UMIN-CTR Clinical Trial

Unique ID issued by UMIN UMIN000016553
Receipt number R000019185
Scientific Title Phase 2 study of bevacizumab beyond progression disease for glioblastoma treated with key therapeutics.
Date of disclosure of the study information 2015/02/28
Last modified on 2023/01/17 08:37:23

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Basic information

Public title

Phase 2 study of bevacizumab beyond progression disease for glioblastoma treated with key therapeutics.

Acronym

BIOMARK

Scientific Title

Phase 2 study of bevacizumab beyond progression disease for glioblastoma treated with key therapeutics.

Scientific Title:Acronym

BIOMARK

Region

Japan


Condition

Condition

Newly diagnosed glioblastoma

Classification by specialty

Neurosurgery

Classification by malignancy

Malignancy

Genomic information

NO


Objectives

Narrative objectives1

The aim of this study is to evaluate efficacy and safety of temozolomide plus bevacizumab with radiotherapy as the 1st line treatment, and of subsequent treatment of bevacizmumab as the 2nd line treatment in newly diagnosed glioblastoma.

Basic objectives2

Safety,Efficacy

Basic objectives -Others


Trial characteristics_1

Exploratory

Trial characteristics_2

Pragmatic

Developmental phase

Phase II


Assessment

Primary outcomes

2-years survival rate of patients who can be treated with continuous bevacizumab from the 1st line treatment to the 2nd line treatment.

Key secondary outcomes

1). 2-years survival rate of all patients.
2). Overall survival of patients who can treated with continuous bevacizumab from the 1st line treatment to the 2nd line treatment.
3). Overall survival of all patients.
4). Progression free survival(the 1st line treatment).
5). KPS maintenance term(the 1st line treatment).
6). Response rate(the 1st line treatment).
7). QoL (Quality of Life):EORTC QLQ-C30,EORTC BN20,MDASI-BT
8). NCF (Neurocognitive Function):MMSE,HVLT-R,TMT,COWA
9). Safety


Base

Study type

Interventional


Study design

Basic design

Single arm

Randomization

Non-randomized

Randomization unit


Blinding

Open -no one is blinded

Control

Historical

Stratification


Dynamic allocation


Institution consideration


Blocking


Concealment



Intervention

No. of arms

1

Purpose of intervention

Treatment

Type of intervention

Medicine

Interventions/Control_1

Temozolomide plus bevacizumab with radiotherapy.
Subsequent treatment of continuous bevacizumab as 2nd line treatment

Interventions/Control_2


Interventions/Control_3


Interventions/Control_4


Interventions/Control_5


Interventions/Control_6


Interventions/Control_7


Interventions/Control_8


Interventions/Control_9


Interventions/Control_10



Eligibility

Age-lower limit

20 years-old <=

Age-upper limit

75 years-old >=

Gender

Male and Female

Key inclusion criteria

(1)Supratentorial, newly diagnosed and histologically confirmed glioblastoma (GBM, WHO GradeIV).
(2)Registration should be completed >=7days and <21days after craniotomy or biopsy, without drainage and infection. Surgical specimens should be available for genetic analyses.
(3)Patients without dissemination nor gliomatosis cerebri.
(4)Have provided written informed consent to enroll and supply the specimens prior to any trial specific procedures.
(5)Age >=20 years, <=75 years.
(6)Karnofsky performance status >=60.
(7)Regardless of the presence of mesurable lesions.
(8)Estimated life expectancy at least 3 months.
(9)Adequate organ function indicated by all of the following.
When there are more than one test results, the latest should be adopted.
1).neutrophil count >=1,500/mm3
2).Platelet count >=10.0*the fourth power of10/mm3
3).Haemoglobin >=9.0g/dL
4).Total bilirubin <=1.5mg/dL
5).AST, ALT <=120IU/L
6).Serum creatinine <=1.5mg/dL
7).Proteinuria <=1+
8).PT-INR <=1.5
NOTE:When treated with warfarin; 1.5<=, <=2.5

Key exclusion criteria

(1)Evidence of recent haemorrhage on postoperative magnetic resonance imaging of the brain.
(2)Any prior chemotherapy, radiotherapy or immunotherapy (including vaccine therapy) for GBM.
(3)Inadequately controlled hypertension.
(4)Prior history of hypertensive crisis, or hypertensive encephalopathy.
(5)New York Heart Association Grade II or greater congestive heart failure.
(6)Other malignancy within 5 years prior to trial enrolment.
(7)Active infection requiring systemic treatment.
(8)Diabetic with continued insulin treatment or uncontrolled.
(9)Have received continued administration of steroids to some systemic disease.
(10)Any of the following medical history within 6 months prior to registration.
1)myocardial infarction or unstable angina
2)stroke or TIAs
3)Significant vascular disease
4)Abdominal fistula or perforation of the digestive tract
5)Intracranial abscess
(11)History of >= grade 2 hemoptysis within 28 days prior to registration.
(12)Evidence of bleeding diathesis or coagulopathy.
(13)Serious non-healing wound, active ulcer or untreated bone fracture.
(14)Pregnancy or lactation, as well as fertile women and men unwilling or unable to use effective means of contraception.
(15)Known hypersensitivity to any of the trial drugs.
(16)Patients with allergy to gadolinium.
(17)Patients with active hepatic disease.
(18)Attending physician has determined unsuitable to participate in the study.

Target sample size

90


Research contact person

Name of lead principal investigator

1st name Ryo
Middle name
Last name Nishikawa

Organization

Saitama International Medical Center, Saitama Medical University

Division name

Department of Neuro-Oncology/Neurosurgery

Zip code

350-1298

Address

1397-1 Yamane, Hidaka-shi, Saitama, 350-1298

TEL

042-984-4111

Email

rnishika@saitama-med.ac.jp


Public contact

Name of contact person

1st name Ryo
Middle name
Last name Nishikawa

Organization

Saitama International Medical Center, Saitama Medical University

Division name

Department of Neuro-Oncology/Neurosurgery

Zip code

350-1298

Address

1397-1 Yamane, Hidaka-shi, Saitama, 350-1298

TEL

042-984-4111

Homepage URL


Email

rnishika@saitama-med.ac.jp


Sponsor or person

Institute

EPS Corporation

Institute

Department

Personal name



Funding Source

Organization

CHUGAI PHARMACUTICAL CO.,LTD.

Organization

Division

Category of Funding Organization

Profit organization

Nationality of Funding Organization

Japan


Other related organizations

Co-sponsor


Name of secondary funder(s)



IRB Contact (For public release)

Organization

MINS IRB

Address

5-20-9-401, Mita, Minato-ku, Tokyo

Tel

03-6416-1868

Email

npo-mins@j-irb.com


Secondary IDs

Secondary IDs

NO

Study ID_1


Org. issuing International ID_1


Study ID_2


Org. issuing International ID_2


IND to MHLW



Institutions

Institutions

北海道大学病院(北海道)、東北大学病院(宮城県)、山形大学医学部附属病院(山形県)、岩手医科大学附属病院(岩手県)、秋田大学医学部附属病院(秋田県)、順天堂大学医学部附属順天堂医院(東京都)、東京大学医学部附属病院(東京都)、国立がん研究センター中央病院(東京都)、日本赤十字社医療センター(東京都)、杏林大学医学部付属病院(東京都)、千葉県がんセンター(千葉県)、埼玉医科大学国際医療センター(埼玉県)、新潟大学医歯学総合病院(新潟県)、筑波大学附属病院(茨城県)、獨協医科大学病院(栃木県)、北里大学病院(神奈川県)、名古屋大学医学部附属病院(愛知県)、藤田医科大学病院(愛知県)、京都大学医学部附属病院(京都府)、国立病院機構京都医療センター(京都府)、国立病院機構大阪医療センター(大阪府)、大阪医科大学附属病院(大阪府)、奈良県立医科大学附属病院(奈良県)、和歌山県立医科大学附属病院(和歌山県)、神戸大学医学部附属病院(兵庫県)、広島大学病院(広島県)、岡山大学病院(岡山県)、愛媛大学附属病院(愛媛県)、九州大学病院(福岡県)、久留米大学病院(福岡県)、熊本大学医学部附属病院(熊本県)、宮崎大学医学部付属病院(宮崎県)、鹿児島大学病院(鹿児島県)、琉球大学医学部附属病院(沖縄県)、弘前大学医学部付属病院(青森県)、東京医科歯科大学医学部付属病院(東京都)、金沢大学附属病院(石川県)、佐賀大学医学部附属病院(佐賀県)、京都府立医科大学病院(京都府)


Other administrative information

Date of disclosure of the study information

2015 Year 02 Month 28 Day


Related information

URL releasing protocol

unpublished

Publication of results

Published


Result

URL related to results and publications

https://doi.org/10.3390/cancers14225522

Number of participants that the trial has enrolled

94

Results

The primary endpoint of BIOMARK was not met (the 2-year survival rate in the BBP group was 27.0% vs. the target of 50%). BBP was initiated in only a small subset (27/90 patients) of the entire cohort, where MGMT-unmethylated tumors were predominant. We identified a novel expression cluster that may predict the prognosis of GBM patients treated with bevacizumab. Further validation of the predictive value of the novel expression classifier is warranted.

