Evaluation of Encorafenib and Cetuximab with FOLFIRI in BRAF V600E Mutated Metastatic Colorectal Cancer Post-Progression on Encorafenib and Cetuximab
- Trial ID
- 2023-508615-24-00
- Protocol
- ECLYPse
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to determine the **efficacy** of Encorafenib and Cetuximab (EC) in combination with FOLFIRI in patients with BRAF V600E mutated metastatic colorectal cancer (mCRC) who are progressing on EC administered in the second line. This is clinically relevant as it aims to evaluate the potential of this combination therapy to improve treatment outcomes in a specific subset of mCRC patients, who typically have limited therapeutic options and poor prognosis.
Secondary objectives include:
- Determining the activity, long-term outcomes, and safety of EC in combination with FOLFIRI in the same patient population.
Participants
The clinical trial involves participants diagnosed with **metastatic colorectal cancer** (mCRC) harboring the BRAF V600E mutation. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a histologically or cytologically confirmed diagnosis of colorectal adenocarcinoma with radiological evidence of metastatic disease. The trial does not include a vulnerable population. Participants must have experienced disease progression while on treatment with EC in a second-line setting and should be fit for subsequent treatment with FOLFIRI. The sponsor has not provided information regarding the total number of participants. Key lifestyle considerations include the ability to take oral medications and adherence to adequate contraception methods for both male and female subjects of childbearing potential. The trial population was selected based on specific inclusion criteria, including adequate bone marrow, renal, hepatic, and cardiac function, as well as the presence of measurable disease according to RECIST 1.1 criteria. Participants must also have a life expectancy of at least three months and an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of a combination therapy involving **encorafenib** and **cetuximab** beyond progression, in conjunction with FOLFIRI, for patients with BRAF V600E mutated metastatic colorectal cancer (mCRC) who have progressed on prior treatment with encorafenib and cetuximab. This is a phase II, randomized, double-blind, controlled trial. The trial is expected to commence on February 12, 2024, and conclude by February 12, 2026, with an estimated duration of 24 months.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as adequate bone marrow, renal, hepatic, and cardiac function, as well as the presence of the BRAF V600E mutation. Following successful screening, participants will be randomized to receive the investigational treatment. Study visits will occur every 8 weeks, during which tumor assessments will be conducted using CT scans of the chest and abdomen to monitor disease progression. The primary endpoint is the 6-month progression-free survival (PFS) rate, with secondary endpoints including overall survival (OS), duration of response (DOR), objective response rate (ORR), disease control rate (DCR), and toxicity.
The expected length of participant involvement is up to 24 months, contingent upon disease progression or the occurrence of adverse events. Conditions that may lead to early termination from the study include significant adverse reactions, withdrawal of consent, or non-compliance with study protocols. The end-of-study visit will involve a final assessment of the participant's health status and documentation of any remaining adverse events. Throughout the trial, participants will receive either intravenous infusions or oral administration of the study drugs, depending on the specific treatment regimen assigned.
Treatment
The clinical trial involves the administration of several **antineoplastic agents** to evaluate their efficacy in patients with BRAF V600E mutated metastatic colorectal cancer. **Irinotecan hydrochloride** is administered as an intravenous (IV) infusion. The pharmaceutical form is coded as PHF00230MIG, with a maximum daily dose of 360 mg and a total dose not exceeding 360 mg over a treatment period of up to 24 weeks. This agent is classified under other antineoplastic agents.
**Fluorouracil**, also administered via IV infusion, shares the same pharmaceutical form code, PHF00230MIG. The maximum daily and total dose is set at 800 mg, with the treatment duration extending to 24 weeks. It is categorized as an antineoplastic agent, specifically an antimetabolite.
**Cetuximab** is another IV infusion treatment in this trial, with a pharmaceutical form code of PHF00230MIG. The maximum daily and total dose is 1000 mg, administered over a 24-week period. Cetuximab is classified as a monoclonal antibody within the antineoplastic agents category.
