Bevacizumab Alone Versus Dose-dense Temozolomide Followed by Bevacizumab for Recurrent Glioblastoma, Phase III

NCT ID: NCT02761070

Last Updated: 2023-03-08

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 146 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-07-11
• Study Completion Date: 2025-11-10

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.

Conditions

Glioblastoma; Recurrence; Progression

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Bevacizumab (BEV) alone

Bevacizumab 10 mg/kg, day 1 div, every 2 weeks

Group Type: ACTIVE_COMPARATOR

Bevacizumab

Intervention Type: DRUG

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)

Group Type: EXPERIMENTAL

Temozolomide

Intervention Type: DRUG

Bevacizumab

Intervention Type: DRUG

Interventions

Temozolomide

Intervention Type: DRUG

Bevacizumab

Intervention Type: DRUG

Other Intervention Names

Temodar; Temodal; Avastin

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

• Minimum Eligible Age: 20 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Japan Clinical Oncology Group

OTHER

Sponsor Role: collaborator

Kyorin University

OTHER

Sponsor Role: lead

Responsible Party

Motoo Nagane

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Motoo Nagane, M.D., Ph.D.

Role: STUDY_CHAIR

Kyorin University Faculty of Medicine, Department of Neurosurgery

Locations

Nagoya University Hospital

Nagoya, Aichi-ken, Japan

Fujita Health University Hospital

Toyoake, Aichi-ken, Japan

Hirosaki University School of Medicine

Hirosaki, Aomori, Japan

Ehime University Graduate School of Medicine

Shizukawa, Ehime, Japan

Kurume University Hospital

Kurume-shi, Fukuoka, Japan

Sapporo Medical University Hospital

Sapporo, Hokkaido, Japan

Kobe University Hospital

Kobe, Hyōgo, Japan

University of Tsukuba Hospital

Tsukuba, Ibaraki, Japan

Iwate Medical University

Morioka, Iwate, Japan

Tohoku University Graduate School of Medicine

Sendai, Miyagi, Japan

Nagasaki University Hospital

Nagasaki, Nagasaki, Japan

Kansai Medical University

Hirakata, Osaka, Japan

Osaka University Graduate School of Medicine

Suita, Osaka, Japan

Saga University Hospital

Saga, Saga-ken, Japan

Saitama Medical University International Medical Center

Hidaka, Saitama, Japan

Dokkyo Medical University

Shimotsuge, Tochigi, Japan

Tokyo Medical And Dental University, Medical Hospital

Bunkyō-Ku, Tokyo, Japan

University of Yamanashi

Chuo-shi, Yamanashi, Japan

Chiba University Hospital

Chiba, , Japan

Kusyu University Graduate School of Medical Sciences

Fukuoka, , Japan

Hiroshima University Hospital

Hiroshima, , Japan

Kagoshima University Graduate School of Medical and Dental Sciences

Kagoshima, , Japan

Kitasato University School of Medicine

Kanagawa, , Japan

Kumamoto University Hospital

Kumamoto, , Japan

Kyoto University Graduate School of Medicine

Kyoto, , Japan

Niigata University Medical & Dental Hospital

Niigata, , Japan

Okayama University Hospital

Okayama, , Japan

Osaka International Cancer Institute

Osaka, , Japan

Nakamura Memorial Hospital

Sapporo, , Japan

Hokkaido University Graduate School of Medicine

Sapporo, , Japan

Shizuoka Canser Center Hospital

Shizuoka, , Japan

National Cancer Center Hospital

Tokyo, , Japan

The University of Tokyo Hospital

Tokyo, , Japan

Keio University Hospital

Tokyo, , Japan

Nihon University School of Medicine Itabashi Hospital

Tokyo, , Japan

Kyorin University Faculty of Medicine, Department of Neurosurgery

Tokyo, , Japan

Yamagata University Hospital

Yamagata, , Japan

Countries

Japan

Other Identifiers

JCOG1308C

Identifier Type: -

Identifier Source: org_study_id