Clinical trial NCT06578559: Phase II Study of ctDNA-guided Encorafenib Plus Cetuximab Retreatment in Patients BRAF V600E Mutated mCRC
Official title: Single Arm Phase II Study of ctDNA-guided Encorafenib Plus Cetuximab Retreatment in Patients With BRAF V600E Mutated mCRC (BRICKET)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Colorectal Cancer
Keywords: ctDNA
Encorafenib
Cetuximab
rechallenge
retreatment
BRAF V600E
Lead sponsor: Gruppo Oncologico del Nord-Ovest
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
name: Pierre Fabre Laboratories
First posted: 2024-08-29
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The aim of this study is to evaluate the activity, in terms of best response according to RECIST criteria 1.1 as assessed by the local investigator, of the ctDNA-guided retreatment with encorafenib plus cetuximab in BRAFV600E mutated mCRC patients experiencing benefit from previous exposure to encorafenib plus cetuximab (+/- chemotherapy) and with BRAFV600E mutated, KRAS, NRAS and MAP2K1 wild-type and MET not amplified status on ctDNA at the time of study entry.

Detailed description: This is a proof-of-concept, multicenter, open-label, single arm one-stage phase II trial of a ctDNA-guided retreatment with encorafenib plus cetuximab for mCRC patients bearing the BRAFV600E mutation and with the key following characteristics:

* initial benefit and then secondary resistance to a previous exposure to encorafenib and cetuximab with or without chemotherapy;
* only one subsequent intervening anti-BRAF and anti-EGFR-free line of therapy;
* confirmed BRAFV600E mutated status and no detectable mutations in KRAS, NRAS, MAP2K1 and no amplification of MET in ctDNA at the time of retreatment;

Eligible patients will receive Encorafenib 300 mg once daily (four 75 mg oral capsules) and Cetuximab 500 mg/sqm iv infusion every 14 days.Treatment will be delivered in 28-day cycles until disease progression, unacceptable toxic effects, withdrawal of consent, initiation of subsequent anticancer therapy, or death.

Eligibility criteria: Inclusion Criteria:

* histologically proven diagnosis of colorectal adenocarcinoma;
* age ≥ 18 years;
* ECOG Performance status ≤ 1;
* BRAFV600E mutated status of primary colorectal cancer and/or related metastasis, by local laboratory assessment according to standard procedures by means of molecular assay on genomic DNA;
* Metastatic disease with at least one measurable lesion according to RECIST 1.1. criteria;
* previous treatment with encorafenib plus cetuximab with or without chemotherapy (i.e., ±FOLFOX/FOLFIRI) in any line, producing a RECIST 1.1 complete/partial response or disease stabilisation, with a PFS of this treatment lasting at least 6 months;
* documentation of RECIST 1.1 disease progression during or after the end of the previous exposure to encorafenib plus cetuximab ± chemotherapy;
* one intervening line of treatment not including any BRAF and EGFR inhibitor, between the end of first exposure to encorafenib plus cetuximab ± chemotherapy and the time of screening;
* at least 4 months elapsed between the end of the previous exposure to encorafenib plus cetuximab ± chemotherapy and the retreatment with encorafenib plus cetuximab;
* previous treatment with immune checkpoint inhibitors (anti-PD-1/PD-L1 alone or in combination with anti-CTLA-4 agent), in the case of MSI-H or dMMR mCRC;
* availability of blood sample for ctDNA analysis within 28 days prior enrolment;
* BRAFV600E mutated status of ctDNA at screening (central laboratory assessment by means of GUARDANT360 CDx, Guardant Health);
* KRAS, NRAS, MAP2K1 wild-type status and MET not amplified status in ctDNA at screening (central laboratory assessment by means of GUARDANT360 CDx, Guardant Health);
* Availability of archival tumour tissue (primary tumour and/or metastases) for biomarker analysis;
* neutrophils \>1.5 x 109/L, Platelets \>100 x 109/L, Hgb \>9 g/dl. Transfusions will be permitted provided the patient has not received more than two units red blood cells in the prior 4 weeks to achieve this criterion.
* adequate renal function characterised by 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;
* adequate hepatic function characterised by the following at screening: Serum total bilirubin ≤ 1.5 × ULN and \< 2 mg/dL. Note: Patients who have a total bilirubin level \> 1.5 × ULN will be allowed if their indirect bilirubin level is ≤ 1.5 × ULN; Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 2.5 × ULN, or ≤ 5 × ULN in presence of liver metastases. In the presence of documented Gilbert's syndrome, a value of total bilirubin \< 3 × ULN is acceptable.
* adequate electrolytes at baseline, defined as serum potassium and magnesium levels within institutional normal limits (Note: replacement treatment to achieve adequate electrolytes will be allowed).
* INR or aPTT ≤ 1.5 × ULN;
* QT interval corrected for heart rate ≤480 msec at screening;
* ability to take oral medications;
* women of childbearing potential must have a negative blood pregnancy test at the screening. For this trial, women of childbearing potential are defined as all women after puberty, unless they are postmenopausal for at least twelve continuous months, are surgically sterile, or are sexually inactive. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient;
* subjects and their partners must be willing to avoid pregnancy from the study screening until 1 month after the last trial treatment. Male subjects with female partners of childbearing potential and female subjects of childbearing potential must, therefore, be willing to use adequate contraception as approved by the investigator. Encorafenib may decrease the efficacy of hormonal contraceptives. Therefore, female patients using hormonal contraception are advised to use an additional or alternative method such as a barrier method (i.e., condom) from the screening phase for at least 1 month following the last dose of study treatment. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject;
* written informed consent to study procedures;
* life expectancy of at least twelve weeks;
* will and ability to comply with the protocol.

