Study of encorafenib plus cetuximab as rechallenge treatment of BRAF V600E-mutant metastatic colorectal cancer patients: the RefIsh trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Vall D Hebron Institute Of Oncology

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

30 Oct 2025 → ongoing

Decision date (initial)

2025-07-31

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Pierre Fabre Ibérica SA

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To evaluate the antitumour activity of encorafenib plus cetuximab as a rechallenge strategy in patients with BRAF V600E-mutant mCRC who had received and responded to a BRAF inhibitor-based treatment, as measured by progression-free survival rate at (4-month PFS).

Secondary objectives 2

1. • To further evaluate the antitumour activity of encorafenib plus cetuximab as a rechallenge strategy in patients with BRAF V600E-mutant mCRC who had received and responded to a BRAF inhibitor- based treatment
2. • To evaluate the safety and tolerability profile of the combination of encorafenib and cetuximab in patients with BRAF V600E-mutant mCRC who had received and responded to a BRAF inhibitor- based treatment.

Conditions and MedDRA coding

Patients with BRAF V600E-mutant metastatic colorectal cancer (mCRC) who had received and responded to a BRAF inhibitor-based treatment.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 17

1. Provision of signed and dated informed consent form.
2. Age ≥18 years at time of informed consent.
3. Histologically- or cytologically confirmed mCRC that is metastatic.
4. Presence of confirmed BRAF V600E mutation.
5. Eligible to receive cetuximab and encorafenib per locally approved label with regard to tumour RAS status.
6. Patients must be previously treated with at least 2 prior regimens for metastatic disease and had demonstrated progressive disease or intolerance to their last regimen. Prior standard chemotherapy must include the following agents: fluoropyrimidine in monotherapy or in combination with irinotecan and/or oxaliplatin with or without anti-VEGF. Combination of chemotherapy with BRAF inhibitor containing regimen are also permitted.
7. Patients must have received BRAF inhibitor plus anti-EGFR combinations (including but not limited to MEK or ERK inhibitors or chemotherapy) treatment for ≥ 4 months. Patients must have had complete response, partial response or stable disease >6 months during the BRAF inhibitor-based treatment.
8. Patients at study enrollment should have at least 4 months of interval since the last administration of BRAF inhibitors
9. Life expectancy >12 weeks, as determined by the investigator.
10. Patients must have progressed during or within 6 months of the last chemotherapy regimen ➢ Patients who received adjuvant/neoadjuvant chemotherapy and had recurrence during or within 6 months of completion of the adjuvant/neoadjuvant chemotherapy are permitted to count the adjuvant/neoadjuvant therapy as one regimen for advanced disease.
11. Measurable disease according to RECIST v1.1.
12. ECOG performance status 0-1.
13. Adequate bone marrow function characterized by the following at screening: a. Absolute neutrophil count (ANC) ≥1.5 x 109/L. b. Platelets ≥100 x 109/L. c. Haemoglobin ≥9.0 g/dL (with or without blood transfusions).
14. Adequate hepatic and renal function characterized by the following at screening: a. Serum total bilirubin ≤1.5 x upper limit of normal (ULN) and <2 mg/dL. Note: Total bilirubin >1.5 x ULN is allowed if direct (conjugated) ≤1.5 x ULN and indirect (unconjugated) bilirubin is ≤4.25 x ULN. Note: Participants with hyperbilirubinemia due to non-hepatic cause (e.g., haemolysis, hematoma) may be enrolled following discussion and agreement with the Sponsor medical monitor. b. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤2.5 x ULN, or ≤5 x ULN in the presence of liver metastases. c. Adequate renal function defined by an estimated creatinine clearance ≥50 mL/min according to the Cockcroft Gault formula or by 24-hour urine collection for creatinine clearance, or according to local institutional standard method. d. Protein < 2+ on dipstick urinalysis or ≤ 1.0 g in a 24-hour urine collection. All patients with ≥2+ protein on dipstick urinalysis at baseline must undergo a 24-hour urine collection for protein. e. Adequate electrolytes, defined as serum potassium and magnesium levels within institutional normal limits. Note: Replacement treatment to achieve adequate electrolytes will be allowed.
15. Adequate cardiac function characterized by the following at screening: • Mean triplicate QT interval corrected for heart rate using Fridericia's formula (QTcF) value ≤480 msec.
16. Able to take oral medications.
17. Highly effective contraception for both male and female subjects if the risk of conceptions exists during and at least up to 2 months after last study medication. See 10.4. Appendix 4.

Exclusion criteria 15

1. Treatment with another investigational drug or participation in another investigational study at enrolment or within 30 days prior to enrolment.
2. Patient unable to comply with the study protocol owing to psychological, social (lack of social support or social exclusion) or geographical reasons.
3. Patient is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study.
4. Known history of chronic pancreatitis.
5. Tumours with microsatellite instability or mismatch repair deficiency if they have not received a PD1/PDL1 inhibitor-based treatment, unless medical contraindication.
6. History of chronic inflammatory bowel disease or Crohn’s disease requiring medical intervention. (immunomodulatory or immunosuppressive medications or surgery) ≤ 12 months before the enrolment in the study.
7. Impaired cardiovascular function or 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 [CABG], coronary angioplasty or stenting) ≤ 6 months prior to start of study treatment. b. Symptomatic congestive heart failure (i.e., Grade 2 or higher), history or current evidence of clinically significant cardiac arrhythmia and/or conduction abnormality ≤ 6 months prior to start of study treatment, except atrial fibrillation and paroxysmal supraventricular tachycardia.
8. Impaired hepatic function, defined as Child-Pugh class B or C.
9. Known history of human immunodeficiency virus (HIV), active hepatitis B virus (HBV) infection or active hepatitis C virus (HCV) infection. Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Patients with past exposure to HBV are also eligible for the study provided they are negative for HBV DNA.
10. Has spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Subjects with clinically inactive brain metastases may be included in the study. Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and the enrolment in the study.
11. Subjects with leptomeningeal carcinomatosis.
12. Impaired gastrointestinal (GI) function or disease that may significantly alter the absorption of encorafenib (e.g., ulcerative diseases, uncontrolled vomiting, malabsorption syndrome, small bowel resection with decreased intestinal absorption).
13. Knowledge of any other disease or medication that may interfere with study treatment.
14. Presence of any contraindication with regard to the study drugs as specified in the corresponding SmPCs.
15. Patients who achieved progression disease as best response while receiving BRAF inhibitor previously

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Progression-free survival rate at 4 months (4-month PFS) according to RECIST V1.1 by Investigator assessment.

Secondary endpoints 6

1. Objective Response Rate (ORR) according to RECIST V1.1 by Investigator assessment.
2. Progression free survival (PFS) according to RECIST V1.1 by Investigator assessment.
3. Overall survival (OS)
4. Clinical efficacy based on the presence absence of acquired genomic mechanism of resistance detected in the NGS baseline to the rechallenge.
5. Incidence and severity of adverse events (AEs), graded by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
6. Change in clinical laboratory test parameters, vital signs, ECGs and echocardiogram/MUGA scans.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Vall D Hebron Institute Of Oncology

Sponsor organisation

Vall D Hebron Institute Of Oncology

Address

Calle Natzaret 115

City

Barcelona

Postcode

08035

Country

Spain

Scientific contact point

Organisation

Vall D Hebron Institute Of Oncology

Contact name

CRO Head

Public contact point

Organisation

Vall D Hebron Institute Of Oncology

Contact name

CRO Head

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 6 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications