Phase I-II Everolimus and Sorafenib in Recurrent High-Grade Gliomas

The goal of Phase 1 of this clinical research study is to find the highest tolerable dose and best schedule of the combination of everolimus and sorafenib that can be given to patients with malignant glioma.

The goal of Phase 2 of this study to learn if the combination of everolimus and sorafenib can help to control malignant glioma. The safety of this combination will also be studied in both phases.

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 rapidly accelerated fibrosarcoma (RAF) mutations, targeting the RAF/methyl ethyl ketone (MEK)/extracellular-signal-regulated kinase (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 Phosphoinositide 3-kinases (PI3K)/Protein kinase B (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 vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), other active targets in malignant glioma.

Objectives

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 months 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 months 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 months progression free survival rate for Anaplastic Glioma (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 greater than or equal to 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).

Eligibility Criteria:
* INCLUSION CRITERIA:

General Inclusion Criteria

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 not otherwise specified (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. 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 National Institutes of Health (NIH).
3. Patients must be greater than or equal to 18 years old.
4. Patients must have a Karnofsky performance status of greater than or equal to 60.
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.
6. Patients must have adequate bone marrow function (white blood cell (WBC) \>= 3.0 x 10\^9/L, absolute neutrophil count (ANC) \>= 1.5 X 10\^9/L, platelet count of \>=100 x 10\^9/L, and hemoglobin \>= 10 gm/dL), adequate liver function (Serum glutamic oxaloacetic transaminase (SGOT) and bilirubin \< 2 times upper limit of normal (ULN), and adequate renal function (creatinine \< 1.7mg/dL or creatinine clearance greater than or equal to 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.
7. Patients must have shown unequivocal radiographic evidence for tumor progression by magnetic resonance imaging (MRI) or computed tomography (CT) scan. 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.
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 post-operatively, 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.
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.
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 positron emission tomography (PET) or Thallium scanning, magnetic resonance (MR) spectroscopy or surgical/pathological documentation of disease.
11. Women of childbearing potential must have a negative beta human chorionic gonadotropin (B-HCG) pregnancy test documented within 7 days prior to taking the first dose of study medications.
12. Patients receiving anti-coagulation treatment with an agent such as warfarin or heparin may be allowed to participate. For patients on warfarin, the international normalized ratio (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. 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.
* Patients must not have received prior therapy with sorafenib, everolimus, or related drugs such as tyrosine kinase inhibitors, vascular endothelial growth factor (VEGF) inhibitors (except bevacizumab), or mTOR inhibitors.

EXCLUSION CRITERIA:

General Exclusion Criteria

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. 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.
3. Patients has an active infection or serious intercurrent medical illness.
4. Patients has any disease that will obscure toxicity or dangerously alter drug metabolism.
5. Patients must not be on enzyme inducing anti-convulsants. If patients were previously on enzyme-inducing antiepileptic drugs (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.
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 diffusing capacity for carbon monoxide (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.
7. Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.
8. Uncontrolled hypertension defined as systolic blood pressure \> 140 mmHg or diastolic pressure \> 90 mmHg, despite optimal medical management.
9. Known human immunodeficiency virus (HIV) infection or chronic or acute Hepatitis B or C. Note: Patients who have a history of hepatitis B virus (HBV) and HCB infection are eligible, however, they must receive prophylactic antiviral therapy for 1-2 weeks prior to receiving study drug
10. Thrombolic or embolic events (except deep vein thrombosis (DVT) or pulmonary embolus) such as a Cerebrovascular accident including transient ischemic attacks within the past 6 months.
11. Pulmonary hemorrhage/bleeding event greater than or equal to Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 within 4 weeks of first dose of study drug.
12. Any other hemorrhage/bleeding event greater than or equal to CTCAE Grade 3 within 4 weeks of first dose of study drug.
13. Serious non-healing wound, non-healing ulcer, or bone fracture.
14. Evidence or history of bleeding diathesis or coagulopathy
15. Major surgery, open biopsy or significant traumatic injury within 4 weeks of first study drug.
16. Use of St. John's Wort, or rifampin (rifampicin), or other strong Cytochrome P450 3A4 (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.
17. Known or suspected allergy to sorafenib, everolimus, or any agent given in the course of this trial.
18. Any condition that impairs patient's ability to swallow whole pills.
19. Any malabsorption problem.
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.
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).
22. Patients who have received prior treatment with an mTOR inhibitor (sirolimus, temsirolimus, everolimus).
23. Patients with a known hypersensitivity to everolimus or other rapamycins (sirolimus, temsirolimus) or to its excipients.
24. History of noncompliance to medical regimens.
25. Patients unwilling to or unable to comply with the protocol.
26. Patients on total daily dose of dexamethasone greater than 16 mg.