Results date posted

2022 Year 12 Month 07 Day

Results Delayed


Results Delay Reason


Date of the first journal publication of results

2022 Year 11 Month 10 Day

Baseline Characteristics

The median age was 60.5 years (range, 22-75 years). Approximately half of patients (52%) had a KPS of 50-80. Most (79%) were not receiving corticosteroids at baseline. MGMT gene promoter methylation was observed in 33% of patients. The percentage of patients with WT IDH1 was 93%, whereas 5% had IDH1 mutations. Those diffuse gliomas with histological features of GBM, which were diagnosed as GBM according to the WHO Classification, 4th Ed., at the time of enrollment, have been re-classified as Astrocytoma, IDH-mutant, CNS WHO grade 4 in the latest WHO Classification, 5th Ed. (WHO CNS5). As such, survival analyses primarily focused on the IDH-wildtype tumors. TERT gene promoter mutation was observed in 66% of patients.

Participant flow

From June 2015 to December 2016, 94 patients were enrolled from 39 sites in Japan.
Data cutoff was 17 January 2019, when all outcome surveys were completed, corresponding with the protocol-specified follow-up. In total, 83 patients discontinued. The major reasons were: AEs (34.0%), progression/recurrence during the second-line treatment (24.5%), and patient decline (18.1%). All 94 patients received protocol-defined primary therapy (Safety Analysis Set). Of these, 90 were diagnosed with GBM by central pathological review and were included in the FAS. Twenty-seven patients received protocol-defined secondary therapy (BBP), and of these, 25 without protocol deviations were included in the BBP group.

Adverse events

Regarding safety, the protocol-defined therapies were generally well tolerated. Frequently observed AEs of special interest for bevacizumab (all grades) included hypertension (42.6%), proteinuria (29.8%), and mucocutaneous bleeding (10.6%). Other common AEs including myelosuppression (all grades) were lymphopenia (50%), neutropenia (27.7%), thrombocytopenia (19.1%), anemia (5.3%), appetite loss (30.9%), constipation (30.9%), nausea (18.1%), and fatigue (13.8%).
Common Grade 3 or 4 AEs were hypertension (29.8%), wound healing complications and cerebral hemorrhage (2.1%, each), and lymphopenia (41.5%). The occurrence of Grade >=3 arterial thromboembolic events was 1.1%. No new unknown toxicities were encountered.

Outcome measures

In the FAS (n = 90), mOS was 25.0 months (95% CI: 21.7-26.3) and mPFS was 14.9 months (95% CI: 11.8-18.3). The 2-year survival rate was 52.4% (90% CI: 43.3%-60.8%), and the 2-year PFS rate was 25.7% (90% CI: 18.3%-33.7%). In patients in the FAS solely with IDH1-WT GBM (n = 85), the mOS was 24.8 months (95% CI: 19.7-26.3) and the mPFS was 14.8 months (95% CI: 11.7-17.2). In the BBP group (n = 25, all IDH1-WT), the mOS and mPFS from the initial diagnosis were 16.8 months (95% CI: 14.0-23.2) and 11.4 months (95% CI: 9.0-17.1), respectively. The 2-year survival rate was 27.0% (90% CI: 13.6%-42.4%), which did not meet the prespecified target value (50%) (primary endpoint). The 2-year PFS rate was 8.0% (90% CI: 2.0%-19.7%). In the BBP group, mOS and mPFS from the initiation of BBP were 5.8 months (95% CI: 3.9-6.9) and 1.9 months (95% CI: 1.1-2.9), respectively.

Plan to share IPD


IPD sharing Plan description



Progress

Recruitment status

Completed

Date of protocol fixation

2015 Year 01 Month 30 Day

Date of IRB

2015 Year 01 Month 30 Day

Anticipated trial start date

2015 Year 06 Month 02 Day

Last follow-up date

2019 Year 01 Month 17 Day

Date of closure to data entry

2019 Year 02 Month 25 Day

Date trial data considered complete

2019 Year 02 Month 28 Day

Date analysis concluded

2019 Year 03 Month 31 Day


Other

Other related information

Genome information management:
This study is exempt from "Ethical Guidelines for Human Genome and Genetic Sequencing Research " as its research object is only somatic cell genome information of tumor tissue. However, the study is carried out with sufficient attention to the donor's personal information.


Management information

Registered date

2015 Year 02 Month 16 Day

Last modified on

2023 Year 01 Month 17 Day



Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000019185


Research Plan
Registered date File name

Research case data specifications
Registered date File name

Research case data
Registered date File name