E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pre-treated BRAFV600E metastatic colorectal adenocarcinoma. |
|
E.1.1.1 | Medical condition in easily understood language |
Spred bowel cancer with a specific (BRAF) mutation. |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The purpose of this study is to evaluate the efficacy and tolerability of cetuximab every second week together with encorafenib in patients with pre-treated, metastatic BRAF-mutated colorectal adenocarcinoma. Primary objective is 2 months Progression Free Survival (PFS) rate. |
|
E.2.2 | Secondary objectives of the trial |
Secondary objectives include Overall Survival (OS), PFS, Response Rate (RR), Toxicity and Correlation between tumor makers and makers of resistance and outcome |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age ≥ 18 years. 2. Histologically verified CRC, adenocarcinoma pMMR or dMMR. 3. Non-resectable and/or metastatic disease. 4. Measurable and/or evaluable non-measurable disease. 5. Presence of BRAFV600E in tumor tissue by a local laboratory using a PCR or NGS-based assay. 6. No known activating RAS mutations according to local assessments. 7. Patients eligible to receive cetuximab. 9. Performance status (WHO) of 0-1. 10. The patient must have progressed on prior systemic treatment for colorectal cancer. In case of dMMR the patient must have progressed on immumotherapy, unles declared unsuitable for treatment with immunotherapy. 11. Adequate hematological function defined as neutrophils 1.5 x 109/l and platelets ≥ 100 x 109/l. 12. Adequate renal function characterized 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. 13. Adequate organ function: bilirubin ≤ 1.5 x UNL (upper normal limit), alanine aminotransferase (ALAT) and/or aspartate aminotransferase. (ASAT) ≤ 2.5 × ULN, or ≤ 5 × ULN in presence of liver metastases. 14. Ability to take oral medications. 15. QT interval corrected for heart rate using Fridericia's formula (QTcF) value ≤480 msec. 16. Woman of childbearing potential must have been tested negative in a serum pregnancy test within 5 days prior to study drug initiation. 17. Male and female patients who have the potential to reproduce must agree to use a highly effective method of birth control. (i.e., pregnancy rate of less than 1 % per year) during the study and for 6 months after the discontinuation of study medication. 18. Written informed consent.
|
|
E.4 | Principal exclusion criteria |
1. Prior treatment with any RAF inhibitor, MEK inhibitor og EGRF inhibitors 2. Untreated/symptomatic brain metastasis (treated brain metastasis must be stable for 4 weeks or more). 3. Known leptomeningeal disease. 4. Use of any herbal medications/supplements or any medications or foods that are strong inhibitors or inducers of cytochrome P450 (CYP) 3A4/5 ≤ 1 week prior to the start of study treatment. 5. Known history of acute or chronic pancreatitis. 6. History of chronic inflammatory bowel disease or Crohn’s disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤ 12 months prior to study drug initiation. 7. Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following: 7.1. 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; 7.2. 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. 7.3. Uncontrolled hypertension defined as persistent systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg despite current therapy. 8. Impaired hepatic function, defined as Child-Pugh class B or C. 9. Impaired gastrointestinal (GI) function or disease that may significantly alter the absorption of encorafenib or (e.g., ulcerative diseases, uncontrolled vomiting, malabsorption syndrome, small bowel resection with decreased intestinal absorption). 10. Therapy for other malignancy within 2 years. 11. History of thromboembolic or cerebrovascular events ≤ 6 months prior to starting study treatment, including transient ischemic attacks, cerebrovascular accidents, or clinically significant pulmonary embolism 12. Treatment with any of the following: 12.1. Cyclical chemotherapy within a period of time that was shorter than the cycle length used for that treatment (e.g., 6 weeks for nitrosourea, mitomycin-C) prior to starting study treatment 12.2. Biologic therapy (e.g., antibodies) except bevacizumab or aflibercept, continuous or intermittent small molecule therapeutics, or any other investigational agents within a period of time that is ≤ 5 half-lives (t1/2) or ≤ 4 weeks (whichever is shorter) prior to starting study treatment 12.3. Bevacizumab or aflibercept therapy ≤ 3 weeks prior to starting study treatment. 13. Radiation therapy that included > 30% of the bone marrow within the last 4 weeks. 14. Residual CTCAE ≥ Grade 2 toxicity from any prior anticancer therapy, with the exception of Grade 2 alopecia or Grade 2 neuropathy. 15. Known history of HIV infection. 16. Active hepatitis B or hepatitis C infection. 17. Known contraindication (e.g. hypersensitivity to the active substances of the treatment or any of their excipients) to receive cetuximab at the planned doses; refer to the most recent cetuximab, SPC or local label as applicable. 18. 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. 19. Pregnant, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test result, or nursing (lactating). 20. Untreated concurrent cutaneous malignancies such as cuSCC 21. Prior enrollment into this clinical study.
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
6 months after end of trial (last visit last patient) |
|
E.5.2 | Secondary end point(s) |
OS PFS RR Toxicity Correlation tumor markers and outcome Correlation between markers of resistance and outcome |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
6 months after end of trial (last visit last patient) |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 5 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |