Sorafenib Tosylate and Temsirolimus in Treating Patients With Recurrent Glioblastoma

Adult Glioblastoma Clinical Trial

Official title:

A Phase I/II Trial of Sorafenib and CCI-779 in Patients With Recurrent Glioblastoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00329719
• Other study ID #: NCI-2009-00652
• Secondary ID: NCI-2009-00652CD
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: March 24, 2006
• Est. completion date: February 2, 2013

Study information

• Verified date: September 2018
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase I/II trial studies the side effects and best dose of temsirolimus when given together with sorafenib tosylate and to see how well they work in treating patients with glioblastoma that has come back. Sorafenib tosylate may stop the growth of tumor cells by blocking blood flow to the tumor. Drugs used in chemotherapy, such as temsirolimus, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Sorafenib tosylate and temsirolimus may also stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving sorafenib tosylate with temsirolimus may kill more tumor cells.

Description:

Primary Objective -

Phase I (closed to accrual as of 01/11/2008):

To establish a maximum tolerable dose of temsirolimus in combination with sorafenib in patients with recurrent glioblastoma not receiving enzyme-inducing anticonvulsants (EIACs).

Phase II (closed to accrual as of 12/07/2012):

To assess the efficacy of temsirolimus and sorafenib in the treatment of recurrent glioblastoma in non-EIAC patients as measured by progression-free survival status at six months (PFS6).

Secondary Objectives -

Phase I (closed to accrual as of 01/11/2008):

I. To define the safety profile of temsirolimus and sorafenib in non-EIAC patients.

II. To assess the evidence of antitumor activity.

Phase II (closed to accrual as of 12/07/2012):

I. To assess the safety and toxicities of temsirolimus and sorafenib in the above-noted patient populations.

Outline: This is a multicenter, phase I, dose-escalation study followed by a phase II study.

Phase I (Arm A): Patients receive sorafenib orally (PO) twice daily (BID) on days 1-28 and temsirolimus intravenously (IV) over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of temsirolimus until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Phase II: Patients are assigned to 1 of 3 treatment groups.

Group 1 (Arm B): Patients receive sorafenib and temsirolimus as in phase I at the MTD. (patients not undergoing surgery)

Group 2 (Arm C): Patients receive sorafenib PO BID on days 1-8 (15 doses) and temsirolimus IV at the MTD on day 1. Patients undergo surgery on day 8. (patients undergoing surgery) After recovering from surgery, patients receive sorafenib and temsirolimus as in phase I at the MTD.

Group 3 (Arm D): Patient receive sorafenib and temsirolimus as in phase I at the MTD. (patients who have received prior anti-vascular endothelial growth factor [VEGF] therapy and are not undergoing surgery)

Biopsy or resected tissue and blood are collected prior to treatment (usually at diagnosis) and analyzed for biomarkers. After completion of study treatment, patients are followed every 6 months for 5 years and then annually thereafter.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 115
• Est. completion date: February 2, 2013
• Est. primary completion date: February 1, 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Central pathology review submission; this review is mandatory prior to registration to confirm eligibility; it should be initiated as soon after surgery as possible

• =< 2 prior systemic chemotherapy regimens

• Histological confirmation of a grade 4 astrocytoma (glioblastoma) or gliosarcoma, at primary diagnosis or recurrence by World Health Organization (WHO) criteria; central pathology review is mandatory prior to study entry to confirm eligibility

• Evidence of tumor progression by magnetic resonance imaging (MRI) or computed tomography (CT) scan following radiation therapy (RT) or following the most recent anti-tumor therapy

• Bidimensionally measurable or evaluable disease by MRI or CT scan

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2

• >= 12 weeks since the completion of RT

• Fixed or decreasing dose of corticosteroids (or no corticosteroids) >= 1 week prior to registration

• >= 1 week from minor surgery other than venous line placement and > 3 weeks from major surgery (except for patients undergoing tumor tissue acquisition)

