Phase I-II Everolimus and Sorafenib in Recurrent High-Grade Gliomas

Phase I-II Everolimus and Sorafenib in Recurrent High-Grade Gliomas
This study is not yet open for participant recruitment.
Verified June 2012 by M.D. Anderson Cancer Center

First Received on September 13, 2011.  
Last Updated on June 21, 2012  
History of Changes
Sponsor: M.D. Anderson Cancer Center
Collaborators: Bayer
Information provided by (Responsible Party): M.D. Anderson Cancer Center Identifier: NCT01434602

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.

Condition Intervention Phase
Brain Neoplasms
Central Nervous System Neoplasms
Drug: Everolimus
Drug: Sorafenib
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I-II Trial Everolimus and Sorafenib in Patients With Recurrent High-Grade Gliomas

Resource links provided by NLM:

Further study details as provided by M.D. Anderson Cancer Center:

Primary Outcome Measures:

  • Six-month Progression Free Survival (PFS) [ Time Frame: Six months from participant registration ] [ Designated as safety issue: Yes ]
    PFS is the number of participants progression free (with no disease progression) six months from registration.

  • Maximum Tolerated Dose (MTD) [ Time Frame: 28 day first cyle ] [ Designated as safety issue: Yes ]
    MTD defined as dose where two participants or less (2 of 6) have Dose Limiting Toxicities (DLTs) at first dose level.

Estimated Enrollment: 118
Study Start Date: November 2012
Estimated Primary Completion Date: November 2018 (Final data collection date for primary outcome measure)


Assigned Interventions
Experimental: Everolimus + Sorafenib

Starting doses Everolimus 5 mg orally daily with Sorafenib 400 mg orally twice daily for a 28 day cycle.
Drug: Everolimus

Phase I Starting dose: 5 mg by mouth daily for a 28 day cycle.

Phase II dose is Phase I Maximum Tolerated Dose.

Other Names:
  • Afinitor
  • RAD001

Drug: Sorafenib

Phase I Starting dose : 400 mg by mouth twice a day for a 28 day cycle.

If two DLTs are encountered at the first dose level, then sorafenib will be given on days 1-7 and 15-21 on a 7 days on 7 days off schedule.

Phase II dose is Phase I Maximum Tolerated Dose.

Other Names:
  • Sorafenib
  • Nexavar
  • BAY 43-9006

Show Detailed Description


Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

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.
  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.
  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 C.
  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.
  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.
  Contacts and Locations

Please refer to this study by its identifier: NCT01434602

Contact: Marta Penas-Prado, MD 713-792-2883

United States, Texas
UT MD Anderson Cancer Center Not yet recruiting
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
Principal Investigator: Marta Penas-Prado, MD UT MD Anderson Cancer Center
  More Information

Additional Information:

No publications provided

Responsible Party: M.D. Anderson Cancer Center Identifier: NCT01434602    
History of Changes
Other Study ID Numbers: BTTC09-01
Study First Received: September 13, 2011
Last Updated: June 21, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by M.D. Anderson Cancer Center:

Malignant glioma
Glioblastoma multiforme
Anaplastic astrocytoma
Anaplastic oligodendroglioma
Anaplastic mixed oligoastrocytoma
Malignant astrocytoma
Recurrent high-grade gliomas
recurrent intracranial malignant glioma
Malignant astrocytoma not otherwise specified
BAY 43-9006

Additional relevant MeSH terms:

Brain Neoplasms
Nervous System Neoplasms
Central Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Antifungal Agents
Anti-Infective Agents
Anti-Bacterial Agents
Protein Kinase Inhibitors
Enzyme Inhibitors processed this record on August 21, 2012

Leave a Reply

You can use these HTML tags

<a href="" title=""> <abbr title=""> <acronym title=""> <b> <blockquote cite=""> <cite> <code> <del datetime=""> <em> <i> <q cite=""> <s> <strike> <strong>




1 × 4 =