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Efficacy of VIC Regimen in BRAF Mutant Metastatic Colorectal Cancer

Primary Purpose

Colorectal Cancer Metastatic

Status

Completed

Phase

Phase 1

Locations

China

Study Type

Interventional

Intervention

Cetuximab

Irinotecan

Vemurafenib

About this trial

This is an interventional treatment trial for Colorectal Cancer Metastatic

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Histologically confirmed diagnosis of metastatic colorectal cancer
Histopathological or ctDNA analysis positive for BRAF V600E mutant
Patients must have had at least undergone one first line treatment with FOLFOX or FOLFIRI or FOLFOXIRI±Bevacizumab before disease progression.
Measurable and assessable disease according to RECIST 1.1 criteria
Adequate hematologic function (Platelet>90×109/L; White blood cells>3.0×109/L; Neutrophils>1.5×109/L; Hb>10.0g/100ml)
Serum bilirubin ≤1.5 times the upper limit of normal (ULN), transaminase ≤5 times ULN
No ascites, normal coagulation function, albumin ≥35g/L
Child-Pugh class A
Serum creatinine is less than the upper limit of normal (ULN), or calculated creatinine clearance rate> 50ml/min (using Cockcroft-Gault equation)
ECOG performance status of grade 0-2
Life expectancy> 3 months
Patients must provide a signed Informed Consent Form
Patients must have good compliance till the end of this study

Exclusion Criteria:

Patients with KRAS and NRAS mutations
Previously received anti-EGFR monoclonal antibodies or EGFR inhibitors, BRAF inhibitors (with the exception of regorafenib)
Patients with known contraindications to receiving cetuximab or irinotecan at the planned dose
Patients with retinal vein occlusion or have current risk factors for retinal vein occlusion (for example, uncontrolled glaucoma or ocular hypertension)
History of acute or chronic pancreatitis
History of chronic inflammatory bowel disease or Crohn's disease requiring medical intervention (immunomodulatory or immunosuppressive drugs or surgery) within 12 months prior to enrollment
Gastrointestinal diseases that may greatly affect the absorption of Vimurafenib (for example, ulcer disease, uncontrolled vomiting, malabsorption syndrome, small bowel resection and reduced intestinal absorption)
Neuromuscular diseases associated with elevated CK (eg, inflammatory myopathy, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)
Patients with any residual CTCAE ≥ Grade 2 toxicity from previous anti-tumor therapy (excluding hair loss or neuropathy of Grade 2 and above)
History of HIV infection
Active hepatitis B or C infection
History of Gilbert syndrome
Interstitial pneumonia or widespread symptomatic interstitial pulmonary fibrosis
Serious uncontrollable systemic complications such as infection or diabetes
Clinically serious cardiovascular diseases such as cerebrovascular accident (within 6 months prior to enrollment), myocardial infarction (within 6 months prior to enrollment), hypertension that cannot be controlled after proper medical treatment, unstable angina pectoris, congestion Heart failure (NYHA 2-4), arrhythmia requiring medication
History of or showing signs of a central nervous system disease (such as primary brain tumors, epilepsy that cannot be controlled by standard treatment, any brain metastases or history of stroke)
Patients must not suffer from other uncontrolled concurrent diseases, including but not limited to hypertensive crisis or hypertensive encephalopathy, active bleeding, uncontrolled infections/diseases, uncontrolled non-malignant medical diseases or use research therapies that could worsen non-malignant medical diseases or mental illnesses/social conditions
No history of other malignant tumors in the past 5 years (excluding skin basal cell carcinoma and/or cervical carcinoma in situ and/or thyroid cancer after radical resection)
Patients allergic to any drugs in the study
Patients must not be pregnant or breastfeeding
Women of reproductive potential (<2 years after the last menstruation) who have not used or refused to use effective non- hormonal contraceptive methods (intrauterine contraceptive ring, barrier contraception combined with spermicidal gel or sterilization) or Men wanting to keep their reproductive potential.
Patients unable or unwilling to comply with the protocol of this clinical trial
Existence of any other diseases, dysfunction caused by metastatic lesions, or suspicious diseases found during physical examination, which may indicate contraindications to the use of the drugs in this study or could bring about high risk of treatment-related complications to the patient

Sites / Locations

Sun Yat-sen University Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

VIC regimen

Arm Description

Patients will receive VIC regimen every 2 weeks: Cetuximab 500mg/m2 IV on Day 1; Irinotecan 180mg/m2 IV on Day 1 (If patient carries UGT*28 7/7 or UGT*6 A/A or UGT*28 6/7 and UGT*6 A/G variants, use Irinotecan IV 150mg/m2 instead); Vemurafenib PO BID on Days 1 to 14 (Dosage: 480mg; 720mg; 960mg, determined by the maximum tolerated dose (MTD) in Phase Ia trial).

