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BRAIN TUMOR TRIALS COLLABORATIVE (BTTC)
Abbreviated Title: Ph 1/2 Everolimus & Sorafenib CC **Protocol \#**: 16C0011 Amendment Letter: D Version Date: 06-15-2018 BTTC Protocol \#: BTTC09-01 NCT Number: NCT01434602 Title: A Phase I-II trial of Everolimus and Sorafenib in Patients with Recurrent High-Grade Gliomas Coordinating Center: BTTC Coordinating Center, Center for Cancer Research, NCI
NCI Principal Investigator: Mark Gilbert, M.D. A,B,C,D,E,F
Neuro Oncology Branch (NOB), CCR, NCI 9030 Old Georgetown Road, Building 82, Room 235 Bethesda, MD 20892 Phone: 240-760-6023 Fax: 240-541-4432 Email: mark.gilbert@nih.gov Investigational Agents: None Commercial Agents: Sorafenib tosylate, hereafter referred to as sorafenib and Everolimus will be supplied from commercial sources by their respective manufacturers, Bayer and Novartis
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bttc roles study chair

Jeffrey J. Raizer, MD 710 North Lake Shore Dr. Abbott Hall, Room 1123 Chicago, IL 60611 Phone: 312-503-4724 Fax: 312-908-5073 Email: jraizer@nm.org FWA00001549  
| LEAD PI Mark R. Gilbert, MD Neuro-Oncology Branch NCI/NINDS National Institutes of Health Bloch Bldg. 82, Rm. 235  9030 Old Georgetown Road  Bethesda, MD 20892  Email: mark.gilbert@nih.gov   | BTTC COORDINATING  CENTER National Cancer Institute,  National Institutes of Health 9030 Old Georgetown Road,  Room 211  Bethesda, MD 20892  Phone: 240-760-6060 Fax: 301-451-5429  Email: NCI_BTTC@mail.nih.gov   |
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a disclaimer statement for bttc

This is a research protocol of the Brain Tumor Trials Collaborative describing an experimental treatment procedure. It is a privileged document and is not intended to be circulated or used for other purposes. The Brain Tumor Trials Collaborative assumes no responsibility for its use outside of the constraints of this research protocol or by investigators other than those approved by the Consortium.
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bttc participating investigators

Note: These sites will be collecting and submitting data to the BTTC Coordinating Center at NCI (e.g. through data entry in C3D) and will not be re-opening to accrual.  
| (e.g. through data entry in C3D) and will not be re-opening to accrual.  Site Name FWA # Participating  Address   | Email                                                                                                   |                                                 |                           |              |
|-------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------|-------------------------------------------------|---------------------------|--------------|
| Investigator David                                                                                                |                                                                                                         |                                                 |                           |              |
| Cleveland Clinic                                                                                                  | FWA00005367                                                                                             | Peereboom,  MD                                  | peerebd@ccf. org          |              |
| 9500 Euclid Ave, R35, Cleveland, OH 44195                                                                         |                                                                                                         |                                                 |                           |              |
| Columbia                                                                                                          | 710 West 168th Street, R9-                                                                              | fi2146@colum                                    |                           |              |
| FWA00005846                                                                                                       | Fabio Iwamoto,                                                                                          |                                                 |                           |              |
| University Medical                                                                                                | M.D.                                                                                                    | 109, New York, NY 10032                         | bia.edu                   |              |
| Center                                                                                                            |                                                                                                         |                                                 |                           |              |
| Henry Ford Health  System                                                                                         | FWA00005846                                                                                             | Tobias                                          | 2799 W Grand Blvd,        | twalber1@hfh |
| Walbert, MD                                                                                                       | Detroit, MI 48202                                                                                       | s.org                                           |                           |              |
| Northwestern  University,                                                                                         |                                                                                                         |                                                 |                           |              |
| Feinberg School of  Medicine                                                                                      | 710 North Lake Shore Drive  Abbott Hall, Room 1123,  Chicago, IL 60611                                  |                                                 |                           |              |
| FWA0001549                                                                                                        | Jeffrey Raizer,  M.D.                                                                                   | jraizer@nm.or g  morris.groves @usoncology.c om |                           |              |
| Texas Oncology -  Austin Brain  Tumor Center                                                                      | FWA00017020                                                                                             | Morris Groves,                                  | 901 W. 38th Street, Suite |              |
| M.D.                                                                                                              | 200, Austin, TX 78705                                                                                   |                                                 |                           |              |
| UF Health Cancer  Center at Orlando  Health                                                                       | nicholas.avger opoulos@orla ndohealth.com                                                               |                                                 |                           |              |
| University of  Kansas Cancer  Center                                                                              | FWA00000384                                                                                             | Nicholas                                        |                           |              |
| Avgeropoulos,  M.D.                                                                                               | 1400 South Orange Ave,  Orlando, FL 32806 2330 Shawnee Mission  Parkway, Suite 210,  Westwood, KS 66205 |                                                 |                           |              |
| FWA00016803                                                                                                       | Michael Salacz,  M.D.                                                                                   | msalacz@kum c.edu                               |                           |              |
| Frances                                                                                                           |                                                                                                         |                                                 |                           |              |
| University of                                                                                                     | Collichio, M.D.                                                                                         | 170 Manning Dr. CB#7305,                        |                           |              |
| FWA00004507                                                                                                       |                                                                                                         |                                                 |                           |              |
| North Carolina at                                                                                                 | Chapel Hill, NC 27599                                                                                   |                                                 |                           |              |
| Chapel Hill                                                                                                       | fcollich@med. unc.edu                                                                                   |                                                 |                           |              |
| Marta PenasPrado, M.D.                                                                                                                   | 1515 Holcombe Blvd,                                                                                     | mpenaspr@m                                      |                           |              |
| Houston, TX 77030                                                                                                 | danderson.org                                                                                           |                                                 |                           |              |
| 1515 Holcombe Blvd,                                                                                               |                                                                                                         |                                                 |                           |              |
| John deGroot,                                                                                                     | jdegroot@mda                                                                                            |                                                 |                           |              |
| Houston, TX 77030                                                                                                 |                                                                                                         |                                                 |                           |              |
| M.D.                                                                                                              | nderson.org                                                                                             |                                                 |                           |              |
| UT MD Anderson                                                                                                    | FWA00000363                                                                                             |                                                 |                           |              |
| Cancer Center                                                                                                     | 1515 Holcombe Blvd,                                                                                     |                                                 |                           |              |
| Monica Loghin,                                                                                                    | mloghin@mda                                                                                             |                                                 |                           |              |
| MD                                                                                                                | Houston, TX 77030                                                                                       | nderson.org                                     |                           |              |
| W.K. Alfred                                                                                                       | 1515 Holcombe Blvd,                                                                                     | wyung@mdan                                      |                           |              |
| Houston, TX 77030                                                                                                 |                                                                                                         |                                                 |                           |              |
| Yung, MD                                                                                                          | derson.org                                                                                              |                                                 |                           |              |
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precis

Background
- Although malignant gliomas display genetic heterogeneity, several key proliferation and survival signaling pathways have been identified.  
- Recent work has focused on targeting these tumor specific pathways in hopes of improving treatment efficacy and minimizing treatment toxicity. Because molecularly targeted agents have been mostly ineffective when used alone, combination therapy that inhibits multiple pathways is an appealing strategy.  
- Sorafenib is an oral multi-kinase inhibitor with effects on tumor proliferation and tumor angiogenesis. Although most GBMs lack RAF mutations, targeting the RAF/MEK/ERK pathway may be beneficial as this pathway may be activated by other genetic alterations upstream from RAF.  
- The mammalian target of rapamycin (mTOR) protein is a downstream component of the PI3K/Akt pathway. Everolimus (everolimus; Novartis) is a novel oral derivative of rapamycin
- Combining everolimus and sorafenib allows targeting of both the PI3K pathway and the RAF-MAPK pathway and in addition targets VEGF and PDGF, other active targets in malignant glioma.
Objectives
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phase 1

- To determine the maximum tolerated dose and safety of everolimus in combination with sorafenib for patients with recurrent malignant gliomas.  
Phase 2  
- 6-month progression free survival rate for glioblastoma patients with no prior bevacizumab exposure treated with everolimus and sorafenib at the maximum tolerated dose as determined in the phase I study.  
- 3-month progression free survival rate for glioblastoma patients with prior bevacizumab exposure treated with everolimus and sorafenib at the maximum tolerated dose as determined in the phase I study.  
- 6-month progression free survival rate for AG patients with no prior bevacizumab exposure treated with everolimus and sorafenib at the maximum tolerated dose as determined in the phase I study.
Eligibility
- Patients with histologically proven recurrent intracranial malignant glioma will be eligible for the phase I/II component of this protocol.  
- Patients must be ≥ 18 years old with a Karnofsky performance status of ≥ 60.  
- No more than 2 prior chemotherapies and 1 relapse. Prior bevacizumab therapy is allowed.
Design  
- This is a phase 1 /2 study of everolimus and sorafenib in patients with recurrent high-grade gliomas.  
- Phase 1: Patients will be treated with daily everolimus (days 1-28) in combination with sorafenib.  
- Phase 2: Patients will be treated with the combination of sorafenib and everolimus.  
Sorafenib will be taken daily for 7 days on, then 7 days off. Everolimus will be taken daily.  
- There is not a defined set maximum number of cycles that a patient may have. Patients may continue with protocol therapy until criteria for "Off Treatment" is met. Patients will then be followed every 3 months for survival status.  
- There will be an accrual of approximately 3-6 eligible patients per cohort to the Phase I
component of the study. Patients removed at any time for toxicity are evaluable. Phase I patients removed from study treatment within 28 days for reasons other than toxicity may be replaced.  
- There will be a total accrual of approximately 82 eligible patients to the Phase II study (34 recurrent GBM with no prior exposure to bevacizumab, 16 recurrent Anaplastic Glioma with no prior exposure to bevacizumab, and 32 glioblastoma with prior exposure to bevacizumab).  
| TABLE OF CONTENTS PRÉCIS 4 TABLE OF CONTENTS 6 1.0 INTRODUCTION 8 Objectives 8 Background 8 2.0 ELIGIBILITY ASSESSMENT AND ENROLLMENT 13 Eligibility Criteria 13 Screening Evaluation 17 Registration Procedures 17 Treatment Assignment and Descriptive Factors 19 Baseline Evaluation 20 3.0 STUDY IMPLEMENTATION 21 Phase 1 Study Design 21 Phase II Study Design 23 Dose Modifications in Phase I (post cycle 1) and Phase II 23 Questionnaires 34 Study Calendar 35 On Study Evaluation 37 Criteria for Removal from Protocol Therapy and Off Study Criteria 39 4.0 CONCOMITANT MEDICATIONS/MEASURES 40 5.0 DATA COLLECTION AND EVALUATION 41 Data Collection 41 Response Criteria 43 Toxicity Criteria 46 6.0 SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING  PLAN 46 Definitions 46 Assessing Causality 48 NCI-IRB And Clinical Director Reporting 48 Guidelines for Reporting Serious Adverse Events to BTTC 49 Reporting to the Study Drug Manufacturers 50 Guidelines & Procedures for reporting Deviations and Unanticipated Problems 52   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| Version Date: 06/15/18                                                                                                                           | Page 7 of 99                                                                                                                                                         |
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| 6.7                                                                                                                                              | DATA AND SAFETY MONITORING Plan                                                                                                                                      |
| STATISTICAL CONSIDERATIONS ..............................................................................................................54      |                                                                                                                                                                      |
| 7.0                                                                                                                                              |                                                                                                                                                                      |
| 7.1                                                                                                                                              | Phase I Component ...................................................................................................................................54              |
| 7.2                                                                                                                                              | Phase II Component                                                                                                                                                   |
| COLLABORATIVE AGREEMENTS.................................................................................................................56      |                                                                                                                                                                      |
| 8.0                                                                                                                                              | Agreement Type                                                                                                                                                       |
| 8.1                                                                                                                                              |                                                                                                                                                                      |
| 9.0                                                                                                                                              | HUMAN SUBJECTS PROTECTIONS                                                                                                                                           |
| 9.1                                                                                                                                              | Rationale for Subject Selection                                                                                                                                      |
| 9.2                                                                                                                                              | Participation of Children                                                                                                                                            |
| 9.3                                                                                                                                              | Participation of Subjects Unable to Give Consent (NCI) ........................................................56                                                    |
| 9.4                                                                                                                                              | Participation of Subjects Unable to Give Consent (BTTC)                                                                                                              |
| Evaluation of Benefits and Risks/Discomforts ..........................................................................57                        |                                                                                                                                                                      |
| 9.5                                                                                                                                              | Risks/Benefits Analysis .....................................................................................................................................57      |
| 9.6                                                                                                                                              |                                                                                                                                                                      |
| 9.7                                                                                                                                              | Consent and Assent Process and Documentation ......................................................................58                                                |
| 10.0                                                                                                                                             | PHARMACEUTICAL INFORMATION .                                                                                                                                         |
| SORAFENIB                                                                                                                                        |                                                                                                                                                                      |
| 10.1                                                                                                                                             | EVEROLimus .......................................................................................................................................................69 |
| 10.2                                                                                                                                             |                                                                                                                                                                      |
| 1.0 MULTICENTER PROCEDURES                                                                                                                       |                                                                                                                                                                      |
| 1.1                                                                                                                                              | General Procedures .....................................................................................................................................81           |
| Principal Investigators ......................................................................................................................81 |                                                                                                                                                                      |
| 1.2                                                                                                                                              |                                                                                                                                                                      |
| 1.3                                                                                                                                              | Procedures for Site Registration .....................................................................................................81                             |
| 1.4                                                                                                                                              | Institutional Review ........................................................................................................................................81      |
| Protocol Revisions and Closure ..........................................................................................................81      |                                                                                                                                                                      |
| 1.5                                                                                                                                              |                                                                                                                                                                      |
| REFERENCES .                                                                                                                                     |                                                                                                                                                                      |
| 12.0                                                                                                                                             |                                                                                                                                                                      |
| 13.0                                                                                                                                             | APPENDICES                                                                                                                                                           |
| 13.1                                                                                                                                             | Appendix: Karnofsky Performance Status and Neurological Function ...........................85                                                                       |
| Appendix:  EIAEDs and Non-EIAEDs......................................................................................86                         |                                                                                                                                                                      |
| 13.2                                                                                                                                             |                                                                                                                                                                      |
| 13.3                                                                                                                                             | Appendix: Drugs known to be metabolized by CYP450 Isoenzymes 2D6 and 3A4 .....87                                                                                     |
| 13.4                                                                                                                                             | Appendix: M.D. Anderson Symptom Inventory (MDASI-BT)........................................92                                                                       |
| Appendix: Pill Diary and Pill Count Documentation Form..............................................94                                           |                                                                                                                                                                      |
| 13.5                                                                                                                                             | Appendix: CCR Problem Report Form..................................................................................97                                                |
| 13.6                                                                                                                                             |                                                                                                                                                                      |
| 13.7                                                                                                                                             | Appendix: Unused Study Drug Disposition Form - Bayer ................................................99                                                              |
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1.0 introduction objectives

