UMIN-CTR Clinical Trial

Basic information
Official scientific title of the study	A multicenter randomized phase III study for recurrent glioblastoma comparing bevacizumab alone with dose-dense temozolomide followed by bevacizumab (JCOG1308C, RE-GEND-pIII)
Title of the study (Brief title)	A multicenter randomized phase III study for recurrent glioblastoma comparing bevacizumab alone with dose-dense temozolomide followed by bevacizumab (JCOG1308C, RE-GEND-pIII)
Region	Japan

Condition
Condition	Glioblastoma at the first relapse or progression
Classification by specialty	Neurosurgery
Classification by malignancy	Malignancy
Genomic information	NO

Objectives
Narrative objectives1	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.
Basic objectives2	Safety,Efficacy
Basic objectives -Others
Trial characteristics_1	Confirmatory
Trial characteristics_2
Developmental phase	Phase III

Assessment
Primary outcomes	Overall survival
Key secondary outcomes	Progression-free survival (PFS), 6-month PFS (6m-PFS), complete response rate, response rate, adverse events, serious adverse events, PFS from bevacizumab (BEV) initiation, 6m-PFS from BEV initiation, overall survival from BEV initiation

Base
Study type	Interventional

Study design
Basic design	Parallel
Randomization	Randomized
Randomization unit	Individual
Blinding	Open -no one is blinded
Control	Active
Stratification	NO
Dynamic allocation	YES
Institution consideration	Institution is considered as adjustment factor in dynamic allocation.
Blocking	NO
Concealment	Central registration

Intervention
No. of arms	2
Purpose of intervention	Treatment
Type of intervention	Medicine
Interventions/Control_1	Arm A: Bevacizumab alone(10 mg/kg, day 1 div, every 2 weeks)
Interventions/Control_2	Arm B: Dose-dense temozolomide (ddTMZ)-bevacizumab (BEV) sequential combination therapy. Temozolomide (120 mg/m2, po, 7 days on/7 days off, every 2 weeks per cycle) up to 48 cycles. The dose will be escalated to 150 mg/m2 at 3rd cycle if the defined conditions are met throughout the first 2 cycles. At recurrence or progression, bevacizumab alone(10 mg/kg, day 1 div, every 2 weeks)
Interventions/Control_3
Interventions/Control_4
Interventions/Control_5
Interventions/Control_6
Interventions/Control_7
Interventions/Control_8
Interventions/Control_9
Interventions/Control_10

Eligibility
Age-lower limit	20 years-old <=
Age-upper limit	75 years-old >=
Gender	Male and Female
Key inclusion criteria	1) Histologically proven diagnosis of glioblastoma (including giant cell glioblastoma and gliosarcoma). 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 anaplastic astrocytoma) 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 intraoperative placement of carmustine wafers for glioblastoma. 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) KPS >= 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.
Key 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 CHO-derived drugs or other recombinant antibodies 17) Gadolinium allergy 18) Positive HIV antibody 19) Positive HBs antigen
Target sample size	210

Research contact person
Name of lead principal investigator	Motoo Nagane
Organization	Kyorin University Faculty of Medicine
Division name	Department of Neurosurgery
Address	6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan
TEL	0422-47-5511(ext2883)
Email	mnagane@ks.kyorin-u.ac.jp

Public contact
Name of contact person	Keiichi Kobayashi
Organization	JCOG1308C Coordinating Office
Division name	Kyorin University Faculty of Medicine, Department of Neurosurgery
Address	6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan
TEL	0422-47-5511(ext7649)
Homepage URL	http://www.jcog.jp/
Email	JCOG_sir@ml.jcog.jp

Sponsor
Institute	Japan Clinical Oncology Group (JCOG)
Institute
Department

Funding Source
Organization	National Cancer Center
Organization
Division
Category of Funding Organization	Other
Nationality of Funding Organization	Japan

Other related organizations
Co-sponsor
Name of secondary funｄer(s)

Secondary IDs
Secondary IDs	YES
Study ID_1	NCT02761070
Org. issuing International ID_1	ClinicalTrials.gov
Study ID_2
Org. issuing International ID_2
IND to MHLW

Institutions

Institutions

北海道大学病院（北海道） 中村記念病院（北海道） 弘前大学医学部附属病院（青森県） 岩手医科大学（岩手県） 東北大学病院（宮城県） 山形大学医学部（山形県） 筑波大学医学医療系（茨城県） 獨協医科大学病院（栃木県） 埼玉医科大学国際医療センター（埼玉県） 千葉大学医学部（千葉県） 国立がん研究センター中央病院（東京都） 日本大学医学部附属板橋病院（東京都） 杏林大学医学部（東京都） 慶應義塾大学病院（東京都） 東京医科歯科大学（東京都） 東京大学医学部（東京都） 北里大学医学部（神奈川県） 新潟大学医歯学総合病院（新潟県） 静岡県立静岡がんセンター（静岡県） 名古屋大学医学部（愛知県） 藤田保健衛生大学（愛知県） 京都大学医学部附属病院（京都府） 大阪大学医学部（大阪府） 大阪国際がんセンター（大阪府） 関西医科大学附属病院（大阪府） 神戸大学医学部（兵庫県） 岡山大学病院（岡山県） 広島大学病院（広島県） 愛媛大学医学部附属病院（愛媛県） 九州大学病院（福岡県） 熊本大学医学部（熊本県） 鹿児島大学医学部・歯学部附属病院（鹿児島県）

Other administrative information
Date of disclosure of the study information	2016 Year 07 Month 11 Day

Progress
Recruitment status	Open public recruiting
Date of protocol fixation	2015 Year 03 Month 19 Day
Anticipated trial start date	2016 Year 07 Month 11 Day
Last follow-up date	2023 Year 07 Month 11 Day
Date of closure to data entry
Date trial data considered complete
Date analysis concluded

Related information
URL releasing protocol
Publication of results	Unpublished
URL releasing results
Results
Other related information	Advanced Medical Care B

Management information
Registered date	2016 Year 07 Month 11 Day
Last modified on	2018 Year 02 Month 27 Day

Link to view the page
URL(English)	https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000024791