Anaplastic Glioma, Brain Tumor, Glioblastoma
Conditions
Keywords
Chemotherapy, Brain Tumor, Glioblastoma, Anaplastic Glioma
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.
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).
Interventions
DRUGeverolimus
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.
DRUGsorafenib
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.
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* INCLUSION CRITERIA: General Inclusion Criteria 1. Patients with histologically proven recurrent intracranial malignant glioma will be eligible for the phase I/II component of this protocol. Malignant glioma includes glioblastoma (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. 6. Patients must have adequate bone marrow function (white blood cell (WBC) \>= 3.0 x 10\^9/L, absolute neutrophil count (ANC) \>= 1.5 X 10\^9/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. 7. 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. 8. Patients having undergone recent resection of recurrent or progressive tumor will be eligible as long as all of the following conditions apply: * They have recovered from the effects of surgery and be \> 3 weeks from surgery. * Residual disease following resection of recurrent malignant glioma is not mandated for eligibility into the study. To best assess the extent of residual disease post-operatively, a CT/ MRI should be done no later than 96 hours in the immediate post-operative period or at least 4 weeks post-operatively, within 14 days prior to registration. If the 96-hour scan is more than 14 days before registration, the scan needs to be repeated. If the steroid dose is increased between the date of imaging and registration, a new baseline MRI/CT is required on a stable steroid dosage for at least 5 days. 9. Patients must have failed prior radiation therapy and must have an interval of greater than or equal to 12 weeks from the completion of radiation therapy to registration; except if patients underwent surgery within 12 weeks and pathology is consistent with recurrent tumor. 10. Patients with prior therapy that included interstitial brachytherapy or stereotactic radiosurgery must have confirmation of true progressive disease rather than radiation necrosis based upon either positron emission tomography (PET) or Thallium scanning, magnetic resonance (MR) spectroscopy or surgical/pathological documentation of disease. 11. 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. 12. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Countries
United States
Participant flow
Pre-assignment details
This study started at MD Anderson under Dr. Gilbert in 2012 and transferred to the National Cancer Institute (NCI).
Participants by arm
| Arm | Count |
|---|---|
| Phase I Dose Level I Sorafenib 400mg Twice Daily + Everolimus 5mg Daily 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. | 6 |
| Phase I Dose Level -1 Sorafenib 400mg Twice Daily, 7 Days on, 7 Off + Everolimus 5mg Daily 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. | 7 |
| Phase 2 Group A Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on 7 Off + Everolimus 5mg Daily 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. | 12 |
| Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily 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. | 40 |
| Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily 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. | 21 |
| Total | 86 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Phase I Dose Escalation | Participant was underdosed (i.e., was taking incorrect dose at home)/Not evaluable | 0 | 1 | 0 | 0 | 0 |
| Phase II Recommended Phase 2 Dose | Active progression before start of treatment | 0 | 0 | 0 | 1 | 0 |
| Phase II Recommended Phase 2 Dose | Bilateral large pulmonary embolisms in the right and left main pulmonary arteries | 0 | 0 | 0 | 1 | 0 |
| Phase II Recommended Phase 2 Dose | Decline in patient condition/health/ADL's | 0 | 0 | 0 | 1 | 0 |
| Phase II Recommended Phase 2 Dose | Physician Decision | 0 | 0 | 0 | 1 | 1 |
| Phase II Recommended Phase 2 Dose | Refused further treatment | 0 | 0 | 0 | 2 | 0 |
| Phase II Recommended Phase 2 Dose | Started new therapy | 0 | 0 | 0 | 1 | 0 |
| Phase II Recommended Phase 2 Dose | Switched to alternative treatment | 0 | 0 | 0 | 1 | 0 |
| Phase II Recommended Phase 2 Dose | Transfer of care | 0 | 0 | 0 | 1 | 0 |
| Phase II Recommended Phase 2 Dose | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | 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 I Dose Level I Sorafenib 400mg Twice Daily + Everolimus 5mg Daily | Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 2 Participants | 6 Participants | 0 Participants | 2 Participants | 12 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 10 Participants | 34 Participants | 6 Participants | 19 Participants | 74 Participants |
| Age, Continuous | 48.65 years STANDARD_DEVIATION 19.32 | 51.34 years STANDARD_DEVIATION 12.13 | 51.74 years STANDARD_DEVIATION 14.34 | 46.90 years STANDARD_DEVIATION 12.8 | 44.09 years STANDARD_DEVIATION 14.43 | 49.23 years STANDARD_DEVIATION 14.46 |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Hispanic | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Missing Ethnicity | 7 Participants | 12 Participants | 27 Participants | 6 Participants | 19 Participants | 71 Participants |
