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

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2016 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT01434602
First received: September 13, 2011
Last updated: August 6, 2016
Last verified: June 2016
  Purpose

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 Tumor
Glioblastoma
Anaplastic Glioma
Drug: everolimus
Drug: sorafenib
Phase 1
Phase 2

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

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • To determine the maximum tolerated dose and safety of everolimus in combination with sorafenib for patients with recurrent malignant gliomas [ Time Frame: completed ] [ Designated as safety issue: Yes ]
  • 6 month progression free survival rate for glioblastoma patients with no prior bevacizumab exposure treated with everolimus and sorafenib [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • 3 month progression free survival rate for glioblastoma patients with prior bevacizumab exposure treated with everolimus and sorafenib at the maximum tolerated dose as determined in the phase I study. [ Time Frame: 3 months ] [ Designated as safety issue: No ]
  • 6 month progression free survival rate for AG patients with no prior bevacizumab exposure treated with everolimus and sorafenib at themaximum tolerated dose as determined in the phase I study [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Estimated Enrollment: 118
Study Start Date: October 2015
Estimated Study Completion Date: July 2020
Estimated Primary Completion Date: July 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: I
Recurrent glioblastoma with no prior exposure to bevacizumab cohort
Drug: everolimus
Patients will be treated with daily everolimus (days 1-28) in combination with sorafenib; There is not a defined set maximum number of cycles that a patient may have; dose escalation from 5mg to 10 mg daily
Drug: sorafenib
Patients will be treated with daily everolimus (days 1-28) in combination with sorafenib; There is not a defined set maximum number of cycles that a patient may have; dose escalation from 400 mg bid, 7 days on and 7 days off to 800 mg bid
Experimental: II
Recurrent glioblastoma with prior exposure to bevacizumab cohort
Drug: everolimus
Patients will be treated with daily everolimus (days 1-28) in combination with sorafenib; There is not a defined set maximum number of cycles that a patient may have; dose escalation from 5mg to 10 mg daily
Drug: sorafenib
Patients will be treated with daily everolimus (days 1-28) in combination with sorafenib; There is not a defined set maximum number of cycles that a patient may have; dose escalation from 400 mg bid, 7 days on and 7 days off to 800 mg bid
Active Comparator: III
Cohort III: A third cohort consisting of 16 patients with anaplastic glioma
Drug: everolimus
Patients will be treated with daily everolimus (days 1-28) in combination with sorafenib; There is not a defined set maximum number of cycles that a patient may have; dose escalation from 5mg to 10 mg daily
Drug: sorafenib
Patients will be treated with daily everolimus (days 1-28) in combination with sorafenib; There is not a defined set maximum number of cycles that a patient may have; dose escalation from 400 mg bid, 7 days on and 7 days off to 800 mg bid

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 99 Years   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • 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 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 at all sites except the 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 Academic PI.

    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 greater than or equal to 3,000/microliters, ANC greater than or equal to 1,500/mm3, platelet count of greater than or equal to 100,000/mm3, and hemoglobin greater than or equal to 10 gm/dl), adequate liver function (SGOT and bilirubin < 2 times 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 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 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 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.

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, VEGF inhibitors (except bevacizumab), or mTOR inhibitors.

EXCLUSION CRITERIA:

General 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. 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 greater than or equal to 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, orrifampin (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 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01434602

Contacts
Contact: Christine E Siegel, C.R.N.P. (301) 594-4023 christine.siegel@nih.gov

Locations
United States, California
Cedars Sinai Medical Center Recruiting
Los Angeles, California, United States, 90048-1804
United States, Florida
UF Health Cancer Center at Orlando Health Recruiting
Orlando, Florida, United States, 32806
United States, Illinois
Northwestern University, Feinberg School of Medicine Recruiting
Chicago, Illinois, United States, 60611
MUSC Hollings Cancer Center Recruiting
Chicago, Illinois, United States, 60612
Rush University Medical Center Recruiting
Chicago, Illinois, United States, 60612
United States, Kansas
University of Kansas Cancer Center Recruiting
Kansas City, Kansas, United States, 66160
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
United States, Michigan
Henry Ford Health Systems Recruiting
Detroit, Michigan, United States, 48202
United States, New York
Columbia University Recruiting
New York, New York, United States, 10032-3784
United States, North Carolina
University of North Carolina at Chapel Hill Recruiting
Chapel Hill, North Carolina, United States
United States, Ohio
Cleveland Clinic Transplantation Clinic Recruiting
Cleveland, Ohio, United States
Ohio State University Recruiting
Columbus, Ohio, United States, 43210-1240
United States, Texas
Texas Oncology Austin Brain Tumor Center Recruiting
Austin, Texas, United States, 78705
Baylor University Medical Center Recruiting
Dallas, Texas, United States
UT, MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
United States, Utah
University of Utah Health Network Recruiting
Salt Lake City, Utah, United States, 84112
United States, Washington
Washington University School of Medicine Recruiting
Seattle, Washington, United States, 98109
United States, Wisconsin
Aurora Health Care Recruiting
Milwaukee, Wisconsin, United States, 53215
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Mark R Gilbert, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01434602     History of Changes
Other Study ID Numbers: 160011  16-C-0011 
Study First Received: September 13, 2011
Last Updated: August 6, 2016
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Chemotherapy
Brain Tumor
Glioblastoma
Anaplastic Glioma

Additional relevant MeSH terms:
Glioblastoma
Glioma
Brain Neoplasms
Astrocytoma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Sorafenib
Everolimus
Sirolimus
Niacinamide
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Protein Kinase Inhibitors

ClinicalTrials.gov processed this record on August 29, 2016