Single arm phase II study of ctDNA-guided encorafenib plus cetuximab retreatment in patients with BRAF V600E mutated mCRC. BRICKET study

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione GONO G.I.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06], Diseases [C] - Neoplasms [C04]

Trial duration

22 Jul 2024 → ongoing

Decision date (initial)

2024-06-21

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Therapy

The primary objective 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 BRAF and EGFR blockade (+/- chemotherapy) and with BRAFV600E mutated, KRAS, NRAS and MAP2K1 wild-type and MET not amplified status on ctDNA at the time of study entry.

Secondary objectives 7

1. Evaluation of progression Free Survival (PFS) according to RECIST 1.1 criteria
2. Evaluation of Overall Survival (OS)
3. Evaluation of incidence and severity of adverse events, graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0
4. Evaluation of therapeutic choice and outcomes of patients undergoing ctDNA screening but dropped-out because of detection of drivers of resistance to BRAF and EGFR inhibition
5. Evaluation of quality of life as measured by Patient Reported Outcomes (PROs) questionnaires
6. Evaluation of early objective response rate (EORR) and Depth of Response (DpR)
7. Evaluation of translational analyses including the correlation between clinical characteristics at ctDNA screening and detected mutational status and ctDNA dynamics in those exposed to the retreatment strategy

Conditions and MedDRA coding

Metastatic colorectal cancer

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 26

1. Histologically proven diagnosis of colorectal adenocarcinoma
2. Age ≥ 18 years
3. ECOG Performance status ≤ 1
4. 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
5. Metastatic disease, with at least one measurable lesion according to RECIST 1.1. criteria
6. 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
7. Documentation of RECIST 1.1 disease progression during or after the end of the previous exposure to encorafenib plus cetuximab ± chemotherapy
8. 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
9. At least 4 months elapsed between the end of the previous exposure to encorafenib plus cetuximab ± chemotherapy and the retreatment with encorafenib plus cetuximab
10. 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
11. Availability of blood sample for ctDNA analysis within 28 days prior enrolment
12. BRAFV600E mutated status of ctDNA at screening (central laboratory assessment by means of GUARDANT360 CDx, Guardant Health)
13. 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)
14. Availability of archival tumour tissue (primary tumour and/or metastases) for biomarker analysis
15. 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
16. 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;
17. 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
18. 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)
19. INR or aPTT ≤ 1.5 × ULN
20. QT interval corrected for heart rate ≤480 msec at screening
21. Ability to take oral medications
22. 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
23. 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
24. Written informed consent to study procedures
25. Life expectancy of at least twelve weeks
26. Will and ability to comply with the protocol

Exclusion criteria 17

1. Known hypersensitivity or contraindications to trial drugs or any component of the trial drugs
2. Known history of acute or chronic pancreatitis within 6 months prior to the start of the treatment
3. 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
4. Impaired hepatic function, defined as Child-Pugh class B or C
5. 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)
6. QT interval corrected for heart rate >480 msec at screening and rate uncontrolled atrial fibrillation and paroxysmal supraventricular tachycardia
7. 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
8. Residual CTCAE ≥ Grade 2 toxicity from any prior anticancer therapy, with the exception of grade 2 alopecia or grade 2 neuropathy
9. Active eye disorders, including keratitis, ulcerative keratitis or severe dry eye
10. Discontinuation of previous treatment with encorafenib and/or cetuximab with or without chemotherapy due to encorafenib- and/or cetuximab-related adverse events
11. 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 antiepileptic 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
12. Leptomeningeal disease
13. 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
14. Treatment with any investigational drug within 30 days prior to enrolment or two investigational agent half-lives (whichever is longer)
15. 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
16. 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
17. Diagnosis of interstitial pneumonitis or pulmonary fibrosis

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Objective Response Rate (ORR) defined as the percentage of patients, relative to the total of enrolled subjects, achieving a complete (CR) or partial (PR) response, according to RECIST 1.1 criteria. The determination of clinical response will be based on investigator-reported measurements. Responses will be evaluated with a chest and abdominal computed tomography (CT) scan every 8 weeks.

Secondary endpoints 9

1. Progression Free Survival (PFS) is defined as the time interval computed from the date of study enrollment to the date of objective progression according to the RECIST criteria (version 1.1) or death, whatever comes first.
2. Overall survival (OS) is defined as the time from the date of study enrollment to the date of death due to any cause. For patients still alive at the time of analysis, the OS time will be censored on the last date the patients were known to be alive.
3. Overall Toxicity Rate is defined as the percentage of patients, relative to the total of enrolled subjects, experiencing any adverse event, according to National Cancer Institute Common Toxicity Criteria (version 5.0)
4. G3/4 Toxicity Rate is defined as the percentage of patients, relative to the total of enrolled subjects, experiencing a specific adverse event of grade 3/4, according to National Cancer Institute Common Toxicity Criteria (version 5.0)
5. Early Objective Response Rate (EORR) is defined as the percentage of patients, relative to the total of the enrolled subjects, achieving a ≥20% decrease in the sum of diameters of RECIST target lesions at week 8 compared to baseline
6. Depth of Response (DpR) is defined as the relative change in the sum of longest diameters of RECIST target lesions at the nadir, in the absence of new lesions or progression of non-target lesions, when compared with baseline
7. Clinical outcomes of the screening failure population include collection of therapeutic choices after ctDNA screening; ORRfailure; PFSfailure of the first line after ctDNA screening; OSfailure. For patients still alive at the time of analysis, the OS time will be censored on the last date the patients were known to be alive.
8. Quality of Life (QoL) is assessed using the EORTC QLQ-C30 and the EORTC QLQ-CR29 questionnaires, will be evaluated from patients who have completed at least one questionnaire item at baseline and during the study period through descriptive summary statistics.
9. Time To Deterioration in Quality of Life (TTD) is defined as the time from baseline to the first onset of a 10-point or greater decrease from study enrollment for functional scales or a 10- point or greater increase for symptom scales or death.

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione GONO G.I.

Sponsor organisation

Fondazione GONO G.I.

Address

Via Goffredo Mameli 3/1

City

Genoa

Postcode

16122

Country

Italy

Scientific contact point

Organisation

Gruppo Oncologico Del Nord Ovest

Contact name

Laura Delliponti

Public contact point

Organisation

Gruppo Oncologico Del Nord Ovest

Contact name

Laura Delliponti

Third parties 5

Locations

1 EU/EEA country · 17 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 8 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