• >= 4 weeks since prior cytotoxic chemotherapy (>= 6 weeks for nitrosoureas)

• >= 2 weeks from cytostatic chemotherapy such as tamoxifen, cis-retinoic acid, or thalidomide (address questions regarding such agents to study chair)

• White blood cells (WBC) >= 3,000/mm^3

• Absolute neutrophil count (ANC) >= 1,500/mm^3

• Platelet count >= 100,000/mm^3

• Hemoglobin (Hgb) >= 10 gm/dL

• Total bilirubin =< 1.5 x upper limit of normal (ULN)

• Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 2.5 x ULN

• Creatinine =< 2.0 x ULN

• Serum cholesterol =< 350 mg/dL

• Serum triglycerides =< 400 mg/dL

• Willingness to provide the biologic specimens as required by the protocol; (please note that the willingness to participate pertains only to the patient and does not factor in the institution?s ability to participate in any part of the translational component)

Exclusion Criteria:

• Prior intratumoral chemotherapy (e.g., Gliadel or IL13-PE38QQR), stereotactic radiosurgery, or interstitial brachytherapy unless there is a separate lesion on MRI which is not part of the previous treatment field or there is proof of recurrent disease based on biopsy, MRI spectroscopy, or positron emission tomography (PET) scan

• Prior CCI-779, sorafenib, or other agents specifically targeting mammalian target of rapamycin (mTOR) or raf; patients receiving prior agents inhibiting VEGF or VEGF receptor (R) (prior anti-VEGF group) are eligible but: 1) must be at least four weeks from last treatment with the agent(s); and 2) must have recovered from any clinically relevant toxicities attributable to this agent(s)

• Evidence of bleeding diathesis or coagulopathy

• Note: Patients on prophylactic anticoagulation therapy (e.g., low-dose warfarin) are eligible provided their coagulation parameter levels are as follows: prothrombin time (International Normalized Ratio [INR] of prothrombin time) < 1.1 x institutional upper limit of normal

• Note: Patients on full-dose anticoagulants (e.g., warfarin) are eligible provided that both of the following criteria are met: a) the patient has an in-range INR (usually between 2 and 3) on a stable dose of oral anticoagulant or on a stable dose of low molecular weight heparin, and b) the patient has no active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices)

• International normalized ration (INR) > 1.5 (unless the patient is on full-dose warfarin)

• Receiving enzyme-inducing antiepileptic drugs (EIAEDs; e.g., phenytoin, fosphenytoin, carbamazepine, phenobarbital, or primidone) or any other potent cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inducer, such as rifampin or St. John?s wort

• Any condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease) that impairs their ability to swallow pills

• Hypertension with systolic blood pressure of > 140 mmHg or diastolic pressure > 90 mmHg; however, patients with well-controlled hypertension are eligible

• Uncontrolled infection

• Pregnant women

• Nursing women

• Men or women of childbearing potential who are unwilling to employ adequate contraception

• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately

• Known hypersensitivity to any of the components of CCI-779 or sorafenib

• Other active malignancy

• Uncontrolled intercurrent illness, including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, psychiatric illness/social situation that would preclude study compliance with study requirements

• Immunocompromised patients (other than that related to the use of corticosteroids) including patients known to be human immunodeficiency virus (HIV) positive; HIV-positive patients on combination antiretroviral therapy are ineligible

• Receiving any investigational agents other than CCI-779 and sorafenib

• Significant intratumoral, intracerebral, or subarachnoid hemorrhage on baseline MRI or CT, or other history of significant intratumoral, intracerebral, or subarachnoid hemorrhage

Related Conditions & MeSH terms

• Adult Glioblastoma
• Adult Gliosarcoma
• Brain Neoplasms
• Glioblastoma
• Gliosarcoma
• Recurrent Adult Brain Neoplasm

