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Phase I/II Evaluation of Everolimus (RAD001), Radiation and Temozolomide (TMZ) Followed by Adjuvant Temozolomide and Everolimus in Newly Diagnosed Glioblastoma


Phase 1/Phase 2
18 Years
N/A
Open (Enrolling)
Both
Brain and Central Nervous System Tumors

Thank you

Trial Information

Phase I/II Evaluation of Everolimus (RAD001), Radiation and Temozolomide (TMZ) Followed by Adjuvant Temozolomide and Everolimus in Newly Diagnosed Glioblastoma


OBJECTIVES:

- To determine the maximum tolerated dose (MTD) of everolimus in combination with
temozolomide and 3D-conformal radiotherapy or intensity-modulated radiotherapy (IMRT)
followed by adjuvant temozolomide with or without everolimus in patients with newly
diagnosed glioblastoma. (Mayo Clinic Rochester [MCR] AND Mayo Clinic Jacksonville [MCJ]
patients only) (Phase I)

- To assess and describe the adverse events of everolimus in combination with
temozolomide and 3D-conformal radiotherapy or IMRT followed by adjuvant temozolomide
with or without everolimus in patients with newly diagnosed glioblastoma. (MCR and MCJ
patients only) (Phase I)

- To assess treatment effectiveness of everolimus in combination with temozolomide and
3D-conformal radiotherapy or IMRT followed by adjuvant temozolomide with or without
everolimus, until progression, in patients with newly diagnosed glioblastoma. (all
North Center Cancer Treatment Group [NCCTG] patients) (Phase II)

- To characterize the toxicities of everolimus in combination with temozolomide and
3D-conformal radiotherapy or IMRT followed by adjuvant temozolomide with or without
everolimus in patients with newly diagnosed glioblastoma. (all NCCTG patients) (Phase
II)

- Evaluate whether suppression of fludeoxyglucose F18 (18FDG) uptake in tumor and normal
brain can be used to determine a biologically effective dose for efficient penetration
of everolimus through the blood-brain barrier. (MCR and MCJ patients only) (Phase I)

- Correlate everolimus levels with 18FDG uptake suppression in tumor and normal brain.
(MCR and MCJ patients only) (Phase I)

- Assess the relationship between efficacy endpoints (i.e., survival, progression-free
survival, and response) and changes in 3'-deoxy-3'-[18F]fluorothymidine (18F-FLT)
uptake for patients treated at MCR. (all NCCTG patients) (Phase II)

- Assess the relationship between efficacy endpoints (i.e., survival, progression-free
survival, and response), and phospho-Akt, PTEN status, and MGMT expression and promoter
methylation status. (all NCCTG patients) (Phase II)

- Assess the relationship between efficacy endpoints (i.e., survival, progression-free
survival, and response) and baseline gene expression signatures from paraffin embedded
pre-treatment tumor samples. (all NCCTG patients) (Phase II)

- Correlate gene expression between paraffin and frozen samples. (all NCCTG patients)
(Phase II)

- Evaluate potential mechanisms of therapy resistance in recurrent tumor samples obtained
at the time of surgery for recurrent disease. (Phase I and II)

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

- Phase I (Mayo Clinic Rochester [MCR] AND Mayo Clinic Jacksonville [MCJ] ONLY):

- Concurrent therapy (courses 1 and 2): Patients receive oral everolimus once weekly
in weeks 1-7 or 1-8 and oral temozolomide once daily in weeks 2-7 or 3-8. Patients
also undergo radiotherapy 5 days a week in either weeks 2-7 or 3-8. Four to six
weeks later, patients proceed to adjuvant therapy. This rest period is defined as
course 2.

- Adjuvant therapy with everolimus and temozolomide (courses 3-8): Patients receive
oral everolimus on days 1, 8, 15, and 22 and oral temozolomide on days 1-5.
Treatment repeats every 28 days for 6 courses in the absence of disease
progression or unacceptable toxicity.

- Adjuvant therapy with everolimus alone (courses 9 and all subsequent courses):
Patients receive oral everolimus on days 1, 8, 15, and 22. Treatment repeats every
28 days in the absence of disease progression our unacceptable toxicity.

- Phase II (Open to MCR center ONLY) (All North Central Cancer Treatment Group [NCCTG]
centers closed to accrual as of 02/17/11):

- Concurrent therapy (courses 1 and 2): Patients receive oral everolimus and oral
temozolomide and 3D-conformal radiotherapy or IMRT as in phase I. Patients will
undergo a 4-6 week rest period in course 2 and then proceed to adjuvant therapy.

- Adjuvant therapy with everolimus and temozolomide (courses 3-8): Patients receive
oral everolimus and oral temozolomide as in phase I.

- Adjuvant therapy with everolimus alone (courses 9 and all subsequent courses):
Patients receive oral everolimus as in phase I.

All patients undergo fludeoxyglucose (FDG)- or fluorothymidine-labeled PET/CT scans at
baseline and periodically during treatment.

Patients undergo blood sample collection periodically for pharmacological studies. Samples
are analyzed for everolimus blood levels and correlated with 18FDG uptake suppression in
tumor and normal brain via LC-MSMS. Previously collected tumor tissue are analyzed for
protein biomarkers including PTEN gene expression levels via fluorescence in situ
hybridization (FISH) and immunohistochemistry (IHC) and phosphorylation on Ser473 and Ser308
of Akt and MGMT expression and promoter methylation via IHC. Samples are also analyzed for
DNA sequencing. Some samples are banked for future studies.

After completion of study treatment, patients are followed every 2 months for 1 year, every
3 months for 1 year, and then every 6 months for 3 years.

PROJECTED ACCRUAL: A total of 138 patients (24 patients in phase I and 114 patients in phase
II) will be accrued for this study.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- Histologically confirmed diagnosis of 1 of the following:

- Glioblastoma multiforme (grade 4 astrocytoma)

- Other grade 4 astrocytoma variants (e.g., giant cell)

- No grade 4 oligodendrogliomas or oligoastrocytomas

- Gliosarcoma

- Newly diagnosed disease

- Measurable disease ≥ 1 cm³ (phase I patients only)

- Some patients may be registered on protocol NCCTG-947252

- No oligodendrogliomas or oligoastrocytomas

PATIENT CHARACTERISTICS:

Inclusion criteria:

- ECOG performance status 0-2

- ANC ≥ 1,500/μL

- Hemoglobin ≥ 9.0 g/dL

- Platelet count ≥ 100,000/μL

- Total bilirubin ≤ 2.5 x institutional upper limit of normal (ULN)

- Serum total cholesterol < 350 mg/dL

- Serum total triglycerides < 400 mg/dL

- AST ≤ 2.5 x ULN

- Creatinine ≤ 1.5 x ULN

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for 60 days after
completion of study therapy

- Must be willing to undergo 2 mandatory research PET or PET/CT scans (all MCR and MCJ
patients in phase I and MCR only patients in phase II)

- Must be willing to abstain from eating or drinking grapefruit or grapefruit juice
during study treatment

- Must be willing to follow a diet low in fat and cholesterol while taking everolimus

- Must be willing to have imaging scans submitted for central review

- Ability to understand and willingness to sign a written informed consent

Exclusion criteria:

- Other active cancers requiring therapy to control disease or prior cancer diagnoses
which pose a greater than 30% risk of death within the next 2 years

- Gastrointestinal tract disease resulting in an inability to take oral medication or a
requirement for IV alimentation, prior surgical procedures affecting absorption, or
active uncontrolled peptic ulcer disease

- Uncontrolled intercurrent illness including, but not limited to, any of the
following:

- Ongoing, uncontrolled, or active (acute or chronic) infection or disorder

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia

- Psychiatric illness/social situations that would limit compliance with study
requirements

- Severely impaired lung function

- Uncontrolled diabetes (fasting serum glucose > 2 x ULN) OR diabetes that would
interfere with the performance of the FDG-PET/CT or FDG-PET scans

- Liver disease (e.g., cirrhosis, chronic active hepatitis, chronic persistent
hepatitis, or history of hepatitis B)

- Known HIV positivity

- Positive hepatitis B antigen (HBsAg) or hepatitis C serology (HCV) tests

- Any history of allergy or intolerance to dacarbazine (DTIC)

