| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Colorectal cancer (BRAF V600E-mutant mCRC) |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Safety Lead-In:
To determine the safety and tolerability of EC + mFOLFOX6 and EC + FOLFIRI
Randomized Phase 3:
To compare the efficacy of EC (Arm A) vs SOC (Control Arm [Arm C]) as measured by PFS
To compare the efficacy EC + mFOLFOX6 or EC + FOLFIRI (Arm B) vs the Control Arm as measured by PFS
|
|
| E.2.2 | Secondary objectives of the trial |
Safety Lead-In:
Assess the overall safety and tolerability of EC + mFOLFOX6 and EC + FOLFIRI
Estimate the efficacy of EC + mFOLFOX6 and EC + FOLFIRI
Estimate the efficacy of EC + mFOLFOX6 and EC + FOLFIRI
Characterize the PK of encorafenib, irinotecan, oxaliplatin and relevant metabolite
Assess drug-drug interaction of encorafenib with irinotecan or oxaliplatin
Randomized Phase 3:
Compare the efficacy of Arm A vs the Control Arm as measured by OS
Compare the efficacy of Arm B vs the Control Arm as measured by OS
Compare the efficacy of Arm A vs the Control Arm as measured by ORR, DOR, PFS, PFS2 and TTR
Compare the efficacy of Arm B vs the Control Arm as measured by ORR, DOR, PFS, PFS2 and TTR
Compare the efficacy of Arm A vs Arm B as measured by OS, PFS, PFS2, ORR, DOR and TTR
Determine the safety and tolerability of EC
Determine the safety and tolerability of EC + mFOLFOX6 or EC + FOLFIRI
For full list please see section 3 of the protocol |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Molecular Prescreening Inclusion Criteria
Age and Sex:
1.SLI: Male or female participants age ≥18 years at the time of informed consent.
Phase 3: Male or female participants age ≥16 years at the time of informed consent/assent.
Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female (Section 10.4.2) participants.
Weight:
2.Body weight ≥40 kg.
Type of Participant and Disease Characteristics:
3.Participants with histologically or cytologically confirmed colorectal adenocarcinoma.
4.Participants with evidence of metastatic disease.
5.Able to provide a sufficient amount of representative tumor specimen for central testing of BRAF V600E mutation status.
Note: Tumor sample must be in an FFPE block, newly collected fixed biopsy sample, or a minimum of 15 unstained slides of analyzable tissue. Participants with fewer than 15 slides of analyzable tissue may be considered eligible if the Sponsor determines that the slides are sufficient for central testing of BRAF V600E mutation status.
Informed Consent/Assent:
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).
Screening Inclusion Criteria
Type of Participant and Disease Characteristics:
7.Participants who have met all Molecular Prescreening inclusion criteria.
8.Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.
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.
10.The Investigator must obtain prior to Cycle 1 Day 1 (SLI) or date of randomization (Phase 3) adequate tumor tissue (primary or metastatic, archival or newly obtained) for submission to a central laboratory for confirmation of BRAF V600E (FFPE block or minimum of 15 unstained slides containing recently cut, 4-5 µm sections on positively charged slides). Participants with fewer than 15 slides of analyzable tissue may be considered eligible if the Sponsor determines that the slides are sufficient for central testing of BRAF V600E mutation status.
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). If at any time in the study there is lack of BRAF V600E confirmation in a total of 6% of the total planned enrollment of the randomized portion of the trial (52 participants) or a discordance between the local assay and the central laboratory of 3% of the total planned enrollment (26 participants), all subsequent participants will be required to have BRAF V600E determined by the central laboratory for treatment (ie, local BRAF testing will no longer be accepted for trial eligibility).
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.
For a full list please see section 5.1 of the protocol. |
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| E.4 | Principal exclusion criteria |
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.
2.Known history of acute or chronic pancreatitis.
3.Leptomeningeal disease.
4.History of chronic inflammatory bowel disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤12 months prior to randomization.
5.Known DPD deficiency; local testing results required prior to starting treatment if recommended by local fluorouracil or capecitabine label or by local guidances.
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 genotype will be excluded from Cohort 1 (EC + FOLFIRI) of the SLI.
b.Phase 3: If the decision is made to include FOLFIRI in Arm B, all 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 the Phase 3 portion.
If the decision is made to include mFOLFOX6 in Arm B, 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.
Other Exclusions:
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.
8.Known RAS-mutant colorectal adenocarcinoma.
9.Locally confirmed dMMR or MSI-H colorectal carcinoma unless participant is unable to receive immune checkpoint inhibitors due to a pre-existing medical condition.
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.
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 Grade ≥2);
c.History 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.
f.Congenital LQTS.
12.Evidence of active noninfectious pneumonitis.
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 (please see below), within 2 weeks prior to start of study intervention.
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.
For a full list please see section 5.3 of the protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety Lead-In:
Incidence of DLTs
Randomized Phase 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 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety Lead-In:
11 month
Randomized Phase 3:
34 month |
|
| E.5.2 | Secondary end point(s) |
Safety Lead-In:
Incidence and severity of AEs graded according to the NCI CTCAE v4.03 and changes in clinical laboratory parameters, vital signs and ECGs
Incidence of dose interruptions, dose modifications and discontinuations due to AEs
ORR by Investigator, defined as the proportion of participants who have achieved a confirmed BOR (CR or PR) per RECIST v1.1
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
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
TTR by Investigator, defined as the time from first dose to first radiographic evidence of response (CR or PR) per RECIST v1.1
OS defined as the time from the first dose to death due to any cause
PK parameters of encorafenib, irinotecan, oxaliplatin and relevant metabolites
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)
Changes in exposures of oxaliplatin on Cycle 1 Day 15 compared to Cycle 1 Day 1 in Cohort 2 (EC + mFOLFOX6)
Randomized Phase 3:
OS, defined as the time from the date of randomization to death due to any cause
ORR by BICR and by Investigator
DOR by BICR and by Investigator
PFS by BICR
OS
PFS by Investigator
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
PFS2, defined as the time from the date of randomization to the second objective disease progression per RECIST v1.1, or death from any cause, whichever occurs first
Incidence and severity of AEs graded according to the NCI CTCAE v4.03 and changes in clinical laboratory parameters, vital signs, and ECGs
PROs as measured by the EORTC QLQ-C30, EQ-5D-5L, PGIS and PGIC.
Trough plasma concentrations of encorafenib and the metabolite LHY746 in Arm A and Arm B
PK parameters of encorafenib and its metabolite LHY746
Summarize MSI-status as determined by retrospective central testing of baseline tumor tissue
BRAF V600E variant allele fraction (VAF) and/or overall mean VAF from cfDNA analysis of plasma samples collected at baseline and on treatment |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety Lead-In:
11 month
Randomized Phase 3:
349month |
|
| 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 | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | 3 |
| 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 | 126 |
| 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 |
| Argentina |
| Australia |
| Belgium |
| Brazil |
| Bulgaria |
| Canada |
| Czech Republic |
| Denmark |
| Finland |
| France |
| Germany |
| India |
| Italy |
| Japan |
| Korea, Republic of |
| Mexico |
| Netherlands |
| New Zealand |
| Norway |
| Poland |
| Portugal |
| Romania |
| Russian Federation |
| Slovakia |
| South Africa |
| Spain |
| Sweden |
| Taiwan |
| Ukraine |
| United Kingdom |
| United States |
|
| 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
|
| End of study will be defined as the point when all participants have been followed for at least 1 year after the randomization date of the last participant enrolled in the Phase 3 portion of the study or at least 80% of participants have an OS event (or are lost to follow-up), whichever occurs later. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| 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 |
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