ENCORAFENIB for Metastatic colorectal cancer (BRAF V600E-mutant)

Inclusion criteria

• {"criterion_text":"- Molecular Prescreening Inclusion Criteria - Age and Sex: 1. SLI: Male or female participants age ≥18 years at the time of informed consent. Phase 3 and Cohort 3: Male or female participants age ≥16 years at the time of informed consent/assent in all countries where permitted. 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. • Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female (Section 10.4.2) participants."}
• {"criterion_text":"- 10. The Investigator must obtain prior to Cycle 1 Day 1 (SLI) or date of randomization (Phase 3 and Cohort 3) adequate tumor tissue (primary or metastatic, archival or newly obtained) for submission to a central laboratory for confirmation of BRAF V600E and tumor tissue assessment. Note: Once BRAF V600E mutation status is determined by the central laboratory (tumor tissue), the results will be considered definitive for eligibility. No repeat testing will be performed. Note: Lack of BRAF V600E confirmation by the central laboratory may be due to discordance between the local assay and central laboratory results (potential false positive local assay results), or due to inadequate or poor sample condition for central testing (indeterminate results). Note: Participants whose sample is determined to be inadequate or who have an indeterminate result on central testing may have additional tumor samples submitted for testing."}
• {"criterion_text":"- 2. Body weight ≥40 kg."}
• {"criterion_text":"- 3. Participants with histologically or cytologically confirmed colorectal adenocarcinoma."}
• {"criterion_text":"- 4. Participants with evidence of Stage IV metastatic disease. 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. Oligometastatic colorectal cancer is characterized by a limited metastatic spread of disease. Oligometastatic disease is defined as the involvement of up to 3 sites with 5 or sometimes more metastases that for their anatomic localization is amenable to local therapies, thus rendering the patient free of disease."}
• {"criterion_text":"- 5. Able to provide a sufficient amount of representative tumor specimen for central testing of BRAF V600E mutation status and tumor tissue assessment Note: Tumor sample can be archival or de novo (newly collected fixed biopsy sample) and must be in an FFPE block, or provide a minimum of 15 unstained slides of analyzable tissue. This tissue specimen should be obtained from a biopsy or surgery that was performed within 2 years prior to study enrollment. Participants with fewer than the required number of slides with analyzable tissue may be considered eligible if the Sponsor determines that the slides are sufficient for central testing."}
• {"criterion_text":"- 6. Capable of giving signed informed consent/assent 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)."}
• {"criterion_text":"- 7. Participants who have met all Molecular Prescreening inclusion criteria."}
• {"criterion_text":"- 8. Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures."}
• {"criterion_text":"- 9. Presence of a BRAF V600E mutation in tumor tissue or blood (eg, ctDNA genetic testing). The following are acceptable: a. Local laboratory assay (PCR or NGS-based only) performed at any time prior to Screening using either tumor tissue or blood. b. Central laboratory assay performed during the Screening period using tumor tissue alone (not blood). Note: For participants enrolled on the basis of a local BRAF mutation assay, tumor samples must be submitted to the central laboratory for BRAF testing as soon as possible following signing of the ICD. The BRAF status must be confirmed no later than 30 days following first dose of study intervention."}

