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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 : September 2, 2021
Sponsor:
Collaborator:
Japan Clinical Oncology Group
Information provided by (Responsible Party):
Motoo Nagane, Kyorin University

Study Description
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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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 146 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)
Actual Study Start Date : July 11, 2016
Estimated Primary Completion Date : November 10, 2025
Estimated Study Completion Date : November 10, 2025

Resource links provided by the National Library of Medicine


Arms and Interventions
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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


Outcome Measures
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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.

  10. 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.

  11. 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.


Eligibility Criteria
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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
  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
Contacts and Locations
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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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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
More Information
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Responsible Party: Motoo Nagane, Professor, Kyorin University
ClinicalTrials.gov Identifier: NCT02761070    
Other Study ID Numbers: JCOG1308C
First Posted: May 4, 2016    Key Record Dates
Last Update Posted: September 2, 2021
Last Verified: August 2021
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