Exclusion Criteria:

* Known hypersensitivity or contraindications to trial drugs or any component of the trial drugs;
* discontinuation of previous treatment with encorafenib and/or cetuximab with or without chemotherapy due to encorafenib- and/or cetuximab-related adverse events;
* symptomatic brain metastases or spinal cord compression. Notes: Patients previously treated or untreated for these conditions who are asymptomatic in the absence of corticosteroid and anti-epileptic therapy are allowed. Brain metastases or spinal cord compression must be stable for ≥ 4 weeks, with imaging (e.g., magnetic resonance imaging \[MRI\] or computed tomography \[CT\]) demonstrating no current evidence of progressive brain metastases or spinal cord compression at screening;
* leptomeningeal disease;
* other co-existing malignancies or malignancies diagnosed within the last 5 years except for adequately treated localised basal and squamous cell carcinoma or cervical cancer in situ;
* treatment with any investigational drug within 30 days prior to enrolment or two investigational agent half-lives (whichever is longer);
* Impaired gastrointestinal function (i.e., 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;
* use of any herbal medications/supplements or any medications or foods that are moderate or strong inhibitors or inducers of CYP3A4/5 ≤1 week prior to the start of treatment;
* diagnosis of interstitial pneumonitis or pulmonary fibrosis;
* known history of acute or chronic pancreatitis within 6 months prior to the start of the treatment;
* history of chronic inflammatory bowel disease or Crohn's disease requiring medical intervention immunomodulatory or immunosuppressive medications or surgery) ≤12 months prior to first dose;
* impaired hepatic function, defined as Child-Pugh class B or C;
* clinically significant cardiovascular diseases, including any of the following:

  * history of acute myocardial infarction, acute coronary syndromes (including unstable angina, coronary artery bypass graft, coronary angioplasty or stenting) ≤6 months prior to registration;
  * congestive heart failure requiring treatment (New York Heart Association Class II and above);
  * recent history (within 1 year prior to registration) or presence of clinically significant cardiac arrhythmias (including uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia);
* QT interval corrected for heart rate \>480 msec at screening and rate uncontrolled atrial fibrillation and paroxysmal supraventricular tachycardia;
* 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 (barrier contraceptive measure or oral contraception) from the screening phase until 1 month after the last trial treatment;
* residual CTCAE ≥ Grade 2 toxicity from any prior anticancer therapy, with the exception of grade 2 alopecia or grade 2 neuropathy
* active eye disorders, including keratitis, ulcerative keratitis or severe dry eye.

Primary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: 8 months after the enrollment of the last patient.
Secondary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: 8 months after the enrollment of the last patient.
measure: Overall Survival (OS)
timeFrame: 8 months after the enrollment of the last patient.
measure: Overall Toxicity Rate
timeFrame: 8 months after the enrollment of the last patient.
measure: Grade 3/4 Toxicity Rate
timeFrame: 8 months after the enrollment of the last patient.
measure: Early Objective Response Rate (EORR)
timeFrame: 8 months after the enrollment of the last patient.
measure: Depth of Response (DpR)
timeFrame: 8 months after the enrollment of the last patient.
measure: Objective Response Rate in the screening failure population (ORR-failure)
timeFrame: 8 months after the enrollment of the last patient.
measure: Progression Free Survival in the screening failure population (PFS-failure)
timeFrame: 8 months after the enrollment of the last patient.
measure: Overall Survival in the screening failure population (OS-failure)
timeFrame: 8 months after the enrollment of the last patient.
measure: Quality of Life as assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30).
timeFrame: Questionnaires will be administered at baseline (cycle 1 day 1), every 8 weeks thereafter, at disease progression and after 30 days following end of study treatment.
measure: Quality of Life as assessed by the European Organization for Research and Treatment of Cancer Quality of Life Module for Colorectal cancer 29 (EORTC QLQ-CR29).
timeFrame: Questionnaires will be administered at baseline (cycle 1 day 1), every 8 weeks thereafter, at disease progression and after 30 days following end of study treatment.
measure: Time To Deterioration in Quality of Life (TTD)
timeFrame: 8 months after the enrollment of the last patient.
Other outcomes:
Locations:
city: Monserrato
country: Italy
facility: L'Azienda Ospedaliero Universitaria di Cagliari
state: CA
city: Meldola
country: Italy
facility: Istituto Romagnolo Per Lo Studio Dei Tumori "Dino Amadori" Irccs Irst
state: FC
city: San Giovanni Rotondo
country: Italy
facility: Fondazione Casa Sollievo Della Sofferenza - Irccs
state: FG
city: Tricase
country: Italy
facility: Pia Fondazione di Culto e di Religione Cardinale G. Panico
state: LE
city: Milan
country: Italy
facility: IRCCS Istituto Nazionale dei Tumori di Milano
state: MI
city: Padova
country: Italy
facility: Istituto Oncologico Veneto Irccs
state: PD
city: Pisa
country: Italy
facility: Azienda Ospedaliero-Universitaria Pisana
state: PI
city: Prato
country: Italy
facility: Nuovo Ospedale di Prato S. STEFANO
state: PO
city: Ravenna
country: Italy
facility: AUSL Romagna
state: RA
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
state: RM
city: Turin
country: Italy
facility: A.O.U. Citta Della Salute E Della Scienza Di Torino Presidio Molinette
state: TO
city: Udine
country: Italy
facility: Azienda Sanitaria Universitaria Friuli Centrale
state: UD
city: Naples
country: Italy
facility: Azienda Ospedaliera Universitaria degli Studi di Campania L. Vanvitelli
Study officials:
affiliation: Department of Translational Research and New Technologies in Medicine and Surgery - University of Pisa
name: Carlotta Antoniotti, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: