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

Glioblastoma Clinical Trial

— RE-GEND  

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)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02761070
• Other study ID #: JCOG1308C
• Status: Active, not recruiting
• Phase: Phase 3
• 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
• 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

Related Conditions & MeSH terms

• Glioblastoma
• Progression
• Recurrence

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