
| o               | o  |
| o               | o  |
| o               | o  |
| o               | o  |
| o               | o  |
| o               |    |
| o               |    |
| o               | o  |
| o               | o  |
| o               | o  |
| o               | o  |
| o               | o  |
| o               | o  |  
| 1.                              |  Your pain at its WORST?    |
|---------------------------------|-----------------------------|
| 2.                              | Your fatigue (tiredness) at |
| its WORST?                      |                             |
| 3.                              | Your nausea at its WORST?   |
| 4.                              | Your disturbed sleep at its |
| WORST?                          |                             |
| s.                              | Your feelings of being      |
| distressed (upset) at its       |                             |
| WORST?                          |                             |
| 6.                              | Your shortness of breath at |
| its WORST?                      |                             |
| 7.                              | Your problem with           |
| remembering things at its       |                             |
| WORST?                          |                             |
| a'                              | Your problem with lack of   |
| appetite at its WORST?          |                             |
| 9.                              | Your feeling drowsy         |
| (sleepy) at its WORST?          |                             |
| 10.  Your having a dry mouth at |                             |
| its WORST?                      |                             |
| 1.                              | Your feeling sad at its     |
| WORST?                          |                             |
| 12.                             | Your vomiting at its        |
| WORST?                          |                             |
| 13.                             | Your numbness or tingling   |
| at its WORST?                   |                             |
| 14. Your weakness on one side   |                             |
| of the body at its WORST?       |                             |
| 15.                             | Your difficulty             |
| understanding at its            |                             |
| WORST?                          |                             |
| 16. Your difficulty speaking    |                             |
| (finding the words) at its      |                             |
| WORST?                          |                             |  
Hospital Chart \#:  
  
Participant Initials:
Part I. How severe are your symptoms?  
People with cancer frequently have symptoms that are caused by their disease or by their treatment. We ask you to rate how severe the following symptoms have been in the last 24 hours. Please select a number from 0
(symptom has not been present) to 10 (the symptom was as bad as you can imagine it could be) for each item.  
Copyright 2000 The University of Texas MD Anderson Cancer Center All rights reserved.  
Page 1 of 2 MDASI-BT - 2006 Participant Number:
5 o o o o o o o o o o o o o o o o  
| 23. General activity?    |
|--------------------------|
| 2. Mood?                 |
| 25. Work (including work |
| around the house)?       |
| 26. Relations with other |
| people?                  |
| 27. Walking?             |
| 2. Enjoyment of life?    |  
| 2   |
|-----|
| o   |
| o   |
| o   |
| o   |
| o   |
| o   |  
| Not     |    |
|---------|----|
| Present |    |
| 0       | 1  |
| o       | o  |
| o       | o  |
| o       | o  |
| o       | o  |
| o       | o  |
| o       | o  |  
| 17. Your seizures at its WORST?   |
|-----------------------------------|
| 18. Your difficulty concentrating |
| at its WORST?                     |
| 19. Your vision at its WORST?     |
| 20. Your change in appearance     |
| at its WORST?                     |
| 21. Your change in bowel pattern  |
| (diarrhea or constipation) at     |
| its WORST?                        |
| 2. Your irritability at its       |
| WORST?                            |  
Date:  
  
  
  
  
Participant Number:  
| Did Not
Interfere   |    |
|---|----|
| 0 | 1  |
| o | o  |
| o | o  |
| o | o  |
| o | o  |
| o | o  |
| o | o  |  
Part II. How have your symptoms interfered with your life?  
| 2   |
|-----|
| o   |
| o   |
| o   |
| o   |
| o   |
| o   |  
Symptoms frequently interfere with how we feel and function. How much have your symptoms interfered with the following items in the last 24 hours?  Please select a number from 0 (symptoms have not interfered) to 10 (symptoms interfered completely) for each item.  
Page 2 of 2 MDASI-BT - 2006  
| As Bad As You   |    |    |    |    |    |    |    |
|-----------------|----|----|----|----|----|----|----|
| Can Imagine     |    |    |    |    |    |    |    |
| 3               | 4  | 5  | 6  | 7  | 8  | g  | 10 |
| o               | o  | o  | o  | o  | o  | o  | o  |
| o               | o  | o  | o  |    |    |    |    |
| o               | o  | o  | o  |    |    |    |    |
| o               | o  | o  |    |    |    |    |    |
| o               | o  | o  | o  | o  |    |    |    |
| o               | o  | o  | o  | o  | o  | o  | o  |
| o               | o  | o  | o  | o  | o  | o  | o  |
| o               | o  | o  | o  | o  | o  | o  | o  |  
| 7   |    |    |    |    |
|-----|----|----|----|----|
| 3   | 4  | 5  | 6  |    |
| o   | o  | o  | o  | o  |
| o   | o  | o  | o  |    |
| o   |    |    |    |    |
| o   | o  | o  | o  | o  |
| o   | o  | o  | o  | o  |
| o   | o  | o  | o  | o  |
| o   | o  |    |    |    |
| o   | o  | o  |    |    |  
| Interfered   |    |    |
|--------------|----|----|
| Completely   |    |    |
| 8            | 9  | 10 |
| o            | o  | o  |
| o            | o  | o  |
| o            | o  | o  |
| o            | o  | o  |
| o            | o  | o  |
| o            | o  |    |
| o            |    |    |  
Abbreviated Title: Ph 1/2 Everolimus & Sorafenib Version Date: 06/15/18
untitled h1
appendix ccr problem report form

