UMIN-CTR Clinical Trial

Public title

A multi-center proof-of-concept phase2 study of encorafenib + binimetinib + cetuximab in patients with BRAF non-V600E mutated metastatic colorectal cancer

Acronym

BIG BANG Study

Scientific Title

A multi-center proof-of-concept phase2 study of encorafenib + binimetinib + cetuximab in patients with BRAF non-V600E mutated metastatic colorectal cancer

Scientific Title:Acronym

BIG BANG Study

Region

Japan

Condition

Colorectal cancer

Classification by specialty

Pneumology

Classification by malignancy

Malignancy

Genomic information

YES

Narrative objectives1

To evaluate the clinical efficacy, safety, and proof-of-concept (POC) of combination therapy consisting of BRAF inhibitor (encorafenib), MEK inhibitor (binimetinib), and an anti-epidermal growth factor receptor (EGFR) antibody (cetuximab) in patients with BRAF non-V600E mutated metastatic CRC.

Basic objectives2

Safety,Efficacy

Basic objectives -Others

Trial characteristics_1

Trial characteristics_2

Developmental phase

Primary outcomes

Confirmed objective response rate by investigators' assessment

Key secondary outcomes

Study type

Interventional

Basic design

Single arm

Randomization

Non-randomized

Randomization unit

Blinding

Open -no one is blinded

Control

Uncontrolled

Stratification

Dynamic allocation

Institution consideration

Blocking

Concealment

No. of arms

1

Purpose of intervention

Treatment

Type of intervention

Medicine

Interventions/Control_1

Combination therapy of encorafenib + binimetinib+ cetuximab
One cycle is 28 days.
Binimetinib: 45 mg, twice daily, oral
Encorafenib: 300 mg, once daily, oral
Cetuximab: 400 mg/m2 for initial dose, 250 mg/m2 for subsequent doses, weekly, intravenous infusion

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

Age-lower limit

20

years-old

<=

Age-upper limit

Not applicable

Gender

Male and Female

Key inclusion criteria

Patients who meet all of the inclusion criteria A and B, and do not fall under the any of exclusion criteria will be enrolled as patients for study treatment.
At least 8 patients with lesions eligible for biopsy should be enrolled in the primary analysis parts; biopsy of lesions of which measurement in accordance with the RECIST version 1.1 is performed is accepted.


Inclusion criteria A
1.Age of 20 years or older on the day of signing informed consent
2.Confirmed diagnosis of advanced (unresectable) or metastatic colorectal cancer (mCRC) by tissue diagnosis
3.Patients who did not respond to or tolerate at least one chemotherapy regimen (including irinotecan or oxaliplatin) containing fluoropyrimidine drugs in the treatment of metastatic CRC, and are thus eligible for second or later line treatment
4.RAS wild-type and BRAF non-V600E mutated CRC. The diagnosis should be based on the results of associated genetic tests, and the record should be available
5.Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1

Inclusion criteria B:
1.Measurable lesions in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
2.Patients with the adequate organ functions
3.Adequate cardiac function characterized by the following at screening
1)Left ventricular ejection fraction (LVEF) over 50% as determined by a MUGA scan or ECHO;
2)Mean triplicate QT interval corrected for heart rate using Fridericia's formula (QTcF) value less than 480 msec
4.Women of childbearing potential who are negative in a urine pregnancy test
5.Female patients and male patients must agree to take appropriate precautions to avoid pregnancy from the day of signing informed consent through 90 days after the final administration of investigational drugs.

Key exclusion criteria

1.History of treatment with epidermal growth factor receptor (EGFR) inhibitors including anti-EGFR antibody drugs
2.History of treatment with BRAF inhibitors or MEK inhibitors
3.History of treatment with regorafenib
4.Symptomatic brain metastases or meningeal dissemination
5.Leptomeningeal disease
6.Medical history, current condition, or risk of retinal vein occlusion
7.Inadequately controlled diabetes requiring insulin therapy
8.Acute or chronic pancreatitis
9.Medical history of clinically significant cardiac diseases
10.Gastrointestinal function or gastrointestinal diseases that significantly interfere with absorption, distribution, metabolism, and excretion of the study drugs
11.No history of other malignant tumors within 3 years before the start of study treatment. In cases of lesions corresponding to carcinoma in situ and intramucosal carcinoma judged to be cured by local therapy, non-metastatic prostate cancer not requiring systemic therapy, and other solid cancers that do not require therapy or are not estimated to be adversely affected by the study treatment, patients will not be excluded from the study when the coordinating committee concludes after consultation that there is no effect on the patient's prognosis.
12.Medical history of thromboembolism within 6 months
13.Concurrent neuromuscular disorder that is associated with the potential of elevated CK
14.Previous treatment with any of the following,
a.cyclical chemotherapy within a period of 14 days
b.bevacizumab, aflibercept, or ramucirumab within 3 weeks
c.biologic therapy (except bevacizumab, aflibercept, or ramucirumab), immunotherapy, marketed small molecular compounds, or non marketed investigational anticancer treatments within 4 weeks, or within a period 5fold the halflife (whichever is shorter)
d.prior radiotherapy to 30% of bone marrow

