Phase 3 Study of Encorafenib and Cetuximab With or Without Chemotherapy Versus Standard Therapy in Metastatic BRAF V600E Mutant Colorectal Cancer
- Trial ID
- 2023-509405-77-00
- Protocol
- C4221015
- Sponsor
- Pfizer Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **safety** and tolerability of the combination of encorafenib and cetuximab (EC) with mFOLFOX6 and FOLFIRI in patients with metastatic BRAF V600E-mutant colorectal cancer. This is clinically relevant as it aims to establish a safe and tolerable treatment regimen for this specific genetic mutation in colorectal cancer, potentially improving patient outcomes.
Secondary objectives include:
- Assessing the overall safety and tolerability of EC combined with mFOLFOX6 and FOLFIRI.
- Estimating and comparing the efficacy of EC combined with mFOLFOX6 and FOLFIRI.
- Characterizing the pharmacokinetics (PK) of encorafenib, irinotecan, oxaliplatin, and relevant metabolites.
- Assessing drug-drug interactions of encorafenib with irinotecan or oxaliplatin.
- Further comparing the efficacy of treatment arms in terms of overall survival (OS), progression-free survival (PFS), and other response metrics.
- Determining the safety and tolerability of EC and EC combined with mFOLFOX6.
Participants
The clinical trial involves a total of **418 participants** diagnosed with **colorectal cancer** characterized by the BRAF V600E mutation. The study population includes both male and female subjects, with an age range starting from 16 years, depending on the country's regulations, and no upper age limit specified. Participants are required to have a body weight of at least 40 kg and must have histologically or cytologically confirmed colorectal adenocarcinoma with evidence of Stage IV metastatic disease. The trial population was selected based on the presence of the BRAF V600E mutation in tumor tissue or blood, confirmed through either local or central laboratory assays. Participants must be capable of providing informed consent and willing to comply with all study procedures, including scheduled visits and lifestyle considerations. The study includes a vulnerable population, as it permits the enrollment of adolescents where local regulations allow. The selection criteria ensure that participants have a sufficient amount of representative tumor specimen for central testing, and they must be able to provide a tumor sample obtained within two years prior to study enrollment.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label, multicenter, Phase 3 study to evaluate the efficacy and safety of **encorafenib** plus **cetuximab** with or without chemotherapy in participants with metastatic **BRAF V600E-mutant colorectal cancer**. The trial includes a safety lead-in phase to assess the tolerability of the combination therapies. The study is expected to run from November 26, 2020, to November 15, 2026, with participant involvement lasting up to 72 weeks, depending on individual response and tolerability.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, weight, and the presence of a **BRAF V600E mutation**. The screening process will involve the collection of tumor tissue for central laboratory confirmation of the mutation. Following successful screening, participants will be randomized into different treatment arms. The trial will include regular follow-up visits to monitor safety, efficacy, and any adverse events, with assessments conducted according to the **Response Evaluation Criteria in Solid Tumors (RECIST) v1.1**. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
Early termination from the study may occur due to disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoints include progression-free survival (PFS) and overall response rate (ORR) as assessed by blinded independent central review. Secondary endpoints encompass overall survival (OS), duration of response (DOR), and quality of life measures. The trial will also evaluate pharmacokinetic parameters and the incidence of dose-limiting toxicities. Participants are required to comply with all scheduled visits, treatment plans, and study procedures to ensure the integrity of the trial data.
Treatment
The clinical trial involves several treatments, including both experimental and non-experimental medications. **Irinotecan hydrochloride trihydrate** is administered as a concentrate for solution for infusion, with a maximum daily dose of 180 mg/m². It is delivered intravenously and is used for a maximum treatment period of 72 weeks. This compound is of chemical origin and is provided by Pfizer Limited.
**Capecitabine** is provided in the form of a film-coated tablet, with a maximum daily dose of 2000 mg/m². It is administered orally and is also used for a maximum treatment period of 72 weeks. Capecitabine is of chemical origin and is supplied by Pfizer Inc.
**Oxaliplatin** is available as a concentrate for solution for infusion, with a maximum daily dose of 130 mg/m². It is administered intravenously and is used for a maximum treatment period of 72 weeks. This compound is of chemical origin and is provided by Accord Healthcare Limited.
**Cetuximab** is administered as a solution for infusion, with a maximum daily dose of 500 mg/m². It is delivered intravenously and is used for a maximum treatment period of 72 weeks. Cetuximab is of biological/biotechnological origin and is supplied by Pfizer Inc.
**Fluorouracil** is provided as a solution for injection or infusion, with a maximum daily dose of 1600 mg/m². It is administered intravenously and is used for a maximum treatment period of 72 weeks. This compound is of chemical origin and is supplied by Accord Healthcare Limited.
