Phase I-II Everolimus and Sorafenib in Recurrent High-Grade Gliomas
Brain Neoplasms - Central Nervous System Neoplasms
Conditions: official terms
Brain Neoplasms - Central Nervous System Neoplasms - Neoplasms - Nervous System Neoplasms
Conditions: Keywords
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
Study Type
Study Phase
Phase 1/Phase 2
Study Design
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Name: Everolimus Type: Drug
Name: Sorafenib Type: Drug
Overall Status
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.
Detailed Description
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 take sorafenib by mouth 2 times each day 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.

You will be given a study drug diary where you will write down the study drugs that you take at home. You should also bring the diary, study drug, and any empty bottles, with you to each study visit.

Study Visits:

Every 2 weeks:

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

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.

- Urine will be collected to check your kidney function.

- 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.
Criteria for eligibility
Healthy Volunteers: No
Maximum Age: N/A
Minimum Age: 18 Years
Gender: Both
Criteria: 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 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. 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 (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(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. Relapse and Treatment Count - Initial diagnosis:Surgical resection+Radiation+Chemotherapy 1;Relapse 1:+/-Surgical resection+Chemotherapy 2; Relapse 2: Patient to be evaluated for enrollment to BTTC09-01.(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 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.

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 >/= 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, or rifampin (rifampicin), or other strong 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 (BTTC/OMCR) 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 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.
University of Texas MD Anderson Cancer Center
Houston, Texas, United States
Status: Recruiting
Start Date
October 2012
M.D. Anderson Cancer Center
M.D. Anderson Cancer Center
Record processing date processed this data on July 28, 2015 page