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

August 31, 2021 updated by: Motoo Nagane, Kyorin University

A Multicenter Randomized Phase III Study for Recurrent Glioblastoma Comparing Bevacizumab Alone With Dose-dense Temozolomide Followed by Bevacizumab (JCOG1308C, RE-GEND-pIII)

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Anticipated)

146

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Japan
      • Chiba, Japan, 260-8677
      • Fukuoka, Japan, 812-8582
        • Recruiting
        • Kusyu University Graduate School of Medical Sciences
        • Contact:
      • Hiroshima, Japan, 734-8551
        • Recruiting
        • Hiroshima University Hospital
        • Contact:
      • Kagoshima, Japan, 890-8520
        • Recruiting
        • Kagoshima University Graduate School of Medical and Dental Sciences
        • Contact:
      • Kanagawa, Japan, 252-0374
        • Recruiting
        • Kitasato University School of Medicine
        • Contact:
      • Kumamoto, Japan, 860-8556
        • Recruiting
        • Kumamoto University Hospital
        • Contact:
      • Kyoto, Japan, 606-8507
        • Recruiting
        • Kyoto University Graduate School of Medicine
        • Contact:
      • Niigata, Japan, 951-8520
        • Recruiting
        • Niigata University Medical & Dental Hospital
        • Contact:
      • Okayama, Japan, 700-8558
      • Osaka, Japan, 541-8567
      • Sapporo, Japan, 060-8570
        • Recruiting
        • Nakamura Memorial Hospital
        • Contact:
      • Sapporo, Japan, 060-8648
        • Recruiting
        • Hokkaido University Graduate School of Medicine
        • Contact:
      • Shizuoka, Japan, 411-8777
        • Recruiting
        • Shizuoka Canser Center Hospital
        • Contact:
          • Nakamasa Hayashi, M.D.
          • Phone Number: +81-55-989-5222
        • Contact:
      • Tokyo, Japan, 104-0045
        • Recruiting
        • National Cancer Center Hospital
        • Contact:
      • Tokyo, Japan, 113-8655
        • Recruiting
        • The University of Tokyo Hospital
        • Contact:
      • Tokyo, Japan, 160-8582
        • Suspended
        • Keio University Hospital
      • Tokyo, Japan, 173-0032
      • Tokyo, Japan, 181-8611
        • Recruiting
        • Kyorin University Faculty of Medicine, Department of Neurosurgery
        • Contact:
        • Contact:
      • Yamagata, Japan, 990-9585
    • Aichi
      • Nagoya, Aichi, Japan, 466-8560
        • Recruiting
        • Nagoya University Hospital
        • Contact:
      • Toyoake, Aichi, Japan, 470-1192
        • Recruiting
        • Fujita Health University Hospital
        • Contact:
    • Aomori
      • Hirosaki, Aomori, Japan, 036-8563
        • Recruiting
        • Hirosaki University School of Medicine
        • Contact:
    • Ehime
      • Shizukawa, Ehime, Japan, 791-0295
        • Recruiting
        • Ehime University Graduate School of Medicine
        • Contact:
          • Takeharu Kunieda, M.D.
          • Phone Number: +81-89-960-5338
    • Fukuoka
      • Kurume-shi, Fukuoka, Japan, 830-0011
        • Recruiting
        • Kurume University Hospital
        • Contact:
    • Hokkaido
      • Sapporo, Hokkaido, Japan, 060-8543
        • Recruiting
        • Sapporo Medical University Hospital
        • Contact:
    • Hyougo
      • Kobe, Hyougo, Japan, 650-0017
        • Recruiting
        • Kobe University Hospital
        • Contact:
    • Ibaraki
      • Tsukuba, Ibaraki, Japan, 305-8576
        • Recruiting
        • University of Tsukuba Hospital
        • Contact:
    • Iwate
      • Morioka, Iwate, Japan, 020-8505
        • Recruiting
        • Iwate Medical University
        • Contact:
    • Miyagi
      • Sendai, Miyagi, Japan, 980-8574
        • Recruiting
        • Tohoku University Graduate School of Medicine
        • Contact:
    • Nagasaki
      • Nagasaki-shi, Nagasaki, Japan, 852-8501
        • Recruiting
        • Nagasaki University Hospital
        • Contact:
          • Takayuki Matsuo, M.D., Ph.D.
          • Phone Number: +81-95-819-7200
    • Osaka
      • Hirakata, Osaka, Japan, 573-1191
        • Suspended
        • Kansai Medical University
      • Suita, Osaka, Japan, 565-0871
    • Saga
      • Saga-shi, Saga, Japan, 849-8501
        • Recruiting
        • Saga University Hospital
        • Contact:
    • Saitama
      • Hidaka, Saitama, Japan, 350-1298
        • Recruiting
        • Saitama Medical University International Medical Center
        • Contact:
        • Contact:
    • Tochigi
      • Shimotsuge, Tochigi, Japan, 321-0293
        • Recruiting
        • Dokkyo Medical University
        • Contact:
    • Tokyo
      • Bunkyō-Ku, Tokyo, Japan, 113-8519
        • Recruiting
        • Tokyo Medical And Dental University, Medical Hospital
        • Contact:
    • Yamanashi
      • Chuo-shi, Yamanashi, Japan, 400-8510
        • Recruiting
        • University of Yamanashi
        • Contact:
          • Hiroyuki Kiuchi, M.D., Ph.D.
          • Phone Number: +81-55-252-1111

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 73 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Bevacizumab (BEV) alone
Bevacizumab 10 mg/kg, day 1 div, every 2 weeks
Drug: Bevacizumab
Other Names:
  • 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 Names:
  • Avastin

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Time to event. Up to 2 years from the last patient in.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Time to event. Up to 2 years from the last patient in.
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
6 months from registration
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.
Through study completion, an average of 1 year
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.
Through study completion, an average of 1 year
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.
Up to 1 year after completion/termination of the protocol treatment.
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.
Up to 1 year after completion/termination of the protocol treatment.
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.
Time to event from initiation of BEV. Up to 2 years from the last patient in.
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
6 months from initiation of BEV
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.
Time to event from initiation of BEV. Up to 2 years from the last patient in.
MMSE non-deterioration rate
Time Frame: MMSE non-deterioration rates will be calculated at 8 and 24 weeks after initiation of protocol treatment
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
KPS non-deterioration rate
Time Frame: KPS non-deterioration rates will be calculated at 8 and 24 weeks after initiation of protocol treatment
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Kyorin University

Collaborators

Japan Clinical Oncology Group

Investigators

  • Study Chair: Motoo Nagane, M.D., Ph.D., Kyorin University Faculty of Medicine, Department of Neurosurgery

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 11, 2016

Primary Completion (Anticipated)

November 10, 2025

Study Completion (Anticipated)

November 10, 2025

Study Registration Dates

First Submitted

April 28, 2016

First Submitted That Met QC Criteria

May 2, 2016

First Posted (Estimate)

May 4, 2016

Study Record Updates

Last Update Posted (Actual)

September 2, 2021

Last Update Submitted That Met QC Criteria

August 31, 2021

Last Verified

August 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • JCOG1308C

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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