Combining Sunitinib, Temozolomide and Radiation to Treat Patients Diagnosed With Glioblastoma

NCT02928575

Last updated date
Study Location
Tom Baker Cancer Center and University of Calgary
Calgary, Alberta, T2N 4N2, Canada
Contact
514-934-1934

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Eligibility Criteria
condition
The disease, disorder, syndrome, illness, or injury that is being studied.
Glioblastoma Multiforme
Sex
Females and Males
Age
Pediatric Trials: 0-17 Years
Adult Trials: 18+ Years
18-70 years
Inclusion Criteria
The factors, or reasons, that allow a person to participate in a clinical study.
Show details

- Histologically documented newly diagnosed GBM patients

- Unmethylated MGMT promoter as determined by Methylation specific-polymerase chain reaction (MGMT(+) tumor)

- Age between 18 to 70

- Karnofsky performance status ≥70

- History and physical examination including neurologic examination within 4 weeks prior to registration

- Systolic blood pressure ≤ 160 mmHg or diastolic pressure ≤ 100mm Hg

- Required blood work within 14 days prior to registration

- Eligible for standard concurrent chemoradiation with TMZ

- Patients must have normal organ and marrow functions as defined below:

- Absolute neutrophil count ≥ 1.5x 109/L

- Platelets ≥100x 109/L

- Hemoglobin ≥80g/L

- International Normalized Ratio ≤1.3

- Creatinine ≤1.5x [upper limit of normal] Or creatinine clearance ≥60 mL/min/1.73m2

- Normal baseline thyroid function as measured by a thyrotropic-stimulating hormone within institutional normal limits

- Adequate liver function: Alanine transaminase or Aspartate transaminase < 2 x upper limit of normal and bilirubin 1.6 mg/dL. No active bleeding or pathologic condition that carries high risk of bleeding (e.g. tumor involving major vessels or known varices)

- Patients who have undergone resection must meet the following conditions:

- Patients must have recovered from the effects of surgery and a minimum of 14 to 28 days must have elapsed from the day of surgery to day of registration. Day of registration is considered the first day of Sunitinib.

- For stereotactic biopsy, a minimum of 14 days must have elapsed prior to registration

- No prior RT to the brain, chemotherapy, or anti-angiogenic therapy

- Estimated life expectancy of at least 6 months

- Premenopausal women must have a negative human chorionic gonadotropin within 14 days prior to registration

- The effects of Sunitinib on the developing human fetus is unknown. Women of childbearing potential and male participants must practice adequate contraception. Should a woman become pregnant or suspect she is pregnant during the study, she should inform her treating physician immediately.

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

Exclusion Criteria
The factors, or reasons, that prevent a person from participating in a clinical study.
Show details


- Histologically documented newly diagnosed GBM patients with methylated MGMT promoter


- Serious medical conditions that might be aggravated by treatment, including but not
limited to: myocardial infarction within 6 months, congestive heart failure, unstable
angina, active cardiomyopathy, unstable ventricular arrhythmia, uncontrolled
hypertension, uncontrolled psychotic disorders, serious infections, active peptic
ulcer disease, active liver disease or cerebrovascular disease with previous stroke


- Patients with a history of coagulopathy


- Evidence of intratumoural or peritumoural hemorrhage deemed significant by the
treating physician


- ≥ 1+ proteinuria on two successive urine dipstick assessments


- thrombolytic therapy within 4 weeks


- Patient with prolonged of corrected QT interval of more than 450 msec in screening EKG
will be excluded


- Women who are pregnant or nursing


- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to Sunitinib


- Previous treatment with Sunitinib or other inhibitors of the vascular endothelial
growth factor signalling axis


- Bleeding disorders


- Concurrent use of anticoagulant or antiplatelet drugs


- Patients with any condition that impairs their ability to swallow Sunitinib (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).


- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with Sunitinib. In addition, these
patients are at increased risk of lethal infections when treated with bone
marrow-suppressive therapy


- Individuals with MRI non-compatible metal in the body, or unable to undergo MRI
procedures.


- Allergy to gadolinium


- Patients with severe liver impairment will not be enrolled in this study.

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Advanced Information
Descriptive Information
Brief Title  ICMJE Combining Sunitinib, Temozolomide and Radiation to Treat Patients Diagnosed With Glioblastoma
Official Title  ICMJE A Phase II Trial of Concurrent Sunitinib, Temozolomide and Radiation Therapy Followed by Adjuvant Temozolomide for Newly Diagnosed Glioblastoma Patients With an Unmethylated MGMT Gene Promoter
Brief Summary The purpose of this study is to determine whether a combination of Sunitinib, Temozolomide and Radiation Therapy would be effective in the treatment of newly diagnosed Glioblastoma patients harboring tumors with unmethylated MGMT promoter.
Detailed Description

Glioblastoma multiforme (GBM), the most common primary brain tumor in adults is known for its highly invasive and angiogenic profile. Despite advances in different modalities of GBM treatment, the overall prognosis of GBM remains dismal. The current standard of care is Radiation Therapy (RT) at a dose of 60 Gy (30 fractions) for 6 weeks with concurrent Temozolomide (TMZ; 75 mg/m2 daily for 6 weeks) followed by adjuvant TMZ (150/200mg/m2 daily, for 5 of 28 days x 6 months). The DNA repair protein O6-methylguanine methyltransferase (MGMT) removes alkyl adducts at the O6 position of guanine and therefore counteracts the cytotoxic effects of alkylating agents such as TMZ. Thus, GBM patients harboring tumors with unmethylated MGMT promoter and increased MGMT protein expression do not derive benefit from TMZ treatment.

Sunitinib (Sutent, SU11248) is an oral multitargeted receptor tyrosine kinase (RTK) inhibitor with anti-angiogenic activities. Sunitinib has been approved by the FDA for the treatment of patients with gastrointestinal stromal tumors after disease progression on or intolerance to imatinib, for the treatment of patients with advanced renal cell carcinoma and for the treatment of patients with unresectable, locally advanced, or metastatic well-differentiated pancreatic neuroendocrine tumors (pNET). Previous pre-clinical data showed the efficacy of sunitinib in GBM. The investigators preclinical data highlighted the differential effect of sunitinib in GBM MGMT-positive tumors with a greater response to sunitinib in combination with RT and TMZ compared to MGMT-negative tumors.

In this phase II trial, Investigator will test the efficacy and the safety of combining Sunitinib with RT and TMZ in newly diagnosed GBM patients displaying tumors with unmethylated MGMT promoter. Based on the investigators preclinical findings, patients with MGMT (+) tumors (do not derive benefit from TMZ treatment) are more likely to respond to sunitinib-based therapy. MGMT promoter methylation will be therefore used as a biomarker for selection of newly diagnosed GBM patients enrolled in this study.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Glioblastoma Multiforme
Intervention  ICMJE
  • Drug: Sunitinib
    Before concurrent treatment, patients will receive sunitinib orally at a dose of 12.5 mg once daily for one week prior to radiation. Patients will then receive a concomitant treatment of sunitinib at a dose of 12.5 mg once daily along with temozolomide (75 mg/m2 daily) along with radiotherapy (60 Gy in 30 fractions) over a period of 6 weeks.
    Other Name: Sutent (SU11248)
  • Drug: Temozolomide
    Temozolomide (75 mg/m2 daily) will be administered along with sunitinib (12.5 mg once daily) and radiotherapy (60 Gy in 30 fractions) over a period of 6 weeks. This concurrent treatment of sunitinib, temozolomide and radiotherapy is followed by a 1 month break after which the adjuvant temozolomide treatment is administered at a dose of 150/200mg/m2 daily, for 5 of 28 days over a period of 6 months.
  • Radiation: Radiation Therapy
    Patients will receive a concomitant treatment of radiotherapy (60 Gy in 30 fractions), sunitinib (12.5 mg once daily) and temozolomide (75 mg/m2 daily) over a period of 6 weeks.
Study Arms  ICMJE Experimental: Sunitinib, Temozolomide and Radiation Therapy
Before concurrent treatment, patients will receive sunitinib orally at a dose of 12.5 mg once daily for one week prior to radiation. Patients will then receive a concomitant treatment of sunitinib at a dose of 12.5 mg once daily along with temozolomide (75 mg/m2 daily) along with radiotherapy (60 Gy in 30 fractions) over a period of 6 weeks. This concurrent treatment of sunitinib, temozolomide and radiotherapy is followed by a 1 month break after which the adjuvant temozolomide treatment is administered at a dose of 150/200mg/m2 daily, for 5 of 28 days over a period of 6 months.
Interventions:
  • Drug: Sunitinib
  • Drug: Temozolomide
  • Radiation: Radiation Therapy
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Unknown status
Estimated Enrollment  ICMJE
 (submitted: October 6, 2016)
45
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2017
Estimated Primary Completion Date December 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Histologically documented newly diagnosed GBM patients
  • Unmethylated MGMT promoter as determined by Methylation specific-polymerase chain reaction (MGMT(+) tumor)
  • Age between 18 to 70
  • Karnofsky performance status ?70
  • History and physical examination including neurologic examination within 4 weeks prior to registration
  • Systolic blood pressure ? 160 mmHg or diastolic pressure ? 100mm Hg
  • Required blood work within 14 days prior to registration
  • Eligible for standard concurrent chemoradiation with TMZ
  • Patients must have normal organ and marrow functions as defined below:

    • Absolute neutrophil count ? 1.5x 109/L
    • Platelets ?100x 109/L
    • Hemoglobin ?80g/L
    • International Normalized Ratio ?1.3
    • Creatinine ?1.5x [upper limit of normal] Or creatinine clearance ?60 mL/min/1.73m2
  • Normal baseline thyroid function as measured by a thyrotropic-stimulating hormone within institutional normal limits
  • Adequate liver function: Alanine transaminase or Aspartate transaminase < 2 x upper limit of normal and bilirubin 1.6 mg/dL. No active bleeding or pathologic condition that carries high risk of bleeding (e.g. tumor involving major vessels or known varices)
  • Patients who have undergone resection must meet the following conditions:

    • Patients must have recovered from the effects of surgery and a minimum of 14 to 28 days must have elapsed from the day of surgery to day of registration. Day of registration is considered the first day of Sunitinib.
    • For stereotactic biopsy, a minimum of 14 days must have elapsed prior to registration
  • No prior RT to the brain, chemotherapy, or anti-angiogenic therapy
  • Estimated life expectancy of at least 6 months
  • Premenopausal women must have a negative human chorionic gonadotropin within 14 days prior to registration
  • The effects of Sunitinib on the developing human fetus is unknown. Women of childbearing potential and male participants must practice adequate contraception. Should a woman become pregnant or suspect she is pregnant during the study, she should inform her treating physician immediately.
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Histologically documented newly diagnosed GBM patients with methylated MGMT promoter
  • Serious medical conditions that might be aggravated by treatment, including but not limited to: myocardial infarction within 6 months, congestive heart failure, unstable angina, active cardiomyopathy, unstable ventricular arrhythmia, uncontrolled hypertension, uncontrolled psychotic disorders, serious infections, active peptic ulcer disease, active liver disease or cerebrovascular disease with previous stroke
  • Patients with a history of coagulopathy
  • Evidence of intratumoural or peritumoural hemorrhage deemed significant by the treating physician
  • ? 1+ proteinuria on two successive urine dipstick assessments
  • thrombolytic therapy within 4 weeks
  • Patient with prolonged of corrected QT interval of more than 450 msec in screening EKG will be excluded
  • Women who are pregnant or nursing
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to Sunitinib
  • Previous treatment with Sunitinib or other inhibitors of the vascular endothelial growth factor signalling axis
  • Bleeding disorders
  • Concurrent use of anticoagulant or antiplatelet drugs
  • Patients with any condition that impairs their ability to swallow Sunitinib (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).
  • HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with Sunitinib. In addition, these patients are at increased risk of lethal infections when treated with bone marrow-suppressive therapy
  • Individuals with MRI non-compatible metal in the body, or unable to undergo MRI procedures.
  • Allergy to gadolinium
  • Patients with severe liver impairment will not be enrolled in this study.
Sex/Gender  ICMJE
Sexes Eligible for Study:All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02928575
Other Study ID Numbers  ICMJE McG 1132
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Bassam Abdulkarim, McGill University Health Centre/Research Institute of the McGill University Health Centre
Study Sponsor  ICMJE Bassam Abdulkarim
Collaborators  ICMJE
  • Pfizer
  • Canadian Cancer Society Research Institute (CCSRI)
Investigators  ICMJE Not Provided
PRS Account McGill University Health Centre/Research Institute of the McGill University Health Centre
Verification Date October 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP