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
Overview
- Phase
- Phase 2
- Intervention
- Sunitinib
- Conditions
- Glioblastoma Multiforme
- Sponsor
- Bassam Abdulkarim
- Enrollment
- 45
- Locations
- 2
- Primary Endpoint
- Tumor Response Rate
- Last Updated
- 9 years ago
Overview
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.
Investigators
Bassam Abdulkarim
PhD, MD
McGill University Health Centre/Research Institute of the McGill University Health Centre
Eligibility Criteria
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
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
Arms & Interventions
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.
Intervention: Sunitinib
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.
Intervention: Temozolomide
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.
Intervention: Radiation Therapy
Outcomes
Primary Outcomes
Tumor Response Rate
Time Frame: 24 weeks
The primary endpoint of this study is tumor response rate and will be assessed using the Response Assessment in Neuro-Oncology criteria (RANO). Tumor response rate will be compared to standard of care in newly diagnosed Glioblastoma Multiforme.
Secondary Outcomes
- Overall Survival(at 6 month post treatment)
- Progression free survival(6 months post treatment)
- Adverse Events(Assessment of toxicity will continue until week 13 post-sunitinib)
- Biomarkers (Cytokines) response(at 6 months post treatment)
- level of functioning(at 6 months post treatment)
- Increase use of corticosteroids(at 6 months post treatment)