Phase 2 Randomized Study of Encorafenib, Cetuximab, and Pembrolizumab in BRAF V600E-Mutant, MSI-H/dMMR Metastatic Colorectal Cancer
- Trial ID
- 2024-512119-34-00
- Protocol
- C4221022
- Sponsor
- Pfizer Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the **efficacy** of a combination therapy consisting of encorafenib, cetuximab, and pembrolizumab (Triplet Arm [Arm A]) versus pembrolizumab alone (Control Arm [Arm B]) in participants with previously untreated BRAF V600E-mutant, MSI-H/dMMR metastatic colorectal cancer. This comparison is clinically relevant as it aims to determine whether the addition of encorafenib and cetuximab to pembrolizumab can enhance treatment outcomes in this specific patient population, potentially offering a more effective therapeutic option.
Secondary objectives include:
- Assessing the overall safety and tolerability of Arm A versus Arm B, which is crucial for understanding the risk-benefit profile of the combination therapy.
- Evaluating the efficacy of Arm A versus Arm B to further substantiate the primary objective findings.
- Confirming the BRAF and MSI status in tumor tissue, which is important for ensuring accurate patient stratification and understanding the molecular characteristics of the tumors.
- Evaluating the effect on patient-reported outcomes (PROs) of Arm A versus Arm B, providing insights into the impact of the treatment on patients' quality of life.
Participants
The clinical trial involves a total of **29 participants** diagnosed with **MSI-H/dMMR metastatic colorectal cancer**. The study population includes both male and female subjects, with an age range starting from 16 years and above, depending on the country's specific age of consent regulations. Participants were selected based on specific molecular and clinical criteria, including the presence of a BRAF V600E mutation and adequate organ function. The trial includes individuals with a confirmed diagnosis of metastatic Stage IV colorectal adenocarcinoma, who have not received prior systemic regimens for metastatic disease. Participants are required to have an **ECOG performance status** of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial population is characterized by their ability to comply with scheduled visits, treatment plans, and other study procedures. Lifestyle considerations such as diet and physical activity are not specified, but participants must be willing to adhere to study requirements. The trial also includes a vulnerable population, ensuring that all participants or their legal guardians provide informed consent. The selection process ensures that participants have measurable disease and available tumor tissue for analysis, either archival or newly obtained.
Plans and Procedures
The clinical trial is a **Phase 2**, randomized, open-label study designed to evaluate the efficacy of a combination therapy involving **encorafenib**, **cetuximab**, and **pembrolizumab** compared to pembrolizumab alone in participants with previously untreated **BRAF V600E-mutant**, **MSI-H/dMMR metastatic colorectal cancer**. The trial is structured to include two arms: the Triplet Arm (Arm A) and the Control Arm (Arm B). Participants will be randomly assigned to one of these arms to receive the respective treatments. The study is expected to span approximately 24 months, with an estimated end date in March 2027.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as adequate bone marrow, hepatic, and renal function, and the presence of measurable disease. Following randomization, participants will attend regular follow-up visits to monitor treatment efficacy and safety, assess progression-free survival (PFS), and record any adverse events (AEs) according to the NCI CTCAE v4.03. The end-of-study visit will conclude the participant's involvement, where final assessments will be conducted, including overall survival (OS) and objective response rates.
The expected length of participant involvement is up to 24 months, contingent upon disease progression or the occurrence of unacceptable toxicity. Conditions that may lead to early termination from the study include significant adverse reactions, withdrawal of consent, or any other medical reasons deemed necessary by the investigator. The primary endpoint of the trial is PFS, defined as the time from randomization until disease progression or death. Secondary endpoints include the incidence and severity of AEs, OS, and changes in quality of life as measured by standardized questionnaires.
Treatment
**Pembrolizumab** is utilized in this clinical trial as a **powder and solvent for solution for injection**. It is administered via **intravenous use**. The maximum daily dose is 400 mg, with a total maximum dose of 7000 mg over a treatment period of up to 24 months. Pembrolizumab is of biological/biotechnological origin, specifically a protein. The study-specific packaging and labeling are in accordance with Annex 13 and country requirements to ensure compliance and participant safety.
**Cetuximab** is provided as a **solution for infusion** and is also administered intravenously. The maximum daily dose is 500 mg/m², with a total maximum dose of 500 mg/m². Cetuximab is of biological/biotechnological origin, excluding advanced therapy investigational medicinal products (ATIMP). The product is packaged and labeled specifically for the study, adhering to Annex 13 and country-specific regulations.
**Encorafenib** is administered in the form of a **hard capsule** and is taken orally. The maximum daily dose is 300 mg, with a total maximum dose of 300 mg. Encorafenib is of chemical origin. Both commercial and clinical image capsules are used, with drug product specifications and stability maintained as per the investigational medicinal product dossier (IMPD). The packaging and labeling are study-specific, following Annex 13 and country requirements.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen. The trial aims to compare the efficacy of the combination of encorafenib, cetuximab, and pembrolizumab against pembrolizumab alone in participants with previously untreated BRAF V600E-mutant, MSI-H/dMMR metastatic colorectal cancer.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Progression-Free Survival (PFS)**, defined as the time from randomization until disease progression based on investigator assessment per RECIST v1.1 or death due to any cause, whichever occurs first. Secondary endpoints include the incidence and severity of adverse events (AEs) graded according to the NCI CTCAE v4.03, overall survival (OS), objective response rate, and duration of response (DOR). Objective response is defined as confirmed complete response (CR) or partial response (PR) based on investigator assessment per RECIST v1.1, from the date of randomization until the date of the first documentation of disease progression, death, or start of new anticancer therapy. DOR is defined as the time from the first response until disease progression or death due to any cause.
Additional secondary endpoints involve the assessment of BRAF and MSI-status through retrospective central testing of baseline tumor tissue, as well as patient-reported outcomes using the EORTC QLQ-C30, EQ-5D-5L, PGIS, and PGIC scores. Changes from baseline in these scores will be evaluated to assess global health status, quality of life, functional and symptom scales, and single items. The schedule for measuring these efficacy parameters will be aligned with the trial protocol, ensuring systematic data collection and analysis throughout the study duration.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Molecular Prescreening Inclusion Criteria: 1. Locally confirmed dMMR or MSI-H disease in tumor tissue or blood (eg. ctDNA genetic testing) as determined by a local laboratory assay in a CLIA- or similarly certified laboratory
- Molecular Prescreening Inclusion Criteria 2. Locally confirmed BRAF V600E mutation in tumor tissue or blood (eg, ctDNA genetic testing) as determined by either PCR or NGS-based local laboratory assay in a CLIA- or similarly certified laboratory.
- Screening Inclusion Criteria - 3. Male or female participants age ≥16 years at the time of informed consent/assent (or the minimum country specific age of consent if >16). In countries or sites where enrollment of adolescents is not permitted (eg, Germany), male or female participants age ≥18 years at the time of informed consent.
- Screening Inclusion Criteria - 4. Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.
- Screening Inclusion Criteria: 5. Histologically or cytologically confirmed metastatic Stage IV colorectal adenocarcinoma. Note: Patients with oligometastatic disease previously treated with curative intent are eligible to participate in the study as long as they have baseline measurable disease per RECIST 1.1.
- Screening Inclusion Criteria: 6. Presence of measurable disease per RECIST v1.1, as assessed by investigator and evidenced by available baseline tumor scan. Note: Baseline scan is defined as the last scan prior to the date of randomization (Section 10.10). Note: Baseline scans will be required to be available for subsequent submission to a central radiology vendor to be assessed by the BICR.
- Screening Inclusion Criteria: 7. Availability of adequate tumor tissue (primary or metastatic; archival or newly obtained; block or slides; see Section 8.6.1). Whenever possible, the archival sample should be from the same tumor block that was used for local BRAF V600E mutation and MSI-H/dMMR testing. It is recommended that the tissue block be obtained from a biopsy or surgery that was performed within 2 years prior to study enrollment. Please consult the study clinician if samples are older. A newly obtained tumor tissue biopsy must be provided prior to randomization for participants unable to provide adequate archival tumor tissue. If a newly obtained biopsy is taken, the biopsy should be taken from a nontarget lesion when possible. Note: Participants with early stage disease (eg, Stages I-III) treated with surgery followed by chemotherapy (eg, treatment in the adjuvant setting) or have received prior systemic neoadjuvant therapy with or without radiation who present with new lesions or evidence of disease recurrence during or within 6 months of the last dose of chemotherapy would be considered as having received 1 prior systemic therapy in the metastatic setting.
- Screening Inclusion Criteria: 8. Have not received prior systemic regimens for metastatic disease. Note: Participants with early stage disease (eg, Stages I-III) treated with surgery followed by chemotherapy (eg, treatment in the adjuvant setting) or have received prior systemic neoadjuvant therapy with or without radiation who present with new lesions or evidence of disease recurrence during or within 6 months of the last dose of chemotherapy would be considered as having received 1 prior systemic therapy in the metastatic setting.
- Screening Inclusion Criteria: 9. ECOG performance status of ≤1.
- Screening Inclusion Criteria: 10. Adequate bone marrow function characterized by the following at screening: a. ANC ≥1.5 × 109/L b. Platelets ≥100 × 109/L c. Hemoglobin ≥9.0 g/dL (without blood transfusions 2 weeks prior to randomization)
- Screening Inclusion Criteria: 11. Adequate hepatic and renal function characterized by the following at screening: a. Serum Tbili ≤1.5 × ULN and < 2 mg/dL. Note: Tbili >1.5 × ULN is allowed if direct (conjugated) ≤ 1.5 × ULN and indirect (unconjugated) bilirubin is ≤ 4.25 × ULN. Note: Participants with documented Gilbert syndrome or hyperbilirubinemia due to non-hepatic cause (eg, hemolysis, hematoma) may be enrolled following discussion and agreement with the sponsor or designee. b. ALT and AST ≤ 2.5 × ULN, or ≤ 5 × ULN in the presence of liver metastases.
- Screening Inclusion Criteria: 12. Capable of giving signed informed consent as described in Appendix 1, which includes compliance with the requirements and restrictions listed in the ICD and in this protocol. Note: Participants ≥ 16 years old that are under guardianship may participate with the consent of their legally authorized guardian if permitted by local regulations. When appropriate, adolescent participants will be included in all discussions (see Sectiopn 10.1.3). Note: The investigator, or a person designated by the investigator, will obtain [written/electronically signed] informed consent/assent from each study participant’s legal guardian (as defined in Appendix 1 [and the participant’s assent, when applicable,] before any study-specific activity is performed [unless a waiver of informed consent has been granted by an IRB/ EC]). All legal guardians should be fully informed, and participants should be informed to the fullest extent possible, about the study in language and terms they are able to understand. The investigator will retain the original copy of each participant's signed consent[/assent document.
Exclusion Criteria
- Colorectal adenocarcinoma that is RAS mutant or for which RAS mutation status is unknown.
- Documented clinical disease progression (eg, worsening of performance status, clinical symptoms, or clinically significant laboratory parameters demonstrating worsening of disease) or radiographic disease progression during the screening period.
- Has active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, ie, without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention.
- Leptomeningeal disease.
- Diagnosis of immunodeficiency or an active autoimmune disease that required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Note: Participants with diabetes type I, vitiligo, psoriasis, controlled asthma, Graves' disease, Hashimoto's disease or hypo- or hyperthyroid disease are exceptions and may participate. Note: Replacement and symptomatic therapies (eg, levothyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) are not considered a form of immunosuppressive agents and are permitted.
- Presence of acute or chronic pancreatitis.
- History of chronic inflammatory bowel disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤ 12 months prior to randomization.
- Unable to swallow, retain, and absorb oral medications.
- Impaired gastrointestinal function (eg, 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.
- Clinically significant cardiovascular diseases, including any of the following: a. History of acute myocardial infarction, acute coronary syndromes (including unstable angina, coronary artery bypass graft, coronary angioplasty or stenting) ≤ 6 months prior to randomization. b. Congestive heart failure requiring treatment (New York Heart Association Grade ≥ 2). c. Recent history (one year) or presence of clinically significant cardiac arrhythmias (including uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia). d. History of thromboembolic or cerebrovascular events ≤ 12 weeks prior to randomization. Examples include transient ischemic attacks, cerebrovascular accidents, hemodynamically significant (ie, massive or sub-massive) deep vein thrombosis or pulmonary emboli. Note: Participants with either deep vein thrombosis or pulmonary emboli that do not result in hemodynamic instability are allowed to enroll as long as they are on a stable dose of anticoagulants for at least 4 weeks. Note: Participants with thromboembolic events related to indwelling catheters (including PICC lines) or other procedures may be enrolled e. Triplicate average QTcF interval ≥480 ms or a history of prolonged QT syndrome. Note: Participants with BBB or with an implanted cardiac pacemaker may enroll into the study upon agreement between the investigator and sponsor or designee. f. Congenital LQTS.
- Has a history of (non-infectious) pneumonitis / interstitial lung disease that required steroids or has current pneumonitis / interstitial lung disease.
- Evidence of active and uncontrolled bacterial or viral infection, with certain exceptions, as noted below, for chronic infection with hepatitis B or hepatitis C, within 2 weeks prior to start of study intervention. Note: For COVID-19/SARS-CoV-2, SARS-CoV-2 testing is not mandated for study entry, and testing should follow local clinical practice standards. Any participant with a positive test result for SARS-CoV-2 infection, is known to have asymptomatic infection or is suspected of having SARS-CoV-2, is excluded. Once the infection resolves, the participant may be considered for re-screening.
- Participants positive for HIV are ineligible unless they meet all of the following: a. A stable regimen of highly active anti-retroviral therapy that is not contraindicated. b. No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections c. A CD4 count >250 cells/mcL, and an undetectable HIV viral load on standard PCR-based tests. Note: Participants with a history of Kaposi sarcoma and/or Multicentric Castleman Disease are not eligible.
- Active hepatitis B or hepatitis C infection
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 11 Jul 2022 | 5 |
 Czechia | Not Recruiting | 11 Jul 2022 | 4 |
 Denmark | Not Recruiting | 11 Jul 2022 | 4 |
 France | Not Recruiting | 11 Jul 2022 | 5 |
 Germany | Not Recruiting | 11 Jul 2022 | 9 |
 Italy | Not Recruiting | 11 Jul 2022 | 15 |
 The Netherlands | Not Recruiting | 11 Jul 2022 | — |
 Norway | Not Recruiting | 11 Jul 2022 | 3 |
 Poland | Not Recruiting | 11 Jul 2022 | 5 |
 Slovakia | Not Recruiting | 11 Jul 2022 | 5 |
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 |
|---|---|---|---|---|---|---|
ENCORAFENIB | Test | — | ORAL USE | 300 | 24 | SUB177218 |
CETUXIMAB | Test | — | INTRAVENOUS USE | 500 | 24 | SUB01178MIG |
PEMBROLIZUMAB | Comparator | — | INTRAVENOUS USE | 400 | 24 | SUB167136 |
PEMBROLIZUMAB | Test | — | INTRAVENOUS USE | 400 | 24 | SUB167136 |