Phase I
- To determine the maximum tolerated dose and safety of everolimus in combination with sorafenib for patients with recurrent malignant gliomas.  
Phase II
1.1.2.1 Primary endpoints:
- 6 month progression free survival rate for glioblastoma patients with no prior bevacizumab exposure treated with everolimus and sorafenib at the maximum tolerated dose as determined in the phase I study.  
- 3 month progression free survival rate for glioblastoma patients with prior bevacizumab exposure treated with everolimus and sorafenib at the maximum tolerated dose as determined in the phase I study.  
- 6 month progression free survival rate for AG patients with no prior bevacizumab exposure treated with everolimus and sorafenib at the maximum tolerated dose as determined in the phase I study.  
1.1.2.2 Secondary endpoints:
- Time to progression and overall survival for recurrent malignant glioma patients
(Group A, Group B, and Group C) treated with everolimus and sorafenib measured from time of study enrollment.  
- Objective response rate for recurrent malignant gliomas (Group A, Group B, and Group C treated with everolimus and sorafenib
- Patient related outcome measures To evaluate the occurrence of symptoms and correlate to disease progression and tolerance to treatment using the MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) self-reporting tool. This will include:  
o To evaluate longitudinal changes in symptom measures and determine the impact of the therapy on these parameters.
o To measure symptom burden over the course of therapy to evaluate differences between patients individual symptom severity, overall mean symptom severity, and difference in scores on the interference items between responders and non-responders.  
o To describe the variability of symptom severity longitudinally over the treatment course and follow-up period.
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background

Glioblastoma (GBM) is the most common primary brain tumor. With optimal treatment, consisting of focal radiotherapy with concurrent chemotherapy, followed by adjuvant chemotherapy, median survival is 14.6 months. (1) Cure is exceptional and most patients have evidence of tumor progression within one year of diagnosis despite treatment. At progression, treatment options are limited and mostly ineffective; most clinical trials demonstrate six month progression free survival rate of only 9-15% and median overall survival is less than 25 weeks from time of tumor progression. (2) Recently, bevacizumab was approved for recurrent GBM based on data from Vredenburgh et al. and Kreisl et al.(3, 4) Data on patients who fail bevacizumab indicate a short survival, on the order of 10 weeks, an approximate PFS 3 and 6 months of 0%. Anaplastic Astrocytoma (WHO grade III astrocytoma), although less aggressive than GBM, is a malignant tumor with a median survival of less than 3 years from diagnosis and estimated 5-year survival of 28% despite best treatment (2, 5) Although malignant gliomas display genetic heterogeneity, several key proliferation and survival signaling pathways have been identified (6). Recent work has focused on targeting these tumor specific pathways in hopes of improving treatment efficacy and minimizing treatment toxicity. Because molecularly targeted agents have been mostly ineffective when used alone, combination therapy that inhibits multiple pathways is an appealing strategy.
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kinase inhibitors

Most growth factors initiate intracellular second messenger signaling systems through activation of tyrosine and/or serine/threonine kinase receptors. The kinase regions catalyze transfer of phosphate groups from adenosine triphosphate (ATP) to transmembrane receptors or signal transducers to initiate signaling pathway activation. The development of kinase inhibitors in cancer treatment has been stimulated by the success of imatinib mesylate in treating chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIT). Imatinib mesylate specifically inhibits kinase activities associated with bcr-abl, c-kit, and PDGF receptor which are improperly regulated in CML and GIT. Research has identified specific aberrant pathways that are thought to be important in malignant gliomas. (6) Specifically inhibiting these aberrant pathways may improve outcome without significant toxicity.  
Vascular endothelial growth factor (VEGF) pathway inhibitors:
Malignant gliomas are highly vascular tumors that depend on angiogenesis for growth and proliferation. VEGF pathway inhibitors were developed to inhibit tumor angiogenesis. Despite promising preclinical results, most VEGF inhibitors failed to yield long term survival benefits as single agents. Success has been achieved by combining inhibitors of VEGF signaling with standard cytotoxic chemotherapy (7). Bevacizumab, an anti-VEGF antibody, has shown encouraging results when combined with irinotecan in a phase II trial for GBM.(4) (8)
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multi-targeted kinase inhibitors

When used alone, targeted agents have been mostly ineffective in the treatment of malignant gliomas. This is thought to be secondary to the existence of multiple parallel or compensatory oncogenic pathways that allow tumor cells to escape and survive. To combat this problem, newergeneration small-molecule kinase inhibitors are designed to target multiple aberrant signaling pathways in the tumors and tumor-associated vasculature. 1.2.3.1 Sorafenib (BAY 43-9006): Sorafenib is an oral multi-kinase inhibitor with effects on tumor proliferation and tumor angiogenesis. (9) It was initially selected based on inhibitory activity against the serine/threonine kinases Raf-1 and wild-type B-Raf, which are pivotal components of the Ras/Raf/MEK/ERK signaling pathway. Inhibitory activity was subsequently demonstrated against tyrosine kinases for vascular endothelial growth factor (VEGF) receptor and platelet-derived growth factor (PDGF) receptor as well as Flt-3 and c-Kit. (9) Although most GBMs lack RAF mutations, targeting the RAF/MEK/ERK pathway may be beneficial as this pathway may be activated by other genetic alterations upstream from Raf. The Raf/MEK/ERK pathway is an important mediator of responses to growth factors, and a strong inducer of genes involved in tumorigenesis, angiogenesis, apoptosis, and tumorigenesis. (10) In preclinical studies, sorafenib demonstrated broad-spectrum anti-tumor activity by inducing complete tumor stasis and inhibition of tumor angiogenesis in a variety of tumor types. In the murine renal adenocarcinoma (Renca) (11) and VHL -/
- xenograft models, sorafenib prevented tumor growth, primarily through the inhibition of tumor-cell-induced angiogenesis and also induced tumor apoptosis and necrosis. The safety and clinical activity of sorafenib, alone (12-15) or in combination (16,17) with chemotherapy, has been examined in a series of phase I studies conducted in patients with solid tumors. Results of a multi-center, randomized, placebo-controlled, double-blind phase III trial of sorafenib in advanced renal cell carcinoma (RCC) were first reported in 2005. (18) There was a progression free survival advantage for the sorafenib group (5.5 months vs 2.8 months). Subsequent overall survival was not different between the groups overall, but when patients who crossed over to receive sorafenib were excluded, there was a survival benefit.
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1.2.3.2 rationale and experience for

Both increased activation of angiogenesis and the MAP Kinase pathway are associated with the mesenchymal/angiogenic phenotype and resistance to standard therapy in newly diagnosed glioblastoma (GBM). Sorafenib is a multi-functional small molecule inhibitor that targets both the Raf/MAP Kinase pathway and VEGF receptors, and is thus a potentially ideal agent for targeting GBM with the mesenchymal/angiogenic phenotype. A Phase I study of single agent sorafenib in recurrent malignant glioma (B. Nabors, PI, NABTT study) has accrued 43 patients, including 27 glioblastoma patients. Dosages up to 800mg BID were tolerated well, with only grade 3 hand-foot syndrome observed in up to 33% of patients at 400mg BID and 800mg BID. Observed toxicities were similar in patients on enzyme-inducing antiepileptics and those not on enzyme-inducing anti-epileptics. Pharmacokinetic parameters also demonstrated no significant differences between enzyme-inducing and non-enzyme inducing antiepileptic medication groups. There were 3 complete responses and 5 partial responses amongst 41 evaluable patients, suggesting significant single agent activity.
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pi3k/akt/mtor pathways

Apoptosis, commonly called programmed cell death in developmental biology, is a major mechanism of cell death in response to many toxic stimuli, including withdrawal of external survival signals and DNA damage. Resistance to apoptosis is one of the hallmarks of cancer. The mammalian target of rapamycin (mTOR) protein is a downstream component of the PI3K/Akt pathway.(6) It regulates proliferation by activating downstream protein kinases required for ribosomal biosynthesis and mRNA translation, thus driving cell cycle progression. Tumors that depend on the activation of the PI3K pathway or that harbor mutations causing constitutive activation of the PI3K pathway may be more susceptible to rapamycin and its derivatives that inhibit mTOR. Activation of the PI3K pathway by overexpression of upstream growth factor receptors (eg. EGFR and/or deletion of PTEN) is significantly associated with increasing tumor grade, decreased levels of apoptosis, and adverse clinical outcome in human gliomas. mTOR is represented by two structurally and functionally distinct multiprotein signaling complexes, mTORC1 (mTOR complex 1, rapamycin sensitive) and mTORC2 (mTOR complex 2, rapamycin insensitive).(19) mTORC1 is mainly activated via the PI3 kinase pathway through AKT (also known as PKB, protein kinase B) and the tuberous sclerosis complex (TSC1/TSC2).(20) Activated AKT phosphorylates TSC2, which lead to the dissociation of TSC1/TSC2 complex, thus inhibiting the ability of TSC2 to act as a GTPase activating protein. This allows Rheb, a small G-protein, to remain in a GTP bound state and to activate mTORC1. AKT can also activate mTORC1 by PRAS40 phosphorylation, thereby relieving the PRAS40-mediated inhibition of mTORC1.(21) mTORC2 (mTOR complex 2) is activated through a currently unknown mechanism, possibly by receptor tyrosine kinase (RTK) signaling.(21) It has been suggested that mTORC2 phosphorylates and activates a different pool of AKT, that is not upstream of mTORC1. Therefore, targeting mTOR is a promising target in the clinical management of glioma patients. A phase II study of temsirolimus, a mTOR inhibitor, in recurrent GBM demonstrated modest efficacy with some evidence of activity based on molecular phenotype. (10) Everolimus (everolimus; Novartis) is a novel oral derivative of rapamycin. It is not clear which molecular determinants predict responsiveness of tumor cells to everolimus. Molecular analysis has revealed that relative sensitivity to everolimus in vitro correlates with the degree of phosphorylation (activation) of the AKT/PKB protein kinase and the S6 ribosomal protein. PTEN status alone may not be predictive of everolimus relative in vitro sensitivity, however in some cases (i.e., GBM) there is also a correlation with PTEN status (active vs inactive). In preclinical models, the administration of everolimus is associated with reduction of protein phosphorylation in target proteins downstream of mTOR, notably phosphorylated S6 (pS6) and p4E-BP1, and occasionally with an increase in phosphorylation AKT (pAKT).
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rationale for combination therapy

Preclinical data suggest that blocking more than one target more effectively inhibits tumor growth. (22) Combining everolimus and sorafenib allows targeting of both the PI3K pathway and the RAF-MAPK pathway and in addition targets VEGF and PDGF, other active targets in malignant glioma. Trials of mTOR inhibition (not everolimus) with sorafenib are underway but the dose of the mTOR inhibitor, in particular CCI-779, being used in one of these trials is sufficiently low that it is likely not therapeutic. We believe that the combination of everolimus and sorafenib will be more tolerable, thus allowing therapeutic doses of both. In addition, continuous oral dosing of both may provide a more sustained pathway inhibition.
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rationale for patient outcomes measures

This study seeks to establish effective therapies at recurrence and improve on current clinical results in patients with glioblastoma. We hypothesize that using a combination of everolimus and sorafenib will result in improved survival. However, given the intensive nature of this regimen, it will be important to determine whether any determined survival benefit is associated with improvements in symptoms or does a worsening of symptoms offset the increase in survival. Precedence for measuring "non-therapeutic" endpoints exists in oncology research. For example, Gemcitabine was approved by the FDA partially as a consequence of the decrease in pain reported in pancreatic patients who were treated, not on the basis of survival improvement which was modest, at best (23). There have been efforts in neuro-oncology to evaluate secondary endpoints using validated instruments as an additional indicator of benefit.  
The M.D. Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) allows the selfreporting of symptom severity and interference with daily activities. The MDASI-BT has demonstrated reliability and validity in the adult primary brain tumor patient population (24). This tool represents a modification of the widely used and validated MDASI, with particular attention to symptoms common in patients with brain tumors. The availability of validated instruments provides an opportunity to prospectively assess the impact of treatment, both positive and negative, on patients. This evaluation of symptom burden in this study will assist in finding the best possible treatment with the least toxicity.  
Summary of Phase I Toxicities Dose Level 1 had 3/6 patients who had a DLT, necessitating a dose reduction to dose level -1. At that level only 1/6 DLTs was seen hence this is the MTD for phase II.  
| (DOSE LEVEL 1)               |                      |                             |     |
|------------------------------|----------------------|-----------------------------|-----|
| Patient 1                    | Grade 3              | HTN                         | DLT |
| Elevated ALT                 | DLT                  |                             |     |
| Hypercholesterolemia         | DLT                  |                             |     |
| Hyperglycemia                | DLT                  |                             |     |
| Grade 4                      | Hypertriglyceridemia | DLT                         |     |
| Patient 2                    | Grade 3              | Lymphopenia                 |     |
| Patient 3                    | Grade 3              | Lymphopenia                 |     |
| Patient 4                    | None                 | N/A                         | n/a |
| Patient 5                    | Grade 3              | Thrombocytopenia Chest Pain | DLT |
| Fatigue                      | DLT                  |                             |     |
| Patient 6                    | Grade 3              | Fatigue                     | DLT |
| Lymphopenia                  |                      |                             |     |
| (DOSE LEVEL -1)              |                      |                             |     |
| Patient 1                    | Grade 3              | Myositis                    | DLT |
| Nausea                       | DLT                  |                             |     |
| Fatigue                      | DLT                  |                             |     |
| Hypertension                 | DLT                  |                             |     |
| Lymphopenia Thrombocytopenia |                      |                             |     |  
| Hypercholesterolemia   | DLT   |     |     |
|------------------------|-------|-----|-----|
| Patient 2,3,4,5,6      | None  | N/A | n/a |
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2.0 eligibility assessment and enrollment

Unless otherwise specified, in the Inclusion Criteria for Phase I or Phase II, all patients must meet the General Eligibility Criteria described below. Eligibility waivers are not permitted. Subjects must meet all of the inclusion and none of the exclusion criteria to be registered to the study. Study treatment may not begin until a subject is registered. See section 2.3 for registration procedures.
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eligibility criteria general inclusion criteria

2.1.1.1 Patients with histologically proven recurrent intracranial malignant glioma will be eligible for the phase I/II component of this protocol. Malignant glioma includes glioblastoma (GBM), Gliosarcoma (GS), anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic mixed oligoastrocytoma (AMO), or malignant astrocytoma NOS (not otherwise specified). Patients will be eligible if the original histology was low-grade glioma and a subsequent histological diagnosis of a malignant glioma is made.  
2.1.1.2 All patients must sign an informed consent indicating that they are aware of the investigational nature of this study. Patients must have signed an authorization for the release of their protected health information at all sites except the NIH.  
2.1.1.3 Patients must be > 18 years old. 2.1.1.4 Patients must have a Karnofsky performance status of > 60. 2.1.1.5 No more than 2 prior chemotherapies and 1 relapse. Prior bevacizumab therapy is allowed.  
- Patients must have recovered from the toxic effects of prior therapy: >3 weeks for biologic therapies or non-cytotoxic therapies, >4 weeks for cytotoxic therapies, and
>6 weeks for nitrosoureas. Any questions related to the definition of non-cytotoxic agents should be directed to the Study Chair.
NOTE: 13 cis-retinoic acid (Accutane) as biologic therapy has a washout period of 14 days.  
2.1.1.6 Patients must have adequate bone marrow function (WBC ≥ 3.0 x 109/L, ANC ≥ 1.5 X
109/L, platelet count of ≥100 x 109/L, and hemoglobin ≥ 10 gm/dL), adequate liver function (SGOT and bilirubin < 2 times ULN), and adequate renal function (creatinine < 1.7mg/dL or creatinine clearance > 60 cc/min) before starting therapy. These tests must be performed within 14 days prior to registration. Eligibility level for hemoglobin may be reached by transfusion.  
2.1.1.7 Patients must have shown unequivocal radiographic evidence for tumor progression by MRI or CT scan as defined by Section **5.2.1.3.5**. A scan should be performed within 14 days prior to registration and on a steroid dose that has been stable or decreasing for
at least 5 days. If the steroid dose is increased between the date of imaging and registration a new baseline MRI/CT is required. The same type of scan, i.e., MRI or CT must be used throughout the period of protocol treatment for tumor measurement. Measurable disease is NOT required. Note: *MRI is the preferable imaging method; CT scan may be used in cases where an MRI cannot be obtained.  
2.1.1.8 Patients having undergone recent resection of recurrent or progressive tumor will be eligible as long as all of the following conditions apply:
- They have recovered from the effects of surgery and be > 3 weeks from surgery.
- Residual disease following resection of recurrent malignant glioma is not mandated for eligibility into the study. To best assess the extent of residual disease postoperatively, a CT/ MRI should be done no later than 96 hours in the immediate post-operative period or at least 4 weeks post-operatively, within 14 days prior to registration. If the 96-hour scan is more than 14 days before registration, the scan needs to be repeated. If the steroid dose is increased between the date of imaging and registration, a new baseline MRI/CT is required on a stable steroid dosage for at least 5 days.  
2.1.1.9 Patients must have failed prior radiation therapy and must have an interval of greater than or equal to 12 weeks from the completion of radiation therapy to registration; except if patients underwent surgery within 12 weeks and pathology is consistent with recurrent tumor.  
2.1.1.11 Women of childbearing potential must have a negative B-HCG pregnancy test documented within 7 days prior to taking the first dose of study medications.  
2.1.1.12 Patients receiving anti-coagulation treatment with an agent such as warfarin or heparin may be allowed to participate. For patients on warfarin, the INR should be measured prior to initiation of sorafenib and monitored at least weekly, or as defined by the local standard of care, until INR is stable.  
Phase I Inclusion Criteria
The following modifications to the general eligibility criteria apply to Phase I patients only.  
- Patients may have had treatment for any number of prior relapses. Relapse is defined as progression following initial therapy (i.e. surgery and radiation+/- chemo if that was used as initial therapy).  
Phase II Inclusion Criteria
- Phase II patients must meet the following Eligibility Criteria in addition to the General Criteria described above. Patients may have had treatment for no more than 1 prior relapse (i.e. failed 2 lines of treatment-initial therapy and therapy for first relapse) at 2nd relapse, treatment per BTTC09-01 is an option; see relapse and treatment count  
2.1.1.10 Patients with prior therapy that included interstitial brachytherapy or stereotactic radiosurgery must have confirmation of true progressive disease rather than radiation necrosis based upon either PET or Thallium scanning, MR spectroscopy or surgical/pathological documentation of disease.
table below). Relapse is defined as progression following initial therapy (i.e. radiation+/- chemo if that was used as initial therapy). The intent therefore is that patients had no more than 2 prior therapies (initial and treatment for 1 relapse). If the patient had a surgical resection for relapsed disease and no anti-cancer therapy was instituted for up to 12 weeks, and the patient undergoes another surgical resection, this is considered as 1 relapse. For patients who had prior therapy for a low-grade glioma, the surgical diagnosis of a high-grade glioma will be considered the first relapse.  
| Relapse and Treatment Count   |    |                                                     |                             |                 |
|-------------------------------|----|-----------------------------------------------------|-----------------------------|-----------------|
| Initial diagnosis             | →  | Surgical resection                                  | Radiation + Chemotherapy #1 |                 |
| Relapse #1                    | →  | +/-                                                 | Surgical                    | Chemotherapy #2 |
| resection                     |    |                                                     |                             |                 |
| Relapse (#2)                  | →  | Patient to be evaluated for enrollment to BTTC09-01 |                             |                 |  
- Patients must not have received prior therapy with sorafenib, everolimus, or related drugs such as tyrosine kinase inhibitors, VEGF inhibitors (except bevacizumab), or mTOR inhibitors.  
General Exclusion Criteria 2.1.4.1 Patients has any significant medical illnesses that in the investigator's opinion cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate this therapy 2.1.4.2 Patients with a history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix), unless in complete remission and off of all therapy for that disease for a minimum of 3 years are ineligible.  
2.1.4.3 Patient has an active infection or serious intercurrent medical illness. 2.1.4.4 Patient has any disease that will obscure toxicity or dangerously alter drug metabolism.
2.1.4.5 Patients is on an enzyme inducing anti-convulsants. If patients were previously on EIAEDs and these have been discontinued, patients must have been off the agent for at least 2 weeks prior to first study drug administration. For patients who need to start an AED or the AED needs to be changed, it is strongly recommended that all efforts should be made to use a non-EIAED.  
2.1.4.6 Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as: Symptomatic congestive heart failure of New York heart Association Class III or IV unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months of start of study drug or any other clinically significant cardiac disease severely impaired lung function as defined as spirometry and DLCO that is 50% of the normal predicted value and/or 02 saturation that is 88% or less at rest on room air, uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN, active (acute or chronic) or uncontrolled severe infections, liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis.  
2.1.4.7 Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.  
2.1.4.8 Uncontrolled hypertension defined as systolic blood pressure > 140 mmHg or diastolic pressure > 90 mmHg, despite optimal medical management.  
2.1.4.9 Known human immunodeficiency virus (HIV) infection or chronic or acute Hepatitis B or C. Note: Patients who have a history of HBV and HCB infection are eligible, however, they must receive prophylactic antiviral therapy for 1-2 weeks prior to receiving study drug (see Section **3.3.2**)
2.1.4.10 Thrombolic or embolic events (except DVT or pulmonary embolus) such as a Cerebrovascular accident including transient ischemic attacks within the past 6 months.  
2.1.4.11 Pulmonary hemorrhage/bleeding event ≥ CTCAE Grade 2 within 4 weeks of first dose of study drug.  
2.1.4.12 Any other hemorrhage/bleeding event ≥ CTCAE Grade 3 within 4 weeks of first dose of study drug.  
2.1.4.13 Serious non-healing wound, non-healing ulcer, or bone fracture. 2.1.4.14 Evidence or history of bleeding diathesis or coagulopathy 2.1.4.15 Major surgery, open biopsy or significant traumatic injury within 4 weeks of first study drug.  
2.1.4.16 Use of St. John's Wort, orrifampin (rifampicin), or other strong CYP34A inducers.  
Dexamethasone is okay as long as the dose is 16 mg /day or less. Note: Patients who are on the above referenced medications may be considered eligible with a washout period of 14 days. Contact the coordinating center to discuss patients with the above aforementioned agents before patient registration.  
2.1.4.17 Known or suspected allergy to sorafenib, everolimus, or any agent given in the course of this trial.  
2.1.4.18 Any condition that impairs patient's ability to swallow whole pills.  
2.1.4.19 Any malabsorption problem. 2.1.4.20 Other malignancies within the past 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin.  
2.1.4.21 Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods. Barrier contraceptives must be used throughout the trial by both sexes. Hormonal contraceptives are not acceptable as a sole method of contraception. (Women of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to administration of everolimus and sorafenib).  
2.1.4.22 Patients who have received prior treatment with an mTOR inhibitor (sirolimus, temsirolimus, everolimus).  
2.1.4.23 Patients with a known hypersensitivity to everolimus or other rapamycins (sirolimus, temsirolimus) or to its excipients.  
2.1.4.24 History of noncompliance to medical regimens.  
2.1.4.25 Patients unwilling to or unable to comply with the protocol.
2.1.4.26 Patients on total daily dose of dexamethasone greater than 16 mg.  
SCREENING EVALUATION
Prior to registration on the study, all patients will undergo the following screening tests within 14 days of registration:  
- A complete medical history, concomitant medication review, physical exam with vital signs (heart rate, blood pressure, respiration rate, height and weight) and neurological examination (to include documentation of the patients Karnofsky Performance Status per Appendix **13.1**)
- Neuro-imaging confirming tumor progression shall be performed on all patients. The scan done prior to study entry documenting progression will be reviewed by the patient's treating physician to confirm progression of disease.  
- Pre-study tests shall include ECG chest X-ray (or CT scan with lung windows) within 30 days of treatment, and laboratory studies including CBC, differential, platelets, serum creatinine, phosphate, lipase, amylase, bilirubin, SGOT, PT, PTT, fasting serum glucose and lipid panel, urinalysis with microanalysis, HBV-DNA, HbsAg, HBsAb (Qualitative), HBcAb, HCV-RNA-PCR and serum pregnancy test for women of childbearing potential. All patients should be screened for hepatitis risk factors and any past illnesses of hepatitis B and hepatitis C infection. All patients with positive HBV-DNA or HBsAg should be treated prophylactically with an antiviral (i.e. Lamivudine) for 1-2 weeks prior to receiving study drug (see Section **3.3.2**). The antiviral treatment should continue throughout the entire study period and for at least 4 weeks after the last dose of everolimus. Patients with viral hepatitis C risk factors should be screened for HCV RNA-PCR. UPC ratio must be obtained if urinalysis has >2+ protein. Pre-study tests (except pregnancy test) must be obtained within 14 days of registration. Pregnancy test must be obtained within 7 days prior to starting the study drugs.  
- Documentation of tumor diagnosis. Following registration, slides from the most recent preregistration biopsy or resection must be submitted for review to local institution if surgery was not done there.  
- Neuro-imaging confirming tumor. (See section 2.5)
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registration procedures

Patients who are candidates for the study will first be evaluated for eligibility by the local investigator. All patients must be registered both locally and centrally with BTTC. BTTC patients will be registered with the BTTC Coordinating Center. All eligibility requirements will be checked prior to registration. The status of all regulatory documents will be checked prior to registration. No patient will be entered on protocol if they do not satisfy all regulatory document and eligibility requirements.
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informed consent

Prior to protocol enrollment and initiation of treatment, subjects must sign and date an Institutional Review Board (IRB) approved consent form.  
Registrations must be completed after the patient has signed the informed consent and has been determined to be eligible by the local investigator. At the time of registration, the following information will be requested by the BTTC Coordinating Center:
- A copy of a completed and signed, protocol specific, Eligibility Checklist form  
- One copy of the signed and dated Informed Consent. - Copies of all source documents to support protocol specific eligibility. Please refer to the Operations Manual for specific source documents required.
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registration at the nci

Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) within 24 hours of signing consent for patients enrolling at the lead institution. A registration Eligibility Checklist from the web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm)
must be completed and hand delivered to the BTTC Coordinating Center or sent via encrypted email to the BTTC Coordinating Center Research Nurse.. After confirmation of consent, available slot, and eligibility, the BTTC CC research nurse will send the registration Eligibility Checklist to CRO ncicentralregistration-l@mail.nih.gov via encrypted email. CRO staff will call pharmacy to advise them of the acceptance of the patient on the protocol prior to the release of any investigational agents. Verification of Registration will be forwarded electronically via e-mail to the research team with a copy to the BTTC Coordinating Center. A recorder is available during non-working hours.
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participating site registration (not applicable

All patients must be registered through the NCI Central Registration Office (CRO). A protocol registration form and cover memo will be supplied by the Coordinating Center, NCI CCR and updates will be provided as needed. Subject eligibility and demographic information is required for registration. To initially register a subject, after the participant has signed consent, complete the top portion of the form and send to NCI BTTC Coordinating Center's Research Nurse, Melanie Herrin, RN, Fax 301-451-5429, email Melanie.Herrin nci_bttc@mail.nih.gov. Once eligibility is confirmed, send the completed eligibility checklist with the attached supporting source documents to NCI BTTC Coordinating Center's Research Nurse, Melanie Herrin, RN. If patient is not eligible, please notify NCI BTTC Coordinating Center's Research Nurse, Melanie Herrin, RN. The CRO will notify you either by e-mail or fax that the protocol registration form has been received. Questions about eligibility should be directed to the NCI BTTC Coordinating Center's Research Nurse, Melanie Herrin, RN. 2.3.3.1 Patient Number for Participating Institutions (Not Applicable as of Amendment C) Once eligibility has been confirmed by the Coordinating Center, the patient from the participating institution will be registered through the Central Registration Office. A Verification of Registration will be received from the Central Registration Office with the assigned patient ID number. The patient ID number is unique to the patient and must be written on all data and correspondence for the patient and used to enter data into the C3D database. The participating site will receive the Verification of Registration via fax or email within one working day of registration.
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initiation of therapy

Treatment may not be initiated until the participating institution receives a faxed or emailed copy of the patient's Registration Verification Letter from the Central Registration Office.
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all patients that are eligible

The BTTC Coordinating Center must be notified in writing of any exceptions to this policy.  
Eligibility Exceptions Eligibility Exceptions will not be granted.
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treatment assignment and descriptive factors

Patients with recurrent malignant glioma will be enrolled into one of the following groups. Accrual goals and endpoints for each group are determined separately as described in the statistical section. There will be an accrual of approximately 3-6 eligible patients per dose level to the Phase I component of the study. Patients removed at any time for toxicity are evaluable. Phase I patients removed from study treatment within 28 days for reasons other than toxicity may be replaced.
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cohorts

| Number   | Name                                             | Description                                                 |
|----------|--------------------------------------------------|-------------------------------------------------------------|
| 1        | Phase 1 (closed)                                 | Patients with Glioblastoma or Anaplastic Glioma             |
| 2A       | Phase 2 Group A                                  | Patients with Glioblastoma with NO prior bevacizumab        |
| (closed) | exposure                                         |                                                             |
| 2B       | Phase 2 Group B                                  | Patients with Glioblastoma with PRIOR bevacizumab  exposure |
| 2C       | Phase 2 Group C                                  | Patients with Anaplastic Glioma with NO prior               |
| (closed) | exposure to bevacizumab (Grade III Glioma Group) |                                                             |
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arms

| Number   | Name             | De`scription                                                                                                   |
|----------|------------------|----------------------------------------------------------------------------------------------------------------|
| 1        | Phase 1 (closed) | Combination of sorafenib (7 days on, 7 days off) and  everolimus daily over a 28-day cycle at escalating doses |  
| 2   | Phase 2   | Combination of sorafenib (7 days on, 7 days off) and  everolimus daily over a 28-day cycle: Sorafenib 400 mg BID PO (days 1-7 and days 15-21)  Everolimus 5 mg PO daily (days 1-28)   |
|-----|-----------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
There will be a total accrual of approximately 82 eligible patients to the Phase II study (34 recurrent GBM with no prior exposure to bevacizumab, 16 recurrent Anaplastic Glioma with no prior exposure to bevacizumab, and 32 glioblastoma with prior exposure to bevacizumab). Subjects in Cohort 1 were directly assigned to Arm 1. Subjects in Cohorts 2A, 2B and 2C will be directly assigned into Arm 2.
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baseline evaluation

After eligibility is confirmed, complete the following baseline study tasks:  
- Patients will complete a baseline MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) (Appendix **13.4**) within 14 days (+ 3 working days) after enrollment on the clinical trial. The MDASI-BT will be completed only by the patient, unless changes in vision or weakness make this difficult. If this occurs, then the caregiver or research assistant may read the questions to the patient or assist with marking the severity number or score as described by the patient. A patient caregiver may complete the questionnaires as a patient-preference proxy if the patient's deficits preclude selfreport.  
- The screening scan can be used as the baseline scan if performed within 14 days of registration on a stable dose of steroids. Patients should not be on a steroid dose higher than 16 mg/day. (Refer to **2.1.1.7** and **2.1.1.8**)
- Document baseline adverse events
- For all women of childbearing potential, negative serum pregnancy test within 7 days of starting treatment.  
- If treatment will start > 14 days after screening evaluations were completed, then repeat the following labs:
o CBC, differential, platelets  
o Serum creatinine, phosphate o lipase, amylase o bilirubin, SGOT
o PT, PTT  
o Fasting serum glucose and fasting lipid panel o Urinalysis with microanalysis; UPC ratio must be obtained if urinalysis has >2+
protein.
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3.0 study implementation

This is a phase 1 /2 study of everolimus and sorafenib in patients with recurrent high-grade gliomas. Patients must initiate study treatment within 96 hours after registration.  
All patients will be monitored for hematologic or serologic evidence of myelosuppression, hepatic injury, renal injury, and electrolyte disturbances and for clinical evidence of other toxicity as is described in section 3.5.
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phase 1 study design drug

Patients will be treated with daily everolimus (days 1-28) in combination with sorafenib (as per the table below).  
The schedule providing highest dose without DLT (as defined above) will be used as the phase II
dose. The dose levels are listed in **Table 3-11**.  
There is not a defined set maximum number of cycles that a patient may have. Patients may continue with protocol therapy until criteria for "Off Treatment" is met. Off treatment criteria could be any of the following events/reasons; disease progression, intolerable side effects (toxicities) and/or withdrawal from study.
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dose escalation

Patients will be treated at the dose levels in **Table 3-11** starting at dose level 1. Initially everolimus and sorafenib will be administered continuously. If two DLTs are encountered at the first dose level (sorafenib 400 mg twice daily and everolimus 5 mg daily) the dose for the next cohort of patients will be decreased to sorafenib 400 mg twice daily 7 days on, 7 days off and everolimus 5 mg daily (dose level -1). If dose level -1 is tolerated, dose escalations will occur along the "b" pathway (-1, 1b, 2b, 3b, 4b). If two DLTs are encountered at dose level 2, the dose for the next cohort of patients will be reduced to sorafenib 400 twice daily, 7 days on 7 days off and everolimus 7.5 mg daily (dose level 1b). Subsequent dose escalations will occur along the "b" pathway (2, 1b, 2b, 3b, 4b).  
The study drugs will be self-administered (by the patients themselves). The investigator will instruct the patient to take the study drug exactly as specified in the protocol. Patients will be instructed to take the study drugs in the morning, at the same time each day. The study drugs must be taken 1 hour before or two hours after food. Consumption of grapefruit juice should be avoided while taking the study drugs. If vomiting occurs, no attempt should be made to replace a dose. All dosages prescribed and dispensed to the patient and all dose changes during the study must be recorded.  
| DOSE     | SORAFENIB   | EVEROLIMUS   |
|----------|-------------|--------------|
| LEVEL -1 | 400 mg BID, | 5 mg daily   |  
| DOSE   | SORAFENIB                        | EVEROLIMUS   |
|--------|----------------------------------|--------------|
| LEVEL  | 7 days on 7 days off             |              |
| 1      | 400 mg BID                       | 5 mg daily   |
| 2      | 400 mg BID                       | 7.5 mg daily |
| 3      | 400 mg BID                       | 10 mg daily  |
| 4      | 600 mg BID                       | 10 mg daily  |
| 1b     | 400 mg BID, 7 days on 7 days off | 7.5 mg daily |
| 2b     | 400 mg BID, 7 days on 7 days off | 10 mg daily  |
| 3b     | 600 mg BID, 7 days on 7 days off | 10 mg daily  |
| 4b     | 800 mg BID, 7 days on 7 days off | 10 mg daily  |  
Note: On the sorafenib 7 days on 7 days off schedule, sorafenib will be given on days 1-7 and 15-21.  
The MTD will be based on the assessment of DLT during the first 28 days of treatment only (cycle1), and will be defined as the dose at which fewer than one-third of patients experience a DLT to one of the study drugs. The MTD is the dose level at which 0/6 or 1/6 patients experience DLT with the next higher dose having at least 2/3 or 2/6 patients encountering DLT. Three patients will be treated at each dose level. If one dose limiting toxicity (DLTs) is encountered an additional 3 patients will be added to that dose level. If at any point two DLTs are encountered within a given dose level, then the MTD has been exceeded and three more patients are treated at the next lower dose (if only three patients were previously treated at that prior dose).
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dose-limiting toxicity

Toxicities will be graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. If multiple toxicities are seen, the presence of DLT should be based on the most severe toxicity experienced. DLT will be defined as any of the following events occurring during treatment with sorafenib and/or everolimus and attributable to one of the study drugs:  
3.1.3.1 Any grade 3 thrombocytopenia, grade 4 anemia, grade 4 neutropenia, or febrile neutropenia of any grade.  
3.1.3.2 Any non-hematologic grade 3 or grade 4 toxicity, excluding alopecia and/or hand/foot reaction.  
3.1.3.3 Failure to recover from toxicities (to grade 1 or less) to be eligible for re-treatment with sorafenib and everolimus within 14 of the last dose of sorafenib and everolimus.
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phase ii study design drug

All patients treated on the phase II cohorts will receive a combination of sorafenib (7 days on, 7 days off) and everolimus daily over a 28-day cycle, as follows:
Sorafenib 400 mg BID PO (days 1-7 and days 15-21) Everolimus 5 mg PO daily (days 1-28)
There is not a defined set of maximum number of cycles that a patient may have. Patients may continue with protocol therapy until criteria for "Off Treatment" is met. See Section **3.7.1.**
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dose modifications in phase i

Patients with stable or responding disease may be retreated at the same dose or at a reduced dose level, depending upon the adverse events observed in the current cycle and any adverse events
(based on the CTCAE v.4) present on the first day of the next cycle. If multiple toxicities are seen, the dose administered in a subsequent cycle should be based on the most severe toxicity experienced in the current cycle. Patients who experience toxicity should have laboratory testing at least weekly until the toxicity has resolved. Toxicities will be graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. If multiple toxicities are seen, the toxicity should be based on the most severe toxicity experienced. Toxicities will be defined as any of the following events occurring during treatment with sorafenib and/or everolimus and attributable to one of the study drugs:
A. Any grade 3 thrombocytopenia, grade 4 anemia, grade 4 neutropenia, or febrile neutropenia of any grade.  
B. Any non-hematologic grade 3 or grade 4 toxicity, excluding alopecia and/or hand/foot reaction.  
C. Failure to recover from grade 3 or 4 toxicities (to grade 1 or less) to be eligible for re-treatment with sorafenib and everolimus within 14 of the last dose of sorafenib and everolimus.
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within treatment cycles

If a patient experiences toxicities during a treatment cycle, the treatment will be immediately suspended until a grade 1 or less toxicity. If the toxicity resolves to less than or equal to grade 1 within 2 weeks, the patient will be retreated at the dose level described in Table **3-2** below. (Refer to Table 3-6 and Table 3-7 for management of everolimus-induced toxicities and Table 3-8, Table 3-9 and Table **3-10** for management of sorafenib-induced toxicities.) If toxicity persists, the patient should be taken off study. Two dose reductions are permitted. Doses that are reduced for sorafenib or everolimus related toxicity will not be re-escalated, even if there is minimal or no toxicity with the reduced dose. Patients whose dose has been reduced for adverse events that are subsequently not felt to be related to sorafenib or everolimus may have the dose re-escalated after completion of one cycle with toxicities less than or equal to grade 1. If any patient has further toxicities that would require additional reductions, or if treatment is held for more than 2 consecutive weeks because of ongoing toxicity, the Study PI will assess if the patient should remain in the study (if the patient has benefited from treatment).  
| DOSE LEVEL           | SORAFENIB                                            | EVEROLIMUS   |
|----------------------|------------------------------------------------------|--------------|
| 1 (starting dose)    | 400 mg BID                                           | 5 mg daily   |
| 7 days on 7 days off |                                                      |              |
| -1                   | 400 mg AM dose  200 mg PM dose  7 days on 7 days off | 5 mg daily   |
| -2                   | 200 mg AM dose  200 mg PM dose  7 days on 7 days off | 5 mg daily   |  
3.3.1.1 Hematologic Toxicity Dose Modifications Based on ANC and Platelet Counts obtained weekly for Phase I and every 2 weeks for Phase II (**sorafenib or everolimus)**: Please note per CTCAE v 4, ANC 750-999 falls within grade 3 adverse event and Platelets 50,000 to <75,000 is grade 2.  
ANC (/mL) Platelets (/mL) **% of Dose Planned** > 1000 and > 75,000 100% 750-999(G3) or 50,000 to < 75,000(G2) hold* < 750 or < 50,000 (G3-G4) hold** * Suspect drug should be held. Upon recovery to ANC > 1,500/mL and platelets to > 100,000/mL, the same dose level will be administered. ** Suspect drug should be held. Upon recovery to ANC > 1,500/mL and platelets to > 100,000/mL, one lower dose levels will be administered.  
3.3.1.2 Non-hematologic Toxicity  
Dose Modifications Based on **sorafenib or everolimus** -Related Non-Hematologic Toxicities:
CTCAEv.4 Grade **% of Dose Planned** 0-2+ 100%+ 3* hold**
4 hold***
+For symptomatic Grade 2 toxicity, the suspect drug dose may be held at the discretion of the local investigator until recovery to CTCAE Grade 0-1, then resume at one dose lower. *Except nausea/vomiting (unless patients are on optimal antiemetic therapy) **Hold suspect drug until recovery to CTCAE Grade 0-1 (or to within 1 grade of starting values for pre-existing laboratory abnormalities), and then resume at one dose level lower.  
***Hold suspect drug until recovery to CTCAE Grade 0-1 (or to within 1 grade of starting values for pre-existing laboratory abnormalities), and then resume at two dose levels lower.
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management of hepatitis 3.3.2.1 management

In cancer patients with hepatitis B, whether carriers or in chronic state, use of antivirals during anticancer therapy has been shown to reduce the risk of hepatitis B virus (HBV) reactivation and associated HBV morbidity and mortality (Loomba et al. 2008).  
3.3.2.1.1 Monitoring and prophylactic treatment for hepatitis B reactivation Table 3-3 provides details of monitoring and prophylactic therapy according to the baseline results of viral load and serologic markers testing.  
| Test                                                                                              | Result                                                                                                                               | Result                                                       | Result                           | Result   | Result                             |
|---------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------|----------------------------------|----------|------------------------------------|
| HBV-DNA                                                                                           | +                                                                                                                                    | + or -                                                       | -                                | -        | -                                  |
| HBsAg                                                                                             | + or -                                                                                                                               | +                                                            | -                                | -        | -                                  |
| HBs Ab                                                                                            | + or -                                                                                                                               | + or -                                                       | + and no  prior HBV  vaccination | + or -   | - or + with prior  HBV vaccination |
| HBc Ab                                                                                            | + or -                                                                                                                               | + or -                                                       | + or -                           | +        | -                                  |
| Recommendation                                                                                    | Prophylaxis treatment  should be started 1-2  weeks prior to first dose  of study drug Monitor HBV-DNA  approximately every 4  weeks | No prophylaxis Monitor HBV-DNA  approximately every 4  weeks | No specific action               |          |                                    |
| Antiviral prophylaxis therapy should continue for at least 4 weeks after last dose of study drug. |                                                                                                                                      |                                                              |                                  |          |                                    |  
Antiviral prophylaxis therapy should continue for at least 4 weeks after last dose of study drug.  
For hepatitis B reactivation, definition and management guidelines, see Table **3-4** Guidelines for management of hepatitis B.
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table 3-4 guidelines for management

| HBV reactivation (with or without clinical signs and symptoms)* For patients with baseline  results:  Treat: Start a second antiviral  AND Positive HBV-DNA Interrupt study drug administration until resolution:  OR  ≤ grade 1 ALT (or baseline ALT, if > grade 1) and  positive HBsAg   ≤ baseline HBV-DNA levels ------------------------------- If resolution occurs within ≤ 28 days study drug should be  re-started at one dose lower, if available. If the patient is  already receiving the lowest dose of study drug according  to the protocol, the patient should restart at the same dose  after resolution. Both antiviral therapies should continue at  least 4 weeks after last dose of study drug.  reactivation is defined as:  [Increase of 1 log in HBV-DNA  relative to baseline HBV-DNA  value OR new appearance of  measurable HBV-DNA]  AND If resolution occurs > 28 days Patients should discontinue  study drug but continue both antiviral therapies at least 4  weeks after last dose of study drug. ALT elevation x 5 ULN  For patients with baseline  results:  Negative HBV-DNA and  HBsAg  Treat: Start first antiviral medication  AND Interrupt study drug administration until resolution:  AND   ≤ baseline HBV-DNA levels If resolution occurs within ≤ 28 days study drug should be  re-started at one dose lower, if available. If the patient is  already receiving the lowest dose of study drug according  to the protocol, the patient should restart at the same dose  after resolution. Antiviral therapy should continue at least 4  weeks after last dose of study drug.  [Positive HBs Ab (with no prior  history of vaccination against  HBV), OR positive HBc Ab]  ------------------------------------- reactivation is defined as: New appearance of measurable  HBV-DNA If resolution occurs > 28 days Patients should discontinue  study drug but continue antiviral therapy at least 4 weeks  after last dose of study drug. * All reactivations of hepatitis B are to be recorded as grade 3 (CTCAE v 4.0 Metabolic  Laboratory/Other: Viral Re-activation), unless considered life threatening by the investigator; in   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
* All reactivations of hepatitis B are to be recorded as grade 3 (CTCAE v 4.0 Metabolic Laboratory/Other: Viral Re-activation), unless considered life threatening by the investigator; in which case, they should be recorded as grade 4 (CTCAE v 4.0 Metabolic Laboratory/Other: Viral Re-activation). Date of viral reactivation is the date on which **both** DNA and ALT criteria were met (e.g. for a patient who was HBV-DNA positive on 01-JAN-10 and whose ALT reached ≥ 5 × ULN on 01-APR-10, the date of viral reactivation is 01-APR-10). 3.3.2.2 Monitoring for hepatitis C The following two categories of patients should be monitored every 4 weeks for HCV reactivation:  
- Patients with detectable HCV RNA-PCR test at baseline. - Patients known to have a history of HCV infection, despite a negative viral load test at baseline (including those that were treated and are considered 'cured')
For definition of hepatitis C reactivation and the management guidelines, see Table 3-5 Guidelines for management of hepatitis C.
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table 3-5 guidelines for management

| HCV reactivation* For patients with baseline  results:                                                                                                 | Discontinue study drug   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------|
| Detectable HCV-RNA,  reactivation is defined as: ALT elevation x 5 ULN  For patients with baseline  results:                                           | Discontinue study drug   |
| Knowledge of past hepatitis C  infection with no detectable  HCV-RNA, reactivation is  defined as: New appearance of detectable  HCV-RNA               |                          |
| * All reactivations of hepatitis C are to be recorded as grade 3 (CTCAE v4.0  Metabolic Laboratory/Other: Viral Re-activation), unless considered life |                          |  
* All reactivations of hepatitis C are to be recorded as grade 3 (CTCAE v4.0 Metabolic Laboratory/Other: Viral Re-activation), unless considered life threatening by the investigator; in which case, they should be recorded as grade 4 (CTCAE v 4.0 Metabolic Laboratory/Other: Viral Re-activation).  
Management of stomatitis/oral mucositis/mouth ulcers CTCAE v 4.0 grade 1-2 stomatitis/oral mucositis/mouth ulcers due to everolimus should lead to using local supportive care such as use of mouthwash (avoid those containing alcohol). The use of topical high potency steroids such as triamcinolone oral paste 0.1% (Kenalog in Orabase®) is allowed. Please refer to section **3.3.1.2** for dose modifications. Suggested guidelines for treatment of stomatitis/oral mucositis/mouth ulcers:  
1. For mild toxicity (grade 1), use conservative measures such as non-alcoholic mouth wash or salt water (0.9%) mouth wash several times a day until resolution.  
2. For more severe toxicity (grade 2 in which case patients have pain but are able to maintain adequate oral alimentation, or grade 3 in which case patients cannot maintain adequate oral alimentation), the suggested treatments are topical analgesic mouth treatments (e.g., local anesthetics such as benzocaine, butyl aminobenzoate, tetracaine hydrochloride, menthol, or phenol) with or without topical corticosteroids, such as triamcinolone oral paste 0.1% (Kenalog in Orabase®).  
3. Agents containing hydrogen peroxide, iodine, and thyme derivatives may tend to worsen mouth ulcers. It is preferable to avoid these agents.  
4. Antifungal agents must be avoided unless a fungal infection is diagnosed. In particular, systemic imidazole antifungal agents (ketoconazole, fluconazole, itraconazole, etc.) should be avoided in all patients due to their strong inhibition of everolimus and sorafenib metabolism, therefore leading to higher everolimus exposures. Therefore, topical antifungal agents are preferred if an infection is diagnosed. Similarly, antiviral agents such as acyclovir should be avoided unless a viral infection is diagnosed.
Note: Stomatitis/oral mucositis should be appropriately graded using the functional grading given on the NCI-CTCAE, version 4.0.
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management of hyperlipidemia

Everolimus causes hyperlipidemia. Treatment of hyperlipidemia should take into account the pretreatment status and dietary habits. Blood tests to monitor hyperlipidemia must be taken in the fasting state. Grade 2 or higher hypercholesterolemia (>300 mg/dL or 7.75 mmol/L) or grade 2 or higher hypertriglyceridemia (>2.5 x upper normal limit) should be treated with a statin or appropriate lipid-lowering medication, in addition to diet. Patients should be monitored clinically and through serum biochemistry for the development of rhabdomyolysis and other adverse events as required in the product label/data sheets for HMG-CoA reductase inhibitors. Please refer to section **3.3.1.2** for dose modifications of everolimus.  
Note: Concomitant therapy with fibrates and an HMG-CoA reductase inhibitor is associated with an increased risk of a rare but serious skeletal muscle toxicity manifested by rhabdomyolysis, markedly elevated creatine kinase (CPK) levels and myoglobinuria, acute renal failure and sometimes death. The risk versus benefit of using this therapy should be determined for individual patients based on their risk of cardiovascular complications of hyperlipidemia.
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management of hyperglycemia

