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

Sponsor
National Cancer Institute (NCI) (NIH)
Overall Status
Completed
CT.gov ID
NCT01434602
Collaborator
(none)
86
Enrollment
1
Location
2
Arms
105.3
Actual Duration (Months)
0.8
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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 or Disease Intervention/Treatment Phase
Phase 1/Phase 2

Detailed Description

Background

  • Although malignant gliomas display genetic heterogeneity, several key proliferation and survival signaling pathways have been identified.

  • Recent work has focused on targeting these tumor specific pathways in hopes of improving treatment efficacy and minimizing treatment toxicity. Because molecularly targeted agents have been mostly ineffective when used alone, combination therapy that inhibits multiple pathways is an appealing strategy.

  • Sorafenib is an oral multi-kinase inhibitor with effects on tumor proliferation and tumor angiogenesis. Although most GBMs lack rapidly accelerated fibrosarcoma (RAF) mutations, targeting the RAF/methyl ethyl ketone (MEK)/extracellular-signal-regulated kinase (ERK) pathway may be beneficial as this pathway may be activated by other genetic alterations upstream from RAF.

  • The mammalian target of rapamycin (mTOR) protein is a downstream component of the Phosphoinositide 3-kinases (PI3K)/Protein kinase B (Akt) pathway. Everolimus (everolimus; Novartis) is a novel oral derivative of rapamycin.

  • Combining everolimus and sorafenib allows targeting of both the PI3K pathway and the RAF-MAPK pathway and in addition targets vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), other active targets in malignant glioma.

Objectives

Phase 1

-To determine the maximum tolerated dose and safety of everolimus in combination with

sorafenib for patients with recurrent malignant gliomas.

Phase 2

  • 6 months progression free survival rate for glioblastoma patients with no prior bevacizumab exposure treated with everolimus and sorafenib at the maximum tolerated dose as determined in the phase I study.

  • 3 months 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.

  • 6 months progression free survival rate for Anaplastic Glioma (AG) patients with no prior bevacizumab exposure treated with everolimus and sorafenib at the maximum tolerated dose as determined in the phase I study.

Eligibility

  • Patients with histologically proven recurrent intracranial malignant glioma will be eligible for the phase I/II component of this protocol.

  • Patients must be >= 18 years old with a Karnofsky performance status of greater than or equal to 60

  • No more than 2 prior chemotherapies and 1 relapse. Prior bevacizumab therapy is allowed.

Design

  • This is a phase 1 /2 study of everolimus and sorafenib in patients with recurrent high-grade gliomas.

  • Phase 1: Patients will be treated with daily everolimus (days 1-28) in combination with sorafenib.

  • Phase 2: Patients will be treated with the combination of sorafenib and everolimus. Sorafenib will be taken daily for 7 days on, then 7 days off. Everolimus will be taken daily.

  • There is not a defined set maximum number of cycles that a patient may have. Patients may continue with protocol therapy until criteria for Off Treatment is met. Patients will then be followed every 3 months for survival status.

  • There will be an accrual of approximately 3-6 eligible patients per cohort to the Phase I component of the study. Patients removed at any time for toxicity are evaluable. Phase I patients removed from study treatment within 28 days for reasons other than toxicity may be replaced.

  • There will be a total accrual of approximately 82 eligible patients to the Phase II study (34 recurrent GBM with no prior exposure to bevacizumab, 16 recurrent Anaplastic Glioma with no prior exposure to bevacizumab, and 32 glioblastoma with prior exposure to bevacizumab).

Study Design

Study Type:
Interventional
Actual Enrollment :
86 participants
Allocation:
Non-Randomized
Intervention Model:
Sequential Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase I-II Trial of Everolimus and Sorafenib in Patients With Recurrent High-Grade Gliomas
Actual Study Start Date :
Oct 2, 2012
Actual Primary Completion Date :
Oct 19, 2020
Actual Study Completion Date :
Jul 13, 2021

Arms and Interventions

Arm Intervention/Treatment
Experimental: 1/Phase I

Daily everolimus (days 1- 28) in combination with sorafenib as per the Phase I dosing table. Maximum tolerated dose. Dose Escalation.

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; Phase I Dose Escalation: 5mg to 10mg daily.
Other Names:
  • Zortress

    • Drug: sorafenib
    Patients will be treated with sorafenib in combination with everolimus (days 1-28); There is not a defined set maximum number of cycles that a patient may have; Phase I Dose Escalation 400mg-600mg twice a day (bid) or 400mg-800mg twice a day, 7 days on and 7 days off.
    Other Names:
  • Nexavar

    		•
    Experimental: 2/Phase II

    Combination of sorafenib and everolimus. Sorafenib 400mg twice daily will be taken for 7 days on, then 7 days off. Everolimus 5mg will be taken daily. Determined from dose escalation in phase I, maximum tolerated dose -1.

    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; Phase I Dose Escalation: 5mg to 10mg daily.
    Other Names:
  • Zortress

    • Drug: sorafenib
    Patients will be treated with sorafenib in combination with everolimus (days 1-28); There is not a defined set maximum number of cycles that a patient may have; Phase I Dose Escalation 400mg-600mg twice a day (bid) or 400mg-800mg twice a day, 7 days on and 7 days off.
    Other Names:
  • Nexavar

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Maximum Tolerated Dose of Everolimus for Participants With Recurrent Malignant Gliomas [First 28 days of treatment only (cycle 1)]

      Maximum tolerated dose of everolimus for participants with recurrent malignant gliomas. MTD is defined as the dose at which fewer than one-third of participants experience a dose limiting toxicity (DLT) to one of the study drugs. A DLT is any grade 3 thrombocytopenia, grade 4 anemia, grade 4 neutropenia, or febrile neutropenia of any grade. Any non-hematologic grade 3 or grade 4 toxicity, excluding alopecia and/or hand/foot reaction. Failure to recover from toxicities (to grade 1 or less) to be eligible for re-treatment with everolimus within 14 days of the last dose of everolimus.

    2. Maximum Tolerated Dose of Sorafenib for Participants With Recurrent Malignant Gliomas [First 28 days of treatment only (cycle 1)]

      Maximum tolerated dose of sorafenib for participants with recurrent malignant gliomas. MTD is defined as the dose at which fewer than one-third of participants experience a dose limiting toxicity (DLT) to one of the study drugs. A DLT is any grade 3 thrombocytopenia, grade 4 anemia, grade 4 neutropenia, or febrile neutropenia of any grade. Any non-hematologic grade 3 or grade 4 toxicity, excluding alopecia and/or hand/foot reaction. Failure to recover from toxicities (to grade 1 or less) to be eligible for re-treatment with sorafenib within 14 days of the last dose of sorafenib.

    3. Percentage of Participants Who Survived Without Disease Progression at 6 Months After Treatment for Glioblastoma Participants With no Prior Bevacizumab Exposure [6 months]

      Percentage of participants who survived without disease progression at 6 months after treatment for glioblastoma participants with no prior bevacizumab exposure. Progression was measured by brain magnetic resonance imaging (MRI) tumor measurements. Progression is defined as >25% increase in the sum of products of perpendicular diameters of enhancing lesions (over baseline if no decrease) on stable or increasing dose of corticosteroids; and/or significant increase in T2-weighted-Fluid-Attenuated Inversion Recovery (T2/FLAIR) non-enhancing lesion on stable or increasing doses of corticosteroids compared to baseline scan or best response following initiation or therapy, not due to co-morbid events (radiation therapy, demyelination, ischemic injury, infection, seizures, postoperative changes, or other treatment effects). Any new lesion.

    4. Percentage of Participants Who Survived Without Disease Progression at 3 Months After Treatment for Glioblastoma Participants With Prior Bevacizumab Exposure [3 months]

      Percentage of participants who survived without disease progression at 3 months after treatment for glioblastoma participants with prior bevacizumab exposure. Progression was measured by brain magnetic resonance imaging (MRI) tumor measurements. Progression is defined as >25% increase in the sum of products of perpendicular diameters of enhancing lesions (over baseline if no decrease) on stable or increasing dose of corticosteroids; and/or significant increase in T2-weighted-Fluid-Attenuated Inversion Recovery (T2/FLAIR) non-enhancing lesion on stable or increasing doses of corticosteroids compared to baseline scan or best response following initiation or therapy, not due to co-morbid events (radiation therapy, demyelination, ischemic injury, infection, seizures, postoperative changes, or other treatment effects). Any new lesion.

    5. Percentage of Participants Who Survived Without Disease Progression at 6 Months After Treatment for Anaplastic Glioma (AG) Participants With no Prior Bevacizumab Exposure [6 months]

      Percentage of participants who survived without disease progression at 6 months after treatment for anaplastic glioma (AG) participants with no prior bevacizumab exposure. Progression was measured by brain magnetic resonance imaging (MRI) tumor measurements. Progression is defined as >25% increase in the sum of products of perpendicular diameters of enhancing lesions (over baseline if no decrease) on stable or increasing dose of corticosteroids; and/or significant increase in T2-weighted-Fluid-Attenuated Inversion Recovery (T2/FLAIR) non-enhancing lesion on stable or increasing doses of corticosteroids compared to baseline scan or best response following initiation or therapy, not due to co-morbid events (radiation therapy, demyelination, ischemic injury, infection, seizures, postoperative changes, or other treatment effects). Any new lesion.

    Secondary Outcome Measures

    1. Median Amount of Time Participants Survives Without Disease Progression for Groups A, B, and C Treated With Everolimus and Sorafenib [Up to 6 months]

      Median amount of time participants survives without disease progression for Groups A, B, and C treated with everolimus and sorafenib. Progression was measured by brain magnetic resonance imaging (MRI) tumor measurements. Progression is defined as >25% increase in the sum of products of perpendicular diameters of enhancing lesions (over baseline if no decrease) on stable or increasing dose of corticosteroids; and/or significant increase in T2-weighted-Fluid-Attenuated Inversion Recovery (T2/FLAIR) non-enhancing lesion on stable or increasing doses of corticosteroids compared to baseline scan or best response following initiation or therapy, not due to co-morbid events (radiation therapy, demyelination, ischemic injury, infection, seizures, postoperative changes, or other treatment effects). Any new lesion.

    2. Objective Response for Participants With Recurrent Malignant Gliomas (Group A, Group B, and Group C) Treated With Everolimus and Sorafenib [After 1 cycle of treatment, or those who exhibit objective progression prior the end of cycle 1 (one cycle = 28 days).]

      Objective response for participants with recurrent malignant gliomas treated with everolimus and sorafenib was assessed by brain magnetic resonance imaging (MRI) tumor measurements. Complete Response is complete disappearance of all CE measurable and evaluable disease. Partial Response is greater than or equal to 50% decrease under baseline in the sum of products of perpendicular diameters of the two largest CE measurable lesions, sustained for at least 4 weeks. Progressive Disease >25% increase in the sum of products of perpendicular diameters of enhancing lesions (over baseline if no decrease) on stable or increasing dose of corticosteroids, significant increase in T2-weighted-Fluid-Attenuated Inversion Recovery (T2/FLAIR) non-enhancing lesion on stable or increasing doses of corticosteroids compared to baseline scan or best response following initiation or therapy, not due to co-morbid events, or any new lesion. Stable Disease does not qualify for CR, PR, or progression.

    3. Median Amount of Time a Participant Survives After Therapy for Participants With Recurrent Malignant Glioma (Group A, Group B, and Group C) Treated With Everolimus and Sorafenib Measured From the Time of Study Enrollment [From the time of study enrollment up to 1.5 years]

      Median amount of time a participant survives after therapy for participants with recurrent malignant glioma (Group A, Group B, and Group C) treated with everolimus and sorafenib measured from the time of study enrollment.

    4. Rate of Participants Symptom Severity [Completed at baseline, before a brain or spine magnetic resonance imaging (MRI)/clinical evaluation, and at cycle 1-2, cycle 4, cycle 6, cycle 8, cycle 10 and cycle 12 (each cycle is 28 days)]

      To evaluate the occurrence of symptoms and correlate to disease progression and tolerance to treatment using the MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) self-reporting tool. The MDASI-BT consists of 23 symptoms rated on an 11-point scale (0 - not present, to 10 - as bad as you can imagine) to indicate the presence and severity of the symptom. We calculated the mean core symptom severity at the time of clinical evaluation.

    5. Rate of Participants Symptom Interference With Function [Completed at baseline, before a brain or spine magnetic resonance imaging (MRI)/clinical evaluation, and at cycle 1-2, cycle 4, cycle 6, cycle 8, cycle 10 and cycle 12 (each cycle is 28 days)]

      To evaluate the occurrence of symptoms and correlate to disease progression and tolerance to treatment using the MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) self-reporting tool. The MDASI-BT consists of 23 symptoms rated on an 11-point scale (0 - did not interfere, to 10 - interfered completely) to indicate the symptoms that interfere with a participant's life in the last 24 hours. We calculated the mean symptom interference at the time of clinical evaluation.

    Other Outcome Measures

    1. Number of Participants With a Dose-limiting Toxicity (DLT) [First 28 days of treatment only (cycle 1)]

      A DLT is any grade 3 thrombocytopenia, grade 4 anemia, grade 4 neutropenia, or febrile neutropenia of any grade. Any non-hematologic grade 3 or grade 4 toxicity, excluding alopecia and/or hand/foot reaction. Failure to recover from toxicities (to grade 1 or less) to be eligible for re-treatment with sorafenib and everolimus within 14 days of the last dose of sorafenib and everolimus.

    2. Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0) [Date treatment consent signed to date off study, approximately 21 months and 18 days, 30 months and twelve days, 83 months and 8 days, and 84 months and 26 days for each group respectively.]

      Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    • 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.

    1. Patients must have adequate bone marrow function (white blood cell (WBC) >= 3.0 x 109/L, absolute neutrophil count (ANC) >= 1.5 X 109/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.

    2. 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.

    1. 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.

    1. 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.

    2. 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.

    3. 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.

    4. 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

    1. 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

    1. 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.

    2. 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.

    3. Any other hemorrhage/bleeding event greater than or equal to CTCAE Grade 3 within 4 weeks of first dose of study drug.

    4. Serious non-healing wound, non-healing ulcer, or bone fracture.

    5. Evidence or history of bleeding diathesis or coagulopathy

    6. Major surgery, open biopsy or significant traumatic injury within 4 weeks of first study drug.

    7. 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.

    1. Known or suspected allergy to sorafenib, everolimus, or any agent given in the course of this trial.

    2. Any condition that impairs patient's ability to swallow whole pills.

    3. Any malabsorption problem.

    4. Other malignancies within the past 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin.

    5. 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).

    6. Patients who have received prior treatment with an mTOR inhibitor (sirolimus, temsirolimus, everolimus).

    7. Patients with a known hypersensitivity to everolimus or other rapamycins (sirolimus, temsirolimus) or to its excipients.

    8. History of noncompliance to medical regimens.

    9. Patients unwilling to or unable to comply with the protocol.

    10. Patients on total daily dose of dexamethasone greater than 16 mg.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda Maryland United States 20892

    Sponsors and Collaborators

    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Mark R Gilbert, M.D., National Cancer Institute (NCI)

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Mark Gilbert, M.D., Principal Investigator, National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT01434602
    Other Study ID Numbers:
    • 160011
    • 16-C-0011
    First Posted:
    Sep 15, 2011
    Last Update Posted:
    Jun 1, 2022
    Last Verified:
    May 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Mark Gilbert, M.D., Principal Investigator, National Cancer Institute (NCI)
    Chemotherapy
    Brain Tumor
    Glioblastoma
    Anaplastic Glioma
    Additional relevant MeSH terms:
    Glioblastoma
    Glioma
    Brain Neoplasms
    Everolimus
    Sorafenib

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail This study started at MD Anderson under Dr. Gilbert in 2012 and transferred to the National Cancer Institute (NCI).
    Arm/Group Title Phase I Dose Level I Sorafenib 400mg Twice Daily + Everolimus 5mg Daily Phase I Dose Level -1 Sorafenib 400mg Twice Daily, 7 Days on, 7 Off + Everolimus 5mg Daily Phase 2 Group A Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily
    Arm/Group Description Phase I Dose Level 1 Dose Escalation Participants with recurrent malignant glioma, with or without prior exposure to bevacizumab will be treated with Sorafenib 400mg twice daily + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Phase I Dose Level -1 Dose Escalation Phase Participants with recurrent malignant glioma, with or without prior exposure to bevacizumab will be treated with Sorafenib 400mg twice daily 7 days on, 7 days off + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Sorafenib will be given on days 1-7 and days 15-21. Phase 2 Recommended Phase 2 Dose Recurrent glioblastoma with no prior exposure to bevacizumab Participants will be treated with Sorafenib 400mg twice daily 7 days on, 7 days off + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Sorafenib will be given on days 1-7 and days 15-21. Phase 2 Recommended Phase 2 Dose Recurrent glioblastoma with prior exposure to bevacizumab Participants will be treated with Sorafenib 400mg twice daily 7 days on, 7 days off + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Sorafenib will be given on days 1-7 and days 15-21. Phase 2 recommended phase 2 dose Participants with Anaplastic Glioma with no prior exposure to bevacizumab (Grade III Glioma Group) will be treated with Sorafenib 400mg twice daily 7 days on, 7 days off + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Sorafenib will be given on days 1-7 and days 15-21.
    Period Title: Phase I Dose Escalation
    STARTED 6 7 0 0 0
    COMPLETED 6 6 0 0 0
    NOT COMPLETED 0 1 0 0 0
    Period Title: Phase I Dose Escalation
    STARTED 0 0 12 40 21
    COMPLETED 0 0 12 31 19
    NOT COMPLETED 0 0 0 9 2