Target sample size

36

Name of lead principal investigator

1st name	Hideaki
Middle name
Last name	Bando

Organization

National Cancer Center Hospital East

Division name

Department of Gastrointestinal Oncology

Zip code

2778577

Address

6-5-1,Kashiwanoha,Kashiwa,Chiba,277-8577,Japan

TEL

04-7133-1111

Email

BIGBANG_core@east.ncc.go.jp

Name of contact person

1st name	Daisuke
Middle name
Last name	Kotani

Organization

National Cancer Center Hospital East

Division name

Department of Gastrointestinal Oncology

Zip code

2778577

Address

6-5-1,Kashiwanoha,Kashiwa,Chiba,277-8577,Japan

TEL

04-7133-1111

Homepage URL

Email

BIGBANG_core@east.ncc.go.jp

Institute

National Cancer Center Hospital Eas

Institute

Department

Personal name

Organization

Japan Agency for Medical Research and Development

Organization

Division

Category of Funding Organization

Government offices of other countries

Nationality of Funding Organization

Co-sponsor

Name of secondary funder(s)

Organization

National Cancer Center Institutional Review Board

Address

5-1-1 Tsukiji, Chuo-ku Tokyo, 104-0045 Japan

Tel

03-3542-2511

Email

irboffice@east.ncc.go.jp

Secondary IDs

NO

Study ID_1

Org. issuing International ID_1

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

愛知県がんセンター中央病院　(愛知県)、国立がん研究センター東病院（千葉県）、九州がんセンター(福岡県)、四国がんセンター(愛媛県)、北海道大学病院(北海道)、聖マリアンナ医科大学病院(神奈川県)

Date of disclosure of the study information

2018

Year

04

Month

01

Day

URL releasing protocol

2020;5(1):e000624. doi: 10.1136/esmoopen-2019-000624. Epub 2020 Sep 30.

Publication of results

Unpublished

URL related to results and publications

TBD

Number of participants that the trial has enrolled

32

Results

In the FAS of the primary analysis part, which was the primprimary endpoint, the number of responding subjects was 2/12, and the ORR (95% CI) was 16.7 (2.1-48.4)%. The lower limit of the 95% CI (2.1%) was below the threshold for the response rate (6%) (p = 0.1595), so no statistically significant difference was observed.
From the viewpoint of efficacy, this protocol treatment could not be statistically judged as a promising treatment.

Results date posted

2025

Year

01

Month

15

Day

Results Delayed

Results Delay Reason

Date of the first journal publication of results

Baseline Characteristics

The median age of the 12 cases in the FAS for the primary analysis part was 69 years, and 41.7% (5/12 cases) were male. The primary site was the cecum in 33.3% (4/12 cases), the ascending colon in 25.0% (3/12 cases), the upper rectum and lower rectum in 16.7% each (2/12 cases), and the rectosigmoid in 8.3% (1/12 cases). The clinical stage at the time of initial onset was IV in 75.0% (9/12 cases), III in 16.7% (2/12 cases), and II in 8.3% (1/12 cases).
The median age of the 20 FAS cases in the anti-EGFR antibody drug refractory part was 59.5 years, and 55.0% (11/20 cases) were male. The primary site was the sigmoid colon in 30.0% (6/20 cases), the rectosigmoid in 20.0% (4/20 cases), the lower rectum in 15.0% (3/20 cases), the cecum, ascending colon, and upper rectum in 10.0% each (2/20 cases), and the transverse colon in 5.0% (1/20 cases). The clinical stage at the time of initial presentation was IV in 65.0% (13/20 cases), III in 25.0% (5/20 cases), II in 5.0% (1/20 cases), and I in 5.0% (1/20 cases).

Participant flow

Of the 32 patients enrolled in this clinical trial, 12 patients with unresectable or recurrent colorectal cancer whose tumor tissue was determined to be positive for BRAF non-V600E gene mutation were included in the primary analysis part, and 20 patients with unresectable or recurrent colorectal cancer whose tumor tissue was determined to be positive for BRAF non-V600E gene mutation and who were refractory to anti-EGFR antibody drugs were included in the anti-EGFR antibody drug refractory part.