**Encorafenib** is available in the form of a hard capsule, with a maximum daily dose of 300 mg. It is administered orally and is used for a maximum treatment period of 72 weeks. Encorafenib is of chemical origin.
**Bevacizumab** is administered as a concentrate for solution for infusion, with a maximum daily dose of 10 mg/kg. It is delivered intravenously and is used for a maximum treatment period of 72 weeks. Bevacizumab is of biological/biotechnological origin and is provided by Pfizer Inc.
**Calcium folinate** is provided as a solution for injection, with a maximum daily dose of 400 mg/m². It is administered intravenously and is used for a maximum treatment period of 72 weeks. This compound is of chemical origin and is supplied by Hospira UK Limited.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to evaluate the safety and efficacy of these treatments in participants with metastatic BRAF V600E mutant colorectal cancer.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the **Progression-Free Survival (PFS)** by blinded independent central review (BICR), defined as the time from the date of randomization to the earliest documented disease progression per RECIST v1.1, or death due to any cause, and the **Overall Response Rate (ORR)** by BICR. These endpoints will be evaluated in the Phase 3 and Cohort 3 segments of the trial.
Secondary endpoints will further assess efficacy through various measures. These include the **Overall Survival (OS)**, defined as the time from the date of randomization to death due to any cause, and the ORR by Investigator. Additional secondary endpoints involve the **Duration of Response (DOR)** by BICR and by Investigator, and the **Time to Response (TTR)** by BICR and by Investigator, defined as the time from the date of randomization to first radiographic evidence of response (CR or PR) per RECIST v1.1. The trial will also measure **PFS2**, defined as the time from the date of randomization to the date of discontinuation of next-line treatment after first objective PD by investigator assessment, the second objective disease progression, or death from any cause, whichever occurs first.
Patient-reported outcomes (PROs) will be evaluated using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer Patients – 30 Item Core Questionnaire (EORTC QLQ-C30), EuroQol-5D-5L (EQ-5D-5L), and anchoring instruments Patient Global Impression of Severity (PGIS) and Patient Global Impression of Change (PGIC). Additionally, the trial will monitor ctDNA levels and BRAF V600 variant allele fraction (VAF) from ctDNA analysis of plasma samples collected at baseline and on treatment.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Molecular Prescreening Inclusion Criteria - Age and Sex: 1. SLI: Male or female participants age ≥18 years at the time of informed consent. Phase 3 and Cohort 3: Male or female participants age ≥16 years at the time of informed consent/assent in all countries where permitted. 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. • Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female (Section 10.4.2) participants.
- Body weight ≥40 kg.
- Participants with histologically or cytologically confirmed colorectal adenocarcinoma.
- Participants with evidence of Stage IV metastatic disease. 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. Oligometastatic colorectal cancer is characterized by a limited metastatic spread of disease. Oligometastatic disease is defined as the involvement of up to 3 sites with 5 or sometimes more metastases that for their anatomic localization is amenable to local therapies, thus rendering the patient free of disease.
- Able to provide a sufficient amount of representative tumor specimen for central testing of BRAF V600E mutation status and tumor tissue assessment Note: Tumor sample can be archival or de novo (newly collected fixed biopsy sample) and must be in an FFPE block, or provide a minimum of 15 unstained slides of analyzable tissue. This tissue specimen should be obtained from a biopsy or surgery that was performed within 2 years prior to study enrollment. Participants with fewer than the required number of slides with analyzable tissue may be considered eligible if the Sponsor determines that the slides are sufficient for central testing.
- Capable of giving signed informed consent/assent 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 Section 10.1.3).
- Participants who have met all Molecular Prescreening inclusion criteria.
- Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.
- Presence of a BRAF V600E mutation in tumor tissue or blood (eg, ctDNA genetic testing). The following are acceptable: a. Local laboratory assay (PCR or NGS-based only) performed at any time prior to Screening using either tumor tissue or blood. b. Central laboratory assay performed during the Screening period using tumor tissue alone (not blood). Note: For participants enrolled on the basis of a local BRAF mutation assay, tumor samples must be submitted to the central laboratory for BRAF testing as soon as possible following signing of the ICD. The BRAF status must be confirmed no later than 30 days following first dose of study intervention.
- The Investigator must obtain prior to Cycle 1 Day 1 (SLI) or date of randomization (Phase 3 and Cohort 3) adequate tumor tissue (primary or metastatic, archival or newly obtained) for submission to a central laboratory for confirmation of BRAF V600E and tumor tissue assessment. Note: Once BRAF V600E mutation status is determined by the central laboratory (tumor tissue), the results will be considered definitive for eligibility. No repeat testing will be performed. Note: Lack of BRAF V600E confirmation by the central laboratory may be due to discordance between the local assay and central laboratory results (potential false positive local assay results), or due to inadequate or poor sample condition for central testing (indeterminate results). Note: Participants whose sample is determined to be inadequate or who have an indeterminate result on central testing may have additional tumor samples submitted for testing.
Exclusion Criteria
- Molecular Prescreening Exclusion Criteria Medical Conditions: 1. Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator’s judgment, make the participant inappropriate for the study.
- Presence of acute or chronic pancreatitis.
- Leptomeningeal disease.
- History of chronic inflammatory bowel disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤12 months prior to randomization.
- Known DPD deficiency; refer to local fluorouracil or capecitabine label or local clinical guidances, for DPD status recommendation prior to starting treatment.
- Gilbert's syndrome or known homozygous UGT1A1*28/*28 or UGT1A1*6/*6 genotypes or double heterozygous UGT1A1*6/*28 genotype: a. SLI: Participants with documented Gilbert's syndrome or known homozygous UGT1A1*28/*28 or UGT1A1*6/*6 genotypes or double heterozygous UGT1A1*6/*28 will be excluded from Cohort 1 (EC + FOLFIRI) of the SLI. b.Phase III: Participants with documented Gilbert's syndrome or known homozygous UGT1A1*28/*28 or UGT1A1*6/*6 genotypes or double heterozygous UGT1A1*6/*28 genotype may be enrolled, but may not receive FOLFOXIRI if randomized to the Control Arm. c. Cohort 3: Participants with documented Gilbert's syndrome or known homozygous UGT1A1*28/*28 or UGT1A1*6/*6 genotypes or double heterozygous UGT1A1*6/*28 genotype will be excluded from Cohort 3 Arm D and Arm E (EC + FOLFIRI and FOLFIRI ± bevacizumab).
- Investigator site staff or Pfizer employees directly involved in the conduct of the study, site staff otherwise supervised by the investigator, and their respective family members.
- Colorectal adenocarcinoma that is RAS mutant or for which RAS mutation status is unknown.
- Locally confirmed dMMR or MSI-H colorectal carcinoma or unknown MSI/MMR status. If participant is locally confirmed dMMR or MSI-H and unable to receive immune checkpoint inhibitors due to a pre existing medical condition, they may be enrolled.
- Screening Exclusion Criteria Medical Conditions: 10. 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 Class II and above); c. Recent history (within 1 year prior to randomization) 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 bundle-branch block (BBB) or with an implanted cardiac pacemaker, may enroll into the study following consultation with the Sponsor. f. Congenital LQTS.
- Evidence of active noninfectious pneumonitis.
- Evidence of active and uncontrolled bacterial or viral infection, with certain exceptions, as noted below, for chronic infection with HIV, hepatitis B or hepatitis C, within 2 weeks prior to start of study intervention.
- 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 (see Section 6.5); 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 26 Nov 2020 | 17 |
 Bulgaria | Not Recruiting | 26 Nov 2020 | 5 |
 Czechia | Not Recruiting | 26 Nov 2020 | 6 |
 Denmark | Not Recruiting | 26 Nov 2020 | 13 |
 Finland | Not Recruiting | 26 Nov 2020 | 7 |
 Germany | Not Recruiting | 26 Nov 2020 | 16 |
 Italy | Not Recruiting | 26 Nov 2020 | 45 |
 The Netherlands | Not Recruiting | 26 Nov 2020 | — |
 Norway | Not Recruiting | 26 Nov 2020 | 7 |
 Poland | Not Recruiting | 26 Nov 2020 | 35 |
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 |
|---|---|---|---|---|---|---|
Calcium Folinate 10 mg/ml Injection | Comparator | INJECTION | INTRAVENOUS USE | 400 | 72 | PRD1173964 |
OXALIPLATIN | Comparator | — | INTRAVENOUS USE | 130 | 72 | SUB09490MIG |
BEVACIZUMAB | Comparator | — | INTRAVENOUS USE | 10 | 72 | SUB16402MIG |
Capecitabine | Comparator | FILM-COATED TABLET | ORAL | 2000 | 72 | PRD11159017 |
CETUXIMAB | Test | — | INTRAVENOUS USE | 500 | 72 | SUB01178MIG |
Irinotecan hydrochloride 20 mg/ml concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 180 | 72 | PRD2980742 |
CAMPTO 20 mg/mL concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 180 | 72 | PRD3700496 |
Oxaliplatin 5mg/ml concentrate for Solution for Infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 130 | 72 | PRD386338 |
Bevacizumab | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 10 | 72 | PRD11159024 |
IRINOTECAN | Comparator | — | INTRAVENOUS USE | 180 | 72 | SUB08295MIG |