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Bevacizumab Alone Versus Dose-dense Temozolomide Followed by Bevacizumab for Recurrent Glioblastoma, Phase III (RE-GEND)

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ClinicalTrials.gov Identifier: NCT02761070
Recruitment Status : Recruiting
First Posted : May 4, 2016
Last Update Posted : February 27, 2019
Sponsor:
Collaborator:
Japan Clinical Oncology Group
Information provided by (Responsible Party):
Motoo Nagane, Kyorin University

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.

Condition or disease Intervention/treatment Phase
Glioblastoma Recurrence Progression Drug: Temozolomide Drug: Bevacizumab Phase 3

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 210 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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 Start Date : July 11, 2016
Estimated Primary Completion Date : July 10, 2022
Estimated Study Completion Date : July 10, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Bevacizumab (BEV) alone
Bevacizumab 10 mg/kg, day 1 div, every 2 weeks
Drug: Bevacizumab
Other Name: Avastin

Experimental: Dose Dense Temozolomide Followed by BEV
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)
Drug: Temozolomide
Other Names:
  • Temodar
  • Temodal

Drug: Bevacizumab
Other Name: Avastin




Primary Outcome Measures :
  1. Overall survival [ Time Frame: Time to event. Up to 2 years from the last patient in. ]
    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.


Secondary Outcome Measures :
  1. Progression-free survival (PFS) [ Time Frame: Time to event. Up to 2 years from the last patient in. ]
    Progression free will be measured from registration until the first occurrence of progression or death.

  2. 6-month progression-free survival (6m-PFS) [ Time Frame: 6 months from registration ]
    Number of patients without progression at 6 months from registration divided by number of all registered

  3. Complete response rate [ Time Frame: Through study completion, an average of 1 year ]
    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.

  4. Response rate [ Time Frame: Through study completion, an average of 1 year ]
    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.

  5. Adverse events [ Time Frame: Up to 1 year after completion/termination of the protocol treatment. ]
    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.

  6. Serious adverse events [ Time Frame: Up to 1 year after completion/termination of the protocol treatment. ]
    Each serious adverse event must be recorded according to CTCAE v4.0 up to 1 year.

  7. Progression-free survival (PFS) from bevacizumab (BEV) initiation [ Time Frame: Time to event from initiation of BEV. Up to 2 years from the last patient in. ]
    Progression free from BEV initiation will be measured from the day of initiation of BEV until the first occurrence of progression or death.

  8. 6-month progression-free survival (6m-PFS) after initiation of bevacizumab (BEV) (Experimental Arm Only) [ Time Frame: 6 months from initiation of BEV ]
    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

  9. Overall survival after initiation of bevacizumab (BEV) [ Time Frame: Time to event from initiation of BEV. Up to 2 years from the last patient in. ]
    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.



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Ages Eligible for Study:   20 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02761070


Contacts
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Contact: Motoo Nagane, M.D., Ph.D. +81-422-47-5511 ext 2883 mnagane@ks.kyorin-u.ac.jp
Contact: Keiichi Kobayashi, M.D., Ph.D. +81-422-47-5511 ext 2883 kekobayashi@kki.biglobe.ne.jp

