Clinical trial NCT05004350: A Study Evaluating the Combination of Encorafenib and Cetuximab Versus Irinotecan/Cetuximab or Infusional 5-fluorouracil (5-FU)/Folinic Acid (FA)/Irinotecan (FOLFIRI)/Cetuximab in Chinese Patients With BRAF V600E Mutant Metastatic Colorectal Cancer.
Official title: A Multicenter, Randomized, Open-label, 2-arm, Phase II Study With a Safety lead-in Phase Evaluating the Combination of Encorafenib and Cetuximab Versus Irinotecan/Cetuximab or Infusional 5-fluorouracil (5-FU)/Folinic Acid (FA)/Irinotecan (FOLFIRI)/Cetuximab in Chinese Patients With BRAF V600E Mutant Metastatic Colorectal Cancer.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: BRAF V600E
Metastatic Colorectal Cancer
Keywords: BRAF V600E
Metastatic Colorectal Cancer
Lead sponsor: Pierre Fabre Medicament
Sponsor class: INDUSTRY
Collaborators: name: Merck KGaA, Darmstadt, Germany
First posted: 2021-08-13
Enrollment: 107
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Encorafenib is currently being developed (with or without binimetinib), in combination with cetuximab, for the treatment of adult patients with B-RAF proto-oncogene, serine/threonine kinase V600E mutant (BRAF V600E) metastatic colorectal cancer (mCRC), who have received prior systemic therapy.


Eligibility criteria: Inclusion Criteria for Molecular Prescreening:

The following inclusion criteria must be met for a participant to be eligible to undergo molecular tumor prescreening:

* Chinese male or female participant with age ≥18 years at the time of informed consent.
* Histologically- or cytologically-confirmed colorectal cancer (CRC) that is metastatic.
* Eligible to receive cetuximab per Chinese approved label with regard to tumor Rat Sarcoma Viral Oncogene Homologue (RAS) mutation status (i.e. approved for Rat Sarcoma Viral Oncogene Homologue Wild Type(RAS wt) status).
* Able to provide a sufficient amount of representative tumor specimen for central prospective laboratory testing of B-RAF Proto-oncogene, Serine/threonine Kinase (BRAF) mutation status and also retrospective RAS wt status and Microsatellite Instability (MSI) testing.

Inclusion Criteria for Treatment Period:

The following inclusion criteria must be met for a participant to be eligible for this study:

* Chinese male or female participant with age ≥18 years at time of informed consent.
* Histologically or cytologically confirmed CRC that is metastatic and unresectable at time of study entry (i.e. not suitable for complete surgical resection at screening).
* Presence of a BRAF V600E mutation in tumor tissue previously determined by a local assay at any time before screening or by the central laboratory.

NOTE: Other protocol defined Inclusion criteria may apply

Exclusion Criteria for Molecular Prescreening:

Participants meeting any of the following criteria are not eligible to undergo molecular tumor prescreening:

* Prior anti-Epidermal Growth Factor Receptor (anti-EGFR) treatment
* More than two prior regimens in the metastatic setting.
* Known contraindication to receive cetuximab or irinotecan at the planned dose according to the most recent cetuximab and irinotecan local label.
* Known history of Gilbert's syndrome or is known to have any of the following genotypes: uridine 5'-diphospho-glucuronosyltransferase (UGT)1A1\*6/\*6, UGT1A1\*28/\*28 or UGT1A1\*6/\*28.
* Leptomeningeal disease.

Exclusion Criteria for Treatment Period:

* Prior treatment with any Proto oncogene Serine/threonine-Protein Kinase (RAF) inhibitor, cetuximab, panitumumab or other EGFR inhibitors.
* Symptomatic brain metastasis.
* Leptomeningeal disease.
* Use of any herbal medications/supplements or any medications or foods that are moderate or strong inhibitors or inducers of cytochrome P450 (CYP)3A4/5 ≤1 week before the start of study intervention.
* Known history of acute or chronic pancreatitis within 6 months before the start of study intervention.