Exclusion criteria

• {"criterion_text":"- Molecular Prescreening Exclusion Criteria Medical Conditions: 1. Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator’s judgment, make the participant inappropriate for the study."}
• {"criterion_text":"- Screening Exclusion Criteria Medical Conditions: 10. 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."}
• {"criterion_text":"- 11. 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 Class II and above); c. Recent history (within 1 year prior to randomization) 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 bundle-branch block (BBB) or with an implanted cardiac pacemaker, may enroll into the study following consultation with the Sponsor. f. Congenital LQTS."}
• {"criterion_text":"- 12. Evidence of active noninfectious pneumonitis."}
• {"criterion_text":"- 13. Evidence of active and uncontrolled bacterial or viral infection, with certain exceptions, as noted below, for chronic infection with HIV, hepatitis B or hepatitis C, within 2 weeks prior to start of study intervention."}
• {"criterion_text":"- 14. 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 (see Section 6.5); 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."}
• {"criterion_text":"- 2. Presence of acute or chronic pancreatitis."}
• {"criterion_text":"- 3. Leptomeningeal disease."}
• {"criterion_text":"- 4. History of chronic inflammatory bowel disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤12 months prior to randomization."}
• {"criterion_text":"- 5. Known DPD deficiency; refer to local fluorouracil or capecitabine label or local clinical guidances, for DPD status recommendation prior to starting treatment."}
• {"criterion_text":"- 6. Gilbert's syndrome or known homozygous UGT1A1*28/*28 or UGT1A1*6/*6 genotypes or double heterozygous UGT1A1*6/*28 genotype: a. SLI: Participants with documented Gilbert's syndrome or known homozygous UGT1A1*28/*28 or UGT1A1*6/*6 genotypes or double heterozygous UGT1A1*6/*28 will be excluded from Cohort 1 (EC + FOLFIRI) of the SLI. b.Phase III: Participants with documented Gilbert's syndrome or known homozygous UGT1A1*28/*28 or UGT1A1*6/*6 genotypes or double heterozygous UGT1A1*6/*28 genotype may be enrolled, but may not receive FOLFOXIRI if randomized to the Control Arm. c. Cohort 3: Participants with documented Gilbert's syndrome or known homozygous UGT1A1*28/*28 or UGT1A1*6/*6 genotypes or double heterozygous UGT1A1*6/*28 genotype will be excluded from Cohort 3 Arm D and Arm E (EC + FOLFIRI and FOLFIRI ± bevacizumab)."}
• {"criterion_text":"- 7. Investigator site staff or Pfizer employees directly involved in the conduct of the study, site staff otherwise supervised by the investigator, and their respective family members."}
• {"criterion_text":"- 8. Colorectal adenocarcinoma that is RAS mutant or for which RAS mutation status is unknown."}
• {"criterion_text":"- 9. Locally confirmed dMMR or MSI-H colorectal carcinoma or unknown MSI/MMR status. If participant is locally confirmed dMMR or MSI-H and unable to receive immune checkpoint inhibitors due to a pre existing medical condition, they may be enrolled."}

Primary endpoints

• {"endpoint_text":"- Safety Lead-In: Incidence of dose-limiting toxicities (DLTs)","definition_or_measurement_approach":""}
• {"endpoint_text":"- Phase 3: • PFS by blinded independent central review (BICR), defined as the time from the date of randomization to the earliest documented disease progression per RECIST v1.1, or death due to any cause • ORR by BICR","definition_or_measurement_approach":"PFS measured by blinded independent central review per RECIST v1.1; ORR measured by BICR."}
• {"endpoint_text":"- Cohort 3: • ORR by BICR","definition_or_measurement_approach":"Objective response rate assessed by blinded independent central review (BICR)."}