| NCI Protocol #:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Protocol Title:  Report version: (select one) ____Initial Report  ____Revised Report  ____Follow-up   |                 |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------|-----------------|
| Site Principal Investigator: Date of problem:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Location of problem: (e.g.,                                                                           | patient's home, |
| doctor's office )                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                       |                 |
| Who identified the problem? (provide role (not name of person): nurse, investigator, monitor,  etc…) Sex: ___ Male ___ Female Age:   ___ Not applicable (more than subject is involved)  Brief Description of Subject (if  applicable)  (Do NOT include personal  identifiers) Diagnosis under study:  Name the problem: (select all that apply)  [ ] Adverse drug reaction  [ ] Abnormal lab value  [ ] Death  [ ] Cardiac Arrest/ code  [ ] Anaphylaxis  [ ] Sepsis/Infection  [ ] Blood product reaction  [ ] Unanticipated surgery/procedure  [ ] Change in status (e.g. increased level of care required)  [ ] Allergy (non-medication)  [ ] Fall  [ ] Injury/Accident (not fall)  [ ] Specimen collection issue  [ ] Informed consent issue  [ ] Ineligible for enrollment  [ ] Breach of PII  [ ] Tests/procedures not performed on schedule  [ ] Other, brief 1-2 word description: _________________________ |                                                                                                       |                 |  
Detailed Description of the problem: (*Include any relevant treatment, outcomes or pertinent* history):
*Is this problem unexpected? *(see the definition of unexpected in the protocol))* __YES __NO
Please explain:
*Is this problem related or possibly related to participation in the research? __YES __NO
Please explain: *Does the problem suggest the research places subjects or others at **a greater risk of harm**
than was previously known or recognized? __YES __NO Please explain:
Is this problem? (*select all that apply*)
[ ] An Unanticipated Problem* that is: [ ] Serious [ ] Not Serious [ ] A Protocol Deviation that is: [ ] Serious [ ] Not Serious [ ] Non-compliance *Note if the 3 criteria starred above are answered, "YES", then this event is also a UP.  
Is the problem also *(select one)* [ ] AE [ ] Non-AE
Have similar problems occurred on this protocol at your site? __YES __NO
If "Yes", how many? ____ **Please describe:**
Describe what steps you have already taken as a result of this problem:
In addition to the NCI IRB, this problem is also being reported to: (*select all that apply*)
[ ] Local IRB [ ] Study Sponsor [ ] Manufacturer : ____________________
[ ] Institutional Biosafety Committee
[ ] Data Safety Monitoring Board [ ] Other: ____________________________________ [ ] None of the above, not applicable INVESTIGATOR'S SIGNATURE: DATE:
13.7 APPENDIX: U NUSED S TUDY D RUG D ISPOSITION F ORM - B AYER  
Bayer HealthCare
untitled h1
unused study drug disposition form

Destruction Or Return Confirmation  
| Study Drug Provided   | Study Drug Unused   | Study Drug Destroyed   | Study Drug Returned   |
|-----------------------|---------------------|------------------------|-----------------------|  
I hereby confirm that the product described above was destroyed or returned (select one) to Bayer on
(date)
(address)
Witness (Pharmacist or PI):  
  
  
  
Please return this form to Amanda Rozner Amanda.rozner@bayer.com. Bayer HealthCare
Pharmaceuticals, "NEW ADDRESS" 100 Bayer Boulevard, P.O. Box 915 Whippany. NJ 07981-0915