In this clinical trial, all 12 patients in the primary analysis part discontinued the protocol treatment, and the reasons for discontinuation were RECIST PD (clear progression of the underlying disease by imaging diagnosis) (10 cases), Clinical PD (clinically clear progression) (1 case), and adverse events (1 case). Similarly, all 20 patients in the anti-EGFR antibody drug refractory part discontinued the protocol treatment, and the reasons for discontinuation were RECIST PD (17 cases), adverse events (2 cases), and death (1 case).

Adverse events

A total of 131 adverse events occurred in all 12 SP patients (100%) in the primary analysis part. Adverse events occurring in 15% or more of subjects (2/12 or more) were dermatitis acneiform in 58.3% (7/12 patients), nausea in 50.0% (6/12 patients), diarrhea, pyrexia, and increased aspartate aminotransferase in 41.7% (5/12 patients), stomatitis, increased alanine aminotransferase, hypoalbuminemia, and decreased appetite in 33.3% (4/12 patients), anemia, and increased blood creatine phosphokinase in 25.0% (3/12 patients), serous retinal detachment, upper abdominal pain, bloody stool, fatigue, malaise, pain, paronychia, decreased lymphocyte count, dysgeusia, insomnia, dry skin, and rash in 16.7% (2/12 patients). Adverse events of Grade 4 or higher included 2 cases of lymphopenia (16.7%; 2/12 cases) and 1 case of hyperuricemia (8.3%; 1/12 cases).
217 adverse events occurred in all 20 SP patients (100%) in the anti-EGFR antibody drug refractory part. Adverse events occurring in 15% or more of subjects (3/20 or more cases) were diarrhea in 60.0% (12/20 cases), nausea in 55.0% (11/20 cases), dermatitis acneiform in 50.0% (10/20 cases), fever in 40.0% (8/20 cases), decreased appetite in 35.0% (7/20 cases), vomiting and fatigue in 30.0% (6/20 cases) each, anemia, paronychia, increased blood creatine phosphokinase, and dry skin in 25.0% (5/20 cases) each, stomatitis and pruritus in 20.0% (4/20 cases) each, and constipation, increased alanine aminotransferase, increased aspartate aminotransferase, and hyponatremia in 15.0% (3/20 cases) each. Adverse events of Grade 4 or higher occurred in 1 case each in 5.0% (1/20 cases), including pericardial effusion, hepatic congestion, malignant pericarditis, and acute kidney injury.

Outcome measures

In the primary analysis part of the FAS, the primary endpoint of the confirmed ORR assessed by the investigator was analyzed (FAS of the primary analysis part). The number of responding subjects was 2/12, and the ORR (95% CI) was 16.7% (2.1-48.4%). The lower limit of the 95% CI for ORR (2.1%) was below the threshold for the response rate (6%) (p = 0.1595), so there was no statistically significant difference.
Secondary endpoints of the primary analysis part of the FAS were the median PFS (95% CI) of 3.3 (0.9-4.6) months, and the 6-month progression-free survival rate (95% CI) of 16.7% (2.7-41.3%). Responses (confirmed) were confirmed in 2/12 subjects, and the median DoR (95% CI) was 4.1 (2.6-not estimable) months. The number of DC subjects was 7/12, and the DCR (95% CI) was 58.3 (27.7-84.8)%. The median OS (95% CI) was 9.7 (3.4-25.5) months. The 6-month overall survival rate (95% CI) was 66.7 (33.7-86.0)%, and the 12-month overall survival rate (95% CI) was 50.0 (20.8-73.6)%.
In the FAS of the anti-EGFR antibody drug refractory part, the number of responding subjects and the ORR (95% CI) were 2/20 and 10.0 (1.2-31.7), respectively. The median PFS (95% CI) was 3.0 (1.9-4.4) months, and the 6-month progression-free survival rate (95% CI) was 11.3 (1.9-30.2)%. Responses (confirmed) were confirmed in 2/20 patients, and the median DoR (95% CI) was 4.6 (3.7-not estimable) months. The number of patients with DC was 11/20, and the DCR (95% CI) was 55.0 (31.5-76.9)%. The median OS (95% CI) was 7.6 (3.6-12.9) months. The 6-month overall survival rate (95% CI) was 55.0 (31.3-73.5)%, and the 12-month overall survival rate (95% CI) was 33.3 (14.1-54.0)%.

Plan to share IPD

IPD sharing Plan description

Recruitment status

Completed

Date of protocol fixation

2018

Year

02

Month

22

Day

Date of IRB

2018

Year

04

Month

18

Day

Anticipated trial start date

2018

Year

05

Month

28

Day

Last follow-up date

2023

Year

09

Month

29

Day

Date of closure to data entry

Date trial data considered complete

Date analysis concluded

Other related information

Registered date

2018

Year

03

Month

23

Day

Last modified on

2025

Year

01

Month

15

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000036377