| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | MSI-H/dMMR metastatic colorectal cancer. | |
| E.1.1.1 | Medical condition in easily understood language | | BRAFV600E mutant, colorectal cancer | |
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 | | E.1.2 | Level | PT | | E.1.2 | Classification code | 10061451 | | E.1.2 | Term | Colorectal cancer | | E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) | |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 | | E.1.2 | Level | PT | | E.1.2 | Classification code | 10052358 | | E.1.2 | Term | Colorectal cancer metastatic | | E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) | |
| 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 | | To compare the efficacy of encorafenib and cetuximab plus pembrolizumab (Triplet Arm [Arm A]) vs pembrolizumab (Control Arm [Arm B]) | |
| E.2.2 | Secondary objectives of the trial | - To assess the overall safety and tolerability of Arm A vs Arm B;
- To assess the efficacy of Arm A vs Arm B;
- To confirm the BRAF and MSI status in tumor tissue;
- To evaluate the effect on PROs of Arm A vs Arm B. | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | Participants are eligible to be included in the study only if all of the following criteria apply:
I. Molecular Prescreening Inclusion Criteria
1. Locally confirmed dMMR or MSI-H disease in tumor tissue or blood (eg. ctDNA genetic testing) as determined by a local laboratory assay in a CLIA- or similarly certified laboratory.
2. Locally confirmed BRAF V600E mutation in tumor tissue or blood (eg, ctDNA genetic testing) as determined by either PCR or NGS-based local laboratory assay in a CLIA- or similarly certified laboratory.
Screening Inclusion Criteria
3. Male or female participants age ≥16 years at the time of informed consent/assent (or the minimum country specific age of consent if >16). In countries or sites where enrollment of adolescents is not permitted (eg, Germany), male or female participants age ≥18 years at the time of informed consent.
Type of Participant and Disease Characteristics:
4. Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.
5. Histologically or cytologically confirmed metastatic Stage IV colorectal adenocarcinoma.
Note: Patients with oligometastatic disease previously treated with curative intent are
eligible to participate in the study as long as they have baseline measurable disease
per RECIST 1.1.
6. Presence of measurable disease per RECIST v1.1, as assessed by investigator and evidenced by available baseline tumor scan.
Note: Baseline scan is defined as the last scan prior to the date of randomization (Section 10.10). Note: Baseline scans will be required to be available for subsequent submission to a central radiology vendor to be assessed by the BICR.
7. Availability of adequate tumor tissue (primary or metastatic; archival or newly obtained; block or slides; see Section 8.6.1). Whenever possible, the archival sample should be from the same tumor block that was used for local BRAF V600E mutation and MSI-H/dMMR testing. It is recommended that the tissue block should be obtained from a biopsy or surgery that was performed within 2 years prior to study enrollment. Please consult the study clinician if samples are older. A newly obtained tumor tissue biopsy must be provided prior to randomization for participants unable to provide adequate archival tumor tissue. If a newly obtained biopsy is taken, the biopsy should be taken from a nontarget lesion when possible.
8. Have not received prior systemic regimens for metastatic disease. Note: Participants with early stage disease (eg, Stages I-III) treated with surgery
followed by chemotherapy (eg, treatment in the adjuvant setting) or have received prior systemic neoadjuvant therapy with or without radiation who present with new lesions or evidence of disease recurrence during or within 6 months of the last dose of chemotherapy would be considered as having received 1 prior systemic therapy in the metastatic setting.
9. ECOG performance status of ≤1.
10. Adequate bone marrow function characterized by the following at screening:
a. ANC ≥1.5 × 109/L
b. Platelets ≥100 × 109/L
c. Hemoglobin ≥9.0 g/dL (without blood transfusions 2 weeks prior to randomization)
11. Adequate hepatic and renal function characterized by the following at screening:
a. Serum Tbili ≤1.5 × ULN and < 2 mg/dL.
Note: Tbili >1.5 × ULN is allowed if direct (conjugated) ≤ 1.5 × ULN and indirect (unconjugated) bilirubin is ≤ 4.25 × ULN.
Note: Participants with documented Gilbert syndrome or hyperbilirubinemia due to non-hepatic cause (eg, hemolysis, hematoma) may be enrolled
following discussion and agreement with the sponsor or designee.
b. ALT and AST ≤ 2.5 × ULN, or ≤ 5 × ULN in the presence of liver metastases.
Informed Consent:
12. Capable of giving signed informed consent as described in Appendix 1, which includes compliance with the requirements and restrictions listed in the ICD and in this protocol.
Note: Participants ≥ 16 years old that are under guardianship may participate with the consent of their legally authorized guardian if permitted by local regulations. When appropriate, adolescent participants will be included in all discussions (see Section
10.1.3).
Note: The investigator, or a person designated by the investigator, will obtain [written/electronically signed] informed consent/assent from each study participant’s legal guardian (as defined in Appendix 1 [and the participant’s assent, when applicable,] before any study-specific activity is performed [unless a waiver of informed consent has been granted by an IRB/ EC]). All legal guardians should be fully informed, and participants should be informed to the fullest extent possible, about the study in language and terms they are able to understand. The investigator will retain the original copy of each participant's signed consent[/assent document. | |
| E.4 | Principal exclusion criteria | Participants are excluded from the study if any of the following criteria apply:
Screening Exclusion Criteria
Medical Conditions:
1. Colorectal adenocarcinoma that is RAS mutant or for which RAS mutation status is unknown.
2. Documented clinical disease progression (eg, worsening of performance status, clinical symptoms, or clinically significant laboratory parameters demonstrating worsening of disease) or radiographic disease progression during the screening period.
3. Has active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, ie, without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention.
4. Leptomeningeal disease.
5. Diagnosis of immunodeficiency or an active autoimmune disease that required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Note: Participants with diabetes type I, vitiligo, psoriasis, controlled asthma,
Graves’ disease, Hashimoto’s disease or hypo- or hyperthyroid disease are exceptions and may participate. Note: Replacement and symptomatic therapies (eg, levothyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) are not considered a form of immunosuppressive agents and are permitted.
6. Presence of acute or chronic pancreatitis.
7. History of chronic inflammatory bowel disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤ 12 months prior to randomization.
8. Unable to swallow, retain, and absorb oral medications.
9. Impaired gastrointestinal function (eg, 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.
10. Clinically significant cardiovascular diseases, including any of the following:
a. History of acute myocardial infarction, acute coronary syndromes (including unstable angina, coronary artery bypass graft, coronary angioplasty or
stenting) ≤ 6 months prior to randomization.
b. Congestive heart failure requiring treatment (New York Heart Association Grade ≥ 2).
c. Recent history (one year) or presence of clinically significant cardiac arrhythmias (including uncontrolled atrial fibrillation or uncontrolled
paroxysmal supraventricular tachycardia).
d. History of thromboembolic or cerebrovascular events ≤ 12 weeks prior to randomization. Examples include transient ischemic attacks, cerebrovascular accidents, hemodynamically significant (ie, massive or sub-massive) deep vein thrombosis or pulmonary emboli. Note: Participants with either deep vein thrombosis or pulmonary emboli that do not result in hemodynamic instability are allowed to enroll as long as they
are on a stable dose of anticoagulants for at least 4 weeks. Note: Participants with thromboembolic events related to indwelling catheters
(including PICC lines) or other procedures may be enrolled
e. Triplicate average QTcF interval ≥480 ms or a history of prolonged QT syndrome. Note: Participants with BBB or with an implanted cardiac pacemaker may enroll into the study upon agreement between the investigator and sponsor or designee.
f. Congenital LQTS.
11. Has a history of (non-infectious) pneumonitis / interstitial lung disease that required steroids or has current pneumonitis / interstitial lung disease.
12. Evidence of active and uncontrolled bacterial or viral infection, with certain exceptions, as noted below, for chronic infection with hepatitis B or hepatitis C, within 2 weeks prior to start of study intervention. Note: For COVID-19/SARS-CoV-2, SARS-CoV-2 testing is not mandated for study entry, and testing should follow local clinical practice standards. Any participant with a positive test result for SARS-CoV-2 infection, is known to have
asymptomatic infection or is suspected of having SARS-CoV-2, is excluded. Once the infection resolves, the participant may be considered for re-screening.
13. Participants positive for HIV are ineligible unless they meet all of the following:
a. A stable regimen of highly active anti-retroviral therapy that is not contraindicated.
b. No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections
c. A CD4 count >250 cells/mcL, and an undetectable HIV viral load on standard PCR-based tests. Note: Participants with a history of Kaposi sarcoma and/or Multicentric Castleman Disease are not eligible.
14. Active hepatitis B or hepatitis C infection
Further exclusion criteria are deatiled in the protocol.
| |
| E.5 End points |
| E.5.1 | Primary end point(s) | | PFS per investigator, defined as the time from randomization until PD based on investigator assessment per RECIST v1.1 or death due to any cause, whichever occurs first. | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | | The primary efficacy analysis of the trial will be the comparison of PFS per investigator assessment between the 2 treatment arms using a stratified log-rank test at 1-sided α = 0.15 and is anticipated to occur approximately 45 months after the first participant is randomized. | |
| E.5.2 | Secondary end point(s) | - Incidence and severity of AEs graded according to the NCI CTCAE v4.03 and changes in clinical laboratory test parameters, vital signs and ECGs
- Incidence of dosing interruptions, dose modifications and permanent discontinuations associated with AEs
- OS, defined as the time from the date of randomization to the date of death due to any cause
- Objective response, defined as confirmed CR or confirmed PR based on investigator assessment per RECIST v1.1, from the date of randomization until
the date of the first documentation of PD, death or start of new anticancer therapy
- DOR, defined as the time from the first response, until PD based on investigator assessment per RECIST v1.1 or death due to any cause, whichever
occurs first
- BRAF and MSI-status as determined by retrospective central testing of baseline tumor tissue;
- EORTC QLQ-C30: change from baseline in the global health status/QoL, functional and symptom scales, and single items
- EQ-5D-5L: change from baseline in the index score and VAS
- PGIS score: change from baseline in the score
- PGIC score | |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | |
| 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 | No |
| 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 | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description | |
| 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 | Yes |
| 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 | 2 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 65 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned | | Australia | | Canada | | United States | | Belgium | | Czechia | | Denmark | | France | | Germany | | Italy | | Netherlands | | Norway | | Poland | | Slovakia | | Spain | | Sweden | | United Kingdom | |
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | 4 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
