Clinical trial NCT02761070: Bevacizumab Alone Versus Dose-dense Temozolomide Followed by Bevacizumab for Recurrent Glioblastoma, Phase III
Official title: A Multicenter Randomized Phase III Study for Recurrent Glioblastoma Comparing Bevacizumab Alone With Dose-dense Temozolomide Followed by Bevacizumab (JCOG1308C, RE-GEND-pIII)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Glioblastoma
Recurrence
Progression
Keywords: glioblastoma
recurrent
dose-dense temozolomide
bevacizumab
Lead sponsor: Kyorin University
Sponsor class: OTHER
Collaborators: name: Japan Clinical Oncology Group
First posted: 2016-05-04
Enrollment: 146
Sex: ALL
Minimum age (years): 20
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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
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

Primary outcomes:
measure: Overall survival
timeFrame: Time to event. Up to 2 years from the last patient in.
Secondary outcomes:
measure: Progression-free survival (PFS)
timeFrame: Time to event. Up to 2 years from the last patient in.
measure: 6-month progression-free survival (6m-PFS)
timeFrame: 6 months from registration
measure: Complete response rate
timeFrame: Through study completion, an average of 1 year
measure: Response rate
timeFrame: Through study completion, an average of 1 year
measure: Adverse events
timeFrame: Up to 1 year after completion/termination of the protocol treatment.
measure: Serious adverse events
timeFrame: Up to 1 year after completion/termination of the protocol treatment.
measure: Progression-free survival (PFS) from bevacizumab (BEV) initiation
timeFrame: Time to event from initiation of BEV. Up to 2 years from the last patient in.
measure: 6-month progression-free survival (6m-PFS) after initiation of bevacizumab (BEV) (Experimental Arm Only)
timeFrame: 6 months from initiation of BEV
measure: Overall survival after initiation of bevacizumab (BEV)
timeFrame: Time to event from initiation of BEV. Up to 2 years from the last patient in.
measure: MMSE non-deterioration rate
timeFrame: MMSE non-deterioration rates will be calculated at 8 and 24 weeks after initiation of protocol treatment
measure: KPS non-deterioration rate
timeFrame: KPS non-deterioration rates will be calculated at 8 and 24 weeks after initiation of protocol treatment
Other outcomes:
Locations:
city: Nagoya
country: Japan
facility: Nagoya University Hospital
state: Aichi
city: Toyoake
country: Japan
facility: Fujita Health University Hospital
state: Aichi
city: Hirosaki
country: Japan
facility: Hirosaki University School of Medicine
state: Aomori
city: Shizukawa
country: Japan
facility: Ehime University Graduate School of Medicine
state: Ehime
city: Kurume-shi
country: Japan
facility: Kurume University Hospital
state: Fukuoka
city: Sapporo
country: Japan
facility: Sapporo Medical University Hospital
state: Hokkaido
city: Kobe
country: Japan
facility: Kobe University Hospital
state: Hyougo
city: Tsukuba
country: Japan
facility: University of Tsukuba Hospital
state: Ibaraki
city: Morioka
country: Japan
facility: Iwate Medical University
state: Iwate
city: Sendai
country: Japan
facility: Tohoku University Graduate School of Medicine
state: Miyagi
city: Nagasaki-shi
country: Japan
facility: Nagasaki University Hospital
state: Nagasaki
city: Hirakata
country: Japan
facility: Kansai Medical University
state: Osaka
city: Suita
country: Japan
facility: Osaka University Graduate School of Medicine
state: Osaka
city: Saga-shi
country: Japan
facility: Saga University Hospital
state: Saga
city: Hidaka
country: Japan
facility: Saitama Medical University International Medical Center
state: Saitama
city: Shimotsuge
country: Japan
facility: Dokkyo Medical University
state: Tochigi
city: Bunkyō-Ku
country: Japan
facility: Tokyo Medical And Dental University, Medical Hospital
state: Tokyo
city: Chuo-shi
country: Japan
facility: University of Yamanashi
state: Yamanashi
city: Chiba
country: Japan
facility: Chiba University Hospital
city: Fukuoka
country: Japan
facility: Kusyu University Graduate School of Medical Sciences
city: Hiroshima
country: Japan
facility: Hiroshima University Hospital
city: Kagoshima
country: Japan
facility: Kagoshima University Graduate School of Medical and Dental Sciences
city: Kanagawa
country: Japan
facility: Kitasato University School of Medicine
city: Kumamoto
country: Japan
facility: Kumamoto University Hospital
city: Kyoto
country: Japan
facility: Kyoto University Graduate School of Medicine
city: Niigata
country: Japan
facility: Niigata University Medical & Dental Hospital
city: Okayama
country: Japan
facility: Okayama University Hospital
city: Osaka
country: Japan
facility: Osaka International Cancer Institute
city: Sapporo
country: Japan
facility: Nakamura Memorial Hospital
city: Sapporo
country: Japan
facility: Hokkaido University Graduate School of Medicine
city: Shizuoka
country: Japan
facility: Shizuoka Canser Center Hospital
city: Tokyo
country: Japan
facility: National Cancer Center Hospital
city: Tokyo
country: Japan
facility: The University of Tokyo Hospital
city: Tokyo
country: Japan
facility: Keio University Hospital
city: Tokyo
country: Japan
facility: Nihon University School of Medicine Itabashi Hospital
city: Tokyo
country: Japan
facility: Kyorin University Faculty of Medicine, Department of Neurosurgery
city: Yamagata
country: Japan
facility: Yamagata University Hospital
Study officials:
affiliation: Kyorin University Faculty of Medicine, Department of Neurosurgery
name: Motoo Nagane, M.D., Ph.D.
role: STUDY_CHAIR
References: