Encorafenib+Cetuximab Beyond Progression in Combination with Folfiri in Patients with Braf V600E Mutated Metastatic Colorectal Cancer Progressing on Encorafenib + Cetuximab

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

3 Jun 2024 → ongoing

Decision date (initial)

2024-04-04

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

PIERRE FABRE PHARMA S.r.l.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy

To determine the efficacy of EC in combination with FOLFIRI in patients with BRAF V600E mutated mCRC progressing on EC administered in second line

Secondary objectives 1

1. To determine the activity, the long-term outcomes and the safety of EC in combination with FOLFIRI in patients with BRAF V600E mutated mCRC progressing on EC administered in second line

Conditions and MedDRA coding

Patients affected by mCRC harbouring BRAF V600E

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 21

1. written informed consent to study procedures
2. age ≥ 18 years
3. histologically or cytologically confirmed diagnosis of colorectal adenocarcinoma
4. radiological evidence of metastatic disease
5. evidence of measurable disease according to RECIST 1.1 criteria
6. presence of BRAF V600E mutation in tumor tissue (primary CRC and/or related metastasis) as previously determined by a local assay at any time prior to screening (only PCR and NGS-based local assays results will be acceptable)
7. disease progression while on treatment with EC received in 2nd line setting. NOTES a) EC administered after disease relapse during treatment or within 6 months following adjuvant therapy will be second line; b) maintenance therapy given in the metastatic setting after a first line doublet or triplet chemotherapy will not be considered a separate regimen
8. best response to previous treatment with EC: CR, PR or SD lasting for at least 3 months
9. patient fit for a subsequent treatment line with FOLFIRI. Patients exposed to irinotecan and fluoropyrimidines during previous line for metastatic disease are eligible, provided that the patient has recovered from G3 toxicity
10. life expectancy ≥ 3 months
11. Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤1
12. Adequate bone marrow function at screening: a) Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L; b) Platelets ≥ 100 × 10^9/L; c) Hemoglobin ≥ 9.0 g/dL; Note: Transfusions will be allowed to achieve this. Transfusions will be permitted provided that the patient has not received more than 2 units red blood cells in the prior 4 weeks to achieve this criteria
13. Adequate renal function at screening: 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
14. Adequate hepatic function at screening: a) serum total bilirubin ≤ 1.5 × ULN; b) alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 2.5 × ULN, or ≤ 5 × ULN in presence of liver metastases
15. Adequate cardiac function characterized by the following at screening: QT interval corrected for heart rate using Fridericia's formula (QTcF) value ≤480 msec.
16. Availability of treatment-naïve, archival FFPE tumor tissue sample
17. Ability to take oral medications
18. Male subjects with female partners of childbearing potential must be willing to use adequate contraception as outlined in Section 5.5 – Contraception, starting with the first dose of study therapy through 180 days after the last dose of treatment. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
19. Women of childbearing potential must have a negative blood or urine pregnancy test at the baseline visit
20. Female subjects of childbearing potential must be willing to use an adequate method of contraception as outlined in Section 5.5 – Contraception, for the course of the study starting with the first dose of study therapy through 180 days ECLYPse Study - Protocol Version 1.0 – 27th Feb, 2023 Pag. 34 | 101 after the last dose of treatment. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
21. Will and ability to comply with the protocol

Exclusion criteria 23

1. patients experiencing PD as best response to EC
2. patients with specific BRAFi/AntiEGFR contraindications
3. patients with specific irinotecan or fluoropyrimidines contraindications
4. patients with DPYD deficiency
5. life expectancy ≤3 months
6. ECOG PS >1
7. Any of the following in the 6 months prior to treatment start: myocardial infarction, acute coronary syndromes (including unstable angina, coronary artery bypass graft [CABG], coronary angioplasty or stenting), congestive heart failure (≥ New York Heart Association Classification Class II), serious cardiac arrhythmia (except atrial fibrillation and appropriately controlled paroxysmal supraventricular tachycardia), cerebrovascular accident, symptomatic pulmonary embolism
8. Congenital long QT syndrome
9. Impaired gastrointestinal function or disease that may significantly alter the absorption of encorafenib (uncontrolled vomiting, malabsorption syndrome, small bowel resection with decreased intestinal absorption)
10. Uncontrolled coagulopathy
11. Patients has a known history of Gilbert's syndrome or is known to have any of the following genotypes: UGT1A1*6/*6, UGT1A1*28/*28, or UGT1A1*6/*28
12. Active infection requiring systemic therapy
13. Known history of acute or chronic pancreatitis
14. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
15. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive)
16. Symptomatic brain metastasis or leptomeningeal disease
17. Prior hypersensitivity or toxicity that would suggest an inability to tolerate administration of the planned dose of investigational products
18. Residual CTCAE > Grade 2 toxicity from any prior anticancer therapy, with the exception of alopecia or neuropathy
19. Any concomitant drugs contraindicated for use with the trial drugs according to the product information of the pharmaceutical companies, including current treatment with a non-topical medication known to be a strong inhibitor of cytochrome P450 (CYP) 3A4 ≤ 1 week prior to the start of study treatment
20. Concomitant use of St. John’s Wort (hypericum perforatum)
21. Other severe, acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or that may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient an inappropriate candidate for the study.
22. Concurrent or previous other malignancy within the past 3 years, with the exception of effectively treated squamous cell or basal cell skin cancer, melanoma in situ, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in situ of the cervix, carcinoma in situ of the colon or rectum, or other noninvasive or indolent malignancy without Sponsor approval
23. 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 during the study and until 180 days after the last trial treatment.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. investigator-assessed 6-month progression-free survival (PFS) rate, defined as the proportion of patients alive and progression-free by the 6-month time point from start of investigational treatment. PFS is defined as the time elapsed between start of investigational treatment and the date of first event. The time-point for PFS is 6 months. Tumor assessment with CT scan of chest and abdomen will performed every 8 weeks from enrollment until evidence of disease progression or death

Secondary endpoints 6

1. PFS (time elapsed from start of investigational treatment to the documentation of disease progression, according to RECIST 1.1, or death due to any cause, whichever occur first)
2. OS (time elapsed from start of investigational treatment to the date of death due to any cause)
3. DOR (time from response, in patients achieving CR or PR, to disease progression or death) Patients not experiencing disease progression or death will be censored at the date of the last follow-up visit.
4. ORR (percentage of patients who achieve PR or CR as measured by RECIST 1.1 criteria)
5. DCR (percentage of patients who achieve PR, CR or SD as measured by RECIST 1.1 criteria)
6. Toxicity (rate of adverse events graded according to NCI-CTCAE version 4.03)

Investigational products

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

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Sponsor organisation

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Address

Largo Francesco Vito 1

City

Rome

Postcode

00168

Country

Italy

Scientific contact point

Organisation

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Contact name

Maria Alessandra Calegari

Public contact point

Organisation

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Contact name

Maria Alessandra Calegari

Locations

1 EU/EEA country · 3 investigational sites

By country

Investigational sites

Country notifications

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

Application history

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