Glioblastoma Multiforme
Conditions
Keywords
Concurrent Radiation Therapy, Temozolomide, Sorafenib, First-line, Glioblastoma Multiforme, Phase II
Brief summary
The mechanism of action of sorafenib makes it an interesting drug to investigate in the treatment of patients with glioblastoma multiforme. Efficacy of agents with anti-angiogenic activity has already been demonstrated and the PDGF receptor target may also be pertinent in glioblastoma. The combination of temozolomide plus sorafenib has been investigated previously in the treatment of patients with advanced melanoma. The combination was generally well tolerated; in previously untreated patients, a standard dose of sorafenib (400mg PO bid) was administered with temozolomide 150mg/m2 PO daily for 5 days, repeated every 28 days (23). In this multicenter phase II study, patients with newly diagnosed glioblastoma will receive standard treatment, including initial debulking surgical resection (if feasible) followed by high-dose radiation therapy with concurrent temozolomide. After completion of radiation therapy, patients will continue treatment with temozolomide (150mg/m2 days 1-5) and sorafenib (400mg PO bid daily), repeated at 28-day intervals for 6 cycles.
Detailed description
All patients entering this study will initially undergo combined modality treatment with concurrent radiation therapy + temozolomide. Four weeks after completing radiation therapy, patients will begin 6 months of follow-up treatment with oral temozolomide plus sorafenib. Combined Modality Therapy - Radiation Therapy Radiotherapy must begin within ≤ 6 weeks of surgery. One treatment of 2.0Gy will be given daily 5 days per week for a total of 60.0Gy over 6 weeks. Temozolomide 75mg/m2 PO will be given daily, beginning on the first day of radiation therapy and continuing through the last day of radiation therapy. After completion of combined modality therapy, patients will have 4 weeks without any therapy. Systemic Therapy Beginning 4 weeks after the completion of radiation therapy, patients will receive 6 months of treatment with temozolomide and sorafenib. Temozolomide 150mg/m2 orally will be administered days 1-5, and repeated every 28 days for 6 courses. Sorafenib 400mg PO bid will be administered on days 1-28, repeated for 6 courses concurrently with temozolomide
Interventions
RADIATIONRadiation Therapy
2 Gy/fraction, single daily fractions M-F, to 60 Gy total
DRUGTemozolomide
In Combined Modality Therapy, administered as 75 mg/m2 by mouth once daily In follow-up systemic therapy, administered as 150 mg/m2 by mouth on days 1-5 every 28 days for 6 cycles
DRUGSorafenib
In follow-up systemic therapy, administered as 400 mg by mouth twice daily for 6 months
Sponsors
Bayer
SCRI Development Innovations, LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histologically confirmed intracranial glioblastoma multiforme (WHO grade 4). 2. Patients who have had partial or complete surgical debulking are eligible, as are those with inoperable glioblastoma. 3. No previous treatment for glioblastoma except for previous surgical debulking (i.e. no previous radiotherapy, local chemotherapy, or systemic therapy). 4. ECOG performance status 0 or 1 (See Appendix C) 5. Age ≥ 18 years 6. Adequate bone marrow function: hemoglobin ≥ 9.0g/dL; ANC ≥ 1500/μL; platelet count ≥ 100,000/μL. 7. Adequate liver function * Total bilirubin ≤ 1.5 x ULN * ALT and AST ≤ 2.5 x ULN 8. Serum creatinine \< 1.5 x ULN 9. Women of child-bearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of treatment. Women must agree to not breast feed while receiving study treatment. 10. Women of child-bearing potential and men must agree to use adequate contraception (barrier method of birth control) while receiving study treatment. Women should use adequate birth control for at least 3 months after the last administration of sorafenib. 11. INR \< 1.5 or PT/PTT within normal limits in patients not receiving anticoagulation. However, patients receiving anticoagulation treatment with an agent such as warfarin or heparin are also eligible. For patients on warfarin, the INR should be measured prior to initiation of sorafenib and monitored at least weekly, or as defined by the local standard of care, until INR is stable. 12. Patients must have the ability to understand and the willingness to sign written informed consent. A signed informed consent must be obtained prior to any study-specific procedures.
Exclusion criteria
1. Patients must have the ability to swallow whole pills. 2. Active cardiac disease: congestive heart failure \> class 2 NYHA (Appendix D); unstable angina or new onset angina within the last 3 months; myocardial infarction within the last 6 months. 3. Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy 4. Uncontrolled hypertension defined as systolic blood pressure \> 150mm Hg or diastolic pressure \> 90mm Hg, despite optimal medical management 5. Known human immunodeficiency virus (HIV) infection or chronic hepatitis B or C infection 6. Active clinically serious infection \> grade 2 7. Thrombotic or embolic events including cerebral vascular accident or TIAs within the past 6 months 8. Pulmonary hemorrhage/bleeding event ≥ grade 2 within 4 weeks of the first dose of sorafenib 9. Any other hemorrhage/bleeding event ≥ grade 3 within 4 weeks of the first dose of sorafenib 10. Serious non-healing wound, ulcer, or bone fracture 11. Evidence or history of bleeding diathesis or coagulopathy 12. Major surgery, open biopsy, or significant traumatic injury within 4 weeks of beginning treatment with sorafenib 13. Use of St. John's Wort or rifampicin 14. Known or suspected allergy to sorafenib or temozolomide 15. Any malabsorption problem 16. Other active malignancies, or treatment for invasive cancer within the last 2 years
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | 18 months | Defined as the duration of time from start of treatment to time of progression or death, whichever comes first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | 18 months | Defined as Day 1 of protocol treatment to date of death from any cause. |
| Objective Response | every 8 weeks until disease progression, estimated 18 months | The number of patients with complete or partial responses measured from the time of initial response to documented tumor progression. Radiologic response was defined using the Macdonald criteria. The Macdonald criteria divides response into 4 types of response based on imaging (MRI) and clinical features, as follows: 1) complete response (CR); 2) partial response (PR); 3) stable disease (SD); and 4) progression (PD). Criteria: CR: disappearance of all enhancing disease (measurable and non-measurable) sustained for at least 4 weeks, no new lesions. No corticosteroids, clinically stable or improved. PR: \>=50% decrease of all measurable enhancing lesions, sustained for at least 4 weeks, no new lesions. Stable or reduced corticosteroids, clinically stable or improved. SD: does not qualify for complete response, partial response or progression. Clinically stable. PD: \>= 25% increase in enhancing lesions, any new lesions. Clinical deterioration. |
Countries
United States
Participant flow
Recruitment details
Between April 2007 and July 2008, 47 patients were enrolled
Participants by arm
| Arm | Count |
|---|---|
| Combination Therapy In the combined modality portion of the study, patients were administered:
Radiation Therapy - 2 Gy/fraction, Single daily fractions M-F, to 60 Gy total Temozolomide - 75 mg/m2 by mouth once daily
Patients took a four week break before beginning follow-up systemic therapy:
Temozolomide - 150 mg /m2 by mouth on days 1-5 every 28 days for 6 cycles Sorafenib - 400 mg by mouth twice a day for 6 months | 47 |
| Total | 47 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Combined Modality | Adverse Event | 2 |
| Combined Modality | Intercurrent Illness - Pneumonia | 1 |
| Combined Modality | Lack of Efficacy | 2 |
| Combined Modality | Worsening Neurologic Symptoms | 2 |
| Follow-up Systemic Therapy | Intercurrent Illness - Pneumonia | 1 |
| Follow-up Systemic Therapy | Lack of Efficacy | 15 |
| Follow-up Systemic Therapy | Physician Decision | 3 |
| No Treatment Interval | Adverse Event | 1 |
| No Treatment Interval | Lack of Efficacy | 8 |
| No Treatment Interval | Physician Decision | 3 |
Baseline characteristics
| Characteristic | Combination Therapy |
|---|---|
| Age, Continuous | 54 years |
| Region of Enrollment United States | 47 participants |
| Sex: Female, Male Female | 16 Participants |
| Sex: Female, Male Male | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 32 / 47 |
| serious Total, serious adverse events | 19 / 47 |
Outcome results
Primary
Progression-free Survival
Defined as the duration of time from start of treatment to time of progression or death, whichever comes first.
Time frame: 18 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Therapy | Progression-free Survival | 6 Months |
Secondary
Objective Response
The number of patients with complete or partial responses measured from the time of initial response to documented tumor progression. Radiologic response was defined using the Macdonald criteria. The Macdonald criteria divides response into 4 types of response based on imaging (MRI) and clinical features, as follows: 1) complete response (CR); 2) partial response (PR); 3) stable disease (SD); and 4) progression (PD). Criteria: CR: disappearance of all enhancing disease (measurable and non-measurable) sustained for at least 4 weeks, no new lesions. No corticosteroids, clinically stable or improved. PR: \>=50% decrease of all measurable enhancing lesions, sustained for at least 4 weeks, no new lesions. Stable or reduced corticosteroids, clinically stable or improved. SD: does not qualify for complete response, partial response or progression. Clinically stable. PD: \>= 25% increase in enhancing lesions, any new lesions. Clinical deterioration.
Time frame: every 8 weeks until disease progression, estimated 18 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Therapy | Objective Response | 13 participants |
Secondary
Overall Survival
Defined as Day 1 of protocol treatment to date of death from any cause.
Time frame: 18 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Therapy | Overall Survival | 12 Months |