Phase II Study of Circulating Tumor DNA-Guided Encorafenib and Cetuximab Retreatment in BRAF V600E Mutated Metastatic Colorectal Cancer Patients
- Trial ID
- 2023-509088-26-00
- Sponsor
- Fondazione GONO G.I.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **activity**, in terms of best response according to RECIST criteria 1.1, of the ctDNA-guided retreatment with encorafenib plus cetuximab in patients with BRAF V600E mutated metastatic colorectal cancer (mCRC). This evaluation is crucial for determining the efficacy of the retreatment strategy in patients who have previously benefited from BRAF and EGFR blockade, with specific genetic profiles at the time of study entry.
Secondary objectives include:
- Evaluation of **progression-free survival** (PFS) according to RECIST 1.1 criteria.
- Evaluation of **overall survival** (OS).
- Assessment of the incidence and severity of adverse events, graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.
- Evaluation of therapeutic choice and outcomes for patients undergoing ctDNA screening but dropped out due to detection of resistance drivers to BRAF and EGFR inhibition.
- Assessment of **quality of life** as measured by Patient Reported Outcomes (PROs) questionnaires.
- Evaluation of early objective response rate (EORR) and depth of response (DpR).
- Evaluation of translational analyses, including the correlation between clinical characteristics at ctDNA screening and detected mutational status and ctDNA dynamics in those exposed to the retreatment strategy.
Participants
The clinical trial involves participants diagnosed with **metastatic colorectal cancer**. The study population includes both male and female subjects, aged 18 years and older, with a focus on individuals who have previously been treated with encorafenib plus cetuximab, with or without chemotherapy. Participants are required to have a histologically confirmed diagnosis of colorectal adenocarcinoma and must exhibit a BRAFV600E mutation, with KRAS, NRAS, and MAP2K1 wild-type status, and MET not amplified status as determined by ctDNA analysis. The trial does not specify the total number of participants, as this information was not provided by the sponsor. The selection criteria emphasize adequate renal and hepatic function, as well as a life expectancy of at least twelve weeks. Participants must be able to take oral medications and comply with the study protocol. Lifestyle considerations such as diet and physical activity are not detailed in the trial information. The trial includes a vulnerable population, and both genders are eligible to participate. Key inclusion criteria include the availability of blood samples for ctDNA analysis and archival tumor tissue for biomarker analysis. The trial does not provide specific details on the participants' general health status beyond the inclusion criteria.
Plans and Procedures
The clinical trial is designed as a **single-arm phase II study** to evaluate the efficacy of **ctDNA-guided retreatment** with **encorafenib** and **cetuximab** in patients with **BRAF V600E mutated metastatic colorectal cancer** (mCRC). The primary objective is to assess the best response according to RECIST criteria 1.1, as determined by local investigators. The trial will involve a series of study visits, beginning with an inclusion visit where participants will undergo screening to confirm eligibility based on specific criteria, including the presence of BRAF V600E mutation and the absence of KRAS, NRAS, and MAP2K1 mutations, as well as MET amplification in ctDNA. The trial is expected to commence in May 2024 and conclude by March 2026, with a maximum treatment period of 120 days for each participant.
Participants will be required to attend regular follow-up visits every 8 weeks, during which clinical responses will be evaluated using chest and abdominal CT scans. These visits will also monitor for adverse events and assess overall health status. The end-of-study visit will mark the completion of the trial for each participant, where final assessments will be conducted to evaluate the overall response and any long-term effects of the treatment. The expected length of participant involvement is approximately 4 months, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent. The trial will also measure secondary endpoints such as progression-free survival, overall survival, and quality of life, using validated questionnaires. Participants must comply with the protocol requirements, including the use of adequate contraception and the ability to take oral medications, to remain in the study.
Treatment
The clinical trial involves the administration of **Erbitux** (cetuximab), a **monoclonal antibody** formulated as a **solution for infusion**. Cetuximab is administered via **intravenous infusion**. The dosage is calculated based on body surface area, with a maximum daily dose of 500 mg/m² and a total maximum dose of 4000 mg/m² over the treatment period. The treatment duration is capped at 120 days. Cetuximab is produced by Merck Europe B.V. and is classified under the ATC code L01FE01. Participant compliance with the infusion schedule is monitored throughout the study.
Additionally, the trial includes the administration of **Braftovi** (encorafenib), a **kinase inhibitor** available in the form of **hard capsules**. Encorafenib is administered **orally** with a maximum daily dose of 300 mg and a total maximum dose of 36000 mg over the treatment period. The treatment duration is also limited to 120 days. Braftovi is manufactured by Pierre Fabre Medicament and is classified under the ATC code L01EC03. Compliance with the oral dosing regimen is monitored to ensure adherence to the prescribed schedule.
No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are utilized in this study. The trial is designed to evaluate the efficacy of the combination of encorafenib and cetuximab in patients with BRAF V600E mutated metastatic colorectal cancer (mCRC), with specific genetic criteria for inclusion based on ctDNA analysis.
Efficacy
The efficacy of the clinical trial will be assessed using several parameters, with the primary endpoint being the **Objective Response Rate (ORR)**. This is defined as the percentage of patients achieving a complete or partial response according to RECIST 1.1 criteria. Clinical responses will be determined based on investigator-reported measurements, with evaluations conducted via chest and abdominal computed tomography (CT) scans every 8 weeks.
Secondary endpoints include **Progression-Free Survival (PFS)**, which measures the time from study enrollment to objective progression or death, and **Overall Survival (OS)**, defined as the time from enrollment to death from any cause. Additional secondary endpoints involve the **Overall Toxicity Rate** and **G3/4 Toxicity Rate**, which assess adverse events according to the National Cancer Institute Common Toxicity Criteria (version 5.0). The **Early Objective Response Rate (EORR)**, **Depth of Response (DpR)**, and clinical outcomes of the screening failure population will also be evaluated. Quality of Life (QoL) will be assessed using the EORTC QLQ-C30 and QLQ-CR29 questionnaires, with Time To Deterioration in Quality of Life (TTD) defined as the time from baseline to a significant decrease in functional scales or increase in symptom scales.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Histologically proven diagnosis of colorectal adenocarcinoma
- Age ≥ 18 years
- ECOG Performance status ≤ 1
- BRAFV600E mutated status of primary colorectal cancer and/or related metastasis, by local laboratory assessment according to standard procedures by means of molecular assay on genomic DNA
- Metastatic disease, with at least one measurable lesion according to RECIST 1.1. criteria
- Previous treatment with encorafenib plus cetuximab with or without chemotherapy (i.e., ±FOLFOX/FOLFIRI) in any line, producing a RECIST 1.1 complete/partial response or disease stabilisation, with a PFS of this treatment lasting at least 6 months
- Documentation of RECIST 1.1 disease progression during or after the end of the previous exposure to encorafenib plus cetuximab ± chemotherapy
- One intervening line of treatment not including any BRAF and EGFR inhibitor, between the end of first exposure to encorafenib plus cetuximab ± chemotherapy and the time of screening
- At least 4 months elapsed between the end of the previous exposure to encorafenib plus cetuximab ± chemotherapy and the retreatment with encorafenib plus cetuximab
- Previous treatment with immune checkpoint inhibitors (anti-PD-1/PD-L1 alone or in combination with anti-CTLA-4 agent), in the case of MSI-H or dMMR mCRC
- Availability of blood sample for ctDNA analysis within 28 days prior enrolment
- BRAFV600E mutated status of ctDNA at screening (central laboratory assessment by means of GUARDANT360 CDx, Guardant Health)
- KRAS, NRAS, MAP2K1 wild-type status and MET not amplified status in ctDNA at screening (central laboratory assessment by means of GUARDANT360 CDx, Guardant Health)
- Availability of archival tumour tissue (primary tumour and/or metastases) for biomarker analysis
- Neutrophils >1.5 x 109/L, Platelets >100 x 109/L, Hgb >9 g/dl. Transfusions will be permitted provided the patient has not received more than two units red blood cells in the prior 4 weeks to achieve this criterion
- Adequate renal function characterised by 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 characterised by the following at screening: Serum total bilirubin ≤ 1.5 × ULN and < 2 mg/dL. Note: Patients who have a total bilirubin level > 1.5 × ULN will be allowed if their indirect bilirubin level is ≤ 1.5 × ULN; Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 2.5 × ULN, or ≤ 5 × ULN in presence of liver metastases. In the presence of documented Gilbert’s syndrome, a value of total bilirubin < 3 × ULN is acceptable
- Adequate electrolytes at baseline, defined as serum potassium and magnesium levels within institutional normal limits (Note: replacement treatment to achieve adequate electrolytes will be allowed)
- INR or aPTT ≤ 1.5 × ULN
- QT interval corrected for heart rate ≤480 msec at screening
- Ability to take oral medications
- Women of childbearing potential must have a negative blood pregnancy test at the screening. For this trial, women of childbearing potential are defined as all women after puberty, unless they are postmenopausal for at least twelve continuous months, are surgically sterile, or are sexually inactive. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient
- Subjects and their partners must be willing to avoid pregnancy from the study screening until 1 month after the last trial treatment. Male subjects with female partners of childbearing potential and female subjects of childbearing potential must, therefore, be willing to use adequate contraception as approved by the investigator. Encorafenib may decrease the efficacy of hormonal contraceptives. Therefore, female patients using hormonal contraception are advised to use an additional or alternative method such as a barrier method (i.e., condom) from the screening phase for at least 1 month following the last dose of study treatment. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
- Written informed consent to study procedures
- Life expectancy of at least twelve weeks
- Will and ability to comply with the protocol
Exclusion Criteria
- Known hypersensitivity or contraindications to trial drugs or any component of the trial drugs
- Known history of acute or chronic pancreatitis within 6 months prior to the start of the treatment
- History of chronic inflammatory bowel disease or Crohn’s disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤12 months prior to first dose
- Impaired hepatic function, defined as Child-Pugh class B or C
- Clinically significant cardiovascular diseases, including any of the following: - history of acute myocardial infarction, acute coronary syndromes (including unstable angina, coronary artery bypass graft, coronary angioplasty or stenting) ≤6 months prior to registration; - congestive heart failure requiring treatment (New York Heart Association Class II and above); - recent history (within 1 year prior to registration) or presence of clinically significant cardiac arrhythmias (including uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia)
- QT interval corrected for heart rate >480 msec at screening and rate uncontrolled atrial fibrillation and paroxysmal supraventricular tachycardia
- 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 (barrier contraceptive measure or oral contraception) from the screening phase until 1 month after the last trial treatment
- Residual CTCAE ≥ Grade 2 toxicity from any prior anticancer therapy, with the exception of grade 2 alopecia or grade 2 neuropathy
- Active eye disorders, including keratitis, ulcerative keratitis or severe dry eye
- Discontinuation of previous treatment with encorafenib and/or cetuximab with or without chemotherapy due to encorafenib- and/or cetuximab-related adverse events
- Symptomatic brain metastases or spinal cord compression. Notes: Patients previously treated or untreated for these conditions who are asymptomatic in the absence of corticosteroid and antiepileptic therapy are allowed. Brain metastases or spinal cord compression must be stable for ≥ 4 weeks, with imaging (e.g., magnetic resonance imaging [MRI] or computed tomography [CT]) demonstrating no current evidence of progressive brain metastases or spinal cord compression at screening
- Leptomeningeal disease
- Other co-existing malignancies or malignancies diagnosed within the last 5 years except for adequately treated localised basal and squamous cell carcinoma or cervical cancer in situ
- Treatment with any investigational drug within 30 days prior to enrolment or two investigational agent half-lives (whichever is longer)
- Impaired gastrointestinal function (i.e., uncontrolled nausea, vomiting or diarrhea, malabsorption syndrome, small bowel resection) or disease which may significantly alter the absorption of oral study intervention or recent changes in bowel function suggesting current or impending bowel obstruction
- Use of any herbal medications/supplements or any medications or foods that are moderate or strong inhibitors or inducers of CYP3A4/5 ≤1 week prior to the start of treatment
- Diagnosis of interstitial pneumonitis or pulmonary fibrosis
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Not Recruiting | 01 May 2024 | 16 |
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 |
|---|---|---|---|---|---|---|
Braftovi 75 mg hard capsules | Test | HARD CAPSULES | ORAL | 300 | 120 | PRD6728382 |
Erbitux 5 mg/mL solution for infusion | Test | SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 500 | 120 | PRD3702716 |