Secondary endpoints

• {"endpoint_text":"- Safety Lead-In: Incidence and severity of adverse events (AEs) graded according to the National Cancer Institute (NCI ) Common Terminology Criteria for Adverse Events (CTCAE) v4.03 and changes in clinical laboratory parameters, vital signs and electrocardiograms (ECGs)","definition_or_measurement_approach":"AEs graded per NCI CTCAE v4.03; changes in labs, vitals, ECGs tracked."}
• {"endpoint_text":"- Safety Lead-In: Incidence of dose interruptions, dose modifications and discontinuations due to AEs","definition_or_measurement_approach":"Incidence of dose interruptions/modifications/discontinuations attributed to AEs."}
• {"endpoint_text":"- Safety Lead-In: ORR by Investigator, defined as the proportion of participants who have achieved a confirmed best overall response (BOR) (complete response [CR] or partial response [PR]) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1","definition_or_measurement_approach":"ORR per RECIST v1.1 as assessed by investigator (confirmed BOR = CR or PR)."}
• {"endpoint_text":"- Safety Lead-In: Duration of response (DOR) by Investigator, defined as the time from the date of first radiographic evidence of response (CR or PR) to the earliest documented disease progression per RECIST v1.1, or death due to any cause","definition_or_measurement_approach":"Time from first radiographic evidence of response to progression or death per RECIST v1.1."}
• {"endpoint_text":"- Safety Lead-In: Progression-free survival (PFS) by Investigator, defined as the time from the first dose to the earliest documented disease progression per RECIST v1.1, or death due to any cause","definition_or_measurement_approach":"Investigator-assessed PFS per RECIST v1.1."}
• {"endpoint_text":"- Safety Lead-In: Time to response (TTR) by Investigator, defined as the time from first dose to first radiographic evidence of response (CR or PR) per RECIST v1.1","definition_or_measurement_approach":"Time from first dose to first radiographic evidence of CR or PR per RECIST v1.1."}
• {"endpoint_text":"- Safety Lead-In: Overall survival (OS) defined as the time from the first dose to death due to any cause","definition_or_measurement_approach":"Time from first dose to death from any cause."}
• {"endpoint_text":"- Safety Lead-In: PK parameters of encorafenib, irinotecan, oxaliplatin and relevant metabolites","definition_or_measurement_approach":"Pharmacokinetic parameters measured for listed agents and metabolites."}
• {"endpoint_text":"- Safety Lead-In: Changes in exposures of irinotecan and its metabolite (SN-38) on Cycle 1 Day 15 compared to Cycle 1 Day 1 in Cohort 1 (EC + FOLFIRI)","definition_or_measurement_approach":"Comparison of PK exposure metrics (irinotecan and SN-38) Cycle 1 Day 15 vs Day 1 in Cohort1."}
• {"endpoint_text":"- Safety Lead-In: Changes in exposures of oxaliplatin on Cycle 1 Day 15 compared to Cycle 1 Day 1 in Cohort 2 (EC + mFOLFOX6)","definition_or_measurement_approach":"Comparison of oxaliplatin PK exposure Cycle1 Day15 vs Day1 in Cohort2."}
• {"endpoint_text":"- Phase 3: - OS, defined as the time from the date of randomization to death due to any cause","definition_or_measurement_approach":"Overall survival measured from randomization to death from any cause."}
• {"endpoint_text":"- Phase 3: - ORR by Investigator","definition_or_measurement_approach":"Investigator-assessed ORR per RECIST v1.1."}
• {"endpoint_text":"- Phase 3: - ORR by BICR (Arm A vs Control Arm, Arm A vs Arm B)","definition_or_measurement_approach":"BICR-assessed ORR comparisons between specified arms."}
• {"endpoint_text":"- Phase 3: - DOR by BICR and by Investigator","definition_or_measurement_approach":"Duration of response assessed by BICR and investigator per RECIST v1.1."}
• {"endpoint_text":"- Phase 3: - PFS by BICR (Arm A vs Control Arm, Arm A vs Arm B)","definition_or_measurement_approach":"BICR-assessed PFS comparisons between specified arms per RECIST v1.1."}
• {"endpoint_text":"- Phase 3: - OS (Arm A vs Control Arm, Arm A vs Arm B)","definition_or_measurement_approach":"Overall survival comparisons between specified arms."}
• {"endpoint_text":"- Phase 3: - PFS by Investigator -\tTTR (by BICR and by Investigator), defined as the time from the date of randomization to first radiographic evidence of response (CR or PR) per RECIST v1.1","definition_or_measurement_approach":"Investigator-assessed PFS and time to response by both BICR and investigator per RECIST v1.1."}
• {"endpoint_text":"- Phase 3: -PFS2, defined as the time from the date of randomization to the date of discontinuation of next-line treatment after first objective PD by investigator assessment, the second objective disease progression, or death from any cause, whichever occurs first","definition_or_measurement_approach":"PFS2 measured from randomization to discontinuation of next-line therapy after first objective PD, second progression, or death."}
• {"endpoint_text":"- Phase 3:- Incidence and severity of AEs graded according to the NCI CTCAE v4.03 and changes in clinical laboratory parameters, vital signs, and ECGs","definition_or_measurement_approach":"AEs graded per NCI CTCAE v4.03; labs, vitals, ECG changes tracked."}
• {"endpoint_text":"- Phase 3: - PRO scores as measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer Patients – 30 Item Core Questionnaire (EORTC QLQ-C30), EuroQol-5D-5L (EQ-5D-5L), and anchoring instruments Patient Global Impression of Severity (PGIS) and Patient Global Impression of Change (PGIC).","definition_or_measurement_approach":"Patient-reported outcomes measured using EORTC QLQ-C30, EQ-5D-5L, PGIS and PGIC."}
• {"endpoint_text":"- Phase 3:- Trough plasma concentrations of encorafenib and the metabolite LHY746 in Arm A and Arm B","definition_or_measurement_approach":"Trough plasma concentrations measured for encorafenib and metabolite LHY746 in specified arms."}
• {"endpoint_text":"- Phase 3: - PK parameters of encorafenib and its metabolite LHY746","definition_or_measurement_approach":"Pharmacokinetic parameter assessment for encorafenib and LHY746."}
• {"endpoint_text":"- Phase 3:- Summarize MSI-status as determined by retrospective central testing of baseline tumor tissue","definition_or_measurement_approach":"Retrospective central testing of baseline tumor tissue for MSI-status summarised."}
• {"endpoint_text":"- Phase 3: - ctDNA levels and BRAF V600 variant allele fraction (VAF) from ctDNA analysis of plasma samples collected at baseline and on treatment","definition_or_measurement_approach":"ctDNA levels and BRAF V600 VAF measured from plasma at baseline and on-treatment."}
• {"endpoint_text":"- Cohort 3: -PFS by BICR, defined as the time from the date of randomization to the earliest documented disease progression per RECIST v1.1, or death due to any cause","definition_or_measurement_approach":"BICR-assessed PFS per RECIST v1.1."}
• {"endpoint_text":"- Cohort 3: -ORR by Investigator","definition_or_measurement_approach":"Investigator-assessed ORR for Cohort 3."}
• {"endpoint_text":"- Cohort 3: -DOR by BICR and by Investigator, defined as the time from the date of first radiographic evidence of response (CR or PR) to the earliest documented disease progression per RECIST v1.1, or death due to any cause","definition_or_measurement_approach":"DOR assessed by BICR and investigator per RECIST v1.1."}
• {"endpoint_text":"- Cohort 3:- PFS by Investigator, defined as the time from the date of randomization to the earliest documented disease progression per RECIST v1.1, or death due to any cause","definition_or_measurement_approach":"Investigator-assessed PFS for Cohort 3 per RECIST v1.1."}
• {"endpoint_text":"- Cohort 3:--OS, defined as the time from the date of randomization to death due to any cause","definition_or_measurement_approach":"Overall survival for Cohort 3 measured from randomization to death."}
• {"endpoint_text":"- Cohort 3:- TTR (by BICR and by Investigator), defined as the time from the date of randomization to first radiographic evidence of response (CR or PR) per RECIST v1.1","definition_or_measurement_approach":"Time to response for Cohort 3 assessed by BICR and investigator."}
• {"endpoint_text":"- Cohort 3:- Incidence and severity of AEs graded according to the NCI CTCAE v4.03 and changes in clinical laboratory parameters, vital signs, and ECGs","definition_or_measurement_approach":"AE incidence and severity graded per NCI CTCAE v4.03; labs/vitals/ECG changes tracked."}
• {"endpoint_text":"- Cohort 3:- PRO scores as measured by the EORTC QLQ-C30, EQ-5D-5L, and anchoring instruments PGIS and PGIC","definition_or_measurement_approach":"PROs measured using EORTC QLQ-C30, EQ-5D-5L, PGIS, PGIC."}
• {"endpoint_text":"- Cohort 3:Trough plasma concentrations of encorafenib and the metabolite LHY746 in Cohort 3 Arm D","definition_or_measurement_approach":"Trough plasma concentrations measured for encorafenib and LHY746 in Cohort3 Arm D."}
• {"endpoint_text":"- Cohort 3:- Summarize MSI-status as determined by retrospective central testing of baseline tumor tissue","definition_or_measurement_approach":"Retrospective central MSI-status testing on baseline tumor tissue."}
• {"endpoint_text":"- Cohort 3:- ctDNA levels and BRAF V600 VAF from ctDNA analysis of plasma samples collected at baseline and on treatment","definition_or_measurement_approach":"ctDNA levels and BRAF V600 VAF measured from plasma baseline and on-treatment."}