Intervention

Procedure:
• Conventional Surgery
Undergo surgery

Other:
• Laboratory Biomarker Analysis
Correlative studies

Drug:
• Sorafenib Tosylate
Given PO
• Temsirolimus
Given IV

Locations

Country	Name	City	State
United States	Medini, Eitan MD (UIA Investigator)	Alexandria	Minnesota
United States	Lehigh Valley Hospital-Cedar Crest	Allentown	Pennsylvania
United States	McFarland Clinic PC-William R Bliss Cancer Center	Ames	Iowa
United States	Providence Alaska Medical Center	Anchorage	Alaska
United States	AnMed Health Cancer Center	Anderson	South Carolina
United States	AnMed Health Hospital	Anderson	South Carolina
United States	Michigan Cancer Research Consortium NCORP	Ann Arbor	Michigan
United States	Saint Joseph Mercy Hospital	Ann Arbor	Michigan
United States	Hospital District Sixth of Harper County	Anthony	Kansas
United States	Rush - Copley Medical Center	Aurora	Illinois
United States	Bronson Battle Creek	Battle Creek	Michigan
United States	Sanford Clinic North-Bemidgi	Bemidji	Minnesota
United States	Lehigh Valley Hospital - Muhlenberg	Bethlehem	Pennsylvania
United States	Spectrum Health Big Rapids Hospital	Big Rapids	Michigan
United States	Mid Dakota Clinic	Bismarck	North Dakota
United States	Saint Alexius Medical Center	Bismarck	North Dakota
United States	Sanford Bismarck Medical Center	Bismarck	North Dakota
United States	Illinois CancerCare-Bloomington	Bloomington	Illinois
United States	Saint Joseph Medical Center	Bloomington	Illinois
United States	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho
United States	Fairview Ridges Hospital	Burnsville	Minnesota
United States	Graham Hospital Association	Canton	Illinois
United States	Illinois CancerCare-Canton	Canton	Illinois
United States	Illinois CancerCare-Carthage	Carthage	Illinois
United States	Memorial Hospital	Carthage	Illinois
United States	Mercy Hospital	Cedar Rapids	Iowa
United States	Oncology Associates at Mercy Medical Center	Cedar Rapids	Iowa
United States	Cancer Center of Kansas - Chanute	Chanute	Kansas
United States	University of Virginia Cancer Center	Charlottesville	Virginia
United States	Rush University Medical Center	Chicago	Illinois
United States	Medical Oncology and Hematology Associates-West Des Moines	Clive	Iowa
United States	Mercy Hospital	Coon Rapids	Minnesota
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	Beaumont Hospital-Dearborn	Dearborn	Michigan
United States	Heartland Cancer Research NCORP	Decatur	Illinois
United States	Iowa Lutheran Hospital	Des Moines	Iowa
United States	Iowa Methodist Medical Center	Des Moines	Iowa
United States	Iowa-Wide Oncology Research Coalition NCORP	Des Moines	Iowa
United States	Medical Oncology and Hematology Associates-Des Moines	Des Moines	Iowa
United States	Medical Oncology and Hematology Associates-Laurel	Des Moines	Iowa
United States	Mercy Capitol	Des Moines	Iowa
United States	Mercy Medical Center - Des Moines	Des Moines	Iowa
United States	Saint John Hospital and Medical Center	Detroit	Michigan
United States	Cancer Center of Kansas - Dodge City	Dodge City	Kansas
United States	Essentia Health Cancer Center	Duluth	Minnesota
United States	Essentia Health Saint Mary's Medical Center	Duluth	Minnesota
United States	Miller-Dwan Hospital	Duluth	Minnesota
United States	Fairview-Southdale Hospital	Edina	Minnesota
United States	Saint Anthony Memorial Hospital	Effingham	Illinois
United States	Cancer Center of Kansas - El Dorado	El Dorado	Kansas
United States	Green Bay Oncology - Escanaba	Escanaba	Michigan
United States	Eureka Hospital	Eureka	Illinois
United States	Illinois CancerCare-Eureka	Eureka	Illinois
United States	Roger Maris Cancer Center	Fargo	North Dakota
United States	Sanford Broadway Medical Center	Fargo	North Dakota
United States	Sanford Clinic North-Fargo	Fargo	North Dakota
United States	Etzell, Paul S MD (UIA Investigator)	Fergus Falls	Minnesota
United States	Lake Region Healthcare Corporation-Cancer Care	Fergus Falls	Minnesota
United States	Swenson, Wade II, MD (UIA Investigator)	Fergus Falls	Minnesota
United States	Genesys Hurley Cancer Institute	Flint	Michigan
United States	Genesys Regional Medical Center-West Flint Campus	Flint	Michigan
United States	Hurley Medical Center	Flint	Michigan
