A Phase I-II Trial Everolimus and Sorafenib in Patients With Recurrent High-Grade Gliomas
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 Office of Multicenter Clinical Research database prior to treatment with study
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. 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/µl, 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. 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: a) They have recovered
from the effects of surgery and be > 3 weeks from surgery. b) 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.
13. 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 I only)
14. Patients may have had treatment for no more than 1 prior relapse. 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.(Phase II only)
15. 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 (Phase II only)
1. Patients must not have 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 must not have active infection or serious intercurrent medical illness.
4. Patients must not have any disease that will obscure toxicity or dangerously alter
5. Patients must not be on enzyme inducing anti-convulsants (EIAED). 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
10. Thrombolic or embolic events (except DVT or pulmonary embolus )such as a
Cerebrovascular accident including transient ischemic attacks within the past 6
11. Pulmonary hemorrhage/bleeding event >/= Common Terminology Criteria for Adverse
Events (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
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
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.
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 14 days prior to administration
of everolimus and sorafenib)
22. Patients who have received prior treatment with an mTOR inhibitor (sirolimus,
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.