Grade 3 hyperglycemia has been observed in patients receiving everolimus therapy. In many cases the affected patients had an abnormal should have their glucose levels monitored during everolimus therapy. Please refer to section **3.3.1.2** for dose modifications.  
Management of non-infectious pneumonitis  
| Worst grade   | Required investigations                                  | Management of                                    |                         |
|---------------|----------------------------------------------------------|--------------------------------------------------|-------------------------|
| pneumonitis   | everolimus dose                                          |                                                  |                         |
| pneumonitis   | adjustment                                               |                                                  |                         |
| Grade 1       | CT scan with lung                                        | No specific                                      |                         |
| windows       | therapy is  required                                     | Administer 100%  of everolimus  dose             |                         |
| Grade 2       | CT scan with lung  windows. Consider  pulmonary function | Symptomatic  only. Prescribe  corticosteroids if | Reduce  everolimus dose | Page 29  
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|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Worst grade                                                                                                                                                                 | Required investigations                                                                                                                                                                                                                  | Management of                                                                                  |                                                                                                                                                                     |
| pneumonitis                                                                                                                                                                 | everolimus dose                                                                                                                                                                                                                          |                                                                                                |                                                                                                                                                                     |
| pneumonitis                                                                                                                                                                 | adjustment                                                                                                                                                                                                                               |                                                                                                |                                                                                                                                                                     |
| testing including:  spirometry, DLCO, and  room air O2 saturation at  rest. Repeat each  subsequent Cycle until  return to within normal  limits. Consider a  bronchoscopy. | cough is                                                                                                                                                                                                                                 | until recovery to ≤                                                                            |                                                                                                                                                                     |
| troublesome.                                                                                                                                                                | grade 1.  Everolimus may also be interrupted  if symptoms are  troublesome.  Patients will be  withdrawn from  the study if they  fail to recover to ≤  grade 1 within 3  weeks.                                                         |                                                                                                |                                                                                                                                                                     |
| Grade 3                                                                                                                                                                     | CT scan with lung  windows and pulmonary  function testing includes:  spirometry, DLCO, and  room air O2 saturation at  rest; Repeat each  subsequent Cycle until  return to normal limits.  Bronchoscopy is  recommended.               | Prescribe  corticosteroids if  infective origin is  ruled out. Taper  as medically  indicated. | Hold treatment  until recovery to ≤  grade 1. May  restart protocol  treatment within 2  weeks at a reduced  dose (by one  level) if evidence  of clinical benefit. |
| Grade 4                                                                                                                                                                     | CT scan with lung  windows and required  pulmonary function  testing includes:  spirometry, DLCO, and  room air O2 saturation at  rest. Repeat each  subsequent Cycle until  return to baseline.  Bronchoscopy is strongly  recommended. | Prescribe  corticosteroids if  infective origin is  ruled out. Taper  as medically  indicated. | Discontinue  treatment.                                                                                                                                             |  
Page 30 Management of suspected everolimus toxicity  
Table 3-7: Criteria for dose-modification in case of suspected everolimus toxicity and reinitiation of everolimus treatment  
| Toxicity                                                                   | Actions                                                                                                                                                                                                                                                                                                          |
|----------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Non-hematological toxicity Grade 2                                         | If the toxicity is tolerable to the                                                                                                                                                                                                                                                                              |
| (except pneumonitis - refer to Table 3-6)                                  | patient, maintain the same dose. If  the toxicity is intolerable to patient,  interrupt everolimus until recovery  to grade ≤1. Then reintroduce  everolimus at same dose. If event returns to grade 2, then  interrupt everolimus until recovery  to grade ≤1. Then reintroduce  everolimus at same dose level. |
| Grade 3 (except hyperlipidemia*) (except pneumonitis - refer to Table 3-6) | Interrupt everolimus until recovery  to grade ≤1. Then reintroduce  everolimus at same dose level. For  pneumonitis consider the use of a  short course of corticosteroids.                                                                                                                                      |
| Grade 4                                                                    | Discontinue everolimus.                                                                                                                                                                                                                                                                                          |
| Hematological toxicity Grade 2 Thrombocytopenia (platelets <75, ≥          | Interrupt everolimus until recovery                                                                                                                                                                                                                                                                              |
| 50x109/L)                                                                  | to grade ≤1 (>75 x109 /L). Then  reintroduce everolimus at initial  dose.  If thrombocytopenia again returns  to grade 2, interrupt everolimus  until recovery to grade ≤1. Then  reintroduce everolimus at same dose  level.                                                                                    |
| Grade 3 Thrombocytopenia (platelets <50, ≥ 25 x109/L)                      | Interrupt everolimus until recovery  to grade ≤1 (platelets ≥ 75 x109 /L).  Then resume everolimus at same  dose level. If grade 3  thrombocytopenia recurs,  discontinue everolimus.                                                                                                                            |
| Grade 4 Thrombocytopenia (platelets < 25                                   | Discontinue everolimus.                                                                                                                                                                                                                                                                                          |
| x109/L)                                                                    |                                                                                                                                                                                                                                                                                                                  | Page 31  
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|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----|-------------------|----------|
| Toxicity                                                                                                                                                                                                                                                                                                                                                                                                                                   | Actions                                                                                                                                                                                                                                                                                                                                                |    |                   |          |
| Grade 3 Neutropenia (neutrophils <1, ≥0.5 x109/L)                                                                                                                                                                                                                                                                                                                                                                                          | Interrupt everolimus until recovery  to grade ≤1 (neutrophils ≥ 1.5 x  109 /L). Then resume everolimus at  the initial dose. If ANC again  returns to Grade 3, hold everolimus  until the ANC ≥ 1.5 x 109 /L. Then  resume everolimus dosing at same  dose level. Discontinue patient  from study therapy for a third  episode of grade 3 neutropenia. |    |                   |          |
| Grade 4 Neutropenia (neutrophils < 0.5 x109/L)                                                                                                                                                                                                                                                                                                                                                                                             | Interrupt everolimus until recovery  to grade ≤ 1 (neutrophils ≥ 1.5 x  109 /L). Then resume everolimus at  the lower dose level. If grade 3 or  grade 4 neutropenia occurs despite  this dose reduction, discontinue  everolimus.                                                                                                                     |    |                   |          |
| Grade 3 febrile neutropenia (not life-threatening)                                                                                                                                                                                                                                                                                                                                                                                         | Interrupt everolimus until resolution  of fever and neutropenia to grade ≤  1. Hold further everolimus until the  ANC ≥ 1,500/mm3 and fever has  resolved. Then resume everolimus  at same dose level. If febrile  neutropenia recurs, discontinue  everolimus.                                                                                        |    |                   |          |
| Grade 4 febrile neutropenia (life-threatening)                                                                                                                                                                                                                                                                                                                                                                                             | Discontinue everolimus.                                                                                                                                                                                                                                                                                                                                |    |                   |          |
| Any                                                                                                                                                                                                                                                                                                                                                                                                                                        | hematological                                                                                                                                                                                                                                                                                                                                          | or | non-hematological | toxicity |
| requiring interruption for ≥ 3 weeks                                                                                                                                                                                                                                                                                                                                                                                                       | Discontinue everolimus                                                                                                                                                                                                                                                                                                                                 |    |                   |          |
| *Grade 3 hyperlipidemia (hypercholesterolemia and/or hypertriglyceridemia)  should be managed using medical therapies (see Sec. 3.3.4).                                                                                                                                                                                                                                                                                                    |                                                                                                                                                                                                                                                                                                                                                        |    |                   |          |
| Patients whose treatment is interrupted or permanently discontinued due to an adverse event or  abnormal laboratory value suspected to be related to everolimus must be followed at least weekly  until the adverse event or abnormal laboratory resolves or returns to grade 1. If a patient requires  a dose delay of > 21 days from the intended day of the next scheduled dose, then the patient must  be discontinued from the study. |                                                                                                                                                                                                                                                                                                                                                        |    |                   |          |  
Management of sorafenib induced skin toxicity It is common for patients treated with sorafenib to experience skin toxicity (rash/desquamation, hand/foot reaction, etc.). Guidelines for management are specified in the table below.  
| Table 3-8: Guidelines for management of sorafenib induced skin toxicity  Skin Toxicity Grade Occurrence Suggested Dose Modification Grade 1: Numbness,  dysesthesia, paresthesia,  tingling, painless swelling,  and erythema or discomfort of  the hands or feet which does  not disrupt the patient's  normal activities. Any occurrence Continue treatment with sorafenib and  consider topical therapy for symptomatic  relief. Grade 2: Painful erythema and  swelling of the hands or feet  and/or discomfort affecting  the patient's normal activities. First occurrence Continue treatment with sorafenib and  consider topical therapy for symptomatic  relief. If no improvement within 7 days,  see below. No improvement  within 7 days or 2nd occurrence Interrupt sorafenib treatment until  toxicity resolves to Grade 0-1. When  resuming treatment, decrease sorafenib  dose by one dose level. Interrupt until resolved to grade 0-1.  When resuming treatment, decrease dose  by two dose levels (from the starting  dose).  Third occurrence  Discontinue sorafenib treatment.  Fourth occurrence  Grade 3: Moist desquamation,  ulceration, blistering or severe  pain of the hands or feet, or  severe discomfort that causes  the patient to be unable to  work or perform activities.  First occurrence Interrupt sorafenib treatment until  toxicity resolves to Grade 0-1. When  resuming treatment, decrease sorafenib  by one dose level.  Second occurrence Interrupt until resolved to grade 0-1.  When resuming treatment, decrease dose  by two dose levels (from the starting  dose).  Third occurrence Discontinue sorafenib treatment.   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Table 3-9: Dose Modifications for Sorafenib-Associated Toxicity1  
| Toxicity                                                                           | Grade 1                              | Grade 2                            | Grade 3*                                                                                            | Grade 4*               |      |       |
|------------------------------------------------------------------------------------|--------------------------------------|------------------------------------|-----------------------------------------------------------------------------------------------------|------------------------|------|-------|
| Nonhematologic                                                                                    | Continue  at the same  dose  level.  | Continue at  the same  dose level. | Withhold dose until toxicity is < 1. When  resuming treatment  reduce dose by one  dose level.      | Discontinue treatment. |      |       |
| Hematologic                                                                        | Continue  at the  same  dose  level. | Continue at  the same  dose level. | Withhold dose until toxicity is grade <2.  When resuming  treatment reduce dose  by one dose level. | Withhold               | dose | until |
| toxicity is grade <2. When  resuming treatment reduce  dose by two dose levels.    |                                      |                                    |                                                                                                     |                        |      |       |
| 1  See separate suggestions for dose modification due to hand-foot skin reactions. |                                      |                                    |                                                                                                     |                        |      |       |  
*Patients who develop grade 3 fever/chills, grade 3 elevation of hepatic transaminases with ALT and AST <10X ULN, grade 3 hyperlipidemia or hyperamylasemia without clinical or other evidence of pancreatitis, grade 3 leukopenia, or grade 3/grade 4 lymphopenia may continue study treatment without interruption at the discretion of the investigator.
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hypertension dose modifications of sorafenib

Hypertension is a known and potentially serious adverse event associated with sorafenib treatment. Patients will have their blood pressure monitored and recorded weekly during the Cycle 1 and then every cycle of the entire treatment period, either at the doctor's office or by using any calibrated electronic device (such as those found at a local drug store or pharmacy). Patients will have a Blood Pressure Diary on which to record the measurements, which will be kept with research chart. If the patient's blood pressure is elevated at any time (>140/100), even outside clinic visits, they should contact their treating physician.  
| Table 3-10: Dose modifications for Sorafenib-associated hypertension Grade Antihypertensive Blood Pressure                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Sorafenib Dose                                       |           |            |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------|-----------|------------|
| (CTCAE v 4.0)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                      | Therapy   | Monitoring |
| Grade 1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | None                                                 | Routine   | No change  |
| Grade 2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Initiate monotherapy                                 | Increase  | frequency  |
| and                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | monitor                                              | (by       |            |
| health                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | professional)                                        |           |            |
| every                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | 2                                                    | days      | until      |
| stabilized                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | No change                                            |           |            |
| (asymptomatic)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | (suggest  dihydropyridine  calcium-channel  blocker) |           |            |
| Grade                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | 2                                                    |           |            |
| (symptomatic/  persistent)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Add agent(s):                                        | Increase  | frequency  |
| and                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | monitor                                              | (by       |            |
| health                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | professional)                                        |           |            |
| every                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | 2                                                    | days      | until      |
| stabilized;                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | continue                                             |           |            |
| qod                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | monitoring                                           | to        |            |
| stabilization                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | after                                                |           |            |
| dosing restarted.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Hold*                                                | Sorafenib |            |
| until                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | symptoms                                             |           |            |
| resolve                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | and                                                  |           |            |
| diastolic BP < 100  mm/Hg.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |                                                      |           |            |
| Ca++ channel blocker  (if not already used),                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                      |           |            |
| OR                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | K+ channel opener (angiotensin  blockers), betablocker, thiazide  diuretic                                                      |           |            |
| Diastolic                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | BP                                                   | >         |            |
| 110 mm Hg                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Resume treatment  at 1 dose level  lower**           |           |            |
| OR Grade 3 Grade 4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Off                                                  | protocol  |            |
| therapy                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                      |           |            |
| * Patients requiring a delay of > 28 days should go off protocol therapy unless, in the  treating physician's opinion, the patient may benefit from continued treatment.  ** Patients requiring >2 dose reductions should go off protocol therapy.  CTCAE v 4.0 definitions Grade 1: asymptomatic, transient (<24 hrs) increase by > 20 mmHg (diastolic) or >  150/100 if previously WNL; intervention not indicated Grade 2: recurrent or persistent (>24 hrs) or symptomatic increase by >20 mmHg  (diastolic) or to >150/100 if previously WNL; monotherapy may be indicated.  Grade 3: requiring more than one drug or more intensive therapy than previously  Grade 4: life threatening (e.g., hypertensive crisis) |                                                      |           |            |  
For treatment or dose modification related questions, please contact the Study Chair or the BTTC Coordinating Center's Research Nurse.
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questionnaires

The MDASI-BT will be utilized for this portion of the study. Full instruments are provided in the Appendix **13.4**. In addition, information regarding demographics and treatment history will be collected as part of the larger study and used in this analysis. The MDASI-BT consists of 23 symptoms rated on an 11-point scale (0 to 10) to indicate the presence and severity of the symptom, with 0 being "not present" and 10 being "as bad as you can imagine." Each symptom is rated at its worst in the last 24 hours. Symptoms included on the instrument include those commonly associated with cancer therapies, those associated with increased intracranial pressure, and those related to focal deficits. The questionnaire also includes ratings of how much symptoms interfered with different aspects of a patient's life in the last 24 hours. These interference items include: general activity, mood, work (includes both work outside the home and housework), relations with other people, walking, and enjoyment of life. The interference items are also measured on 0 - 10 scales. The average time to complete these instruments is 5 minutes. The MDASI-BT has been translated into 18 languages (24, 25).  
| STUDY CALENDAR                                                                                                                                                                                               |                    |                                              |         |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------|----------------------------------------------|---------|
| STUDIES TO BE OBTAINED                                                                                                                                                                                       | PRE                | DURING                                       | OFF     |
| TREATMENT                                                                                                                                                                                                    | TREATMENT          | TREATMENT                                    |         |
| Consent & HIPAA Authorization                                                                                                                                                                                | X                  |                                              |         |
| History                                                                                                                                                                                                      | X1                 |                                              |         |
| Physical exam (including vital signs)                                                                                                                                                                        | X1                 | X5                                           |         |
| and Neurologic Examination  Karnofsky Performance Status                                                                                                                                                     | X1                 | X5                                           |         |
| Blood Pressure                                                                                                                                                                                               | X1                 | X14, X5                                      |         |
| CBC, with differential, platelets                                                                                                                                                                            | X1                 | X4 , X15                                     |         |
| PT, PTT                                                                                                                                                                                                      | X1                 |                                              |         |
| Serum creatinine,                                                                                                                                                                                            | phosphate, lipase, |                                              |         |
| amylase,                                                                                                                                                                                                     | bilirubin,         | SGOT,                                        | fasting |
| serum glucose, fasting lipid panel                                                                                                                                                                           | X1                 | X5 , X15                                     |         |
| HBV-DNA, HbsAg, HBsAb, HBcAb,                                                                                                                                                                                | X1                 |                                              |         |
| HCV-RNA-PCR                                                                                                                                                                                                  | X1                 | X5 (times 2) or  X5 (times 4) then  X6 , X16 |         |
| MDASI Symptom Assessment X5 (times 2) or X5 (times 4) whichever  is applicable per sections 3.6.1.2 and 3.6.1.5 MRI or CT (brain) (X5 (times 2) or X5 (times 4) whichever  is applicable per section 3.6.1.2 | X10                | X5 (times 2) or  X5 (times 4) then  X6       |         |
| ECG                                                                                                                                                                                                          | X3                 |                                              |         |
| Chest X-ray or chest CT                                                                                                                                                                                      | X3                 |                                              |         | Page 36  
| Version Date: 06/15/18                                                                                                                                                                                   | Page 36 of 99   |           |        |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------|-----------|--------|
| STUDIES TO BE OBTAINED                                                                                                                                                                                   | PRE             | DURING    | OFF    |
| TREATMENT                                                                                                                                                                                                | TREATMENT       | TREATMENT |        |
| Urinalysis with microanalysis                                                                                                                                                                            | X1              |           |        |
| Serum pregnancy test (β-HCG)                                                                                                                                                                             | X2              |           |        |
| UPC ratio                                                                                                                                                                                                | X12             | X12       |        |
| Urine Dipstick/urinalysis                                                                                                                                                                                | X1              | X5 , X15  |        |
| HBV-DNA, HCV-RNA-PCR                                                                                                                                                                                     | X9              |           |        |
| Prophylactic antiviral agent                                                                                                                                                                             | X11             | X11       | X11    |
| (i.e. Lamivudine) Documentation of tumor diagnosis                                                                                                                                                       | X X             | X5        |        |
| Information                                                                                                                                                                                              | on              | drug      | doses, |
| concomitant medications and doses,  (baseline and treatment related)  toxicity monitoring Measurable lesions with  measurements-tumor response (X5 or X6 , whichever is applicable per  section 3.6.1.2) | X               | X5 , X6   |        |
| Follow up for survival by phone or  clinic visit on patients who discontinue  treatment due to progression                                                                                               | X7              |           |        |
| Follow up for survival by phone or  clinic visit, for those who come off  treatment other than progression  should be followed until progression or  institution of new anti- tumor therapy              | X7              |           |        |
| Adverse Events Notation                                                                                                                                                                                  | X               | X13       |        |
| X1 To be performed within 14 days of registration                                                                                                                                                        |                 |           |        |  
X1 To be performed within 14 days of registration X2 To be performed within 14 days prior to starting study treatment X3 To be performed within 30 days prior to starting study treatment X4 To be performed every 2 weeks during treatment X5 To be performed every 4 weeks during treatment (prior to each cycle);
X6 To be performed every 2 months during treatment (every other month)
X7 To be performed every 3 months X8 To be performed weekly for Phase I Cycle 1 X9 To be performed on Cycle 1 Day 1 and Day 1 of all subsequent cycles. Applicable to patients that are on antiviral prophylaxis treatment or positive HBV antibodies, and patients with positive HCV RNA- PCR results at screening and/or a history of past infection (even if treated or considered cured).  
X10 To be performed within 14 days (+3 working days) after enrollment on the clinical trial. X11 All patients with positive HBV-DNA or HBsAg should be treated prophylactically with antiviral agent to be given 1 -2 weeks prior to study drugs, and should continue throughout the entire study period, to last until at least 4 weeks after the last dose of everolimus.  
X12 If urinalysis has > 2+ protein present, then UPC will be obtained X13 To be performed at the end of each cycle X14 To be performed weekly during Cycle 1 X15 Lab work (blood draws/urine) has a window of +/- 3 days of the cycle X16 MRI/CT imaging has a window of within 7 days of new cycle
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on study evaluation general requirements