United States	Cancer Center of Kansas - Fort Scott	Fort Scott	Kansas
United States	Unity Hospital	Fridley	Minnesota
United States	Galesburg Cottage Hospital	Galesburg	Illinois
United States	Illinois CancerCare-Galesburg	Galesburg	Illinois
United States	Altru Cancer Center	Grand Forks	North Dakota
United States	Cancer Research Consortium of West Michigan NCORP	Grand Rapids	Michigan
United States	Mercy Health Saint Mary's	Grand Rapids	Michigan
United States	Spectrum Health at Butterworth Campus	Grand Rapids	Michigan
United States	Green Bay Oncology at Saint Vincent Hospital	Green Bay	Wisconsin
United States	Green Bay Oncology Limited at Saint Mary's Hospital	Green Bay	Wisconsin
United States	Saint Vincent Hospital Cancer Center at Saint Mary's	Green Bay	Wisconsin
United States	Saint Vincent Hospital Cancer Center Green Bay	Green Bay	Wisconsin
United States	Saint Francis Hospital	Greenville	South Carolina
United States	Smilow Cancer Hospital Care Center at Saint Francis	Hartford	Connecticut
United States	Illinois CancerCare-Havana	Havana	Illinois
United States	Mason District Hospital	Havana	Illinois
United States	Geisinger Medical Center-Cancer Center Hazleton	Hazleton	Pennsylvania
United States	Hopedale Medical Complex - Hospital	Hopedale	Illinois
United States	Hutchinson Area Health Care	Hutchinson	Minnesota
United States	Cancer Center of Kansas-Independence	Independence	Kansas
United States	Green Bay Oncology - Iron Mountain	Iron Mountain	Michigan
United States	Allegiance Health	Jackson	Michigan
United States	Mayo Clinic in Florida	Jacksonville	Florida
United States	Joliet Oncology-Hematology Associates Limited	Joliet	Illinois
United States	Illinois CancerCare-Kewanee Clinic	Kewanee	Illinois
United States	Kewanee Hospital	Kewanee	Illinois
United States	Cancer Center of Kansas-Kingman	Kingman	Kansas
United States	Sparrow Hospital	Lansing	Michigan
United States	Lawrence Memorial Hospital	Lawrence	Kansas
United States	Cancer Center of Kansas-Liberal	Liberal	Kansas
United States	Southwest Medical Center	Liberal	Kansas
United States	Nebraska Cancer Research Center	Lincoln	Nebraska
United States	Meeker County Memorial Hospital	Litchfield	Minnesota
United States	Saint Mary Mercy Hospital	Livonia	Michigan
United States	Illinois CancerCare-Macomb	Macomb	Illinois
United States	Mcdonough District Hospital	Macomb	Illinois
United States	Holy Family Memorial Hospital	Manitowoc	Wisconsin
United States	Minnesota Oncology Hematology PA-Maplewood	Maplewood	Minnesota
United States	Saint John's Hospital - Healtheast	Maplewood	Minnesota
United States	Bay Area Medical Center	Marinette	Wisconsin
United States	Mercy Medical Center - North Iowa	Mason City	Iowa
United States	Cancer Center of Kansas - McPherson	McPherson	Kansas
United States	Franciscan Saint Anthony Health-Michigan City	Michigan City	Indiana
United States	Abbott-Northwestern Hospital	Minneapolis	Minnesota
United States	Hennepin County Medical Center	Minneapolis	Minnesota
United States	Minnesota Cooperative Group Outreach Program	Minneapolis	Minnesota
United States	Virginia Piper Cancer Institute	Minneapolis	Minnesota
United States	Holy Family Medical Center	Monmouth	Illinois
United States	Illinois CancerCare-Monmouth	Monmouth	Illinois
United States	Mercy Health Mercy Campus	Muskegon	Michigan
United States	New Ulm Medical Center	New Ulm	Minnesota
United States	Cancer Center of Kansas - Newton	Newton	Kansas
United States	Bromenn Regional Medical Center	Normal	Illinois
United States	Community Cancer Center Foundation	Normal	Illinois
United States	Illinois CancerCare-Community Cancer Center	Normal	Illinois
United States	Green Bay Oncology - Oconto Falls	Oconto Falls	Wisconsin
United States	Alegent Health Bergan Mercy Medical Center	Omaha	Nebraska
United States	Alegent Health Immanuel Medical Center	Omaha	Nebraska
United States	Alegent Health Lakeside Hospital	Omaha	Nebraska
United States	Creighton University Medical Center	Omaha	Nebraska
United States	Missouri Valley Cancer Consortium	Omaha	Nebraska
United States	Illinois CancerCare-Ottawa Clinic	Ottawa	Illinois
United States	Ottawa Regional Hospital and Healthcare Center	Ottawa	Illinois
United States	Cancer Center of Kansas - Parsons	Parsons	Kansas
United States	Illinois CancerCare-Pekin	Pekin	Illinois
United States	OSF Saint Francis Radiation Oncology at Pekin Cancer Treatment Center	Pekin	Illinois
United States	Pekin Hospital	Pekin	Illinois
United States	Illinois CancerCare-Peoria	Peoria	Illinois
United States	Methodist Medical Center of Illinois	Peoria	Illinois
United States	OSF Saint Francis Medical Center	Peoria	Illinois
United States	Proctor Hospital	Peoria	Illinois
United States	Illinois CancerCare-Peru	Peru	Illinois
United States	Illinois Valley Hospital	Peru	Illinois
United States	Saint Joseph Mercy Oakland	Pontiac	Michigan
United States	Lake Huron Medical Center	Port Huron	Michigan
United States	Cancer Center of Kansas - Pratt	Pratt	Kansas
United States	Illinois CancerCare-Princeton	Princeton	Illinois
United States	Perry Memorial Hospital	Princeton	Illinois
United States	Rapid City Regional Hospital	Rapid City	South Dakota
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	North Memorial Medical Health Center	Robbinsdale	Minnesota
United States	Mayo Clinic	Rochester	Minnesota
United States	Rutherford Hospital	Rutherfordton	North Carolina
United States	Saint Mary's of Michigan	Saginaw	Michigan
United States	Coborn Cancer Center at Saint Cloud Hospital	Saint Cloud	Minnesota
United States	Saint Cloud Hospital	Saint Cloud	Minnesota
United States	Metro Minnesota Community Oncology Research Consortium	Saint Louis Park	Minnesota
United States	Park Nicollet Clinic - Saint Louis Park	Saint Louis Park	Minnesota
United States	Regions Hospital	Saint Paul	Minnesota
United States	Saint Joseph's Hospital - Healtheast	Saint Paul	Minnesota
United States	United Hospital	Saint Paul	Minnesota
United States	Cancer Center of Kansas - Salina	Salina	Kansas
United States	Mayo Clinic in Arizona	Scottsdale	Arizona
United States	Virginia Mason Medical Center	Seattle	Washington
United States	Saint Francis Regional Medical Center	Shakopee	Minnesota
United States	HSHS Saint Nicholas Hospital	Sheboygan	Wisconsin
United States	Mercy Medical Center-Sioux City	Sioux City	Iowa
United States	Saint Luke's Regional Medical Center	Sioux City	Iowa
United States	Siouxland Regional Cancer Center	Sioux City	Iowa
United States	Avera Cancer Institute	Sioux Falls	South Dakota
United States	Avera McKennan Hospital and University Health Center	Sioux Falls	South Dakota
United States	Medical X-Ray Center	Sioux Falls	South Dakota
United States	Sanford Cancer Center Oncology Clinic	Sioux Falls	South Dakota
United States	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota
United States	Spartanburg Medical Center	Spartanburg	South Carolina
United States	Illinois CancerCare-Spring Valley	Spring Valley	Illinois
United States	Saint Margaret's Hospital	Spring Valley	Illinois
United States	Geisinger Medical Group	State College	Pennsylvania
United States	Lakeview Hospital	Stillwater	Minnesota
United States	Green Bay Oncology - Sturgeon Bay	Sturgeon Bay	Wisconsin
United States	Munson Medical Center	Traverse City	Michigan
United States	Carle Cancer Center	Urbana	Illinois
United States	The Carle Foundation Hospital	Urbana	Illinois
United States	Ridgeview Medical Center	Waconia	Minnesota
United States	Saint John Macomb-Oakland Hospital	Warren	Michigan
United States	Cancer Center of Kansas - Wellington	Wellington	Kansas
United States	Associates In Womens Health	Wichita	Kansas
United States	Cancer Center of Kansas - Wichita	Wichita	Kansas
United States	Cancer Center of Kansas-Wichita Medical Arts Tower	Wichita	Kansas
United States	Via Christi Regional Medical Center	Wichita	Kansas
United States	Wichita NCI Community Oncology Research Program	Wichita	Kansas
United States	Geisinger Wyoming Valley/Henry Cancer Center	Wilkes-Barre	Pennsylvania
United States	Rice Memorial Hospital	Willmar	Minnesota
United States	Cancer Center of Kansas - Winfield	Winfield	Kansas
United States	Southeast Clinical Oncology Research (SCOR) Consortium NCORP	Winston-Salem	North Carolina
United States	Minnesota Oncology Hematology PA-Woodbury	Woodbury	Minnesota
United States	Woodwinds Health Campus	Woodbury	Minnesota
United States	Metro Health Hospital	Wyoming	Michigan

