CETUXIMAB for Metastatic colorectal cancer

Inclusion criteria

• {"criterion_text":"- Histologically proven diagnosis of colorectal adenocarcinoma\n- 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\n- Availability of blood sample for ctDNA analysis within 28 days prior enrolment\n- BRAFV600E mutated status of ctDNA at screening (central laboratory assessment by means of GUARDANT360 CDx, Guardant Health)\n- 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)\n- Availability of archival tumour tissue (primary tumour and/or metastases) for biomarker analysis\n- 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\n- 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;\n- 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\n- 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)\n- INR or aPTT ≤ 1.5 × ULN\n- Age ≥ 18 years\n- QT interval corrected for heart rate ≤480 msec at screening\n- Ability to take oral medications\n- 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\n- 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\n- Written informed consent to study procedures\n- Life expectancy of at least twelve weeks\n- Will and ability to comply with the protocol\n- ECOG Performance status ≤ 1\n- 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\n- Metastatic disease, with at least one measurable lesion according to RECIST 1.1. criteria\n- 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\n- Documentation of RECIST 1.1 disease progression during or after the end of the previous exposure to encorafenib plus cetuximab ± chemotherapy\n- 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\n- At least 4 months elapsed between the end of the previous exposure to encorafenib plus cetuximab ± chemotherapy and the retreatment with encorafenib plus cetuximab"}

Exclusion criteria

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

Primary endpoints

• {"endpoint_text":"- 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.","definition_or_measurement_approach":"ORR defined as % of patients achieving CR or PR per RECIST 1.1 by investigator-reported measurements; responses evaluated with chest and abdominal CT scan every 8 weeks."}

Secondary endpoints

• {"endpoint_text":"- 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.","definition_or_measurement_approach":"PFS measured from enrollment to objective progression per RECIST 1.1 or death."}
• {"endpoint_text":"- 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.","definition_or_measurement_approach":"OS measured from enrollment to death; censoring at last known alive date for survivors."}
• {"endpoint_text":"- 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)","definition_or_measurement_approach":"Overall Toxicity Rate = % of patients with any AE graded per NCI CTCAE v5.0."}
• {"endpoint_text":"- 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)","definition_or_measurement_approach":"G3/4 Toxicity Rate = % of patients experiencing grade 3 or 4 AEs per NCI CTCAE v5.0."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"EORR = % of patients with ≥20% decrease in sum of RECIST target lesion diameters at week 8 vs baseline."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"DpR = relative change in sum of longest diameters at nadir vs baseline (no new lesions or progression of non-target lesions)."}
• {"endpoint_text":"- 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.","definition_or_measurement_approach":"Outcomes collected for screening-failure population include subsequent therapies and ORRfailure, PFSfailure, OSfailure with censoring of OS as described."}
• {"endpoint_text":"- 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.","definition_or_measurement_approach":"QoL assessed via EORTC QLQ-C30 and QLQ-CR29; evaluated descriptively among patients with baseline and on-study responses."}
• {"endpoint_text":"- 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.","definition_or_measurement_approach":"TTD measured from baseline to first ≥10-point worsening on functional scales or ≥10-point worsening on symptom scales or death."}

Italy

Earliest CTIS Part Ii Submission Date

24-04-2024

Latest Decision Or Authorization Date

21-06-2024

Processing Time Days

58

Number Of Sites

17

Number Of Participants

16

Primary sponsor

Full Name

Gruppo Oncologico Del Nord Ovest

Organisation Type

Patient organisation/association

Country Of Registered Address

Italy

Third parties

• {"country":"Italy","full_name":"DataRiver","duties_or_roles":"sponsorDuties code: 7","organisation_type":"SME"}
• {"country":"Italy","full_name":"Azienda Ospedaliero Universitaria Pisana","duties_or_roles":"Safekeeping of biological samples for future analysis","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"United States","full_name":"Guardant Health Inc.","duties_or_roles":"BRAF, KRAS, NRAS and MAP2K1 mutational status and MET amplification status on plasma sample (ct-DNA) at the time of screening","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Italy","full_name":"Opis S.r.l.","duties_or_roles":"sponsorDuties code: 12","organisation_type":"Pharmaceutical company"}
• {"country":"Italy","full_name":"Depo-pack S.r.l.","duties_or_roles":"IMP management (labeling, distribution)","organisation_type":"Pharmaceutical company"}