3.6.1.1 CBC with differential and platelets will be performed every two weeks during treatment. Creatinine, bilirubin, SGOT, phosphate, lipase, amylase, fasting glucose, serum lipid panel and urinalysis/urine dipstick will be performed every four weeks (+/- 3 days) prior to each cycle. If > 2+ protein is present on urine dipstick/urinalysis, then UPC should be obtained.
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3.6.1.2 brain mri/ct

3.6.1.2.1 A brain MRI/CT will be done monthly x 2 then every other month, within 7 days of new cycle.
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or

3.6.1.2.2 For Phase II patients enrolled to the bevacizumab failure cohort, MRI/CT will be done every 4 weeks x 4, then every 8 weeks thereafter, within 7 days of new cycle.
Note: *MRI is the preferable imaging method, CT scan may be used in cases where an MRI cannot be obtained.  
3.6.1.3 All relevant information regarding drug doses, concomitant medications, and doses, measurable lesions with measurements, tumor response, laboratory examinations, and treatment-related toxicities shall be documented in the patient's medical record and flow sheets.  
3.6.1.4 A complete physical exam (with vital signs) and neurologic exam (to include documentation of the patients Karnofsky Performance Status) will be performed monthly. The MDASI-BT will be completed at baseline and at the time of each evaluation that includes an imaging study.
3.6.1.5 The patient will complete the MDASI-BT (Appendix **13.4**) at the time of clinical evaluation with MRI as long as the clinical therapy is being administered, unless clinical deterioration makes self-report not possible before that time. The time when patients are unable to complete the self-report questionnaires will be used as part of the study analysis. The MDASI-BT will be completed only by the patient, unless changes in vision or weakness make this difficult. If this occurs, then the caregiver or research assistant may read the questions to the patient or assist with marking the severity number or score as described by the patient. A patient caregiver may complete the questionnaires as a patient-preference proxy if the patient's deficits preclude selfreport.  
3.6.1.6 Patients on antiviral prophylaxis treatment or positive HBV antibodies should be tested for HBV-DNA on Cycle 1 Day 1 and Day 1 of all subsequent cycles (every 28 days) to monitor for re-activation. If re-activation is confirmed, everolimus must be interrupted or discontinued according to the guidance in Table 6-3. Patients with positive HCV RNA-PCR results at screening and/or a history of past infection (even if treated and considered 'cured') should have HCV RNA-PCR testing performed on Cycle 1 Day 1 and Day 1 of all subsequent cycles (every 28 days) to monitor for reactivation. Everolimus must be discontinued if HCV reactivation is confirmed according to the guidance in Table **3-5**.  
3.6.1.7 All patients will be followed for overall survival, when possible.  
a) Patients who discontinue treatment due to progression will be followed for survival every 3 months by phone call or clinic visit.  
b) Patients who come off therapy for reasons other than progression should be followed until progression or institution of new anti-tumor therapy. They should then be followed for survival.  
Phase I Requirements 3.6.2.1 Phase I patients will be evaluated for adverse events at least weekly during their first cycle of therapy (by either phone contact or personal visit). These adverse events will be reported to the Lead PI and the BTTC Coordinating Center weekly.  
3.6.2.2 Adverse events for subsequent cycles will be reported to BTTC Coordinating Center at the end of each cycle. In addition all serious adverse events will be reported to the BTTC Coordinating Center and the Lead PI, as directed in section 6.4 Phase II Requirements 3.6.3.1 Phase II patients will be evaluated for adverse events at the end of each cycle. In addition, all serious adverse events will be reported to the BTTC Coordinating Center and the Lead PI as directed in section 6.4
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follow-up

When a subject is removed from treatment as per section **3.7.1**, they should continue to be followed until removed from protocol. Follow up for survival should be done every 3 months by phone or clinic visit on patients who discontinue treatment due to progression. Those who come off treatment other than progression should be followed every 3 months by phone call or clinic visit until progression or institution of new anti- tumor therapy. Survival status will only be collected by phone or clinic visit. This data must be recorded on the appropriate follow up case report form.
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criteria for removal from protocol

Patients must be followed by the same type of brain scan, as was used for baseline tumor measurements, and will be removed from study if progression is documented after any cycle of treatment. Patients with stable disease, partial or complete response will continue on therapy as defined in Section 3.0.  
3.7.1.2 Unacceptable toxicity (as defined by the investigator).  
3.7.1.3 The patient may withdraw from the study at any time for any reason. 3.7.1.4 Medical or psychiatric illness which in the investigator's judgment renders the patient incapable of further therapy.  
3.7.1.5 Treatment delay due to toxicity greater than 21 days measured from the start of the preceding cycle.
Off Study Criteria 3.7.2.1 Participant requests to be withdrawn from study  
3.7.2.2 Institution of new anti-tumor therapy 3.7.2.3 Investigator discretion
3.7.2.4 Death All reasons for discontinuation of treatment must be documented in the flow sheets.  
Off Protocol Therapy and Off Study Procedure Authorized staff must notify Central Registration Office (CRO) when a subject is taken off protocol therapy and when a subject is taken off study.  
- NCI site: Complete the Participant Status Updates Form available from the web site
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page. Hand deliver the completed form to the BTTC Coordinating Center Research Nurse or send via encrypted email.  
- Participating sites: The Participant Status Update Form will be supplied by the BTTC
Coordinating Center's Research Nurse. Sites will send the completed form by secure fax to 240-541-4432 or by secure email (NIH Secure Email and File Transfer Service [SEFT]).  
- BTTC Coordinating Center: The BTTC Research Nurse will review the Participant Status Updates Form and forward to the Central Registration Office (CRO).
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4.0 concomitant medications/measures

G-CSF Administration: Routine prophylactic use of G-CSF is not permitted. However, therapeutic use in patients with serious neutropenic complications, such as sepsis, may be considered at the investigator's discretion.  
Corticosteroids should be used in the smallest dose to control symptoms of cerebral edema and mass effect, and discontinued if possible. Patients must not be on a dexamethasone dose of greater than 16 mg/ day. Anti-seizure medications should be used as indicated. If for unavoidable clinical reasons (severe allergies, toxicities etc.) a patients AED is switched to the alternate AED group the following guidelines must be followed:
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every effort should be made

Patients, who were previously on a non-EIAED and need to change anticonvulsants, should be started on another non-EIAED if at all possible. No delays in treatment would be required. Patients who were previously on a non- EIAED and were inadvertently and temporarily changed to an EIAED, should immediately be started on another non-EIAED. The patient may continue the current treatment dose while a non- EIAED is re-started. Patients who were previously on a non-EIAED and need to permanently change anticonvulsant, but who cannot change to another non-EIAED may continue the current treatment dose for the next 2 weeks while an EIAED is started. FOLLOWING THIS 2 WEEK PERIOD, THE SUBSEQUENT TREATMENT DOSE MUST BE DISCUSSED WITH THE STUDY CHAIR. In some cases this dose may be higher than the previously used dose.  
Febrile neutropenia may be managed according to the local institution's Infectious Disease guidelines. Measures may include appropriate laboratory testing, including blood and urine cultures and the institution of broad-spectrum antibiotics. If a source for the fever is not identified or the fever resolves when the neutrophil count recovers, antibiotics may be discontinued and the patient observed. Antiemetics: The use of antiemetics will be left to the investigators' discretion. Other Concomitant Medications: Therapies considered necessary for the well-being of the patient may be given at the discretion of the investigator. Other concomitant medications should be avoided except for analgesics, chronic treatments for concomitant medical conditions, or agents required for life-threatening medical problems. All concomitant medications must be recorded. Other Anticancer or Experimental Therapies: No other anticancer therapy (including chemotherapy, radiation, hormonal treatment or immunotherapy) of any kind is permitted during the study period. No other drug under investigation may be used concomitantly with the study drug. Surgery: If neurosurgical management is required for reasons not due to tumor progression, these procedures must be documented, including the indications for surgery, the surgical operative note and pathology report. If possible, defer surgery for 4 weeks from last dose of therapy. Patients who undergo resection for presumed tumor
progression but are shown to only have treatment associated changes can resume treatment once they have recovered from the surgical procedure. Everolimus treatment can only resume > 1 week after surgery.
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5.0 data collection and evaluation

Certain BTTC participating institutions have collected baseline data of relevance to this clinical trial including certain identifiable private information, such as patient treatment dates. For purposes of this clinical trial, these BTTC participating institutions will transfer these data to NCI through direct data entry in the NCI-designated study database (C3D) and via secure transfer through the NIH's Secure Email and File Transfer Service (SEFT) system, in accordance with their applicable laws, regulations, and policies. The BTTC Research Nurse will provide instructions to these BTTC participating institutions for use of C3D and SEFT. The PI at the site will be responsible for overseeing entry of data into an in-house password protected electronic system and ensuring data accuracy, consistency and timeliness. The principal investigator, associate investigators/research nurses and/or a contracted data manager will assist with the data management efforts. Data on this study will be entered into C3D and Scribe/Labmatrix. Designated research staff from the registering institution will enter the data via remote electronic data entry. The protocol specific electronic forms are to be used by the participating site. All investigators will utilize these forms for Baseline, Treatment, Adverse Events, Tumor Evaluation, Off Treatment, Survival, and Offstudy data.  
All data obtained during the conduct of the protocol will be kept in secure network drives or in approved alternative sites that comply with NIH security standards. Primary and final analyzed data will have identifiers so that research data can be attributed to an individual human subject participant. All AEs, including clinically significant abnormal findings on laboratory evaluations, regardless of severity, will be followed until return to baseline or stabilization of event. Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention and have an attribution of at least possibly related to the agent/intervention should be recorded and reported as per Sections 6.3 and **6.5.** An abnormal laboratory value will be recorded in the database as an AE **only** if the laboratory abnormality is characterized by any of the following:  
- Results in discontinuation from the study - Is associated with clinical signs or symptoms - Requires treatment or any other therapeutic intervention - Is associated with death or another serious adverse event, including hospitalization. - Is judged by the Investigator to be of significant clinical impact
If any abnormal laboratory result is considered clinically significant, the investigator will provide details about the action taken with respect to the test drug and about the patient's outcome.  
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect subject confidentiality and trial data has occurred, the IRB will be notified.  
Source Documentation Timeframes The following information will be entered into C3D and Scribe/Labmatrix within the indicated timeframes. In addition, the source documents should be provided to the BTTC Coordinating Center's Research Nurse, fax 301-451-5429, or email within the indicated timeframe.  
| Data Set / Source Documents                                                                               | Schedule for Submission                    |
|-----------------------------------------------------------------------------------------------------------|--------------------------------------------|
| Regulatory Documents                                                                                      | Prior to Patient Registration              |
| (as described in the BTTC Operations Manual)  Eligibility Checklist                                       | Prior to Patient Registration              |
| Copy of signed & dated Informed Consent w/                                                                | Prior to Patient Registration              |
| HIPAA Authorization  Pathology Report (from the most recent preregistration diagnostic biopsy or surgery)                                                                                                           | Prior to registration                      |
| Baseline Data (To include prior disease/treatment history, and  baseline clinical evaluation information) | Within 14 days after the registration date |
| Baseline MDASI - BT Questionnaire                                                                         | Within 14 days after the registration date |
| Baseline Source Documents                                                                                 | Within 14 days after the registration date |
| Database Entry Timeframes                                                                                 |                                            |  
The following data should be entered into C3D/Labmatrix within the specified timeframes. Source documentation will be kept at the participating site.  
| Treatment (Cycle) Data (To include treatment, response, AE, and  clinical evaluation information)                                                 | Within 40 days after the first day of each  treatment cycle.                                                                       |
|---------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------|
| Off Treatment Data                                                                                                                                | Within 10 days after the last date of any modality  of protocol treatment                                                          |
| Follow-up (Survival) Data                                                                                                                         | Within 52 days after the last treatment date and  then every 90 days until Off Study (unless  otherwise specified by the protocol) |
| Non-Treatment Data (May include Quality of Life questionnaires  (MDASI-BT), Specimen Tracking  information, Pathology Specimen  Submission, etc.) | Within 10 days after each scheduled assessment,  event, or activity                                                                |
| Off Study Data                                                                                                                                    | Within 10 days after the date the patient is  removed from the study.                                                              |
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confidentiality safety data