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free Survival	The primary endpoint is the proportion of patients alive and progression-free 6 months after study treatment initiation.; If more than 41 evaluable patients are accrued in group 1 or group 3, the additional patients will not be used to evaluate the decision rule for that group or otherwise used in any decision-making processes. However, they will be included in the final point and confidence interval estimates for that group.; The 'success' probability, i.e., 6-month progression-free survival percentage, for each of group 1 and group 3 will be estimated as the number of evaluable patients still alive at 6 months divided by the total number of evaluable patients followed for at least 6 months. Ninety-five percent confidence intervals for the 'success' probability will be calculated according to the approach of Duffy and Santner.; Progression is defined as a 25% increase in product of perpendicular diameters of contrast enhancement or mass or appearance of new lesions.	At 6 months
Secondary	Overall Survival	The overall survival distribution will be estimated using the method of Kaplan-Meier.	From start of study registration to death due to any cause or until last follow-up, up to 5 years
Secondary	Objective Response, as Determined by a Neurological Exam, MRI, and/or CT Measurement	The proportion of patients in each response category will be summarized and 90% confidence intervals calculated assuming that the incidence of response is binomially distributed.	Up to 5 years
Secondary	Progression-free Survival	Kaplan-Meier survival curves will be used to estimate progression-time distributions.	Time from study registration to date of disease progression or last follow-up, assessed up to 5 years