Outcomes

Primary Outcome Measures

Overall response rate from the date of first drug administration until the date of first documented progression or date of death, whichever came first.

The proportion of patients who achieved a complete or partial response as their best overall response based on RECIST v1.1 criteria

Secondary Outcome Measures

Progression free survival from the date of first drug administration until the date of first documented progression or date of death, whichever came first.

The length of time during and after the treatment of the disease, that a patient lives with the disease without its aggravation

Overall Survival from the date of first drug administration until the date of death from any cause.

The length of time from the start of treatment that patients diagnosed are still alive

Number of patients with adverse events and severity according to NCI CTCAE v5.0

Summary of the Adverse events experienced during treatment related to the drug used in this study

Full Information

NCT ID

NCT04790448

First Posted

March 7, 2021

Last Updated

February 13, 2023

Sponsor

Sun Yat-sen University

1. Study Identification

Unique Protocol Identification Number

NCT04790448

Brief Title

Efficacy of VIC Regimen in BRAF Mutant Metastatic Colorectal Cancer

Official Title

A Phase Ia/II, Single Arm Trial on the Efficacy of Vemurafenib in Combination With Irinotecan and Cetuximab in BRAF V600E-Mutant Metastatic Colorectal Cancer

Study Type

Interventional

2. Study Status

Record Verification Date

February 2023

Overall Recruitment Status

Completed

Study Start Date

July 27, 2020 (Actual)

Primary Completion Date

December 31, 2021 (Actual)

Study Completion Date

December 31, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Sun Yat-sen University

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

5. Study Description

Brief Summary

This prospective, multicenter, single arm clinical trial was designed to evaluate the efficacy and safety of Vemurafenib in combination with Irinotecan and Cetuximab in the treatment of BRAF V600E-Mutant Metastatic Colorectal Cancer.

Detailed Description

PRIMARY OBJECTIVES: To evaluate the Overall Response Rate (ORR) of v-raf murine sarcoma viral oncogene homolog B (BRAF) V600E mutant metastatic colorectal cancer patients treated with Vemurafenib in combination with Irinotecan and Cetuximab (VIC regimen). SECONDARY OBJECTIVES: To evaluate the Progression Free Survival (PFS), Overall Survival (OS), safety and toxicity of VIC regimen in the treatment of BRAF V600E mutant colon cancer. EXPLORATORY OBJECTIVES: Mechanism of primary and secondary resistance to VIC regimen in the treatment of BRAF V600E mutant colon cancer. OUTLINE: Patients receive Cetuximab and Irinotecan intravenously on day 1 and Vemurafenib orally (PO) twice daily (BID) on days 1 to 14. Courses are repeated every 2 weeks in the absence of disease progression or unacceptable toxicity.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Colorectal Cancer Metastatic

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

37 (Actual)

8. Arms, Groups, and Interventions

Arm Title

VIC regimen

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Cetuximab

Other Intervention Name(s)

C225, Erbitux

Intervention Description

Route of administration: Intravenous

Intervention Type

Drug

Intervention Name(s)

Irinotecan

Other Intervention Name(s)

CPT-11, Camptothecin-11, Camptosar

Intervention Description

Route of administration: Intravenous

Intervention Type

Drug

Intervention Name(s)

Vemurafenib

Other Intervention Name(s)

Zelboraf

Intervention Description

Route of administration: Oral

Primary Outcome Measure Information:

Title

Overall response rate from the date of first drug administration until the date of first documented progression or date of death, whichever came first.

Description

The proportion of patients who achieved a complete or partial response as their best overall response based on RECIST v1.1 criteria

Time Frame

up to 17 months

Secondary Outcome Measure Information:

Title

Progression free survival from the date of first drug administration until the date of first documented progression or date of death, whichever came first.

Description

The length of time during and after the treatment of the disease, that a patient lives with the disease without its aggravation

Time Frame

up to 17 months

Title

Overall Survival from the date of first drug administration until the date of death from any cause.