Denmark

Earliest CTIS Part Ii Submission Date

19-03-2024

Latest Decision Or Authorization Date

07-05-2024

Processing Time Days

49

Number Of Sites

5

Number Of Participants

13

Slovakia

Earliest CTIS Part Ii Submission Date

19-03-2024

Latest Decision Or Authorization Date

07-05-2024

Processing Time Days

49

Number Of Sites

5

Number Of Participants

1

Germany

Earliest CTIS Part Ii Submission Date

19-03-2024

Latest Decision Or Authorization Date

12-04-2024

Processing Time Days

24

Number Of Sites

8

Number Of Participants

16

Netherlands

Earliest CTIS Part Ii Submission Date

30-04-2024

Latest Decision Or Authorization Date

07-05-2024

Processing Time Days

7

Number Of Sites

3

Number Of Participants

22

Finland

Earliest CTIS Part Ii Submission Date

19-03-2024

Latest Decision Or Authorization Date

11-04-2024

Processing Time Days

23

Number Of Sites

4

Number Of Participants

7

Italy

Earliest CTIS Part Ii Submission Date

10-05-2024

Latest Decision Or Authorization Date

07-05-2024

Processing Time Days

-1

Number Of Sites

9

Number Of Participants

45

Czechia

Earliest CTIS Part Ii Submission Date

11-04-2024

Latest Decision Or Authorization Date

11-04-2024

Number Of Sites

3

Number Of Participants

6

Norway

Earliest CTIS Part Ii Submission Date

25-04-2024

Latest Decision Or Authorization Date

25-04-2024

Number Of Sites

3

Number Of Participants

7

Sweden

Earliest CTIS Part Ii Submission Date

22-04-2024

Latest Decision Or Authorization Date

07-05-2024

Processing Time Days

15

Number Of Sites

2

Number Of Participants

4

Belgium

Earliest CTIS Part Ii Submission Date

22-04-2024

Latest Decision Or Authorization Date

17-04-2024

Processing Time Days

-5

Number Of Sites

7

Number Of Participants

17

Poland

Earliest CTIS Part Ii Submission Date

24-04-2024

Latest Decision Or Authorization Date

07-05-2024

Processing Time Days

13

Number Of Sites

4

Number Of Participants

35

Spain

Earliest CTIS Part Ii Submission Date

24-04-2024

Latest Decision Or Authorization Date

12-04-2024

Processing Time Days

-12

Number Of Sites

13

Number Of Participants

122

Bulgaria

Earliest CTIS Part Ii Submission Date

29-04-2024

Latest Decision Or Authorization Date

07-05-2024

Processing Time Days

8

Number Of Sites

6

Number Of Participants

5

Primary sponsor

Full Name

Pfizer Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

Parexel International Corporation

Responsibilities

CRO services (sponsor duties code 13)

Name

Ppd Inc.

Responsibilities

Study Management; provision of laboratory/PK services

Name

PPD Global Central Labs (S) Pte Ltd / PPD Global Clinical Labs

Responsibilities

Laboratory kit provision, central lab services

Name

Cytel Inc.

Responsibilities

Patient data programming / statistical programming

Name

Signant Health

Responsibilities

Electronic patient reported outcomes

Third parties

• {"country":"Belgium","full_name":"CellCarta","duties_or_roles":"BRAF test","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Singapore","full_name":"PPD Global Central Labs (S) Pte Ltd","duties_or_roles":"Providing laboratory kits for clinical sites for sample collection","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Parexel International Corporation","duties_or_roles":"CRO services (sponsor duties code 13)","organisation_type":"Industry"}
• {"country":"United States","full_name":"Ppd Inc.","duties_or_roles":"Study Management; providing laboratory/PK support (sponsor duties include Study Management, PK - Encorafenib and LHY746)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"PPD Global Clinical Labs","duties_or_roles":"Providing laboratory kits for clinical sites for sample collection","organisation_type":"Industry"}
• {"country":"Belgium","full_name":"PPD Global Central Labs","duties_or_roles":"Providing laboratory kits for clinical sites for sample collection","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Cytel Inc.","duties_or_roles":"Patient Data Programming; statistical programming","organisation_type":"Industry"}
• {"country":"United States","full_name":"Signant Health","duties_or_roles":"Electronic Patient Reported Outcomes","organisation_type":"Industry"}
• {"country":"Canada","full_name":"Syneos Health Clinique Inc.","duties_or_roles":"PK = Oxaliplatin (site/PK support)","organisation_type":"Hospital/Clinic/Other health care facility (contracted service)"}
• {"country":"Belgium","full_name":"CellCarta (site contact repeated)","duties_or_roles":"BRAF test (contact Bea.Pauwels@cellcarta.com)","organisation_type":"Laboratory/Research/Testing facility"}