NOTE: Other protocol defined Exclusion criteria may apply

Primary outcomes:
measure: Safety Lead-in Phase: Incidence of Dose Limiting Toxicities (DLTs) during the DLT-evaluation period (which is the first 28 days after the first dose of study intervention in the SLI)
timeFrame: Day 1 to Day 28
measure: Randomized Phase 2: Progression-free Survival (PFS) by Blinded (to treatment received) Independent Central Review (BICR)
timeFrame: Day 1 through to study completion, approximately from 12 to 29 months
Secondary outcomes:
measure: Safety Lead-in Phase: Type and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03
timeFrame: Informed consent through to study completion, approximately from 18 to 35 months
measure: Safety Lead-in Phase: Incidence of treatment-emergent adverse events (TEAEs) related to notable or abnormal changes from baseline of physical examinations
timeFrame: Day 1 through to study completion, approximately from 18 to 35 months
measure: Safety Lead-in Phase: Incidence of treatment-emergent adverse events (TEAEs) related to notable or abnormal changes in vital signs from baseline of vital sign examinations.
timeFrame: Day 1 through to study completion, approximately from 18 to 35 months
measure: Safety Lead-in Phase: Incidence of treatment-emergent adverse events (TEAEs) related to notable or abnormal changes from baseline of 12-lead electrocardiograms (ECGs)
timeFrame: Day 1 through to study completion, approximately from 18 to 35 months
measure: Safety Lead-in Phase: Incidence of treatment-emergent adverse events (TEAEs) related to notable changes in clinical safety laboratory parameters from baseline.
timeFrame: Day 1 through to study completion, approximately from 18 to 35 months
measure: Safety Lead-in Phase: Incidence of development of of keratoacanthoma and/or squamous cell carcinoma and new primary melanoma by dermatological examinations
timeFrame: Screening (Day -28 to -1) through to study completion, approximately from 18 to 35 months
measure: Safety Lead-in Phase: Performance status assessment using the Eastern Co-operative Oncology Group (ECOG) performance status scale
timeFrame: Screening (Day -28 to -1) through to study completion, approximately from 18 to 35 months
measure: Safety Lead-in Phase: Incidence of dose interruptions, dose modifications and discontinuations due to adverse events (AEs)
timeFrame: Day 1 until end of treatment, approximately 1 year
measure: Safety Lead-in Phase: Plasma concentrations of encorafenib
timeFrame: Day 1 of Cycles 1 and 2; Each cycle = 28 days
measure: Safety Lead-in Phase: Serum concentrations of cetuximab
timeFrame: Day 1 of Cycles 1 and 2; Each cycle = 28 days
measure: Safety Lead-in Phase; Pharmacokinetic (PK) parameter derived from plasma concentration of encorafenib area under curve (AUC) in Chinese participants
timeFrame: Day 1 of Cycles 1 and 2; Each cycle = 28 days
measure: Safety Lead-in Phase: Pharmacokinetic (PK) parameter derived from serum concentration of cetuximab area under curve (AUC) in Chinese participants
timeFrame: Day 1 of Cycles 1 and 2; Each cycle = 28 days
measure: Safety Lead-in Phase: Pharmacokinetic (PK) parameter derived from plasma concentration of encorafenib minimum concentration (Cmin) in Chinese participants
timeFrame: Day 1 of Cycles 1 and 2; Each cycle = 28 days
measure: Safety Lead-in Phase: Pharmacokinetic (PK) parameter derived from serum concentration of cetuximab minimum concentration (Cmin) in Chinese participants
timeFrame: Day 1 of Cycles 1 and 2; Each cycle = 28 days
measure: Safety Lead-in Phase: Pharmacokinetic (PK) parameter derived from plasma concentration of encorafenib maximum concentration (Cmax) in Chinese participants
timeFrame: Day 1 of Cycles 1 and 2; Each cycle = 28 days
measure: Safety Lead-in Phase: Pharmacokinetic (PK) parameter derived from serum concentration of cetuximab maximum concentration (Cmax) in Chinese participants
timeFrame: Day 1 of Cycles 1 and 2; Each cycle = 28 days
measure: Safety Lead-in Phase: Objective response rate (ORR)
timeFrame: Day 1 through to study completion, approximately from 18 to 35 months
measure: Safety Lead-in Phase: Duration of Response (DOR) (months); defined for responders complete response (CR) or partial response (PR) only, is duration of time from the date of the first documented response to the earliest date of disease progression
timeFrame: Day 1 through to study completion, approximately from 18 to 35 months
measure: Randomized Phase 2: Progression-free survival (PFS)
timeFrame: Day 1 through to study completion, approximately from 12 to 29 months
measure: Randomized Phase 2: Overall Response Rate (ORR)
