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Clinical Trial Details — Status: Active, not recruiting

Administrative data

NCT number NCT02761070
Other study ID # JCOG1308C
Secondary ID
Status Active, not recruiting
Phase Phase 3
First received
Last updated
Start date July 11, 2016
Est. completion date November 10, 2025

Study information

Verified date March 2023
Source Kyorin University
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


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.


Recruitment information / eligibility

Status Active, not recruiting
Enrollment 146
Est. completion date November 10, 2025
Est. primary completion date November 10, 2025
Accepts healthy volunteers No
Gender All
Age group 20 Years to 75 Years
Eligibility 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. ?Peptide vaccination, immune checkpoint inhibitors, antibodies: 4 weeks. ?Bevacizumab: 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

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
Temozolomide

Bevacizumab


Locations

Country Name City State
Japan Tokyo Medical And Dental University, Medical Hospital Bunkyo-Ku Tokyo
Japan Chiba University Hospital Chiba
Japan University of Yamanashi Chuo-shi Yamanashi
Japan Kusyu University Graduate School of Medical Sciences Fukuoka
Japan Saitama Medical University International Medical Center Hidaka Saitama
Japan Kansai Medical University Hirakata Osaka
Japan Hirosaki University School of Medicine Hirosaki Aomori
Japan Hiroshima University Hospital Hiroshima
Japan Kagoshima University Graduate School of Medical and Dental Sciences Kagoshima
Japan Kitasato University School of Medicine Kanagawa
Japan Kobe University Hospital Kobe Hyougo
Japan Kumamoto University Hospital Kumamoto
Japan Kurume University Hospital Kurume-shi Fukuoka
Japan Kyoto University Graduate School of Medicine Kyoto
Japan Iwate Medical University Morioka Iwate
Japan Nagasaki University Hospital Nagasaki-shi Nagasaki
Japan Nagoya University Hospital Nagoya Aichi
Japan Niigata University Medical & Dental Hospital Niigata
Japan Okayama University Hospital Okayama
Japan Osaka International Cancer Institute Osaka
Japan Saga University Hospital Saga-shi Saga
Japan Hokkaido University Graduate School of Medicine Sapporo
Japan Nakamura Memorial Hospital Sapporo
Japan Sapporo Medical University Hospital Sapporo Hokkaido
Japan Tohoku University Graduate School of Medicine Sendai Miyagi
Japan Dokkyo Medical University Shimotsuge Tochigi
Japan Ehime University Graduate School of Medicine Shizukawa Ehime
Japan Shizuoka Canser Center Hospital Shizuoka
Japan Osaka University Graduate School of Medicine Suita Osaka
Japan Keio University Hospital Tokyo
Japan Kyorin University Faculty of Medicine, Department of Neurosurgery Tokyo
Japan National Cancer Center Hospital Tokyo
Japan Nihon University School of Medicine Itabashi Hospital Tokyo
Japan The University of Tokyo Hospital Tokyo
Japan Fujita Health University Hospital Toyoake Aichi
Japan University of Tsukuba Hospital Tsukuba Ibaraki
Japan Yamagata University Hospital Yamagata

Sponsors (2)

Lead Sponsor Collaborator
Kyorin University Japan Clinical Oncology Group

Country where clinical trial is conducted

Japan, 

Outcome

Type Measure Description Time frame Safety issue
Primary Overall survival Overall survival will be measured from registration until death for any reason. If the patient is alive at last follow-up, the patient will be censored at the last time of confirmation of survival. Time to event. Up to 2 years from the last patient in.
Secondary Progression-free survival (PFS) Progression free will be measured from registration until the first occurrence of progression or death. Time to event. Up to 2 years from the last patient in.
Secondary 6-month progression-free survival (6m-PFS) Number of patients without progression at 6 months from registration divided by number of all registered 6 months from registration
Secondary Complete response rate Complete response rate is defined as the rate of complete response after chemotherapy in cases with measurable lesions through completion/termination of the protocol treatment. Through study completion, an average of 1 year
Secondary Response rate Response rate is defined as the rate of complete response/partial response after chemotherapy in cases with measurable lesions through completion/termination of the protocol treatment. Through study completion, an average of 1 year
Secondary Adverse events Each adverse event must be graded as the worst grade observed during the entire treatment period of each treatment protocol according to Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) up to 1 year. Up to 1 year after completion/termination of the protocol treatment.
Secondary Serious adverse events Each serious adverse event must be recorded according to CTCAE v4.0 up to 1 year. Up to 1 year after completion/termination of the protocol treatment.
Secondary Progression-free survival (PFS) from bevacizumab (BEV) initiation Progression free from BEV initiation will be measured from the day of initiation of BEV until the first occurrence of progression or death. Time to event from initiation of BEV. Up to 2 years from the last patient in.
Secondary 6-month progression-free survival (6m-PFS) after initiation of bevacizumab (BEV) (Experimental Arm Only) Number of patients without progression at 6 months from the day of initiation of BEV divided by number of all second-line (BEV) treated in Experimental Arm 6 months from initiation of BEV
Secondary Overall survival after initiation of bevacizumab (BEV) Overall survival from the day of initiation of BEV until death for any reason. If the patient is alive at last follow-up, the patient will be censored at the last time of confirmation of survival. Time to event from initiation of BEV. Up to 2 years from the last patient in.
Secondary MMSE non-deterioration rate The MMSE (Mini Mental Status Examination) non-deterioration rate is calculated from the number of patients who underwent baseline MMSE evaluation prior to initiation of protocol treatment as a denominator and the number of those whose MMSE score (normal (30-24), mild decrease (23-20), intermediate decrease (19-10), severe decrease (9-0)) at 16 weeks improved or maintained from that at baseline as a numerator among all eligible patients. MMSE non-deterioration rates will be calculated at 8 and 24 weeks after initiation of protocol treatment
Secondary KPS non-deterioration rate The KPS non-deterioration rate is calculated from the number of patients whose KPS was recorded prior to initiation of protocol treatment as a denominator and the number of those whose KPS score at 16 weeks improved or maintained from that at baseline as a numerator among all eligible patients. In case KPS is not recorded, it is considered as deterioration. KPS non-deterioration rates will be calculated at 8 and 24 weeks after initiation of protocol treatment
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