Locations
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Japan
Nagoya University Hospital Recruiting
Nagoya, Aichi, Japan, 466-8560
Contact: Toshihiko Wakabayashi, M.D., Ph.D.    +81-52-741-2111    wakabat@med.nagoya-u.ac.jp   
Fujita Health University Hospital Recruiting
Toyoake, Aichi, Japan, 470-1192
Contact: Yuichi Hirose, M.D., Ph.D.    +81-562-93-2111    yhirose@fujita-hu.ac.jp   
Hirosaki University School of Medicine Recruiting
Hirosaki, Aomori, Japan, 036-8563
Contact: Kenichiro Asano, M.D.    +81-172-39-5111    asanoken@hirosaki-u.ac.jp   
Ehime University Graduate School of Medicine Recruiting
Shizukawa, Ehime, Japan, 791-0295
Contact: Shohei Kouno, M.D.    +81-89-960-5338    kouno1220@gmail.com   
Sapporo Medical University Hospital Recruiting
Sapporo, Hokkaido, Japan, 060-8543
Contact: Nobuhiro Mikuni, M.D.    +81-11-611-2111    mikunin@sapmed.ac.jp   
Kobe University Hospital Recruiting
Kobe, Hyougo, Japan, 650-0017
Contact: Takashi Sasayama, M.D.    +81-78-382-5111    takasasa@med.kobe-u.ac.jp   
University of Tsukuba Hospital Recruiting
Tsukuba, Ibaraki, Japan, 305-8576
Contact: Eiichi Ishikawa, M.D.    +81-29-853-3900    e-ishikawa@md.tsukuba.ac.jp   
Iwate Medical University Recruiting
Morioka, Iwate, Japan, 020-8505
Contact: Takaaki Beppu, M.D.    +81-19-651-5111    tbeppu@iwate-med.ac.jp   
Tohoku University Graduate School of Medicine Recruiting
Sendai, Miyagi, Japan, 980-8574
Contact: Masayuki Kanamori, M.D.    +81-22-717-7000    mkanamori@med.tohoku.ac.jp   
Kansai Medical University Recruiting
Hirakata, Osaka, Japan, 573-1191
Contact: Akio Asai, M.D.    +81-72-804-0101    aasaikun@hirakata.kmu.ac.jp   
Contact: Masahiro Nonaka, M.D.    +81-72-804-0101    nonakamasa65@gmail.com   
Osaka University Graduate School of Medicine Recruiting
Suita, Osaka, Japan, 565-0871
Contact: Naoki Kagawa, M.D.    +81-6-6879-3652    nkagawa@nsurg.med.osaka-u.ac.jp   
Saitama Medical University International Medical Center Recruiting
Hidaka, Saitama, Japan, 350-1298
Contact: Ryo Nishikawa, M.D., Ph.D.    +81-42-984-4111    rnishika@saitama-med.ac.jp   
Contact: Kazuhiko Misima, M.D., Ph.D.    +81-42-984-4111    kmishima@saitama-med.ac.jp   
Dokkyo Medical University Recruiting
Shimotsuge, Tochigi, Japan, 321-0293
Contact: Keisuke Ueki, M.D., Ph.D.    +81-282-86-1111    kueki-tky@umin.ac.jp   
Tokyo Medical And Dental University, Medical Hospital Recruiting
Bunkyō-Ku, Tokyo, Japan, 113-8519
Contact: Taketoshi Maehara, M.D.    +81-3-3813-6111    maehara.nsrg@tmd.ac.jp   
Chiba University Hospital Recruiting
Chiba, Japan, 260-8677
Contact: Yasuo Iwadate, M.D.    +81-43-222-7171    iwadatey@faculty.chiba-u.jp   
Kusyu University Graduate School of Medical Sciences Recruiting
Fukuoka, Japan, 812-8582
Contact: Masahiro Mizoguchi, M.D.    +81-92-642-5524    mmizoguc@ns.med.kyushu-u.ac.jp   
Hiroshima University Hospital Recruiting
Hiroshima, Japan, 734-8551
Contact: Kazuhiko Sugiyama, M.D.    +81-82-257-5227    sugiyama-hma@umin.ac.jp   
Kagoshima University Graduate School of Medical and Dental Sciences Recruiting
Kagoshima, Japan, 890-8520
Contact: Koji Yoshimoto, M.D., Ph.D.    +81-99-275-5111    kyoshimo@m.kufm.kagoshima-u.ac.jp   
Kitasato University School of Medicine Recruiting
Kanagawa, Japan, 252-0374
Contact: Toshihiro Kumabe, M.D., Ph.D.    +81-3-3972-8111    kuma@kitasato-u.ac.jp   
Kumamoto University Hospital Recruiting
Kumamoto, Japan, 860-8556
Contact: Akitake Mukasa, M.D., Ph.D.    +81-96-344-2111    mukasa@kumamoto-u.ac.jp   
Kyoto University Graduate School of Medicine Recruiting
Kyoto, Japan, 606-8507
Contact: Yoshiki Arakawa, M.D.    +81-75-366-7776    yarakawa@kuhp.kyoto-u.ac.jp   
Niigata University Medical & Dental Hospital Recruiting
Niigata, Japan, 951-8520
Contact: Manabu Natsumeda, M.D.    +81-25-223-6161    mnatsumeda@bri.niigata-u.ac.jp   
Okayama University Hospital Recruiting
Okayama, Japan, 700-8558
Contact: Isao Date, M.D.    +81-86-223-7151    idate333@md.okayama-u.ac.jp   
Osaka International Cancer Institute Recruiting
Osaka, Japan, 541-8567
Contact: Noriko Okita, M.D.    +81-6-6945-1181    yokita4246@gmail.com   
Nakamura Memorial Hospital Recruiting
Sapporo, Japan, 060-8570
Contact: Kenichi Sato, M.D.    +81-11-231-8555    satoken@med.nmh.or.jp   
Hokkaido University Graduate School of Medicine Recruiting
Sapporo, Japan, 060-8648
Contact: Hiroyuki Kobayashi, M.D.    +81-11-716-1161    hiro-ko@med.hokudai.ac.jp   
Shizuoka Canser Center Hospital Recruiting
Shizuoka, Japan, 411-8777
Contact: Yoko Nakasu, M.D.    +81-55-989-5222    y.nakasu@scchr.jp   
Contact: Kouichi Mitsuya, M.D.    +81-55-989-5222    k.mitsuya@scchr.jp   
National Cancer Center Hospital Recruiting
Tokyo, Japan, 104-0045
Contact: Yoshitaka Narita, M.D., Ph.D.    +81-3-542-2511    yonarita@ncc.go.jp   
The University of Tokyo Hospital Recruiting
Tokyo, Japan, 113-8655
Contact: Shota Tanaka, M.D.    +81-3-5800-8853    tanakas-tky@umin.ac.jp   
Keio University Hospital Recruiting
Tokyo, Japan, 160-8582
Contact: Hikaru Sasaki, M.D.    +81-3-3353-1211    hsasaki@a5.keio.jp   
Nihon University School of Medicine Itabashi Hospital Recruiting
Tokyo, Japan, 173-0032
Contact: Atsuo Yoshino, M.D.    +81-3-3972-8111    yoshino.atsuo@nihon-u.ac.jp   
Contact: Shun Yamamuro, M.D.    +81-3-3972-8111    yamamuro.shun@nihon-u.ac.jp   
Kyorin University Faculty of Medicine, Department of Neurosurgery Recruiting
Tokyo, Japan, 181-8611
Contact: Keiichi Kobayashi, M.D., Ph.D.    +81-422-47-5511    kekobayashi@kki.biglobe.ne.jp   
Contact: Motoo Nagane, M.D., Ph.D.    +81-422-47-5511    mnagane@ks.kyorin-u.ac.jp   
Yamagata University Hospital Recruiting
Yamagata, Japan, 990-9585
Contact: Yukihiko Sonoda, M.D.    +81-23-633-1122    ysonoda@med.id.yamagata-u.ac.jp   
Sponsors and Collaborators
Kyorin University
Japan Clinical Oncology Group
Investigators
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Study Chair: Motoo Nagane, M.D., Ph.D. Kyorin University Faculty of Medicine, Department of Neurosurgery

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Responsible Party: Motoo Nagane, Professor, Kyorin University
ClinicalTrials.gov Identifier: NCT02761070     History of Changes
Other Study ID Numbers: JCOG1308C
First Posted: May 4, 2016    Key Record Dates
Last Update Posted: February 27, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Motoo Nagane, Kyorin University:
glioblastoma
recurrent
dose-dense temozolomide
bevacizumab

Additional relevant MeSH terms:
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Glioblastoma
Recurrence
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Disease Attributes
Pathologic Processes
Bevacizumab
Temozolomide
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action