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Title A Phase I-II Trial of Everolimus and Sorafenib in Patients with Recurrent High Grade Gliomas

IRB BTTC3312

CC 13-042

Hospital Main Campus

Disease Brain

Drug Everolimus, Sorafenib

Description

1. To determine the maximum tolerated dose and safety of everolimus in combination with sorafenib for patients with recurrent malignant gliomas.

1. Time to progression and overall survival for recurrent malignant glioma patients (Group A, Group B, and grade III glioma group) treated with everolimus and sorafenib measured from time of study enrollment.
2. Objective response rate for recurrent malignant gliomas (Group A, Group B, and grade III glioma group) treated with everolimus and sorafenib
3. 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:
   1. To evaluate longitudinal changes in symptom measures and determine the impact of the therapy on these parameters.
   2. 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.
   3. To describe the variability of symptom severity longitudinally over the treatment course and follow-up period.

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 multiforme (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. 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. Patients must be registered in the MDACC OMCR database prior to treatment with study drug.
3. Patients must be ≥ 18 years old.
4. Patients must have a Karnofsky performance status of ≥ 60.
5. No more than 2 prior chemotherapies and 1 relapse. Prior bevacizumab therapy is allowed.
   1. 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.
6. Patients must have adequate bone marrow function (WBC ≥ 3,000/�l, ANC ≥ 1,500/mm3, platelet count of ≥ 100,000/mm3, 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.
7. Patients must have shown unequivocal radiographic evidence for tumor progression by MRI or CT scan as defined by Section 9.3.4.5. 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 MR/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:
   1. They have recovered from the effects of surgery and be > 3 weeks from surgery.
   2. 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 PET or Thallium scanning, MR spectroscopy or surgical/pathological documentation of disease.
11. Women of childbearing potential must have a negative B-HCG pregnancy test documented within 14 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 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.

Exclusion Criteria

1. Patients must not have any significant medical illnesses that in the investigators opinion cannot be adequately controlled with appropriate therapy or would compromise the patients ability to tolerate this therapy
2. Patients with a history of any other cancer (except non-melanoma skin cancer or carcinoma insitu 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 must not have active infection or serious intercurrent medical illness.
4. Patients must not have 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 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 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 HBV and HCV infection are eligible, however, they must receive prophylactic antiviral therapy for 1-2 weeks prior to receiving study drug (see Section 6.4.2).
10. Thrombolic or embolic events (except DVT or pulmonary embolus) such as a Cerebrovascular accident including transient ischemic attacks within the past 6 months.
11. Pulmonary hemorrhage/bleeding event ≥ CTCAE Grade 2 within 4 weeks of first dose of study drug.
12. Any other hemorrhage/bleeding event > 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. Johns Wort, orrifampin (rifampicin), or other strong CYP34A inducers. Dexamethasone is okay as long as the dose is 16 mg /day or less.
17. Known or suspected allergy to sorafenib, everolimus, or any agent given in the course of this trial.
18. Any condition that impairs patients 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 14 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.