NEOADJUVANT AND ADJUVANT CHEMOTHERAPY WITH ENCORAFENIB, BINIMETINIB PLUS CETUXIMAB IN PATIENTS WITH SURGICALLY RESECTABLE BRAF V600E MUTANT COLORECTAL METASTASIS

JRCT ID: jRCT2031220025

Registered date:16/04/2022

Basic Information

• Recruitment status: Pending
• Health condition(s) or Problem(s) studied: Patients with surgically resectable BRAF V600E mutant colorectal metastasis
• Date of first enrollment: 25/04/2022
• Target sample size: 32
• Study type: Interventional

Intervention(s)

The regimen of chemotherapy prescribed is as follows.
Encorafenib: 300 mg once daily
Binimetinib: 45 mg twice daily
Cetuximab: 400 mg/m2 (initial dose), and 250 mg/m2 (from the second dose onward) once weekly.
Setting 4 weeks (28 days) as one cycle, three cycles each of neoadjuvant and adjuvant chemotherapy will be given. After completion of the protocol treatment, the patients will be followed up. The treatment regimen after recurrence will not be specified.

Outcome(s)

• Primary Outcome: 1-year progression-free surviva

Secondary Outcome

-Progression free survival
-Overall survival
-Disease free survival
-1 year progression free survival rate by central image reading
-Objective response rate
-Pathological complete response of distant metastatic lesions, assessed by pathologists at each institution
-Pathological complete response of the primary lesion, assessed by pathologists at each institution
-Protocol treatment completion rate
-R0 resection rate
-Incidence of adverse events
-Incidence of surgery related complications

Key inclusion & exclusion criteria

• Age minimum: >= 20age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

1. Patients who have provided written consent for participation in the study.
2. Patients aged 20 years or older at the time of providing informed consent.
3. Patients with ECOG Performance Status of 0 or 1.
4. Patients histologically diagnosed as having adenocarcinoma or adenosquamous carcinoma of the colon or rectum as the primary site.
5. Patients assessed as positive for RAS (KRAS/NRAS) wild-type and BRAF V600E mutation by analysis of tumor tissues or blood specimens.
6. Patients in whom distant metastasis*2 (regardless of whether it was synchronous or metachronous to the primary tumor*3) detected by imaging examination*1 within 28 days of the date of enrollment and in whom macroscopic complete resection (R0 or R1 resection) is feasible for all the lesions (including the primary tumor in the case of synchronous metastasis and including local recurrence in the case of metachronous metastasis).
7. In the case of metachronous distant metastasis, R0 or R1 resection of the primary tumor has been achieved*3.
8. Patients can tolerate surgery based on the function of distant metastatic organs (liver, lung, etc.) and general conditions.
9. Patients without a history of prior treatment for the distant metastasis after being initially diagnosed with distant metastasis*4, 5.
10. The laboratory test results performed within 28 days before enrollment meet the following functional requirements of organs.
Neutrophil Neutrophil count of above 1500/mm3
(ii) Platelet count of above 100000/mm3
(iii) Hemoglobin of above 9.0 g/dL.
(iv) Serum creatinine of less than 1.5 mg/dL or calculated (with the Cockcroft-Gault formula*) or measured creatinine clearance of above 45 mL/min
(v) T-Bil of under 2.0 mg/dL (Patients with Gilbert's syndrome can be enrolled if approved by the coordinating committee even though T-Bil of above 2.0 mg/dL.)
(vi) ALT and AST of less than 100 U/L (less than 200 U/L in the presence of liver metastasis)
11. Patients who can take oral medication.
12. Female patients with childbearing potential must agree to use highly effective contraception for the period from informed consent to at least 60 days after the last administration of the investigational products. Male patients must agree to use contraception for the period from the start of investigational product administration to at least 90 days after the last administration of the investigational products.

*1: Thoracoabdominopelvic CT or MRI is essential. Contrast-enhanced CT or MRI is recommended but not essential. Contrast-enhanced liver MRI and thin-sliced CT are recommended for liver metastasis and lung metastasis, respectively, but they are not essential. It is recommended to perform comprehensive evaluation by including other imaging examinations such as ultrasonography and PET. However, imaging diagnosis by ultrasonography or PET examination alone is not permitted.
*2: Regardless of measurability specified in the revised RECIST guideline (version 1.1), patients with non-measurable lesions only are also eligible.
*3: "Synchronous metastasis" represents the condition in which the primary tumor is present at the time of diagnosis of distant metastasis, and "metachronous metastasis" represents the condition in which the primary tumor has already been resected at the time of diagnosis of distant metastasis.
*4: For distant metastasis diagnosed during adjuvant chemotherapy after the resection of the primary tumor, patients will be eligible if no chemotherapy has been performed since the establishment of the definitive diagnosis of distant metastasis, but ineligible if chemotherapy has been continued even after the establishment of the diagnosis of distant metastasis.
*5: Resection of a small number of lesions of peritoneal dissemination or metastatic lesions for the purpose of biopsy (R2 resection) during surgery for primary tumor (including colostomy and bypass surgery) is permitted.

Exclude criteria

1. Patients with a history of previous treatment with anti-EGFR antibody drugs, RAF inhibitors, or MEK inhibitors.
2. Patients with any other unresectable advanced and recurrent cancer. However, patients with the following cancers may be enrolled: basal cell carcinoma considered to be cured by local therapy, stage I squamous cell carcinoma, superficial bladder cancer, lesions equivalent to carcinoma in situ or intramucosal carcinoma, or non-metastatic prostate cancer not requiring systemic treatment. In addition, patients who are judged to be eligible by the coordinating committee may be enrolled.
3. Patients in whom R0 or R1 resection is not feasible unless tumor shrinkage or elimination is achieved by chemotherapy.
4. Patients with a history or finding of cardiovascular risk fall into any of the following:
i. Patients with a left ventricular ejection rate below the lower limit of the normal range.
ii. Patients with a history or finding of clinically significant, poorly controlled arrhythmia. Exception: patients whose atrial fibrillation has been well controlled for more than 30 days before enrollment may be enrolled.
iii. Patients with a history of acute coronary syndrome (including myocardial infarction and unstable angina), coronary angioplasty, or stent placement within 6 months before enrollment.
iv. A history or finding of Class II or higher congestive heart failure according to the New York Heart Association Functional Classification.
v. Treatment-resistant hypertension (defined as a condition with a systolic blood pressure of > 140 mmHg and diastolic blood pressure of > 90 mmHg that cannot be controlled with antihypertensive medication).
vi. Patients with an implantable cardioverter-defibrillator or permanent pacemaker.
5. Patients with poorly controlled diabetes or other diseases that may interfere with the toxicity evaluation.
6. Patients with a history or finding of retinal and neuromuscular diseases that fall into any of the following:
- Patients with concurrent, or history or finding of retinal vein occlusion (RVO), or risk factors (such as uncontrollable glaucoma, high intraocular pressure, hyperviscosity syndrome, or hypercoagulation syndrome) for RVO.
- Patients with concurrent or a history of retinal degenerative diseases other than RVO (central serous chorioretinopathy, retinal detachment, age-related macular degeneration, etc.)
- Patients with neuromuscular disorders that may cause an elevated CK (such as inflammatory myopathy, muscular dystrophy, amyotrophic lateral sclerosis, or spinal muscular atrophy).
7. Pregnant or breastfeeding women.
8. Patients with significant and unstable psychiatric disorders or other medical illnesses that could interfere with subject safety, consent, or compliance with the clinical trial procedures.
9. Patients who do not have an intention or are not capable of adhering to the procedures specified in the protocol.
10. Patients with other serious, acute, or chronic abnormalities that are medically significant.
11. Patients whose enrollment in this study is deemed inappropriate by the principal investigator or sub-investigator.

Related Information

• Primary Sponsor: Yoshino Takayuki
• Source(s) of Monetary Support: Japan Agency for Medical Research and Development