| Race/Ethnicity, Customized Not Hispanic | 0 Participants | 0 Participants | 13 Participants | 0 Participants | 0 Participants | 13 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 3 Participants | 6 Participants |
| Race/Ethnicity, Customized White | 6 Participants | 10 Participants | 37 Participants | 5 Participants | 18 Participants | 76 Participants |
| Region of Enrollment United States | 7 participants | 12 participants | 40 participants | 6 participants | 21 participants | 86 participants |
| Sex: Female, Male Female | 1 Participants | 5 Participants | 16 Participants | 1 Participants | 8 Participants | 31 Participants |
| Sex: Female, Male Male | 6 Participants | 7 Participants | 24 Participants | 5 Participants | 13 Participants | 55 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 6 | 6 / 7 | 9 / 12 | 19 / 40 | 11 / 21 |
| other Total, other adverse events | 6 / 6 | 7 / 7 | 12 / 12 | 38 / 40 | 20 / 21 |
| serious Total, serious adverse events | 3 / 6 | 2 / 7 | 3 / 12 | 12 / 40 | 2 / 21 |
Outcome results
Primary
Maximum Tolerated Dose of Everolimus for Participants With Recurrent Malignant Gliomas
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)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants | Maximum Tolerated Dose of Everolimus for Participants With Recurrent Malignant Gliomas | 5 mg |
Primary
Maximum Tolerated Dose of Sorafenib for Participants With Recurrent Malignant Gliomas
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)
Population: The dosing schedule for the MTD is 400mg twice a day (BID) 7 days on/7 days off.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants | Maximum Tolerated Dose of Sorafenib for Participants With Recurrent Malignant Gliomas | 400 mg |
Primary
Percentage of Participants Who Survived Without Disease Progression at 3 Months After Treatment for Glioblastoma Participants With Prior Bevacizumab Exposure
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants | Percentage of Participants Who Survived Without Disease Progression at 3 Months After Treatment for Glioblastoma Participants With Prior Bevacizumab Exposure | 12.9 Percentage of participants |
Primary
Percentage of Participants Who Survived Without Disease Progression at 6 Months After Treatment for Anaplastic Glioma (AG) Participants With no Prior Bevacizumab Exposure
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants | Percentage of Participants Who Survived Without Disease Progression at 6 Months After Treatment for Anaplastic Glioma (AG) Participants With no Prior Bevacizumab Exposure | 26.7 Percentage of participants |
Primary
Percentage of Participants Who Survived Without Disease Progression at 6 Months After Treatment for Glioblastoma Participants With no Prior Bevacizumab Exposure
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants | Percentage of Participants Who Survived Without Disease Progression at 6 Months After Treatment for Glioblastoma Participants With no Prior Bevacizumab Exposure | 8.33 Percentage of participants |
Secondary
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
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Participants | 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 | 7.75 Months |
| Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | 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 | 4.77 Months |
| Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | 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 | 11.97 Months |
Secondary
Median Amount of Time Participants Survives Without Disease Progression for Groups A, B, and C Treated With Everolimus and Sorafenib
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Participants | Median Amount of Time Participants Survives Without Disease Progression for Groups A, B, and C Treated With Everolimus and Sorafenib | 1.92 Months |
| Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Median Amount of Time Participants Survives Without Disease Progression for Groups A, B, and C Treated With Everolimus and Sorafenib | 1.17 Months |
| Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Median Amount of Time Participants Survives Without Disease Progression for Groups A, B, and C Treated With Everolimus and Sorafenib | 1.87 Months |
Secondary
Objective Response for Participants With Recurrent Malignant Gliomas (Group A, Group B, and Group C) Treated With Everolimus and Sorafenib
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).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| All Participants | Objective Response for Participants With Recurrent Malignant Gliomas (Group A, Group B, and Group C) Treated With Everolimus and Sorafenib | Stable Disease | 8 Participants |
| All Participants | Objective Response for Participants With Recurrent Malignant Gliomas (Group A, Group B, and Group C) Treated With Everolimus and Sorafenib | Progressive Disease | 4 Participants |