timeFrame: Day 1 through to study completion, approximately from 12 to 29 months
measure: Randomized Phase 2: Duration of Response (DOR)
timeFrame: Day 1 through to study completion, approximately from 12 to 29 months
measure: Randomized Phase 2: Disease control rate (DCR)
timeFrame: Day 1 through to study completion, approximately from 12 to 29 months
measure: Randomized Phase 2: Time to Response (TTR)
timeFrame: Day 1 through to study completion, approximately from 12 to 29 months
measure: Randomized Phase 2: Overall Survival (OS)
timeFrame: Day 1 through to study completion, approximately from 12 to 29 months
measure: Randomized Phase 2: Type and severity of adverse events (AEs) and serious adverse events (SAEs) according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03
timeFrame: Informed consent date through to study completion, approximately from 12 to 29 months
measure: Randomized Phase 2: Incidence of treatment-emergent adverse events (TEAEs) related to notable or abnormal changes from baseline of physical examinations
timeFrame: Day 1 through to study completion, approximately from 12 to 29 months
measure: Randomized Phase 2: Incidence of treatment-emergent adverse events (TEAEs) related to notable changes in vital signs from baseline.
timeFrame: Day 1 through to study completion, approximately from 12 to 29 months
measure: Incidence of treatment-emergent adverse events (TEAEs) related to notable or abnormal changes to electrocardiogram evaluations from baseline
timeFrame: Day 1 through to study completion, approximately from 12 to 29 months
measure: Randomized Phase 2: Incidence of treatment-emergent adverse events (TEAEs) related to notable changes in clinical safety laboratory parameters from baseline.
timeFrame: Day 1 through to study completion, approximately from 12 to 29 months
measure: Randomized Phase 2: Incidence of development of keratoacanthoma and/or squamous cell carcinoma and new primary melanoma by dermatological examinations
timeFrame: Day 1 through to study completion, approximately from 12 to 29 months
measure: Randomized Phase 2: To determine the performance status using the Eastern Co-operative Oncology Group (ECOG) performance status scale.
timeFrame: Day 1 through to study completion, approximately from 12 to 29 months
measure: Randomized Phase 2: To determine if there is any change from baseline in the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer Patients (EORTC QLQ-C30) questionnaire scores
timeFrame: Day 1 through to study completion, approximately from 12 to 29 months
measure: Randomized Phase 2: To determine if there is any change from baseline in the European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) questionnaire scores.
timeFrame: Day 1 through to study completion, approximately from 12 to 29 months
measure: Randomized Phase 2: To determine if there is any change from baseline in the Functional Assessment of Cancer Therapy-Colon Cancer (FACT-C) questionnaire scores
timeFrame: Day 1 through to study completion, approximately from 12 to 29 months
measure: Randomized Phase 2: To determine if there is any changes in the Patient Global Impression of Change (PGIC) questionnaire scores.
timeFrame: Day 1 through to study completion, approximately from 12 to 29 months
measure: Randomized Phase 2: Plasma concentrations of encorafenib
timeFrame: Day 1 of Cycles 1 and 2; Each cycle = 28 days
measure: Randomized Phase 2: Serum concentrations of cetuximab
timeFrame: Day 1 of Cycles 1 and 2; Each cycle = 28 days
measure: Randomized Phase 2; Pharmacokinetic (PK) parameter derived from plasma concentration of encorafenib area under curve (AUC) in Chinese participants
timeFrame: Day 1 of Cycles 1 and 2; Each cycle = 28 days
measure: Randomized Phase 2: Pharmacokinetic (PK) parameter derived from serum concentration of cetuximab area under curve (AUC) in Chinese participants
timeFrame: Day 1 of Cycles 1 and 2; Each cycle = 28 days
measure: Randomized Phase 2: Pharmacokinetic (PK) parameter derived from plasma concentration of encorafenib minimum concentration (Cmin) in Chinese participants
timeFrame: Day 1 of Cycles 1 and 2; Each cycle = 28 days
measure: Randomized Phase 2: Pharmacokinetic (PK) parameter derived from serum concentration of cetuximab minimum concentration (Cmin) in Chinese participants
timeFrame: Day 1 of Cycles 1 and 2; Each cycle = 28 days
measure: Randomized Phase 2: Pharmacokinetic (PK) parameter derived from plasma concentration of encorafenib maximum concentration (Cmax) in Chinese participants
timeFrame: Day 1 of Cycles 1 and 2; Each cycle = 28 days
measure: Randomized Phase 2: Pharmacokinetic (PK) parameter derived from serum concentration of cetuximab maximum concentration (Cmax) in Chinese participants
timeFrame: Day 1 of Cycles 1 and 2; Each cycle = 28 days
measure: Randomized Phase 2: Population pharmacokinetic (PK) analysis using the ARRAY 818 302 study PK data
timeFrame: Day 1 through to study completion, approximately from 12 to 29 months
Other outcomes:
measure: Randomized Phase 2: Changes from baseline in blood Carcinoembryonic Antigen (CEA) and Cancer Antigen 19-9 (CA19-9) at the beginning of each cycle and at the end of treatment
timeFrame: Screening (Day -28 to -1) through to study completion, approximately from 12 to 29 months
measure: Randomized Phase 2: Microsatellite Instability (MSI) status in Formalin-fixed and Paraffin Embedded (FFPE) samples using established Polymerase Chain Reaction (PCR) assays in tumor sample versus germline control at screening
timeFrame: Screening (Day -28 to Day -1)
Locations:
city: Beijing
country: China
facility: Beijing Cancer Hospital
state: Beijing
city: Beijing
country: China
facility: Peking Union Medical College Hospital, Chinese Academy of Medical Sciences
state: Beijing
city: Fuzhou
country: China
facility: Fujian Medical University - Fujian Provincial Cancer Hospital
state: Fujian
city: Xiamen
country: China
facility: The First Affiliated Hospital of Xiamen University
state: Fujian
city: Foshan
country: China
facility: The First People's Hospital of Foshan
state: Guangdong
city: Guangzhou
country: China
facility: Cancer Center of Guangzhou Medical University
state: Guangdong
city: Guangzhou
country: China
facility: The Sixth Affiliated Hospital Sun Yat-Sen University
state: Guangdong
city: Shantou
country: China
facility: Cancer Hospital Affiliated to Shantou University Medical College
state: Guangdong
city: Shenzhen
country: China
facility: Peking University Shenzhen Hospital
state: Guangdong
city: Baoding
country: China
facility: The Affiliated Hospital of Hebei University
state: Hebei
city: Harbin
country: China
facility: Harbin Medical University Cancer Hospital
state: Heilongjiang
city: Zhengzhou
country: China
facility: Henan Cancer Hospital
state: Henan
city: Zhengzhou
country: China
facility: The First Affiliated Hospital of Zhengzhou University
state: Henan
city: Wuhan
country: China
facility: Union Hospital Tongji medical college Huazhong University of Science and Technology
state: Hubei
city: Wuhan
country: China
facility: Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology
state: Hubei
city: Wuhan
country: China
facility: Zhongnan Hospital of Wuhan University
state: Hubei
city: Changsha
country: China
facility: Xiangya Hospital Central South University
state: Hunan
city: Changzhou
country: China
facility: The First People's Hospital of Changzhou
state: Jiangsu
city: Ganzhou
country: China
facility: First Affiliated Hospital of Gannan Medical University
state: Jiangxi
city: Nanchang
country: China
facility: The First Affiliated Hospital of Nanchang University
state: Jiangxi
city: Nanchang
country: China
facility: The Second Affiliated Hospital of Nanchang University
state: Jiangxi
city: Changchun
country: China
facility: The First Hospital of Jilin University
state: Jilin
city: Jinzhou
country: China
facility: The First Affiliated Hospital of Jinzhou Medical University
state: Liaoning
city: Shenyang
country: China
facility: The First Hospital of China Medical University
state: Liaoning
city: Shenyang
country: China
facility: Liaoning Cancer Hospital & Institute
state: Liaoning
city: Xi'an
country: China
facility: Shaanxi Provincial People's Hospital
state: Shaanxi
city: Shanghai
country: China
facility: Zhongshan Hospital Fudan University
state: Shanghai
city: Shanghai
country: China
facility: Huashan Hospital Fudan University
state: Shanghai
city: Shanghai
country: China
facility: Xinhua Hospital Affilliated to Shanghai Jiaotong University School of Medicine
state: Shanghai
city: Shanghai
country: China
facility: Shanghai East Hospital, Tongji University
state: Shanghai
city: Neijiang
country: China
facility: The Second People's Hospital of Neijiang
state: Sichuan
city: Tianjin
country: China
facility: Tianjin Medical University Cancer Institute and Hospital
state: Tianjin
city: Hangzhou
country: China
facility: The First Affiliated Hospital - Zhejiang University School of Medicine
state: Zhejiang
city: Hangzhou
country: China
facility: Sir Run Run Shaw Hospital - Zhejiang University School of Medicine
state: Zhejiang
Study officials:
affiliation: Peking University Cancer Hospital & Institute
name: Shen Lin, MD
role: PRINCIPAL_INVESTIGATOR
References: