- -
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.