    Baseline Characteristics

    Arm/Group Title Phase I Dose Level I Sorafenib 400mg Twice Daily + Everolimus 5mg Daily Phase I Dose Level -1 Sorafenib 400mg Twice Daily, 7 Days on, 7 Off + Everolimus 5mg Daily Phase 2 Group A Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on 7 Off + Everolimus 5mg Daily Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily Total
    Arm/Group Description Phase I Dose Level 1 Dose Escalation Participants with recurrent malignant glioma, with or without prior exposure to bevacizumab will be treated with Sorafenib 400mg twice daily + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Phase I Dose Level -1 Dose Escalation Phase Participants with recurrent malignant glioma, with or without prior exposure to bevacizumab will be treated with Sorafenib 400mg twice daily 7 days on, 7 days off + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Sorafenib will be given on days 1-7 and days 15-21. Phase 2 Recommended Phase 2 Dose Recurrent glioblastoma with no prior exposure to bevacizumab Participants will be treated with Sorafenib 400mg twice daily 7 days on, 7 days off + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Sorafenib will be given on days 1-7 and days 15-21. Phase 2 Recommended Phase 2 Dose Recurrent glioblastoma with prior exposure to bevacizumab Participants will be treated with Sorafenib 400mg twice daily 7 days on, 7 days off + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Sorafenib will be given on days 1-7 and days 15-21. Phase 2 recommended phase 2 dose Participants with Anaplastic Glioma with no prior exposure to bevacizumab (Grade III Glioma Group) will be treated with Sorafenib 400mg twice daily 7 days on, 7 days off + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Sorafenib will be given on days 1-7 and days 15-21. Total of all reporting groups
    Overall Participants 6 7 12 40 21 86
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    6
    100%
    5
    71.4%
    10
    83.3%
    34
    85%
    19
    90.5%
    74
    86%
    >=65 years
    0
    0%
    2
    28.6%
    2
    16.7%
    6
    15%
    2
    9.5%
    12
    14%
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    46.90
    (12.80)
    48.65
    (19.32)
    51.34
    (12.13)
    51.74
    (14.34)
    44.09
    (14.43)
    49.23
    (14.46)
    Sex: Female, Male (Count of Participants)
    Female
    1
    16.7%
    1
    14.3%
    5
    41.7%
    16
    40%
    8
    38.1%
    31
    36%
    Male
    5
    83.3%
    6
    85.7%
    7
    58.3%
    24
    60%
    13
    61.9%
    55
    64%
    Race/Ethnicity, Customized (Count of Participants)
    Black or African American
    0
    0%
    0
    0%
    1
    8.3%
    2
    5%
    0
    0%
    3
    3.5%
    White
    5
    83.3%
    6
    85.7%
    10
    83.3%
    37
    92.5%
    18
    85.7%
    76
    88.4%
    Unknown
    1
    16.7%
    1
    14.3%
    0
    0%
    1
    2.5%
    3
    14.3%
    6
    7%
    Other
    0
    0%
    0
    0%
    1
    8.3%
    0
    0%
    0
    0%
    1
    1.2%
    Missing Ethnicity
    6
    100%
    7
    100%
    12
    100%
    27
    67.5%
    19
    90.5%
    71
    82.6%
    Hispanic
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    2
    9.5%
    2
    2.3%
    Not Hispanic
    0
    0%
    0
    0%
    0
    0%
    13
    32.5%
    0
    0%
    13
    15.1%
    Region of Enrollment (participants) [Number]
    United States
    6
    100%
    7
    100%
    12
    100%
    40
    100%
    21
    100%
    86
    100%

    Outcome Measures

    1. Primary Outcome
    Title Maximum Tolerated Dose of Everolimus for Participants With Recurrent Malignant Gliomas
    Description Maximum tolerated dose of everolimus for participants with recurrent malignant gliomas. MTD is defined as the dose at which fewer than one-third of participants experience a dose limiting toxicity (DLT) to one of the study drugs. A DLT is any grade 3 thrombocytopenia, grade 4 anemia, grade 4 neutropenia, or febrile neutropenia of any grade. Any non-hematologic grade 3 or grade 4 toxicity, excluding alopecia and/or hand/foot reaction. Failure to recover from toxicities (to grade 1 or less) to be eligible for re-treatment with everolimus within 14 days of the last dose of everolimus.
    Time Frame First 28 days of treatment only (cycle 1)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title All Participants
    Arm/Group Description All participants with recurrent malignant glioma, with or without prior exposure to bevacizumab on phase I dose level 1 and phase I dose level-1. Phase I Dose Level 1: Sorafenib 400mg twice daily + Everolimus 5 mg daily by mouth (days 1-28). Phase I Dose Level -1: Sorafenib 400mg twice daily 7 days on, 7 days off + Everolimus 5 mg daily by mouth (days 1-28). Sorafenib will be given on days 1-7 and days 15-21. There is not a defined set maximum number of cycles that a participant may have.
    Measure Participants 13
    Number [mg]
    5
    2. Primary Outcome
    Title Maximum Tolerated Dose of Sorafenib for Participants With Recurrent Malignant Gliomas
    Description Maximum tolerated dose of sorafenib for participants with recurrent malignant gliomas. MTD is defined as the dose at which fewer than one-third of participants experience a dose limiting toxicity (DLT) to one of the study drugs. A DLT is any grade 3 thrombocytopenia, grade 4 anemia, grade 4 neutropenia, or febrile neutropenia of any grade. Any non-hematologic grade 3 or grade 4 toxicity, excluding alopecia and/or hand/foot reaction. Failure to recover from toxicities (to grade 1 or less) to be eligible for re-treatment with sorafenib within 14 days of the last dose of sorafenib.
    Time Frame First 28 days of treatment only (cycle 1)

    Outcome Measure Data

    Analysis Population Description
    The dosing schedule for the MTD is 400mg twice a day (BID) 7 days on/7 days off.
    Arm/Group Title All Participants
    Arm/Group Description All participants with recurrent malignant glioma, with or without prior exposure to bevacizumab on phase I dose level 1 and phase I dose level-1. Phase I Dose Level 1: Sorafenib 400mg twice daily + Everolimus 5 mg daily by mouth (days 1-28). Phase I Dose Level -1: Sorafenib 400mg twice daily 7 days on, 7 days off + Everolimus 5 mg daily by mouth (days 1-28). Sorafenib will be given on days 1-7 and days 15-21. There is not a defined set maximum number of cycles that a participant may have.
    Measure Participants 13
    Number [mg]
    400
    3. Primary Outcome
    Title Percentage of Participants Who Survived Without Disease Progression at 6 Months After Treatment for Glioblastoma Participants With no Prior Bevacizumab Exposure
    Description Percentage of participants who survived without disease progression at 6 months after treatment for glioblastoma participants with no prior bevacizumab exposure. Progression was measured by brain magnetic resonance imaging (MRI) tumor measurements. Progression is defined as >25% increase in the sum of products of perpendicular diameters of enhancing lesions (over baseline if no decrease) on stable or increasing dose of corticosteroids; and/or significant increase in T2-weighted-Fluid-Attenuated Inversion Recovery (T2/FLAIR) non-enhancing lesion on stable or increasing doses of corticosteroids compared to baseline scan or best response following initiation or therapy, not due to co-morbid events (radiation therapy, demyelination, ischemic injury, infection, seizures, postoperative changes, or other treatment effects). Any new lesion.
    Time Frame 6 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Phase 2 Group A Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily
    Arm/Group Description Phase 2 Recommended Phase 2 Dose Recurrent glioblastoma with no prior exposure to bevacizumab Participants will be treated with Sorafenib 400mg twice daily 7 days on, 7 days off + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Sorafenib will be given on days 1-7 and days 15-21.
    Measure Participants 12
    Number (95% Confidence Interval) [Percentage of participants]
    8.33
    138.8%
    4. Primary Outcome
    Title Percentage of Participants Who Survived Without Disease Progression at 3 Months After Treatment for Glioblastoma Participants With Prior Bevacizumab Exposure
    Description Percentage of participants who survived without disease progression at 3 months after treatment for glioblastoma participants with prior bevacizumab exposure. Progression was measured by brain magnetic resonance imaging (MRI) tumor measurements. Progression is defined as >25% increase in the sum of products of perpendicular diameters of enhancing lesions (over baseline if no decrease) on stable or increasing dose of corticosteroids; and/or significant increase in T2-weighted-Fluid-Attenuated Inversion Recovery (T2/FLAIR) non-enhancing lesion on stable or increasing doses of corticosteroids compared to baseline scan or best response following initiation or therapy, not due to co-morbid events (radiation therapy, demyelination, ischemic injury, infection, seizures, postoperative changes, or other treatment effects). Any new lesion.
    Time Frame 3 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily
    Arm/Group Description Phase 2 Recommended Phase 2 Dose Recurrent glioblastoma with prior exposure to bevacizumab Participants will be treated with Sorafenib 400mg twice daily 7 days on, 7 days off + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Sorafenib will be given on days 1-7 and days 15-21.
    Measure Participants 40
    Number (95% Confidence Interval) [Percentage of participants]
    12.9
    215%
    5. Primary Outcome
    Title Percentage of Participants Who Survived Without Disease Progression at 6 Months After Treatment for Anaplastic Glioma (AG) Participants With no Prior Bevacizumab Exposure
    Description Percentage of participants who survived without disease progression at 6 months after treatment for anaplastic glioma (AG) participants with no prior bevacizumab exposure. Progression was measured by brain magnetic resonance imaging (MRI) tumor measurements. Progression is defined as >25% increase in the sum of products of perpendicular diameters of enhancing lesions (over baseline if no decrease) on stable or increasing dose of corticosteroids; and/or significant increase in T2-weighted-Fluid-Attenuated Inversion Recovery (T2/FLAIR) non-enhancing lesion on stable or increasing doses of corticosteroids compared to baseline scan or best response following initiation or therapy, not due to co-morbid events (radiation therapy, demyelination, ischemic injury, infection, seizures, postoperative changes, or other treatment effects). Any new lesion.
    Time Frame 6 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily
    Arm/Group Description Phase 2 recommended phase 2 dose Participants with Anaplastic Glioma with no prior exposure to bevacizumab (Grade III Glioma Group) will be treated with Sorafenib 400mg twice daily 7 days on, 7 days off + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Sorafenib will be given on days 1-7 and days 15-21.
    Measure Participants 21
    Number (95% Confidence Interval) [Percentage of participants]
    26.7
    445%
    6. Secondary Outcome
    Title Median Amount of Time Participants Survives Without Disease Progression for Groups A, B, and C Treated With Everolimus and Sorafenib
    Description Median amount of time participants survives without disease progression for Groups A, B, and C treated with everolimus and sorafenib. Progression was measured by brain magnetic resonance imaging (MRI) tumor measurements. Progression is defined as >25% increase in the sum of products of perpendicular diameters of enhancing lesions (over baseline if no decrease) on stable or increasing dose of corticosteroids; and/or significant increase in T2-weighted-Fluid-Attenuated Inversion Recovery (T2/FLAIR) non-enhancing lesion on stable or increasing doses of corticosteroids compared to baseline scan or best response following initiation or therapy, not due to co-morbid events (radiation therapy, demyelination, ischemic injury, infection, seizures, postoperative changes, or other treatment effects). Any new lesion.
    Time Frame Up to 6 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Phase 2 Group A Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily
    Arm/Group Description Phase 2 Recommended Phase 2 Dose Recurrent glioblastoma with no prior exposure to bevacizumab Participants will be treated with Sorafenib 400mg twice daily 7 days on, 7 days off + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Sorafenib will be given on days 1-7 and days 15-21. Phase 2 Recommended Phase 2 Dose Recurrent glioblastoma with prior exposure to bevacizumab Participants will be treated with Sorafenib 400mg twice daily 7 days on, 7 days off + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Sorafenib will be given on days 1-7 and days 15-21. Phase 2 recommended phase 2 dose Participants with Anaplastic Glioma with no prior exposure to bevacizumab (Grade III Glioma Group) will be treated with Sorafenib 400mg twice daily 7 days on, 7 days off + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Sorafenib will be given on days 1-7 and days 15-21.
    Measure Participants 12 40 21
    Median (95% Confidence Interval) [Months]
    1.92
    1.17
    1.87
    7. Secondary Outcome
    Title Objective Response for Participants With Recurrent Malignant Gliomas (Group A, Group B, and Group C) Treated With Everolimus and Sorafenib
    Description Objective response for participants with recurrent malignant gliomas treated with everolimus and sorafenib was assessed by brain magnetic resonance imaging (MRI) tumor measurements. Complete Response is complete disappearance of all CE measurable and evaluable disease. Partial Response is greater than or equal to 50% decrease under baseline in the sum of products of perpendicular diameters of the two largest CE measurable lesions, sustained for at least 4 weeks. Progressive Disease >25% increase in the sum of products of perpendicular diameters of enhancing lesions (over baseline if no decrease) on stable or increasing dose of corticosteroids, significant increase in T2-weighted-Fluid-Attenuated Inversion Recovery (T2/FLAIR) non-enhancing lesion on stable or increasing doses of corticosteroids compared to baseline scan or best response following initiation or therapy, not due to co-morbid events, or any new lesion. Stable Disease does not qualify for CR, PR, or progression.
    Time Frame After 1 cycle of treatment, or those who exhibit objective progression prior the end of cycle 1 (one cycle = 28 days).