Description

The length of time from the start of treatment that patients diagnosed are still alive

Time Frame

up to 17 months

Title

Number of patients with adverse events and severity according to NCI CTCAE v5.0

Description

Summary of the Adverse events experienced during treatment related to the drug used in this study

Time Frame

up to 6 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Histologically confirmed diagnosis of metastatic colorectal cancer Histopathological or ctDNA analysis positive for BRAF V600E mutant Patients must have had at least undergone one first line treatment with FOLFOX or FOLFIRI or FOLFOXIRI±Bevacizumab before disease progression. Measurable and assessable disease according to RECIST 1.1 criteria Adequate hematologic function (Platelet>90×109/L; White blood cells>3.0×109/L; Neutrophils>1.5×109/L; Hb>10.0g/100ml) Serum bilirubin ≤1.5 times the upper limit of normal (ULN), transaminase ≤5 times ULN No ascites, normal coagulation function, albumin ≥35g/L Child-Pugh class A Serum creatinine is less than the upper limit of normal (ULN), or calculated creatinine clearance rate> 50ml/min (using Cockcroft-Gault equation) ECOG performance status of grade 0-2 Life expectancy> 3 months Patients must provide a signed Informed Consent Form Patients must have good compliance till the end of this study Exclusion Criteria: Patients with KRAS and NRAS mutations Previously received anti-EGFR monoclonal antibodies or EGFR inhibitors, BRAF inhibitors (with the exception of regorafenib) Patients with known contraindications to receiving cetuximab or irinotecan at the planned dose Patients with retinal vein occlusion or have current risk factors for retinal vein occlusion (for example, uncontrolled glaucoma or ocular hypertension) History of acute or chronic pancreatitis History of chronic inflammatory bowel disease or Crohn's disease requiring medical intervention (immunomodulatory or immunosuppressive drugs or surgery) within 12 months prior to enrollment Gastrointestinal diseases that may greatly affect the absorption of Vimurafenib (for example, ulcer disease, uncontrolled vomiting, malabsorption syndrome, small bowel resection and reduced intestinal absorption) Neuromuscular diseases associated with elevated CK (eg, inflammatory myopathy, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy) Patients with any residual CTCAE ≥ Grade 2 toxicity from previous anti-tumor therapy (excluding hair loss or neuropathy of Grade 2 and above) History of HIV infection Active hepatitis B or C infection History of Gilbert syndrome Interstitial pneumonia or widespread symptomatic interstitial pulmonary fibrosis Serious uncontrollable systemic complications such as infection or diabetes Clinically serious cardiovascular diseases such as cerebrovascular accident (within 6 months prior to enrollment), myocardial infarction (within 6 months prior to enrollment), hypertension that cannot be controlled after proper medical treatment, unstable angina pectoris, congestion Heart failure (NYHA 2-4), arrhythmia requiring medication History of or showing signs of a central nervous system disease (such as primary brain tumors, epilepsy that cannot be controlled by standard treatment, any brain metastases or history of stroke) Patients must not suffer from other uncontrolled concurrent diseases, including but not limited to hypertensive crisis or hypertensive encephalopathy, active bleeding, uncontrolled infections/diseases, uncontrolled non-malignant medical diseases or use research therapies that could worsen non-malignant medical diseases or mental illnesses/social conditions No history of other malignant tumors in the past 5 years (excluding skin basal cell carcinoma and/or cervical carcinoma in situ and/or thyroid cancer after radical resection) Patients allergic to any drugs in the study Patients must not be pregnant or breastfeeding Women of reproductive potential (<2 years after the last menstruation) who have not used or refused to use effective non- hormonal contraceptive methods (intrauterine contraceptive ring, barrier contraception combined with spermicidal gel or sterilization) or Men wanting to keep their reproductive potential. Patients unable or unwilling to comply with the protocol of this clinical trial Existence of any other diseases, dysfunction caused by metastatic lesions, or suspicious diseases found during physical examination, which may indicate contraindications to the use of the drugs in this study or could bring about high risk of treatment-related complications to the patient

Facility Information:

Facility Name

Sun Yat-sen University Cancer Center

City

Guangzhou

State/Province

Guangdong

ZIP/Postal Code

510060

Country

China

12. IPD Sharing Statement

Plan to Share IPD

Undecided

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Efficacy of VIC Regimen in BRAF Mutant Metastatic Colorectal Cancer

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