| All Participants | Objective Response for Participants With Recurrent Malignant Gliomas (Group A, Group B, and Group C) Treated With Everolimus and Sorafenib | Complete Response | 0 Participants |
| All Participants | Objective Response for Participants With Recurrent Malignant Gliomas (Group A, Group B, and Group C) Treated With Everolimus and Sorafenib | Partial Response | 0 Participants |
| All Participants | Objective Response for Participants With Recurrent Malignant Gliomas (Group A, Group B, and Group C) Treated With Everolimus and Sorafenib | Not Evaluable | 0 Participants |
| Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Objective Response for Participants With Recurrent Malignant Gliomas (Group A, Group B, and Group C) Treated With Everolimus and Sorafenib | Progressive Disease | 17 Participants |
| Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Objective Response for Participants With Recurrent Malignant Gliomas (Group A, Group B, and Group C) Treated With Everolimus and Sorafenib | Complete Response | 0 Participants |
| Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Objective Response for Participants With Recurrent Malignant Gliomas (Group A, Group B, and Group C) Treated With Everolimus and Sorafenib | Partial Response | 0 Participants |
| Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Objective Response for Participants With Recurrent Malignant Gliomas (Group A, Group B, and Group C) Treated With Everolimus and Sorafenib | Stable Disease | 16 Participants |
| Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Objective Response for Participants With Recurrent Malignant Gliomas (Group A, Group B, and Group C) Treated With Everolimus and Sorafenib | Not Evaluable | 7 Participants |
| Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Objective Response for Participants With Recurrent Malignant Gliomas (Group A, Group B, and Group C) Treated With Everolimus and Sorafenib | Not Evaluable | 2 Participants |
| Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Objective Response for Participants With Recurrent Malignant Gliomas (Group A, Group B, and Group C) Treated With Everolimus and Sorafenib | Stable Disease | 10 Participants |
| Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Objective Response for Participants With Recurrent Malignant Gliomas (Group A, Group B, and Group C) Treated With Everolimus and Sorafenib | Complete Response | 0 Participants |
| Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Objective Response for Participants With Recurrent Malignant Gliomas (Group A, Group B, and Group C) Treated With Everolimus and Sorafenib | Progressive Disease | 7 Participants |
| Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Objective Response for Participants With Recurrent Malignant Gliomas (Group A, Group B, and Group C) Treated With Everolimus and Sorafenib | Partial Response | 2 Participants |
Secondary
Rate of Participants Symptom Interference With Function
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)
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Participants | Rate of Participants Symptom Interference With Function | Cycle 2 | 5.0 score on a scale | Standard Deviation 0.1 |
| All Participants | Rate of Participants Symptom Interference With Function | Cycle 1 | 4.2 score on a scale | Standard Deviation 3.7 |
| All Participants | Rate of Participants Symptom Interference With Function | Baseline | 5.0 score on a scale | Standard Deviation 2.7 |
| Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Interference With Function | Cycle 2 | 2.8 score on a scale | Standard Deviation 3.7 |
| Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Interference With Function | Baseline | 1.5 score on a scale | Standard Deviation 1.6 |
| Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Interference With Function | Cycle 1 | 2.3 score on a scale | Standard Deviation 2.4 |
| Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Interference With Function | Cycle 4 | 0.3 score on a scale | Standard Deviation 0 |
| Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Interference With Function | Cycle 1 | 3.3 score on a scale | Standard Deviation 2.9 |
| Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Interference With Function | Cycle 4 | 2.8 score on a scale | Standard Deviation 3.1 |
| Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Interference With Function | Baseline | 2.3 score on a scale | Standard Deviation 2.3 |
| Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Interference With Function | Cycle 2 | 4.3 score on a scale | Standard Deviation 3 |
| Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Interference With Function | Baseline | 3.4 score on a scale | Standard Deviation 2.7 |
| Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Interference With Function | Cycle 2 | 6.4 score on a scale | Standard Deviation 2.2 |
| Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Interference With Function | Cycle 4 | 4.2 score on a scale | Standard Deviation 3.3 |
| Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Interference With Function | Cycle 1 | 4.1 score on a scale | Standard Deviation 2.8 |
| Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Interference With Function | Cycle 10 | 1.6 score on a scale | Standard Deviation 2.9 |
| Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Interference With Function | Cycle 1 | 2.5 score on a scale | Standard Deviation 2.3 |
| Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Interference With Function | Cycle 2 | 1.8 score on a scale | Standard Deviation 2.4 |
| Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Interference With Function | Cycle 12 | 1.2 score on a scale | Standard Deviation 1.6 |
| Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Interference With Function | Cycle 4 | 3.3 score on a scale | Standard Deviation 3.2 |
| Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Interference With Function | Cycle 6 | 2.0 score on a scale | Standard Deviation 2.8 |
| Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Interference With Function | Cycle 8 | 2.4 score on a scale | Standard Deviation 3.2 |
| Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Interference With Function | Baseline | 2.1 score on a scale | Standard Deviation 2.6 |
Secondary
Rate of Participants Symptom Severity
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)
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Participants | Rate of Participants Symptom Severity | Cycle 1 | 3.8 score on a scale | Standard Deviation 1 |
| All Participants | Rate of Participants Symptom Severity | Baseline | 3.9 score on a scale | Standard Deviation 1.4 |
| All Participants | Rate of Participants Symptom Severity | Cycle 2 | 3.5 score on a scale | Standard Deviation 1.3 |
| Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Severity | Cycle 4 | 0.4 score on a scale | Standard Deviation 0 |
| Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Severity | Cycle 2 | 1.9 score on a scale | Standard Deviation 1.4 |
| Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Severity | Cycle 1 | 1.6 score on a scale | Standard Deviation 1.5 |
| Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Severity | Baseline | 1.3 score on a scale | Standard Deviation 0.9 |
| Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Severity | Cycle 2 | 2.3 score on a scale | Standard Deviation 1.7 |
| Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Severity | Cycle 1 | 2.2 score on a scale | Standard Deviation 1.8 |
| Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Severity | Cycle 4 | 1.3 score on a scale | Standard Deviation 0.7 |
| Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Severity | Baseline | 1.5 score on a scale | Standard Deviation 1.2 |
| Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Severity | Cycle 4 | 3.5 score on a scale | Standard Deviation 2.1 |
| Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Severity | Baseline | 2.0 score on a scale | Standard Deviation 1.2 |
| Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Severity | Cycle 1 | 2.5 score on a scale | Standard Deviation 1.5 |
| Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Severity | Cycle 2 | 3.4 score on a scale | Standard Deviation 1.4 |
| Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Severity | Cycle 2 | 1.5 score on a scale | Standard Deviation 1.3 |
| Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Severity | Cycle 1 | 1.8 score on a scale | Standard Deviation 1.2 |
| Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Severity | Baseline | 1.3 score on a scale | Standard Deviation 0.9 |
| Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Severity | Cycle 4 | 1.8 score on a scale | Standard Deviation 1.2 |
| Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Severity | Cycle 6 | 1.4 score on a scale | Standard Deviation 1.4 |
| Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Severity | Cycle 8 | 1.8 score on a scale | Standard Deviation 1.5 |
| Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Severity | Cycle 10 | 1.5 score on a scale | Standard Deviation 1.2 |
| Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Rate of Participants Symptom Severity | Cycle 12 | 1.4 score on a scale | Standard Deviation 1 |
Other Pre-specified
Number of Participants With a Dose-limiting Toxicity (DLT)
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)
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Participants | Number of Participants With a Dose-limiting Toxicity (DLT) | 3 Participants |
| Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Number of Participants With a Dose-limiting Toxicity (DLT) | 1 Participants |
Other Pre-specified
Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)
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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Participants | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0) | 6 Participants |
| Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0) | 7 Participants |
| Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0) | 12 Participants |
| Phase 2 Group B Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0) | 38 Participants |
| Phase 2 Group C Dose Level -1 Sorafenib 400mg Twice Daily 7 Days on, 7 Off + Everolimus 5mg Daily | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0) | 20 Participants |