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Phase 2 Group A Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on 7 Off + Everolimus 5mg Daily Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily
    Arm/Group Description Phase 2 Recommended Phase 2 Dose Recurrent glioblastoma with no prior exposure to bevacizumab Participants will be treated with Sorafenib 400mg twice daily 7 days on, 7 days off + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Sorafenib will be given on days 1-7 and days 15-21. Phase 2 Recommended Phase 2 Dose Recurrent glioblastoma with prior exposure to bevacizumab Participants will be treated with Sorafenib 400mg twice daily 7 days on, 7 days off + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Sorafenib will be given on days 1-7 and days 15-21. Phase 2 recommended phase 2 dose Participants with Anaplastic Glioma with no prior exposure to bevacizumab (Grade III Glioma Group) will be treated with Sorafenib 400mg twice daily 7 days on, 7 days off + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Sorafenib will be given on days 1-7 and days 15-21.
    Measure Participants 12 40 21
    Complete Response
    0
    0%
    0
    0%
    0
    0%
    Partial Response
    0
    0%
    0
    0%
    2
    16.7%
    Progressive Disease
    4
    66.7%
    17
    242.9%
    7
    58.3%
    Stable Disease
    8
    133.3%
    16
    228.6%
    10
    83.3%
    Not Evaluable
    0
    0%
    7
    100%
    2
    16.7%
    8. Secondary Outcome
    Title Median Amount of Time a Participant Survives After Therapy for Participants With Recurrent Malignant Glioma (Group A, Group B, and Group C) Treated With Everolimus and Sorafenib Measured From the Time of Study Enrollment
    Description Median amount of time a participant survives after therapy for participants with recurrent malignant glioma (Group A, Group B, and Group C) treated with everolimus and sorafenib measured from the time of study enrollment.
    Time Frame From the time of study enrollment up to 1.5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Phase 2 Group A Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily
    Arm/Group Description Phase 2 Recommended Phase 2 Dose Recurrent glioblastoma with no prior exposure to bevacizumab Participants will be treated with Sorafenib 400mg twice daily 7 days on, 7 days off + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Sorafenib will be given on days 1-7 and days 15-21. Phase 2 Recommended Phase 2 Dose Recurrent glioblastoma with prior exposure to bevacizumab Participants will be treated with Sorafenib 400mg twice daily 7 days on, 7 days off + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Sorafenib will be given on days 1-7 and days 15-21. Phase 2 recommended phase 2 dose Participants with Anaplastic Glioma with no prior exposure to bevacizumab (Grade III Glioma Group) will be treated with Sorafenib 400mg twice daily 7 days on, 7 days off + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Sorafenib will be given on days 1-7 and days 15-21.
    Measure Participants 12 40 21
    Median (95% Confidence Interval) [Months]
    7.75
    4.77
    11.97
    9. Secondary Outcome
    Title Rate of Participants Symptom Severity
    Description To evaluate the occurrence of symptoms and correlate to disease progression and tolerance to treatment using the MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) self-reporting tool. The MDASI-BT consists of 23 symptoms rated on an 11-point scale (0 - not present, to 10 - as bad as you can imagine) to indicate the presence and severity of the symptom. We calculated the mean core symptom severity at the time of clinical evaluation.
    Time Frame Completed at baseline, before a brain or spine magnetic resonance imaging (MRI)/clinical evaluation, and at cycle 1-2, cycle 4, cycle 6, cycle 8, cycle 10 and cycle 12 (each cycle is 28 days)

    Outcome Measure Data

    Analysis Population Description
    78/86 participants were evaluable for this outcome measure. 1 participant had active progression before start of treatment, 3 participants did not have data available (no confirmed treatment dates), and 4 participants were missing questionnaires, thus were not counted. 0 analyzed = Participants were taken off therapy before reaching the timepoint.
    Arm/Group Title Phase 1 Dose LEvel 1 Sorafenib 400mg Twice Daily + Everolimus 5mg Daily Phase 1 Dose Level -1 Sorafenib 400mg Twice Daily 7 Days On, & Days Off + Everolimus Daily Phase 2 Group A Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on 7 Off + Everolimus 5mg Daily Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily
    Arm/Group Description Phase I Dose Level 1 Dose Escalation Participants with recurrent malignant glioma, with or without prior exposure to bevacizumab will be treated with Sorafenib 400mg twice daily + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Phase I Dose Level -1 Dose Escalation Phase Participants with recurrent malignant glioma, with or without prior exposure to bevacizumab will be treated with Sorafenib 400mg twice daily 7 days on, 7 days off + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Sorafenib will be given on days 1-7 and days 15-21. Phase 2 Recommended Phase 2 Dose Recurrent glioblastoma with no prior exposure to bevacizumab Participants will be treated with Sorafenib 400mg twice daily 7 days on, 7 days off + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Sorafenib will be given on days 1-7 and days 15-21. Phase 2 Recommended Phase 2 Dose Recurrent glioblastoma with prior exposure to bevacizumab Participants will be treated with Sorafenib 400mg twice daily 7 days on, 7 days off + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Sorafenib will be given on days 1-7 and days 15-21. Phase 2 recommended phase 2 dose Participants with Anaplastic Glioma with no prior exposure to bevacizumab (Grade III Glioma Group) will be treated with Sorafenib 400mg twice daily 7 days on, 7 days off + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Sorafenib will be given on days 1-7 and days 15-21.
    Measure Participants 6 7 11 35 19
    Baseline
    3.9
    (1.4)
    1.3
    (0.9)
    1.5
    (1.2)
    2.0
    (1.2)
    1.3
    (0.9)
    Cycle 1
    3.8
    (1.0)
    1.6
    (1.5)
    2.2
    (1.8)
    2.5
    (1.5)
    1.8
    (1.2)
    Cycle 2
    3.5
    (1.3)
    1.9
    (1.4)
    2.3
    (1.7)
    3.4
    (1.4)
    1.5
    (1.3)
    Cycle 4
    0.4
    (0)
    1.3
    (0.7)
    3.5
    (2.1)
    1.8
    (1.2)
    Cycle 6
    1.4
    (1.4)
    Cycle 8
    1.8
    (1.5)
    Cycle 10
    1.5
    (1.2)
    Cycle 12
    1.4
    (1.0)
    10. Secondary Outcome
    Title Rate of Participants Symptom Interference With Function
    Description To evaluate the occurrence of symptoms and correlate to disease progression and tolerance to treatment using the MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) self-reporting tool. The MDASI-BT consists of 23 symptoms rated on an 11-point scale (0 - did not interfere, to 10 - interfered completely) to indicate the symptoms that interfere with a participant's life in the last 24 hours. We calculated the mean symptom interference at the time of clinical evaluation.
    Time Frame Completed at baseline, before a brain or spine magnetic resonance imaging (MRI)/clinical evaluation, and at cycle 1-2, cycle 4, cycle 6, cycle 8, cycle 10 and cycle 12 (each cycle is 28 days)