- Significant traumatic injury within the past 21 days

- Severe allergy to sulfa medications

- Inability to tolerate levofloxacin with dapsone or pentamidine (inhaled or IV)

PRIOR CONCURRENT THERAPY:

Inclusion criteria:

- At least 1 week, but no more than 6 weeks since prior surgical resection or biopsy

- Must comply with antibiotic prophylaxis with either trimethoprim/sulfamethoxazole
(daily or 3 times per week), oral dapsone (daily) combined with daily levofloxacin,
or monthly pentamidine (inhaled or IV) combined with daily levofloxacin

Exclusion criteria:

- Prior chemotherapy for any brain tumor

- Prior temozolomide or mTOR inhibitor therapies

- Any prior cranial radiotherapy

- Planned immunization with attenuated live vaccines ≤ 7 days prior to and during study
period

- At least 21 days since prior major surgery (excluding neurosurgical biopsy, resection
of brain tumor, or treatment of immediate post-neurosurgical complication [e.g.,
intracranial hematoma])

- Concurrent or prior treatment for this cancer with any other investigational agents

- Concurrent enzyme-inducing anticonvulsants (EIACs) or other strong inducers of CYP3A4
(i.e., carbamazepine, phenytoin, phenobarbital/primidone, rifabutin, rifampin, or St.
John's wort)

- Concurrent therapeutic doses of warfarin

- Low molecular weight heparin is allowed

- Concurrent systematic leukocyte growth factors (e.g., G-CSF or GM-CSF), except for
the treatment of severe neutropenia

- Concurrent drugs or substances known to inhibit or induce CYP3A

- Other concurrent chronic treatment with immunosuppressive agents except dexamethasone

- Other concurrent anticancer agents

- Concurrent live vaccines

Type of Study:

Interventional

Study Design:

Primary Purpose: Treatment

Outcome Measure:

MTD of everolimus in combination with temozolomide and 3D-conformal radiotherapy or intensity-modulated radiotherapy (IMRT) followed by adjuvant temozolomide with or without everolimus (Phase I)

Safety Issue:

Yes

Principal Investigator

Jann N. Sarkaria, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Mayo Clinic

Authority:

United States: Federal Government

Study ID:

CDR0000573917

NCT ID:

NCT00553150

Start Date:

March 2009

Completion Date:

Related Keywords:

  • Brain and Central Nervous System Tumors
  • adult gliosarcoma
  • adult giant cell glioblastoma
  • adult glioblastoma
  • adult anaplastic astrocytoma
  • adult diffuse astrocytoma
  • adult pilocytic astrocytoma
  • adult subependymal giant cell astrocytoma
  • Glioblastoma
  • Nervous System Neoplasms
  • Central Nervous System Neoplasms

Name

Location

Mayo Clinic ScottsdaleScottsdale, Arizona  85259
Mayo Clinic - JacksonvilleJacksonville, Florida  32224
Mayo Clinic Cancer CenterRochester, Minnesota  55905
CCOP - WichitaWichita, Kansas  67214-3882
Hurley Medical CenterFlint, Michigan  48503
CCOP - Missouri Valley Cancer ConsortiumOmaha, Nebraska  68131
CCOP - Illinois Oncology Research AssociationPeoria, Illinois  61602
CCOP - Metro-MinnesotaSaint Louis Park, Minnesota  55416
Cedar Rapids Oncology AssociatesCedar Rapids, Iowa  52403
Mercy Medical Center - Sioux CitySioux City, Iowa  51104
Siouxland Hematology-Oncology Associates, LLPSioux City, Iowa  51101
St. Luke's Regional Medical CenterSioux City, Iowa  51104
CCOP - Michigan Cancer Research ConsortiumAnn Arbor, Michigan  48106
Saint Joseph Mercy Cancer CenterAnn Arbor, Michigan  48106-0995
Oakwood Cancer Center at Oakwood Hospital and Medical CenterDearborn, Michigan  48123-2500
Genesys Hurley Cancer InstituteFlint, Michigan  48503
Van Elslander Cancer Center at St. John Hospital and Medical CenterGrosse Pointe Woods, Michigan  48236
Sparrow Regional Cancer CenterLansing, Michigan  48912-1811
St. John Macomb HospitalWarren, Michigan  48093
MeritCare BemidjiBemidji, Minnesota  56601
Fairview Ridges HospitalBurnsville, Minnesota  55337
Mercy and Unity Cancer Center at Mercy HospitalCoon Rapids, Minnesota  55433
Duluth Clinic Cancer Center - DuluthDuluth, Minnesota  55805-1983
CCOP - DuluthDuluth, Minnesota  55805
Miller - Dwan Medical CenterDuluth, Minnesota  55805
Fairview Southdale HospitalEdina, Minnesota  55435
Mercy and Unity Cancer Center at Unity HospitalFridley, Minnesota  55432
Hutchinson Area Health CareHutchinson, Minnesota  55350
HealthEast Cancer Care at St. John's HospitalMaplewood, Minnesota  55109
Hennepin County Medical Center - MinneapolisMinneapolis, Minnesota  55415
Virginia Piper Cancer Institute at Abbott - Northwestern HospitalMinneapolis, Minnesota  55407
St. Francis Cancer Center at St. Francis Medical CenterShakopee, Minnesota  55379
Park Nicollet Cancer CenterSt. Louis Park, Minnesota  55416
Regions Hospital Cancer Care CenterSt. Paul, Minnesota  55101
United HospitalSt. Paul, Minnesota  55102
Ridgeview Medical CenterWaconia, Minnesota  55387
MeritCare BroadwayFargo, North Dakota  58122
CCOP - MeritCare HospitalFargo, North Dakota  58122
Sanford Cancer Center at Sanford USD Medical CenterSioux Falls, South Dakota  57117-5039
Medical X-Ray Center, PCSioux Falls, South Dakota  57105
Rapid City Regional HospitalRapid City, South Dakota  57709
Methodist Medical Center of IllinoisPeoria, Illinois  61636
CCOP - Cancer Research for the OzarksSpringfield, Missouri  65807
CCOP - Montana Cancer ConsortiumBillings, Montana  59101
CCOP - ColumbusColumbus, Ohio  43206
CCOP - DaytonKettering, Ohio  45429
Hinsdale, Illinois  60521
Charles M. Barrett Cancer Center at University HospitalCincinnati, Ohio  45267-0526
Wesley Medical CenterWichita, Kansas  67214
Hulston Cancer Center at Cox Medical Center SouthSpringfield, Missouri  65807
St. John's Regional Health CenterSpringfield, Missouri  65804
Via Christi Cancer Center at Via Christi Regional Medical CenterWichita, Kansas  67214
St. Vincent Hospital Regional Cancer CenterGreen Bay, Wisconsin  54307-3508
Green Bay Oncology, Limited - EscanabaEscanaba, Michigan  49431
Dickinson County Healthcare SystemIron Mountain, Michigan  49801
St. Mary's Hospital Medical Center - Green BayGreen Bay, Wisconsin  54303
Green Bay Oncology, Limited at St. Vincent Hospital Regional Cancer CenterGreen Bay, Wisconsin  54301-3526
Green Bay Oncology, Limited at St. Mary's HospitalGreen Bay, Wisconsin  54303
Bay Area Cancer Care Center at Bay Area Medical CenterMarinette, Wisconsin  54143
Green Bay Oncology, Limited - Oconto FallsOconto Falls, Wisconsin  54154
Green Bay Oncology, Limited - Sturgeon BaySturgeon Bay, Wisconsin  54235
Hematology-Oncology Centers of the Northern Rockies - BillingsBillings, Montana  59101
St. Peter's HospitalHelena, Montana  59601
Kalispell Regional Medical CenterKalispell, Montana  59901
Glacier Oncology, PLLCKalispell, Montana  59901
Montana Cancer Center at St. Patrick Hospital and Health Sciences CenterMissoula, Montana  59802
Montana Cancer Specialists at Montana Cancer CenterMissoula, Montana  59802
Adena Regional Medical CenterChillicothe, Ohio  54601
Doctors Hospital at Ohio HealthColumbus, Ohio  43228
Riverside Methodist Hospital Cancer CareColumbus, Ohio  43214
Grady Memorial HospitalDelaware, Ohio  43015
Fairfield Medical CenterLancaster, Ohio  43130
Strecker Cancer Center at Marietta Memorial HospitalMarietta, Ohio  45750
Licking Memorial Cancer Care Program at Licking Memorial HospitalNewark, Ohio  43055
Community Hospital of Springfield and Clark CountySpringfield, Ohio  45505
Genesis - Good Samaritan HospitalZanesville, Ohio  43701
Saint Francis/Mount Sinai Regional Cancer Center at Saint Francis Hospital and Medical CenterHartford, Connecticut  06105
Mount Carmel Health - West HospitalColumbus, Ohio  43222
Morgan Cancer Center at Lehigh Valley Hospital - Cedar CrestAllentown, Pennsylvania  18105
Saint Alphonsus Cancer Care Center at Saint Alphonsus Regional Medical CenterBoise, Idaho  83706
St. Joseph Medical CenterBloomington, Illinois  61701
Graham HospitalCanton, Illinois  61520
Memorial HospitalCarthage, Illinois  62321
Eureka Community HospitalEureka, Illinois  61530
Mason District HospitalHavana, Illinois  62644
McDonough District HospitalMacomb, Illinois  61455
BroMenn Regional Medical CenterNormal, Illinois  61761
Community Cancer CenterNormal, Illinois  61761
Community Hospital of OttawaOttawa, Illinois  61350
Oncology Hematology Associates of Central Illinois, PC - OttawaOttawa, Illinois  61350
Cancer Treatment Center at Pekin HospitalPekin, Illinois  61554
Oncology Hematology Associates of Central Illinois, PC - PeoriaPeoria, Illinois  61615
OSF St. Francis Medical CenterPeoria, Illinois  61637
Illinois Valley Community HospitalPeru, Illinois  61354
Perry Memorial HospitalPrinceton, Illinois  61356
St. Francis Hospital and Health Centers - Beech Grove CampusBeech Grove, Indiana  46107
Bettendorf, Iowa  52722
Mercy Regional Cancer Center at Mercy Medical CenterCedar Rapids, Iowa  52403
Cancer Center of Kansas, PA - Dodge CityDodge City, Kansas  67801
Immanuel Medical CenterOmaha, Nebraska  68122
Creighton University Medical CenterOmaha, Nebraska  68131-2197
Samaritan North Cancer Care CenterDayton, Ohio  45415
Grandview HospitalDayton, Ohio  45405
David L. Rike Cancer Center at Miami Valley HospitalDayton, Ohio  45409
Good Samaritan HospitalDayton, Ohio  45406
Blanchard Valley Medical AssociatesFindlay, Ohio  45840
Charles F. Kettering Memorial HospitalKettering, Ohio  45429
Middletown Regional HospitalMiddletown, Ohio  45044
UVMC Cancer Care Center at Upper Valley Medical CenterTroy, Ohio  45373-1300
Ruth G. McMillan Cancer Center at Greene Memorial HospitalXenia, Ohio  45385
Welch Cancer Center at Sheridan Memorial HospitalSheridan, Wyoming  82801
Cancer Resource Center - LincolnLincoln, Nebraska  68510
Altru Cancer Center at Altru HospitalGrand Forks, North Dakota  58201
Reid Hospital & Health Care ServicesRichmond, Indiana  47374
McFarland Clinic, PCAmes, Iowa  50010
Cancer Center of Kansas, PA - ChanuteChanute, Kansas  66720
Cancer Center of Kansas, PA - El DoradoEl Dorado, Kansas  67042
Cancer Center of Kansas - Fort ScottFort Scott, Kansas  66701
Cancer Center of Kansas-IndependenceIndependence, Kansas  67301
Cancer Center of Kansas, PA - KingmanKingman, Kansas  67068
Lawrence Memorial HospitalLawrence, Kansas  66044
Cancer Center of Kansas, PA - LiberalLiberal, Kansas  67905
Cancer Center of Kansas, PA - NewtonNewton, Kansas  67114
Cancer Center of Kansas, PA - ParsonsParsons, Kansas  67357
Cancer Center of Kansas, PA - PrattPratt, Kansas  67124
Cancer Center of Kansas, PA - SalinaSalina, Kansas  67401
Cancer Center of Kansas, PA - WellingtonWellington, Kansas  67152
Cancer Center of Kansas, PA - WichitaWichita, Kansas  67214
Associates in Womens Health, PA - North ReviewWichita, Kansas  67208
Cancer Center of Kansas, PA - WinfieldWinfield, Kansas  67156
Foote Memorial HospitalJackson, Michigan  49201
St. Mary Mercy HospitalLivonia, Michigan  48154
St. Joseph Mercy OaklandPontiac, Michigan  48341-2985
Mercy Regional Cancer Center at Mercy HospitalPort Huron, Michigan  48060
Seton Cancer Institute at Saint Mary's - SaginawSaginaw, Michigan  48601
Willmar Cancer Center at Rice Memorial HospitalWillmar, Minnesota  56201
Billings Clinic - DowntownBillings, Montana  59107-7000
Bozeman Deaconess Cancer CenterBozeman, Montana  59715
St. James Healthcare Cancer CareButte, Montana  59701
Great Falls Clinic - Main FacilityGreat Falls, Montana  59405
Sletten Cancer Institute at Benefis HealthcareGreat Falls, Montana  59405
Northern Montana HospitalHavre, Montana  59501
Kalispell Medical Oncology at KRMCKalispell, Montana  59901
Alegant Health Cancer Center at Bergan Mercy Medical CenterOmaha, Nebraska  68124
Grant Medical Center Cancer CareColumbus, Ohio  43215
Wayne HospitalGreenville, Ohio  45331
Knox Community HospitalMount Vernon, Ohio  43050
Mount Carmel St. Ann's Cancer CenterWesterville, Ohio  43081
Lehigh Valley Hospital - MuhlenbergBethlehem, Pennsylvania  18017
Genesys Regional Medical CenterGrand Blanc, Michigan  48439-8066
Galesburg Clinic, PCGalesburg, Illinois  61401
St. Vincent Healthcare Cancer Care ServicesBillings, Montana  59101
Illinois CancerCare - BloomingtonBloomington%, Illinois  61701
Illinois CancerCare - CantonCanton, Illinois  61520
Illinois CancerCare - CarthageCarthage, Illinois  62321
Illinois CancerCare - EurekaEureka, Illinois  61530
Illinois CancerCare - GalesburgGalesburg, Illinois  61401
Illinois CancerCare - HavanaHavana, Illinois  62644
Illinois CancerCare - Kewanee ClinicKewanee, Illinois  61443
Illinois CancerCare - MacombMacomb, Illinois  61455
Trinity Cancer Center at Trinity Medical Center - 7th Street CampusMoline, Illinois  61265
OSF Holy Family Medical CenterMonmouth, Illinois  61462
Illinois CancerCare - MonmouthMonmouth, Illinois  61462
Illinois CancerCare - Community Cancer CenterNormal, Illinois  61761
Illinois CancerCare - PekinPekin, Illinois  61603
Illinois CancerCare - PeruPeru, Illinois  61354
Illinois CancerCare - PrincetonPrinceton, Illinois  61356
Illinois CancerCare - Spring ValleySpring Valley, Illinois  61362
Precision Radiotherapy at University PointeWest Chester, Ohio  45069
Minnesota Oncology - MaplewoodMaplewood, Minnesota  55109
Humphrey Cancer Center at North Memorial Outpatient CenterRobbinsdale, Minnesota  55422-2900
Lakeview HospitalStillwater, Minnesota  55082
Minnesota Oncology - WoodburyWoodbury, Minnesota  55125
Lakeside HospitalOmaha, Nebraska  68130
New Ulm Medical CenterNew Ulm, Minnesota  56073
Roger Maris Cancer Center at MeritCare HospitalFargo, North Dakota  58122
Cancer Center of Kansas, PA - McPhersonMcPherson, Kansas  67460
Mercy Clinic Cancer and Hematology - RollaRolla, Missouri  65401