All documents, investigative reports, or information relating to the patient are strictly confidential. Any patient specific reports (i.e. Pathology Reports, MRI Reports, Operative Reports, etc.)
submitted to the BTTC Coordinating Center must have the patient's full name & social security number "blacked out" and the assigned patient ID number and protocol number written in. Patient initials may be included or retained for cross verification of identification. All patients receiving study agents will be evaluated for safety. The safety parameters include all laboratory tests and hematological abnormalities, CNS observations, physical examination findings, and spontaneous reports of adverse events reported to the investigator by patients. All toxicities encountered during the study will be evaluated according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and recorded prior to each course of therapy. Life-threatening toxicities that are unexpected and assessed to be possibly related to the study agent/s should be reported immediately as per Section **6.5.**
Information about all adverse events, whether volunteered by the subject, discovered by investigator questioning, or detected through physical examination, laboratory test or other means, will be collected and recorded on the Adverse Event Case Report Form and followed as appropriate. An adverse event is any undesirable sign, symptom or medical condition occurring after starting study drug (or therapy) even if the event is not considered to be related to study drug. Medical conditions/diseases present before starting study treatment are only considered adverse events if they worsen after starting study treatment (any procedures specified in the protocol). Adverse events occurring before starting study treatment but after signing the informed consent form are recorded on the Baseline Evaluations Case Report Form. Abnormal laboratory values or test results constitute adverse events only if they induce clinical signs or symptoms or require therapy, and are also recorded on the Adverse Events Case Report Form.  
Data Sharing with Pharmaceutical Collaborators, Bayer and Novartis NCI may share data from this study with pharmaceutical collaborators, Bayer and Novartis, pursuant to the NCI M-CRADAs with each company. Specifically, the collaborators may access and review analytical results and primary quantitative and empirical data including identifiable private information in accordance with the terms of the M-CRADAs.
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response criteria

The primary efficacy endpoint for BTTC studies will be progression free survival (PFS) at six months from patient registration for bevacizumab naïve patients and at 3 months for patients with prior bevacizumab treatment. However, objective response status should be measured and recorded. All measurements will be performed on the axial MRI T1 post contrast images when possible, although coronal images may be used if axial is not optimal for measurements (or CT post contrast if MRI is contraindicated). The same plane should be used for all measurements. Tumor size is defined as the largest (contrast enhancing) cross sectional area (largest cross-sectional diameter x largest diameter perpendicular to it).  
- Evaluable for toxicity: All patients will be evaluated for toxicity from the time of their first treatment with Sorafenib or Everolimus.  
- Evaluable for objective response: Only those patients who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response. These patients will have their response classified according to the definitions stated below. (Note: Patients who exhibit objective disease progression prior to the end of cycle 1 will also be considered evaluable.)
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definitions of response

5.2.1.1 Measurable Disease: Bi-dimensionally measurable CE lesions with clearly defined margins by CT or MRI scan, with a minimal diameter of 1 cm, and visible on 2 axial slices which are at least 5 mm apart with 0 mm skip. Measurement of tumor around a cyst or surgical cavity, if necessary, requires a minimum thickness of 3 mm.  
5.2.1.2 Non-measurable Disease (contrast enhancing): Uni-dimensionally measurable lesions, masses with margins not clearly defined, lesions with maximal diameter < 1 cm.
5.2.1.3 Objective Status, To Be Recorded at Each Evaluation: If there are too many measurable lesions to measure at each evaluation, choose the largest two to be followed before a patient is entered on study. The remaining lesions will be considered evaluable for the purpose of objective status determination. Unless progression is observed, objective status can only be determined when ALL measurable and evaluable sites and lesions are assessed.
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5.2.1.3.1 complete response (cr)

Complete disappearance of all CE measurable and evaluable disease. No new lesions. No evidence of non-evaluable disease. All measurable, evaluable and non-evaluable lesions and sites must be assessed using the same techniques as baseline. Patients must be on no steroids. There must be stable or improved non-enhancing (T2/FLAIR) lesions. Stable or improved clinically. Note: Patients with non-measurable disease cannot have a partial response. The best possible response is stable disease.
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5.2.1.3.2 partial response (pr)

Greater than or equal to 50% decrease under baseline in the sum of products of perpendicular diameters of the two largest CE measurable lesions, sustained for at least 4 weeks. In the absence of a confirming scan 4 weeks later, this scan will be considered only stable disease. If more than two clearly defined lesions exist, the remaining lesions will be considered as evaluable. No progression of evaluable or non-measurable disease. No new lesions. All measurable and evaluable lesions and sites must be assessed using the same techniques as baseline. *The steroid* dose at the time of the scan evaluation should be no greater than the maximum dose used in the first 8 weeks from initiation of therapy. Stable or improved non-enhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids compared to baseline. Stable or improved clinically. Note: Patients with non-measurable disease cannot have a partial response. The best response possible is stable disease. 5.2.1.3.3 Partial Response, Non-Measurable (PRNM)
Not applicable.  
5.2.1.3.4 Stable/No Response Does not qualify for CR, PR, or progression. The designation of stable disease requires a minimum of 4-week duration. All measurable and non-measurable sites must be assessed using the same techniques as baseline. Stable non-enhancing (T2/FLAIR) lesions on same or lower dose of steroids as compared to the baseline scan. In the event that the steroid dose has been increased, the last scan considered to show stable disease will be the scan obtained when the corticosteroid dose was equivalent to the baseline dose.
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5.2.1.3.5 progression

a. >25% increase in the sum of products of perpendicular diameters of enhancing lesions (over baseline if no decrease) on stable or increasing dose of corticosteroids. and/or b. Significant increase in T2/FLAIR non-enhancing lesion on stable or increasing doses of corticosteroids compared to baseline scan or best response following initiation or therapy, not due to co-morbid events (radiation therapy, demyelination, ischemic injury, infection, seizures, postoperative changes, or other treatment effects).  
c. Any new lesion
d. Clear clinical deterioration not attributable to other causes apart from the tumor
(e.g., seizures, medication side effects, complications of therapy, cerebrovascular events, infection, etc.). The definition of clinical deterioration is left to the discretion of the treating physician, but it is recommended that a decrease in 20% of KPS or from any baseline to 50% or less be considered, unless attributable to comorbid events.  
e. Failure to return for evaluation due to death or deteriorating condition.
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5.2.1.3.6 unknown

Progression has not been documented and one or more measurable or evaluable sites have not been assessed.
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best response

This will be calculated from the sequence of objective statuses. For patients with all disease sites assessed every evaluation period, the best response will be defined as the best objective status as measured according to Section **5.2.1**. If the response does not persist at the next regular scheduled MRI, the response will still be recorded based on the prior scan, but will be designated as a non-sustained response. If the response is sustained, e. g. still present on the subsequent MRI, it will be recorded as a sustained response, lasting until the time of tumor progression. Best response is unknown if the patient does not qualify for a best response or increasing disease and if all objective status determinations before progression are unknown.
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neurological exam

Although not used for determining response, it is useful to evaluate improvement in the neurologic exam, (as compared to the baseline assessment), that should coincide with objective measurement of tumor size.  
+2 Definitely better  
| +1   | Possibly better   |
|------|-------------------|
| 0    | Unchanged         |
| -1   | Possibly worse    |  
Performance Status:
Patients will be graded according to Karnofsky Performance Status (see Appendix **13.1**).
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time to treatment failure

From date of registration to the date of first observation of progressive disease (as defined in Section **5.2.1**), non-reversible neurologic progression or permanently increased steroid requirement (applies to stable disease only), death due to any cause, or early discontinuation of treatment. If a patient is registered on the pre-operative portion of the study, the start date for calculation of time to event will be the date of first post-operative study drug administration.
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time to death

From date of registration to date of death due to any cause.  
Evaluability Patients are required to receive at least 2 weeks of treatment of both agents, and the protocol defined evaluations are performed per protocol to be considered evaluable. Inevaluable patients will be replaced.
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toxicity criteria

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

Any untoward medical occurrence in a human subject, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the subject's participation in research, whether or not considered related to the subject's participation in the research.
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suspected adverse reaction

Suspected adverse reaction means any adverse event for which there is a reasonable possibility that the drug caused the adverse event. For the purposes of IND safety reporting, 'reasonable possibility' means there is evidence to suggest a causal relationship between the drug and the adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means any adverse event caused by a drug.
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unexpected adverse reaction

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

An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious Adverse Event or if it compromises the safety, welfare or rights of subjects or others.  
Serious Adverse Event An adverse event or suspected adverse reaction is considered serious if in the view of the investigator or the sponsor, it results in any of the following:
- Death, - A life-threatening adverse drug experience - Inpatient hospitalization or prolongation of existing hospitalization  
- Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions
- A congenital anomaly/birth defect. - Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse drug experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.  
Disability A substantial disruption of a person's ability to conduct normal life functions.  
Life-threatening adverse drug experience Any adverse event or suspected adverse reaction that places the patient or subject, in the view of the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction that had it occurred in a more severe form, might have caused death.  
Protocol Deviation (NIH Definition)
Any change, divergence, or departure from the IRB-approved research protocol.  
Non-compliance (NIH Definition)
The failure to comply with applicable NIH Human Research Protections Program (HRPP) policies, IRB requirements, or regulatory requirements for the protection of human research subjects.
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unanticipated problem

Any incident, experience, or outcome that:
- Is unexpected in terms of nature, severity, or frequency in relation to
(a) the research risks that are described in the IRB-approved research protocol and informed consent document; Investigator's Brochure or other study documents, and
(b) the characteristics of the subject population being studied; AND  
- Is related or possibly related to participation in the research; AND
- Suggests that the research places subjects or others at a *greater risk of harm* (including physical, psychological, economic, or social harm) than was previously known or recognized.
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assessing causality

Investigators are required to assess whether there is a reasonable possibility that the study agent/s caused or contributed to an adverse event. The following general guidance may be used.  
Yes: If the temporal relationship of the clinical event to the study agent/s administration makes a causal relationship possible, and other drugs, therapeutic interventions or underlying conditions do not provide a sufficient explanation for the observed event. No: If the temporal relationship of the clinical event to the study agent/s administration makes a causal relationship unlikely, or other drugs, therapeutic interventions or underlying conditions provide a sufficient explanation for the observed event.
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nci-irb and clinical director reporting

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

Brief interruption and delay in the 28-day cycle may occasionally be required due to travel delays, airport closure, inclement weather, family responsibilities, security alerts and government holidays, etc. This can also extend to complications of disease not attributable to disease progression or protocol therapy. These delays will not be considered protocol deviations. We expect 1-2 anticipated delays per patient. However, any interruption more than 14 calendar days will not be permitted. If the rate of these events exceeds the rate of more than 2 anticipated delays per patient, the events will be classified and reported as though they are unanticipated problems.
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multi-institutional guidelines 6.3.4.1 irb approvals

The Lead PI will provide the NCI IRB with a copy of the participating institution's approved yearly continuing review. Registration will be halted at any participating institution in which a current continuing approval is not on file at the NCI IRB. 6.3.4.2 Amendments and Consents The Lead PI will provide the NCI IRB with copies of all amendments, consents and approvals from each participating institution.
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guidelines for reporting serious adverse

| What to Report?                                                                                                                                          | When to Report?                                                                                                                                             |                                                                                         |                        |           |
|----------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------|------------------------|-----------|
| 1.                                                                                                                                                       | All Deaths, except that due to progressive  disease, occurring from the time the  consent is signed through 30 days after the  last day of active treatment | Within 1 working day (24 hours) from the time  the research team becomes aware of event |                        |           |
| 2.                                                                                                                                                       | Other                                                                                                                                                       | Serious                                                                                 | Unexpected             | Suspected |
| Adverse Reactions (that did not result in  death) occurring from the time the consent  is signed through 30 days after the last day  of active treatment | Within 5 working                                                                                                                                            | days from the time the                                                                  |                        |           |
| research team becomes aware of event                                                                                                                     |                                                                                                                                                             |                                                                                         |                        |           |
| 3.                                                                                                                                                       | All protocol deviations, non-compliance                                                                                                                     | Within 5 working                                                                        | days from the time the |           |
| and unanticipated problems                                                                                                                               | research team becomes aware of event                                                                                                                        |                                                                                         |                        |           |  
| What to Report?                      | When to Report?                                                                                                                                                                                                                                                                                                 |                  |      |                   |
|--------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------|------|-------------------|
| 4.                                   | Pregnancy, although not itself a serious  adverse event, should also be reported on a  serious adverse event form and be followed  up to determine outcome, including  spontaneous or voluntary termination,  details of birth, and the presence or absence  of any birth defects or congenital  abnormalities. | Within 5 working | days | from the time the |
| research team becomes aware of event |                                                                                                                                                                                                                                                                                                                 |                  |      |                   |  
The CCR problem report form will be used to submit adverse events to BTTC. See Appendix 13.6.  
Participating centers must also submit the report to their IRB in accordance with their institutional policies. The BTTC Coordinating Center will maintain documentation of all Serious Adverse Events from each institution. The BTTC Coordinating Center will notify all investigators of any serious and unexpected adverse experiences that are possibly related to the study agent/s. The investigators are to file a copy with their protocol file and send a copy to their IRB according to their local IRB's policies and procedures.