    Outcome Measure Data

    Analysis Population Description
    78/86 participants were evaluable for this outcome measure. 1 participant had active progression before start of treatment, 3 participants did not have data available (no confirmed treatment dates), and 4 participants were missing questionnaires, thus were not counted. 0 analyzed = Participants were taken off therapy before reaching the timepoint.
    Arm/Group Title Phase I Dose Level I Sorafenib 400mg Twice Daily + Everolimus 5mg Daily Phase I Dose Level -1 Sorafenib 400mg Twice Daily, 7 Days on, 7 Off + Everolimus 5mg Daily Phase 2 Group A Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on 7 Off + Everolimus 5mg Daily Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily
    Arm/Group Description Phase I Dose Level 1 Dose Escalation Participants with recurrent malignant glioma, with or without prior exposure to bevacizumab will be treated with Sorafenib 400mg twice daily + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Phase I Dose Level -1 Dose Escalation Phase Participants with recurrent malignant glioma, with or without prior exposure to bevacizumab will be treated with Sorafenib 400mg twice daily 7 days on, 7 days off + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Sorafenib will be given on days 1-7 and days 15-21. Phase 2 Recommended Phase 2 Dose Recurrent glioblastoma with no prior exposure to bevacizumab Participants will be treated with Sorafenib 400mg twice daily 7 days on, 7 days off + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Sorafenib will be given on days 1-7 and days 15-21. Phase 2 Recommended Phase 2 Dose Recurrent glioblastoma with prior exposure to bevacizumab Participants will be treated with Sorafenib 400mg twice daily 7 days on, 7 days off + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Sorafenib will be given on days 1-7 and days 15-21. Phase 2 recommended phase 2 dose Participants with Anaplastic Glioma with no prior exposure to bevacizumab (Grade III Glioma Group) will be treated with Sorafenib 400mg twice daily 7 days on, 7 days off + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Sorafenib will be given on days 1-7 and days 15-21.
    Measure Participants 6 7 11 35 19
    Baseline
    5.0
    (2.7)
    1.5
    (1.6)
    2.3
    (2.3)
    3.4
    (2.7)
    2.1
    (2.6)
    Cycle 1
    4.2
    (3.7)
    2.3
    (2.4)
    3.3
    (2.9)
    4.1
    (2.8)
    2.5
    (2.3)
    Cycle 2
    5.0
    (0.1)
    2.8
    (3.7)
    4.3
    (3.0)
    6.4
    (2.2)
    1.8
    (2.4)
    Cycle 4
    0.3
    (0)
    2.8
    (3.1)
    4.2
    (3.3)
    3.3
    (3.2)
    Cycle 6
    2.0
    (2.8)
    Cycle 8
    2.4
    (3.2)
    Cycle 10
    1.6
    (2.9)
    Cycle 12
    1.2
    (1.6)
    11. Other Pre-specified Outcome
    Title Number of Participants With a Dose-limiting Toxicity (DLT)
    Description A DLT is any grade 3 thrombocytopenia, grade 4 anemia, grade 4 neutropenia, or febrile neutropenia of any grade. Any non-hematologic grade 3 or grade 4 toxicity, excluding alopecia and/or hand/foot reaction. Failure to recover from toxicities (to grade 1 or less) to be eligible for re-treatment with sorafenib and everolimus within 14 days of the last dose of sorafenib and everolimus.
    Time Frame First 28 days of treatment only (cycle 1)

    Outcome Measure Data

    Analysis Population Description
    Phase II is not applicable for this outcome measure. 6/7 subjects were evaluable in Dose Level-1 because one participant was excluded for under-dosing.
    Arm/Group Title Phase I Dose Level I Sorafenib 400mg Twice Daily + Everolimus 5mg Daily Phase I Dose Level -1 Sorafenib 400mg Twice Daily, 7 Days on, 7 Off + Everolimus 5mg Daily
    Arm/Group Description Phase I Dose Level 1 Dose Escalation Participants with recurrent malignant glioma, with or without prior exposure to bevacizumab will be treated with Sorafenib 400mg twice daily + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Phase I Dose Level -1 Dose Escalation Phase Participants with recurrent malignant glioma, with or without prior exposure to bevacizumab will be treated with Sorafenib 400mg twice daily 7 days on, 7 days off + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Sorafenib will be given on days 1-7 and days 15-21.
    Measure Participants 6 6
    Count of Participants [Participants]
    3
    50%
    1
    14.3%
    12. Other Pre-specified Outcome
    Title Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)
    Description Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
    Time Frame Date treatment consent signed to date off study, approximately 21 months and 18 days, 30 months and twelve days, 83 months and 8 days, and 84 months and 26 days for each group respectively.

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Phase I Dose Level I Sorafenib 400mg Twice Daily + Everolimus 5mg Daily Phase I Dose Level -1 Sorafenib 400mg Twice Daily, 7 Days on, 7 Off + Everolimus 5mg Daily Phase 2 Group A Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily
    Arm/Group Description Phase I Dose Level 1 Dose Escalation Participants with recurrent malignant glioma, with or without prior exposure to bevacizumab will be treated with Sorafenib 400mg twice daily + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Phase I Dose Level -1 Dose Escalation Phase Participants with recurrent malignant glioma, with or without prior exposure to bevacizumab will be treated with Sorafenib 400mg twice daily 7 days on, 7 days off + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Sorafenib will be given on days 1-7 and days 15-21. Phase 2 Recommended Phase 2 Dose Recurrent glioblastoma with no prior exposure to bevacizumab Participants will be treated with Sorafenib 400mg twice daily 7 days on, 7 days off + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Sorafenib will be given on days 1-7 and days 15-21. Phase 2 Recommended Phase 2 Dose Recurrent glioblastoma with prior exposure to bevacizumab Participants will be treated with Sorafenib 400mg twice daily 7 days on, 7 days off + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Sorafenib will be given on days 1-7 and days 15-21. Phase 2 recommended phase 2 dose Participants with Anaplastic Glioma with no prior exposure to bevacizumab (Grade III Glioma Group) will be treated with Sorafenib 400mg twice daily 7 days on, 7 days off + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Sorafenib will be given on days 1-7 and days 15-21.
    Measure Participants 6 7 12 40 21
    Count of Participants [Participants]
    6
    100%
    7
    100%
    12
    100%
    38
    95%
    20
    95.2%

    Adverse Events

    Time Frame Date treatment consent signed to date off study, approximately 21 months and 18 days, 30 months and twelve days, 83 months and 8 days, and 84 months and 26 days for each group respectively.
    Adverse Event Reporting Description
    Arm/Group Title Phase I Dose Level I Sorafenib 400mg Twice Daily + Everolimus 5mg Daily Phase I Dose Level -1 Sorafenib 400mg Twice Daily, 7 Days on, 7 Off + Everolimus 5mg Daily Phase 2 Group A Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily
    Arm/Group Description Phase I Dose Level 1 Dose Escalation Participants with recurrent malignant glioma, with or without prior exposure to bevacizumab will be treated with Sorafenib 400mg twice daily + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Phase I Dose Level -1 Dose Escalation Phase Participants with recurrent malignant glioma, with or without prior exposure to bevacizumab will be treated with Sorafenib 400mg twice daily 7 days on, 7 days off + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Sorafenib will be given on days 1-7 and days 15-21. Phase 2 Recommended Phase 2 Dose Recurrent glioblastoma with no prior exposure to bevacizumab Participants will be treated with Sorafenib 400mg twice daily 7 days on, 7 days off + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Sorafenib will be given on days 1-7 and days 15-21. Phase 2 Recommended Phase 2 Dose Recurrent glioblastoma with prior exposure to bevacizumab Participants will be treated with Sorafenib 400mg twice daily 7 days on, 7 days off + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Sorafenib will be given on days 1-7 and days 15-21. Phase 2 recommended phase 2 dose Participants with Anaplastic Glioma with no prior exposure to bevacizumab (Grade III Glioma Group) will be treated with Sorafenib 400mg twice daily 7 days on, 7 days off + Everolimus 5 mg daily by mouth (days 1-28). There is not a defined set maximum number of cycles that a patient may have. Sorafenib will be given on days 1-7 and days 15-21.
    All Cause Mortality
    Phase I Dose Level I Sorafenib 400mg Twice Daily + Everolimus 5mg Daily Phase I Dose Level -1 Sorafenib 400mg Twice Daily, 7 Days on, 7 Off + Everolimus 5mg Daily Phase 2 Group A Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 5/6 (83.3%) 6/7 (85.7%) 9/12 (75%) 19/40 (47.5%) 11/21 (52.4%)
    Serious Adverse Events
    Phase I Dose Level I Sorafenib 400mg Twice Daily + Everolimus 5mg Daily Phase I Dose Level -1 Sorafenib 400mg Twice Daily, 7 Days on, 7 Off + Everolimus 5mg Daily Phase 2 Group A Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 3/6 (50%) 2/7 (28.6%) 3/12 (25%) 12/40 (30%) 2/21 (9.5%)
    Gastrointestinal disorders
    Gastrointestinal disorders - Other, Acute Sigmoid Diverticulitis 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 1/21 (4.8%) 1
    Nausea 0/6 (0%) 0 1/7 (14.3%) 1 0/12 (0%) 0 3/40 (7.5%) 3 0/21 (0%) 0
    Vomiting 0/6 (0%) 0 1/7 (14.3%) 1 0/12 (0%) 0 2/40 (5%) 2 0/21 (0%) 0
    General disorders
    Fatigue 0/6 (0%) 0 1/7 (14.3%) 1 0/12 (0%) 0 0/40 (0%) 0 0/21 (0%) 0
    Infections and infestations
    Wound infection 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Injury, poisoning and procedural complications
    Fall 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 1/21 (4.8%) 1
    Investigations
    Platelet count decreased 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Weight loss 0/6 (0%) 0 1/7 (14.3%) 1 0/12 (0%) 0 0/40 (0%) 0 0/21 (0%) 0
    Metabolism and nutrition disorders
    Dehydration 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 1/21 (4.8%) 1
    Hypertriglyceridemia 1/6 (16.7%) 1 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 0/21 (0%) 0
    Hyponatremia 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 1/21 (4.8%) 1
    Musculoskeletal and connective tissue disorders
    Generalized muscle weakness 0/6 (0%) 0 1/7 (14.3%) 1 0/12 (0%) 0 1/40 (2.5%) 1 1/21 (4.8%) 2
    Muscle weakness left-sided 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 2/40 (5%) 2 0/21 (0%) 0
    Myositis 0/6 (0%) 0 1/7 (14.3%) 1 0/12 (0%) 0 0/40 (0%) 0 0/21 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, Malignant neoplasm 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, Specify 1/6 (16.7%) 1 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 0/21 (0%) 0
    Nervous system disorders
    Cerebrospinal fluid leakage 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Dysarthria 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Dysphasia 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 1/21 (4.8%) 1
    Edema cerebral 0/6 (0%) 0 1/7 (14.3%) 1 0/12 (0%) 0 0/40 (0%) 0 0/21 (0%) 0
    Facial muscle weakness 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Facial nerve disorder 1/6 (16.7%) 1 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 0/21 (0%) 0
    Headache 0/6 (0%) 0 1/7 (14.3%) 1 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Intracranial hemorrhage 1/6 (16.7%) 1 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 1/21 (4.8%) 1
    Ischemia cerebrovascular 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Memory impairment 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Nervous system disorders - Other, altered mental status 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Seizure 0/6 (0%) 0 0/7 (0%) 0 2/12 (16.7%) 3 1/40 (2.5%) 1 0/21 (0%) 0
    Stroke 0/6 (0%) 0 0/7 (0%) 0 1/12 (8.3%) 1 0/40 (0%) 0 0/21 (0%) 0
    Psychiatric disorders
    Confusion 0/6 (0%) 0 1/7 (14.3%) 1 0/12 (0%) 0 0/40 (0%) 0 0/21 (0%) 0
    Skin and subcutaneous tissue disorders
    Scalp pain 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Vascular disorders
    Hypertension 0/6 (0%) 0 1/7 (14.3%) 1 0/12 (0%) 0 0/40 (0%) 0 0/21 (0%) 0
    Hypotension 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Thromboembolic event 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 3/40 (7.5%) 3 0/21 (0%) 0
    Other (Not Including Serious) Adverse Events
    Phase I Dose Level I Sorafenib 400mg Twice Daily + Everolimus 5mg Daily Phase I Dose Level -1 Sorafenib 400mg Twice Daily, 7 Days on, 7 Off + Everolimus 5mg Daily Phase 2 Group A Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 6/6 (100%) 7/7 (100%) 12/12 (100%) 38/40 (95%) 20/21 (95.2%)
    Blood and lymphatic system disorders
    Anemia 3/6 (50%) 4 0/7 (0%) 0 0/12 (0%) 0 2/40 (5%) 9 1/21 (4.8%) 1
    Blood and lymphatic system disorders - Other, Leukopenia 1/6 (16.7%) 1 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 0/21 (0%) 0
    Thrombotic thrombocytopenic purpura 1/6 (16.7%) 2 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 0/21 (0%) 0
    Cardiac disorders
    Chest pain - cardiac 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 1/21 (4.8%) 1
    Sinus tachycardia 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Ear and labyrinth disorders
    Ear pain 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Hearing impaired 2/6 (33.3%) 2 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Endocrine disorders
    Hypothyroidism 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Eye disorders
    Blurred vision 1/6 (16.7%) 1 1/7 (14.3%) 1 0/12 (0%) 0 0/40 (0%) 0 3/21 (14.3%) 3
    Conjunctivitis 0/6 (0%) 0 0/7 (0%) 0 1/12 (8.3%) 1 0/40 (0%) 0 0/21 (0%) 0
    Dry eye 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 1/21 (4.8%) 1
    Eye disorders - Other, specify 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 1/21 (4.8%) 1
    Eye disorders - Other, Left Homonymous Hemianopsia 0/6 (0%) 0 0/7 (0%) 0 1/12 (8.3%) 1 0/40 (0%) 0 0/21 (0%) 0
    Eye disorders - Other, left peripheral vision loss 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Eye disorders - Other, RIGHT HEMIANOPSIA 0/6 (0%) 0 0/7 (0%) 0 1/12 (8.3%) 1 0/40 (0%) 0 0/21 (0%) 0
    Eye disorders - Other, visual field deficit 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Eye pain 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Papilledema 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 2/21 (9.5%) 2
    Gastrointestinal disorders
    Abdominal distension 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 2/40 (5%) 2 0/21 (0%) 0
    Abdominal pain 1/6 (16.7%) 1 0/7 (0%) 0 2/12 (16.7%) 3 0/40 (0%) 0 1/21 (4.8%) 1
    Constipation 1/6 (16.7%) 1 2/7 (28.6%) 2 1/12 (8.3%) 1 2/40 (5%) 2 0/21 (0%) 0
    Diarrhea 1/6 (16.7%) 1 2/7 (28.6%) 3 2/12 (16.7%) 2 14/40 (35%) 18 6/21 (28.6%) 6
    Dry mouth 0/6 (0%) 0 0/7 (0%) 0 1/12 (8.3%) 1 1/40 (2.5%) 1 1/21 (4.8%) 1
    Dyspepsia 2/6 (33.3%) 2 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 0/21 (0%) 0
    Dysphagia 2/6 (33.3%) 2 0/7 (0%) 0 1/12 (8.3%) 1 2/40 (5%) 2 0/21 (0%) 0
    Fecal incontinence 1/6 (16.7%) 1 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 0/21 (0%) 0
    Flatulence 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 2/21 (9.5%) 2
    Gastrointestinal disorders - Other, Constipation 0/6 (0%) 0 0/7 (0%) 0 1/12 (8.3%) 1 0/40 (0%) 0 0/21 (0%) 0
