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A Phase I-II Trial Everolimus and Sorafenib in Patients With Recurrent High-Grade Gliomas

Phase 1/Phase 2
18 Years
Open (Enrolling)
Brain Neoplasms, Central Nervous System Neoplasms

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Trial Information

A Phase I-II Trial Everolimus and Sorafenib in Patients With Recurrent High-Grade Gliomas

Study Drugs:

Sorafenib is designed to stop cell growth and to block the formation of new blood vessels
(the tubes that carry blood around the body), which are involved in the growth and
development of tumors.

Everolimus is designed to block a special protein in tumor cells and block the formation of
new blood vessels, which is important in tumor growth.

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a study
Phase based on when you join this study.

If you are enrolled in Phase 1, you will be assigned to 1 of 6 dose levels of the
combination of everolimus and sorafenib based on when you join this study. You will remain
on the same dose level for the entire study. Up to 3 participants will be enrolled at each
dose level. The first 3 participants in each group will receive the lowest dose level.
Each set of 3 new participants will receive a higher dose than the one before it, if no
intolerable side effects were seen. This will continue until the highest tolerable dose of
study drugs given in combination is found.

If you are enrolled in Phase 2, you will receive the combination of everolimus and sorafenib
at the highest dose and on the same schedule that was tolerated in Phase 1. Up to 82
participants will be enrolled in the Phase 2 part of the study.

Study Drug Administration:

Each cycle is 28 days.

You will take everolimus by mouth 1 time a day every day while you are on study.

You should take everolimus whole without chewing them. You should take everolimus without
food (1 hour before or 2 hours after eating), with at least 1 cup (8 oz.) of water in the
morning, at the same time each day. You must not drink grapefruit juice or eat grapefruit
products while taking everolimus.

You will either take sorafenib by mouth 2 times every day or on Days 1-7 and Days 15-21 of
every cycle.

You should take sorafenib without food (1 hour before or 2 hours after eating), with at
least 1 cup (8 oz.) of water.

You may take the study drugs at the same time.

If you vomit while taking the study drugs, you should not take more capsules before the next
scheduled dose.

Study Visits:

Every 2 weeks:

- Blood (about 1-2 teaspoons) will be drawn for routine tests.

- Urine will be collected to check your kidney function.

Every 4 weeks:

- You will have a neurologic exam.

- Your performance status will be recorded.

- Blood (about 2 teaspoons) will be drawn to check your pancreatic function, and test
your blood fat level.

- You will be asked about any drugs you may be taking and if you have had any side
effects. (For the first cycle, this is every week if you are in Phase 1.)

- Your blood pressure will be recorded (For the first cycle, this is every week).

Every 4 weeks for the first 2 cycles or the first 4 cycles (if you received bevacizumab
previously), then every 8 weeks:

- You will have a brain MRI scan or CT scans to check the status of the disease.

- You will complete the quality-of-life questionnaire.

At any time during the study, extra tests may be performed if the doctor thinks they are
needed for your safety. The study doctor will tell you more about any extra tests.

Length of Study:

You will remain on study treatment for as long as you are benefitting. You will be taken off
study early if the disease gets worse, if intolerable side effects occur, or if you are
unable to follow study directions.

Long-Term Follow-Up Visit:

After you stopped taking the study drugs, the study staff will call you every 3 months to
check how you are doing. Each phone call will take about 5 minutes.

This is an investigational study. Everolimus is FDA approved and commercially available for
the treatment of kidney cancer and certain types of brain tumors. Sorafenib is FDA approved
and commercially available for the treatment of kidney cancer. The combination of
everolimus and sorafenib to treat brain tumors is investigational. At this time, this
combination is only being used in research.

Up to 118 participants will take part in this multicenter study. Up to 30 will be enrolled
at MD Anderson.

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 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/┬Ál, 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)

Exclusion Criteria:

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
drug metabolism.

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
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, 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,
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.

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Six-month Progression Free Survival (PFS)

Outcome Description:

PFS is the number of participants progression free (with no disease progression) six months from registration.

Outcome Time Frame:

Six months from participant registration

Safety Issue:


Principal Investigator

Marta Penas-Prado, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

UT MD Anderson Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

October 2012

Completion Date:

Related Keywords:

  • Brain Neoplasms
  • Central Nervous System Neoplasms
  • Malignant glioma
  • Glioblastoma multiforme
  • GBM
  • Gliosarcoma
  • GS
  • Anaplastic astrocytoma
  • AA
  • Anaplastic oligodendroglioma
  • AO
  • Anaplastic mixed oligoastrocytoma
  • AMO
  • Malignant astrocytoma
  • Recurrent high-grade gliomas
  • recurrent intracranial malignant glioma
  • Malignant astrocytoma not otherwise specified
  • NOS
  • Everolimus
  • Afinitor
  • RAD001
  • Sorafenib
  • Nexavar
  • BAY 43-9006
  • Brain Neoplasms
  • Neoplasms
  • Glioma
  • Nervous System Neoplasms
  • Central Nervous System Neoplasms



UT MD Anderson Cancer CenterHouston, Texas  77030