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

NCT01434602 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 16001116-C-0011
• Study Type: interventional
• Target: 86
• Locations: 1 country
• Sites: 1

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.

Conditions

Brain Tumor; Glioblastoma; Anaplastic Glioma

Keywords

Chemotherapy; Brain Tumor; Glioblastoma; Anaplastic Glioma

Outcome Measures

Primary Outcomes (5)

• 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.

  First 28 days of treatment only (cycle 1)

• 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.

  First 28 days of treatment only (cycle 1)

• 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.

  6 months

• 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.

  3 months

• 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.

  6 months

Secondary Outcomes (5)

• Median Amount of Time Participants Survives Without Disease Progression for Groups A, B, and C Treated With Everolimus and Sorafenib

  Up to 6 months

• 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).

• 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

• 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)

• 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)

Other Outcomes (2)

• Number of Participants With a Dose-limiting Toxicity (DLT)

  First 28 days of treatment only (cycle 1)

• 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.

Study Arms (2)

1/Phase I

EXPERIMENTAL

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

Drug: everolimus; Drug: sorafenib

2/Phase II

EXPERIMENTAL

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; Drug: sorafenib

Interventions

everolimus DRUG

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.

Also known as: Zortress

1/Phase I; 2/Phase II

sorafenib DRUG

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.

Also known as: Nexavar

1/Phase I; 2/Phase II

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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).
• Patients must be greater than or equal to 18 years old.
• Patients must have 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

You may not qualify if:

• 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
• 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.
• Patients has an active infection or serious intercurrent medical illness.
• Patients has any disease that will obscure toxicity or dangerously alter drug metabolism.
• 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.
• 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.
• Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.
• Uncontrolled hypertension defined as systolic blood pressure \> 140 mmHg or diastolic pressure \> 90 mmHg, despite optimal medical management.
• Known human immunodeficiency virus (HIV) infection or chronic or acute Hepatitis B or C. 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
• 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.
• 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.
• Any other hemorrhage/bleeding event greater than or equal to CTCAE Grade 3 within 4 weeks of first dose of study drug.
• Serious non-healing wound, non-healing ulcer, or bone fracture.
• Evidence or history of bleeding diathesis or coagulopathy
• Major surgery, open biopsy or significant traumatic injury within 4 weeks of first study drug.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Brain Neoplasms; Glioblastoma

Interventions

Everolimus; Sorafenib

Condition Hierarchy (Ancestors)

Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals; Phenylurea Compounds; Urea; Amides; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring

Limitations and 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.

Results Point of Contact

• Title: Dr. Mark R. Gilbert
• Organization: National Cancer Institute

mark.gilbert@nih.gov

240-760-6023

Study Officials

• Mark R Gilbert, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: September 13, 2011
• First Posted: September 15, 2011
• Study Start: October 2, 2012
• Primary Completion: October 19, 2020
• Study Completion: July 13, 2021
• Last Updated: June 1, 2022
• Results First Posted: February 1, 2022

Record last verified: 2022-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)