    Gastrointestinal disorders - Other, Diverticulitis 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 1/21 (4.8%) 1
    Gastrointestinal disorders - Other, Epigastric Pain 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Gastrointestinal disorders - Other, Gas Pain 0/6 (0%) 0 0/7 (0%) 0 1/12 (8.3%) 4 0/40 (0%) 0 0/21 (0%) 0
    Gastrointestinal disorders - Other, specify 0/6 (0%) 0 0/7 (0%) 0 2/12 (16.7%) 3 0/40 (0%) 0 0/21 (0%) 0
    Gastrointestinal disorders - Other, Loose Stools 0/6 (0%) 0 0/7 (0%) 0 1/12 (8.3%) 1 0/40 (0%) 0 0/21 (0%) 0
    Gastrointestinal disorders - Other, Loss of Appetite 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 1/21 (4.8%) 1
    Gastrointestinal pain 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 1/21 (4.8%) 1
    Hemorrhoidal hemorrhage 0/6 (0%) 0 0/7 (0%) 0 1/12 (8.3%) 1 0/40 (0%) 0 0/21 (0%) 0
    Hemorrhoids 0/6 (0%) 0 1/7 (14.3%) 1 0/12 (0%) 0 2/40 (5%) 2 0/21 (0%) 0
    Mucositis oral 0/6 (0%) 0 2/7 (28.6%) 2 2/12 (16.7%) 2 3/40 (7.5%) 4 1/21 (4.8%) 1
    Nausea 0/6 (0%) 0 1/7 (14.3%) 1 3/12 (25%) 4 9/40 (22.5%) 10 2/21 (9.5%) 2
    Oral dysesthesia 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Oral pain 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Retroperitoneal hemorrhage 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Vomiting 0/6 (0%) 0 0/7 (0%) 0 2/12 (16.7%) 2 7/40 (17.5%) 7 2/21 (9.5%) 2
    General disorders
    Chills 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 2/40 (5%) 2 1/21 (4.8%) 1
    Edema face 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 1/21 (4.8%) 1
    Edema limbs 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 3/40 (7.5%) 3 0/21 (0%) 0
    Facial pain 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Fatigue 5/6 (83.3%) 5 4/7 (57.1%) 4 8/12 (66.7%) 12 15/40 (37.5%) 19 11/21 (52.4%) 15
    Fever 1/6 (16.7%) 1 1/7 (14.3%) 1 0/12 (0%) 0 1/40 (2.5%) 1 1/21 (4.8%) 1
    Flu like symptoms 0/6 (0%) 0 1/7 (14.3%) 1 0/12 (0%) 0 1/40 (2.5%) 1 1/21 (4.8%) 2
    Gait disturbance 3/6 (50%) 3 1/7 (14.3%) 2 1/12 (8.3%) 1 4/40 (10%) 4 1/21 (4.8%) 1
    General disorders and administration site conditions - Other, Insect Bite 0/6 (0%) 0 0/7 (0%) 0 1/12 (8.3%) 1 0/40 (0%) 0 0/21 (0%) 0
    General disorders and administration site conditions - Other, Lip Swelling 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 1/21 (4.8%) 1
    General disorders and administration site conditions - Other, Onychocryptosis 0/6 (0%) 0 0/7 (0%) 0 1/12 (8.3%) 1 0/40 (0%) 0 0/21 (0%) 0
    Injection site reaction 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Irritability 0/6 (0%) 0 0/7 (0%) 0 1/12 (8.3%) 1 0/40 (0%) 0 1/21 (4.8%) 1
    Localized edema 0/6 (0%) 0 0/7 (0%) 0 1/12 (8.3%) 1 0/40 (0%) 0 0/21 (0%) 0
    Pain 1/6 (16.7%) 1 0/7 (0%) 0 2/12 (16.7%) 2 2/40 (5%) 2 1/21 (4.8%) 1
    Pain in extremity 0/6 (0%) 0 0/7 (0%) 0 2/12 (16.7%) 3 2/40 (5%) 2 1/21 (4.8%) 1
    Immune system disorders
    Immune system disorders - Other, Right Underarm Abscess 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Infections and infestations
    Eye infection 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 1/21 (4.8%) 1
    Infections and infestations - Other, MRSA pneumonia 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Infections and infestations - Other, Tinea Cruris 0/6 (0%) 0 0/7 (0%) 0 1/12 (8.3%) 1 0/40 (0%) 0 0/21 (0%) 0
    Infections and infestations - Other, Vaginal Yeast Infection 0/6 (0%) 0 0/7 (0%) 0 1/12 (8.3%) 1 0/40 (0%) 0 0/21 (0%) 0
    Mucosal infection 1/6 (16.7%) 1 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 0/21 (0%) 0
    Pharyngitis 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Sinusitis 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 1/21 (4.8%) 1
    Upper respiratory infection 0/6 (0%) 0 0/7 (0%) 0 1/12 (8.3%) 1 0/40 (0%) 0 1/21 (4.8%) 1
    Urinary tract infection 1/6 (16.7%) 1 0/7 (0%) 0 1/12 (8.3%) 3 0/40 (0%) 0 1/21 (4.8%) 1
    Vaginal infection 0/6 (0%) 0 0/7 (0%) 0 1/12 (8.3%) 2 0/40 (0%) 0 0/21 (0%) 0
    Injury, poisoning and procedural complications
    Bruising 1/6 (16.7%) 1 1/7 (14.3%) 1 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Fall 0/6 (0%) 0 0/7 (0%) 0 1/12 (8.3%) 2 2/40 (5%) 2 0/21 (0%) 0
    Investigations
    Activated partial thromboplastin time prolonged 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 6 0/21 (0%) 0
    Alanine aminotransferase increased 2/6 (33.3%) 2 0/7 (0%) 0 1/12 (8.3%) 1 4/40 (10%) 4 1/21 (4.8%) 1
    Alkaline phosphatase increased 1/6 (16.7%) 1 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 0/21 (0%) 0
    Aspartate aminotransferase increased 1/6 (16.7%) 1 0/7 (0%) 0 0/12 (0%) 0 2/40 (5%) 2 1/21 (4.8%) 1
    Cardiac troponin I increased 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Cholesterol high 3/6 (50%) 4 3/7 (42.9%) 4 2/12 (16.7%) 2 7/40 (17.5%) 10 1/21 (4.8%) 1
    INR increased 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 2 0/21 (0%) 0
    Investigations - Other, specify 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 1/21 (4.8%) 1
    Investigations - Other, Hypertriglyceridemia 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 1/21 (4.8%) 1
    Investigations - Other, specify 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 1/21 (4.8%) 1
    Lipase increased 0/6 (0%) 0 1/7 (14.3%) 1 1/12 (8.3%) 2 2/40 (5%) 3 0/21 (0%) 0
    Lymphocyte count decreased 3/6 (50%) 6 1/7 (14.3%) 6 0/12 (0%) 0 8/40 (20%) 10 3/21 (14.3%) 8
    Lymphocyte count increased 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 2 0/21 (0%) 0
    Neutrophil count decreased 1/6 (16.7%) 1 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 2/21 (9.5%) 6
    Platelet count decreased 3/6 (50%) 4 1/7 (14.3%) 6 4/12 (33.3%) 5 9/40 (22.5%) 12 4/21 (19%) 5
    Serum amylase increased 0/6 (0%) 0 1/7 (14.3%) 2 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Weight gain 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Weight loss 1/6 (16.7%) 1 2/7 (28.6%) 2 1/12 (8.3%) 1 2/40 (5%) 2 1/21 (4.8%) 1
    White blood cell decreased 3/6 (50%) 3 1/7 (14.3%) 1 3/12 (25%) 3 4/40 (10%) 4 4/21 (19%) 9
    Metabolism and nutrition disorders
    Anorexia 2/6 (33.3%) 2 2/7 (28.6%) 2 2/12 (16.7%) 2 5/40 (12.5%) 5 4/21 (19%) 4
    Dehydration 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 3/40 (7.5%) 5 0/21 (0%) 0
    Hyperglycemia 2/6 (33.3%) 2 1/7 (14.3%) 1 4/12 (33.3%) 7 6/40 (15%) 7 0/21 (0%) 0
    Hyperkalemia 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Hypernatremia 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 2/40 (5%) 3 0/21 (0%) 0
    Hypersomnia 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Hypertriglyceridemia 3/6 (50%) 5 3/7 (42.9%) 4 5/12 (41.7%) 5 6/40 (15%) 7 1/21 (4.8%) 1
    Hypoalbuminemia 1/6 (16.7%) 1 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 1/21 (4.8%) 1
    Hypocalcemia 1/6 (16.7%) 1 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 5 1/21 (4.8%) 4
    Hypokalemia 0/6 (0%) 0 0/7 (0%) 0 1/12 (8.3%) 2 3/40 (7.5%) 3 0/21 (0%) 0
    Hypomagnesemia 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Hyponatremia 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 3/40 (7.5%) 3 1/21 (4.8%) 1
    Hypophosphatemia 0/6 (0%) 0 2/7 (28.6%) 2 0/12 (0%) 0 2/40 (5%) 4 0/21 (0%) 0
    Metabolism and nutrition disorders - Other, appetite decrease 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 1/21 (4.8%) 1
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/6 (0%) 0 0/7 (0%) 0 2/12 (16.7%) 2 0/40 (0%) 0 0/21 (0%) 0
    Back pain 1/6 (16.7%) 1 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 2/21 (9.5%) 2
    Chest wall pain 1/6 (16.7%) 1 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 0/21 (0%) 0
    Generalized muscle weakness 1/6 (16.7%) 1 0/7 (0%) 0 0/12 (0%) 0 4/40 (10%) 4 2/21 (9.5%) 2
    Muscle weakness left-sided 2/6 (33.3%) 2 0/7 (0%) 0 1/12 (8.3%) 1 3/40 (7.5%) 3 1/21 (4.8%) 1
    Muscle weakness right-sided 1/6 (16.7%) 2 0/7 (0%) 0 1/12 (8.3%) 1 5/40 (12.5%) 5 1/21 (4.8%) 2
    Muscle weakness upper limb 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Musculoskeletal and connective tissue disorder - Other, Left Hip Pain 0/6 (0%) 0 0/7 (0%) 0 1/12 (8.3%) 1 0/40 (0%) 0 0/21 (0%) 0
    Musculoskeletal and connective tissue disorder - Other, specify 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Myalgia 0/6 (0%) 0 0/7 (0%) 0 1/12 (8.3%) 1 2/40 (5%) 2 2/21 (9.5%) 2
    Non-cardiac chest pain 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Osteoporosis 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, Left wrist ganglio cyst 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 1/21 (4.8%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 2/40 (5%) 2 0/21 (0%) 0
    Nervous system disorders
    Ataxia 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 1/21 (4.8%) 1
    Cognitive disturbance 2/6 (33.3%) 2 0/7 (0%) 0 1/12 (8.3%) 1 3/40 (7.5%) 3 1/21 (4.8%) 1
    Concentration impairment 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 2/40 (5%) 2 0/21 (0%) 0
    Depressed level of consciousness 1/6 (16.7%) 1 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 0/21 (0%) 0
    Dizziness 1/6 (16.7%) 3 1/7 (14.3%) 1 3/12 (25%) 3 3/40 (7.5%) 3 3/21 (14.3%) 3
    Dysarthria 0/6 (0%) 0 0/7 (0%) 0 1/12 (8.3%) 1 2/40 (5%) 2 0/21 (0%) 0
    Dysgeusia 0/6 (0%) 0 0/7 (0%) 0 1/12 (8.3%) 1 0/40 (0%) 0 0/21 (0%) 0
    Dysphasia 2/6 (33.3%) 3 0/7 (0%) 0 3/12 (25%) 3 1/40 (2.5%) 1 1/21 (4.8%) 1
    Facial muscle weakness 0/6 (0%) 0 1/7 (14.3%) 1 0/12 (0%) 0 0/40 (0%) 0 1/21 (4.8%) 2
    Facial nerve disorder 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Headache 1/6 (16.7%) 1 2/7 (28.6%) 2 5/12 (41.7%) 5 9/40 (22.5%) 11 7/21 (33.3%) 11
    Lethargy 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 1/21 (4.8%) 1
    Memory impairment 2/6 (33.3%) 2 1/7 (14.3%) 1 2/12 (16.7%) 3 0/40 (0%) 0 2/21 (9.5%) 4
    Nervous system disorders - Other, Left Sixth Cranial Nerve Palsy 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Nervous system disorders - Other, Migraine headache 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Nervous system disorders - Other, Pronator Drift Left Upper Extremity 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 1/21 (4.8%) 1
    Nervous system disorders - Other, Unsteady Gait 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 1/21 (4.8%) 1
    Nervous system disorders - Other, aphasia 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Nervous system disorders - Other, cerebral edema 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Nervous system disorders - Other, right-sided numbness 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 1/21 (4.8%) 1
    Paresthesia 1/6 (16.7%) 1 0/7 (0%) 0 0/12 (0%) 0 3/40 (7.5%) 5 0/21 (0%) 0
    Peripheral sensory neuropathy 2/6 (33.3%) 2 0/7 (0%) 0 1/12 (8.3%) 1 0/40 (0%) 0 1/21 (4.8%) 1
    Pyramidal tract syndrome 0/6 (0%) 0 2/7 (28.6%) 2 0/12 (0%) 0 0/40 (0%) 0 0/21 (0%) 0
    Seizure 3/6 (50%) 8 2/7 (28.6%) 3 1/12 (8.3%) 1 1/40 (2.5%) 1 0/21 (0%) 0
    Somnolence 0/6 (0%) 0 1/7 (14.3%) 1 0/12 (0%) 0 1/40 (2.5%) 1 1/21 (4.8%) 1
    Tremor 1/6 (16.7%) 1 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 0/21 (0%) 0
    Psychiatric disorders
    Agitation 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 3/21 (14.3%) 3
    Anxiety 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 2/21 (9.5%) 2
    Confusion 0/6 (0%) 0 0/7 (0%) 0 2/12 (16.7%) 2 7/40 (17.5%) 8 3/21 (14.3%) 4
    Delirium 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Depression 1/6 (16.7%) 1 0/7 (0%) 0 1/12 (8.3%) 1 4/40 (10%) 4 0/21 (0%) 0
    Insomnia 1/6 (16.7%) 1 2/7 (28.6%) 2 2/12 (16.7%) 2 1/40 (2.5%) 1 2/21 (9.5%) 2
    Personality change 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 1/21 (4.8%) 1
    Psychiatric disorders - Other, Dysphoric Mood 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 1/21 (4.8%) 1
    Psychiatric disorders - Other, Mood Alteration - Irritability 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 1/21 (4.8%) 1
    Renal and urinary disorders
    Proteinuria 0/6 (0%) 0 0/7 (0%) 0 1/12 (8.3%) 1 3/40 (7.5%) 3 2/21 (9.5%) 2
    Urinary frequency 1/6 (16.7%) 1 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 0/21 (0%) 0
    Urinary incontinence 2/6 (33.3%) 2 0/7 (0%) 0 0/12 (0%) 0 2/40 (5%) 2 0/21 (0%) 0
    Urinary tract pain 0/6 (0%) 0 0/7 (0%) 0 1/12 (8.3%) 1 0/40 (0%) 0 0/21 (0%) 0
    Urinary urgency 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Allergic rhinitis 0/6 (0%) 0 0/7 (0%) 0 1/12 (8.3%) 1 2/40 (5%) 2 0/21 (0%) 0
    Atelectasis 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Bronchospasm 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 1/21 (4.8%) 1
    Cough 2/6 (33.3%) 2 0/7 (0%) 0 0/12 (0%) 0 3/40 (7.5%) 3 0/21 (0%) 0
    Dyspnea 1/6 (16.7%) 1 1/7 (14.3%) 1 0/12 (0%) 0 3/40 (7.5%) 5 2/21 (9.5%) 2
    Epistaxis 0/6 (0%) 0 0/7 (0%) 0 1/12 (8.3%) 1 3/40 (7.5%) 3 1/21 (4.8%) 2
    Hiccups 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 1/21 (4.8%) 1
    Hoarseness 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Nasal congestion 1/6 (16.7%) 1 1/7 (14.3%) 1 0/12 (0%) 0 0/40 (0%) 0 1/21 (4.8%) 1
    Pneumonitis 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Respiratory, thoracic and mediastinal disorders - Other, Sinus Congestion 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 1/21 (4.8%) 1
    Respiratory, thoracic and mediastinal disorders - Other, acute respiratory failure 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Respiratory, thoracic and mediastinal disorders - Other, pneumonia 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 1/21 (4.8%) 1
    Respiratory, thoracic and mediastinal disorders - Other, specify 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 1/21 (4.8%) 1
    Sneezing 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 1/21 (4.8%) 1
    Sore throat 1/6 (16.7%) 1 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Voice alteration 0/6 (0%) 0 0/7 (0%) 0 1/12 (8.3%) 1 0/40 (0%) 0 0/21 (0%) 0
    Wheezing 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 2/40 (5%) 2 0/21 (0%) 0
    Skin and subcutaneous tissue disorders
    Alopecia 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 2/40 (5%) 2 0/21 (0%) 0
    Dry skin 0/6 (0%) 0 1/7 (14.3%) 1 2/12 (16.7%) 2 2/40 (5%) 2 2/21 (9.5%) 2
    Erythema multiforme 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Palmar-plantar erythrodysesthesia syndrome 0/6 (0%) 0 1/7 (14.3%) 2 1/12 (8.3%) 3 3/40 (7.5%) 7 2/21 (9.5%) 4
    Pruritus 0/6 (0%) 0 1/7 (14.3%) 1 1/12 (8.3%) 1 1/40 (2.5%) 1 4/21 (19%) 4
    Rash acneiform 1/6 (16.7%) 1 1/7 (14.3%) 1 1/12 (8.3%) 2 2/40 (5%) 2 3/21 (14.3%) 3
    Rash maculo-papular 0/6 (0%) 0 0/7 (0%) 0 1/12 (8.3%) 1 5/40 (12.5%) 7 6/21 (28.6%) 11
    Scalp pain 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 1/21 (4.8%) 1
    Skin and subcutaneous tissue disorders - Other, Left ear lesion 0/6 (0%) 0 1/7 (14.3%) 1 0/12 (0%) 0 0/40 (0%) 0 0/21 (0%) 0
    Skin and subcutaneous tissue disorders - Other, Rash, perianal 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Skin and subcutaneous tissue disorders - Other, Rash; erythema annulare centrifugum 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 1/21 (4.8%) 2
    Skin and subcutaneous tissue disorders - Other, Right chest abrasion 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Skin and subcutaneous tissue disorders - Other, Skin sloughing 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 1/21 (4.8%) 1
    Skin and subcutaneous tissue disorders - Other, desquamation 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Skin and subcutaneous tissue disorders - Other, dry scalp 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 1/21 (4.8%) 1
    Skin and subcutaneous tissue disorders - Other, rash 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Skin and subcutaneous tissue disorders - Other, seborrheic Dermatitis 0/6 (0%) 0 0/7 (0%) 0 1/12 (8.3%) 1 0/40 (0%) 0 0/21 (0%) 0
    Skin and subcutaneous tissue disorders - Other, under breasts, beginning on rt shoulder 0/6 (0%) 0 0/7 (0%) 0 1/12 (8.3%) 1 0/40 (0%) 0 0/21 (0%) 0
    Skin and subcutaneous tissue disorders - Other, under breasts, groin area 0/6 (0%) 0 0/7 (0%) 0 1/12 (8.3%) 1 0/40 (0%) 0 0/21 (0%) 0
    Skin and subcutaneous tissue disorders - Other, specify 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 1/40 (2.5%) 1 0/21 (0%) 0
    Vascular disorders
    Hot flashes 0/6 (0%) 0 0/7 (0%) 0 0/12 (0%) 0 0/40 (0%) 0 1/21 (4.8%) 1
    Hypertension 3/6 (50%) 4 1/7 (14.3%) 1 2/12 (16.7%) 4 12/40 (30%) 18 2/21 (9.5%) 5
    Hypotension 0/6 (0%) 0 0/7 (0%) 0 1/12 (8.3%) 1 1/40 (2.5%) 1 0/21 (0%) 0
    Thromboembolic event 0/6 (0%) 0 0/7 (0%) 0 1/12 (8.3%) 1 2/40 (5%) 2 0/21 (0%) 0

    Limitations/Caveats

    This study specifically addressed the question of whether the experimental regimen had benefit in the 2 important categories of recurrent glioblastoma: those who were bevacizumab treatment naive and those participants who had failed prior bevacizumab. Different efficacy metrics were used so that the "prior bevacizumab treatment arm" passed the Stage 1 of the 2-stage design, whereas the "bevacizumab naïve" did not. This is an important concept for future studies in recurrent glioblastoma.

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Dr. Mark R. Gilbert
    Organization National Cancer Institute
    Phone 240-760-6023
    Email mark.gilbert@nih.gov
    Responsible Party:
    Mark Gilbert, M.D., Principal Investigator, National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT01434602
    Other Study ID Numbers:
    • 160011
    • 16-C-0011
    First Posted:
    Sep 15, 2011
    Last Update Posted:
    Jun 1, 2022
    Last Verified:
    May 1, 2022