**Encorafenib** is administered orally, with a pharmaceutical form code of PHF00006MIG. The maximum daily and total dose is 300 mg, with a treatment period of up to 24 weeks. It is categorized as a protein kinase inhibitor among antineoplastic agents.
**Folinic acid**, also known as sodium folinate, is administered via IV infusion with a pharmaceutical form code of PHF00231MIG. The maximum daily and total dose is 800 mg, with a treatment duration of 24 weeks. It serves as a detoxifying agent for antineoplastic treatment.
All treatments are administered in accordance with the specified dosing schedules, and participant compliance is monitored throughout the trial to ensure adherence to the protocol. The trial does not include any placebo or comparator treatments, focusing solely on the efficacy of the experimental medications in combination therapy.
Efficacy
The efficacy of the investigational treatment in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is the investigator-assessed 6-month **progression-free survival (PFS)** rate, defined as the proportion of patients who are alive and progression-free at the 6-month time point from the start of the investigational treatment. PFS is calculated as the time elapsed between the start of the investigational treatment and the date of the first event, with tumor assessments conducted via CT scans of the chest and abdomen every 8 weeks until evidence of disease progression or death.
Secondary endpoints include additional measures of efficacy such as overall survival (OS), which is the time elapsed from the start of the investigational treatment to the date of death from any cause. The duration of response (DOR) will be measured from the time of response, in patients achieving complete response (CR) or partial response (PR), to disease progression or death. The overall response rate (ORR) will be determined by the percentage of patients achieving PR or CR as measured by RECIST 1.1 criteria. Disease control rate (DCR) will be assessed as the percentage of patients achieving PR, CR, or stable disease (SD) according to RECIST 1.1 criteria. Additionally, the rate of adverse events will be evaluated according to NCI-CTCAE version 4.03 to assess the toxicity of the treatment.
Inclusion and Exclusion Criteria
Inclusion Criteria
- written informed consent to study procedures
- age ≥ 18 years
- histologically or cytologically confirmed diagnosis of colorectal adenocarcinoma
- radiological evidence of metastatic disease
- evidence of measurable disease according to RECIST 1.1 criteria
- presence of BRAF V600E mutation in tumor tissue (primary CRC and/or related metastasis) as previously determined by a local assay at any time prior to screening (only PCR and NGS-based local assays results will be acceptable)
- disease progression while on treatment with EC received in 2nd line setting. NOTES a) EC administered after disease relapse during treatment or within 6 months following adjuvant therapy will be second line; b) maintenance therapy given in the metastatic setting after a first line doublet or triplet chemotherapy will not be considered a separate regimen
- best response to previous treatment with EC: CR, PR or SD lasting for at least 3 months
- patient fit for a subsequent treatment line with FOLFIRI. Patients exposed to irinotecan and fluoropyrimidines during previous line for metastatic disease are eligible, provided that the patient has recovered from G3 toxicity
- life expectancy ≥ 3 months
- Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤1
- Adequate bone marrow function at screening: a) Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L; b) Platelets ≥ 100 × 10^9/L; c) Hemoglobin ≥ 9.0 g/dL; Note: Transfusions will be allowed to achieve this. Transfusions will be permitted provided that the patient has not received more than 2 units red blood cells in the prior 4 weeks to achieve this criteria
- Adequate renal function at screening: serum creatinine ≤ 1.5 × upper limit of normal (ULN), or calculated by Cockroft-Gault formula, or directly measured creatinine clearance ≥ 50 mL/min at screening
- Adequate hepatic function at screening: a) serum total bilirubin ≤ 1.5 × ULN; b) alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 2.5 × ULN, or ≤ 5 × ULN in presence of liver metastases
- Adequate cardiac function characterized by the following at screening: QT interval corrected for heart rate using Fridericia's formula (QTcF) value ≤480 msec.
- Availability of treatment-naïve, archival FFPE tumor tissue sample
- Ability to take oral medications
- Male subjects with female partners of childbearing potential must be willing to use adequate contraception as outlined in Section 5.5 – Contraception, starting with the first dose of study therapy through 180 days after the last dose of treatment. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
- Women of childbearing potential must have a negative blood or urine pregnancy test at the baseline visit
- Female subjects of childbearing potential must be willing to use an adequate method of contraception as outlined in Section 5.5 – Contraception, for the course of the study starting with the first dose of study therapy through 180 days ECLYPse Study - Protocol Version 1.0 – 27th Feb, 2023 Pag. 34 | 101 after the last dose of treatment. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
- Will and ability to comply with the protocol
Exclusion Criteria
- patients experiencing PD as best response to EC
- patients with specific BRAFi/AntiEGFR contraindications
- patients with specific irinotecan or fluoropyrimidines contraindications
- patients with DPYD deficiency
- life expectancy ≤3 months
- ECOG PS >1
- Any of the following in the 6 months prior to treatment start: myocardial infarction, acute coronary syndromes (including unstable angina, coronary artery bypass graft [CABG], coronary angioplasty or stenting), congestive heart failure (≥ New York Heart Association Classification Class II), serious cardiac arrhythmia (except atrial fibrillation and appropriately controlled paroxysmal supraventricular tachycardia), cerebrovascular accident, symptomatic pulmonary embolism
- Congenital long QT syndrome
- Impaired gastrointestinal function or disease that may significantly alter the absorption of encorafenib (uncontrolled vomiting, malabsorption syndrome, small bowel resection with decreased intestinal absorption)
- Uncontrolled coagulopathy
- Patients has a known history of Gilbert's syndrome or is known to have any of the following genotypes: UGT1A1*6/*6, UGT1A1*28/*28, or UGT1A1*6/*28
- Active infection requiring systemic therapy
- Known history of acute or chronic pancreatitis
- Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
- Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive)
- Symptomatic brain metastasis or leptomeningeal disease
- Prior hypersensitivity or toxicity that would suggest an inability to tolerate administration of the planned dose of investigational products
- Residual CTCAE > Grade 2 toxicity from any prior anticancer therapy, with the exception of alopecia or neuropathy
- Any concomitant drugs contraindicated for use with the trial drugs according to the product information of the pharmaceutical companies, including current treatment with a non-topical medication known to be a strong inhibitor of cytochrome P450 (CYP) 3A4 ≤ 1 week prior to the start of study treatment
- Concomitant use of St. John’s Wort (hypericum perforatum)
- Other severe, acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or that may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient an inappropriate candidate for the study.
- Concurrent or previous other malignancy within the past 3 years, with the exception of effectively treated squamous cell or basal cell skin cancer, melanoma in situ, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in situ of the cervix, carcinoma in situ of the colon or rectum, or other noninvasive or indolent malignancy without Sponsor approval
- Pregnant or lactating women. Women of childbearing potential with either a positive or no pregnancy test at baseline. Postmenopausal women must have been amenorrhoeic for at least 12 months to be considered of non-childbearing potential. Sexually active males and females (of childbearing potential) unwilling to practice contraception during the study and until 180 days after the last trial treatment.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Not Recruiting | 12 Feb 2024 | 25 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
IRINOTECAN | Test | PHF00230MIG | IV INFUSION | 360 | 24 | SCP139021 |
FLUOROURACIL | Test | PHF00230MIG | IV INFUSION | 800 | 24 | SCP1160311 |
CETUXIMAB | Test | PHF00230MIG | IV INFUSION | 1000 | 24 | SCP185672 |
ENCORAFENIB | Test | PHF00006MIG | ORAL | 300 | 24 | SCP31830044 |
SODIUM FOLINATE | Test | PHF00231MIG | IV INFUSION | 800 | 24 | SCP12696792 |