Bevacizumab Alone Versus Dose-dense Temozolomide Followed by Bevacizumab for Recurrent Glioblastoma, Phase III
Bevacizumab Alone Versus Dose-dense Temozolomide Followed by Bevacizumab for Recurrent Glioblastoma, Phase III
The aim of this Phase III study is to evaluate the superiority of dose-dense temozolomide
 (ddTMZ) followed by bevacizumab at ddTMZ failure for glioblastoma at first recurrence or
 progression, comparing to bevacizumab alone.
Glioblastoma (GBM), the most frequent malignant primary brain tumor, has yet been incurable
 despite recent progress on its standard of care using TMZ as the main trunk of initial
 therapy in the newly diagnosed setting. One of the main reasons accounting for the dismal
 prognosis would attribute to lack of active therapeutic regimens at recurrence.

 Bevacizumab, a humanized monoclonal antibody against cardinal angiogenic factor vascular
 endothelial growth factor (VEGF), has recently shown efficacy for recurrent GBM, and has been
 approved in Japan, thereby being a standard care for recurrent GBM. Since there is no
 effective drugs or regimens developed at bevacizumab failure, insertion of another active
 drug prior to bevacizumab induction would enhance survival time for patients with recurrent
 GBM.

 In Japan, there are currently only few chemotherapeutic agents approved and available for
 GBM. Among them rechallenge with alternating dosing of TMZ have shown certain efficacy with
 acceptable toxicities for patients with TMZ-pretreated recurrent GBM, thus being a good
 candidate for the regimen used prior to bevacizumab at recurrence.

 The present proposal of sequential administration of dose dense TMZ (7/14d) followed by
 bevacizumab wishes to define a new standard of care for recurrent disease and hopes to
 identify the subgroups of patients with progressive or recurrent glioblastoma that respond
 particularly well to dose-dense temozolomide regimens.

 This study is carried out as a JCOG Brain Tumor Study Group multicenter randomized phase III
 trial under approval by Advanced Medical Care B system, Ministry of Health, Labour and
 Welfare, Japan.
Inclusion Criteria:

 1. Histologically proven diagnosis of glioblastoma (including giant cell glioblastoma and
 gliosarcoma) by WHO2007 criteria.

 2. For patients who did not undergo surgery for recurrent disease; pre-registration
 contrast MRI should confirm; (i)progressive or recurrent glioblastoma; (ii)no evidence
 of acute or subacute cerebral hemorrhage at enrolment; (iii)presence of a measurable
 lesion.

 3. For patients who underwent surgery for recurrent disease; (i)progressive or recurrent
 glioblastoma must be confirmed on contrast MRI before reoperation; (ii)glioblastoma or
 anaplastic astrocytoma must be histologically identified in the tissue resected at
 reoperation; (iii)presence of measurable lesions is not mandatory on pre-registration
 contrast MRI (more than 4 days after reoperation); (iv)no MRI evidence of aggravating
 cerebral hemorrhage.

 4. No evidence of tumors in the cerebellum, brain stem, optic nerve, olfactory nerve, and
 pituitary gland.

 5. No evidence of meningeal dissemination or gliomatosis cerebri.

 6. Prior treatment for newly-diagnosed glioblastoma (or diffuse astrocytoma (Grade II) or
 anaplastic astrocytoma (Grade III)) with postoperative TMZ administered concomitantly
 with radiotherapy (>=54 Gy for <=69 years old; >=30 Gy for >=70 years old) and at
 least for two cycles (5/28d) as an adjuvant treatment have been given.

 7. No history of prior treatment with stereotactic radiotherapy (ex.
 Gamma-knife/Cyberknife), proton beam irradiation, neutron capture therapy, and
 chemotherapies except standard dose TMZ and immunotherapy (vaccines, immune checkpoint
 inhibitors, antibodies etc.), bevacizumab (12 weeks or more after termination of prior
 upfront bevacizumab use) that were combined with TMZ, and intraoperative placement of
 carmustine wafers, for glioblastoma (including diffuse astrocytoma (Grade II) and
 anaplastic astrocytoma (Grade III) at onset) diagnosed with WHO2007 criteria.

 Time periods required from the last day of the prior treatment indicated at
 registration.

 ①Peptide vaccination, immune checkpoint inhibitors, antibodies: 4 weeks.

 ②Bevacizumab: 12 weeks.

 8. More than 90 days after completion of radiotherapy. For those who underwent
 reoperation, between 21 and 28 days postoperatively.

 9. Age between 20 and 75 years at enrolment.

 10. Karnofsky Performance Status >= 60 within 14 days before enrolment.

 11. No prior treatment with chemotherapy, molecular targeted therapy, or radiotherapy to
 head and neck area for other malignancies.

 12. Adequate organ function.

 13. Written informed consent.

 Exclusion Criteria:

 1. Synchronous or metachronous (within 5 years) malignancy, except for carcinoma in situ
 or mucosal tumors curatively treated with local therapy

 2. Active infection requiring systemic therapy

 3. Body temperature >= 38 degrees Celsius at registration

 4. Women during pregnancy, possible pregnancy, within 28 days after delivery, or
 breast-feeding

 5. Psychosis or with psychotic symptom

 6. Continuous systemic use of immunosuppressant except for steroid

 7. Uncontrolled diabetes mellitus or routine administration of insulin

 8. Unstable angina within 3 weeks, with a history of myocardial infarction within 6
 months, or New York Heart Association (NYHA) class II or greater congestive heart
 failure

 9. Inadequately controlled hypertension (cannot be controlled to a systolic pressure of
 >= 150 mmHg and a diastolic pressure of >= 100 mmHg)

 10. History of symptomatic cerebrovascular disorder (including subarachnoid hemorrhage,
 cerebral infarction and transient ischemic attack) within 6 months or history of
 vascular disorder requiring intervention (including venous/arterial thrombosis or
 embolism and aortic aneurysm) within 6 moths

 11. History of grade >= 2 hemoptysis within 28 days

 12. History of hemorrhagic tendency (e.g., coagulation disorder) or any grade >= 3
 hemorrhage within 28 days

 13. History of gastrointestinal perforation, fistula, abdominal abscess or uncontrolled
 peptic ulcer within 6 months

 14. Interstitial pneumonia, pulmonary fibrosis, or severe lung emphysema

 15. Severe non-healing wound or traumatic fracture at enrolment

 16. Hypersensitivity to Chinese Hamster Ovary-derived drugs or other recombinant
 antibodies

 17. Gadolinium allergy

 18. Positive HIV antibody

 19. Positive Hepatitis B (HB)s antigen