A study of patients with colorectal cancer that have a genetic abnormality in the BRAF gene taking encorafenib plus cetuximab with or without chemotherapy versus standard of care therapy

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Pfizer Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

16 Feb 2021 → ongoing

Decision date (initial)

2024-04-17

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Pfizer Inc.

External identifiers

EU CT number

2023-509405-77-00

EudraCT number

2020-001288-99

ClinicalTrials.gov

NCT04607421

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Pharmacokinetic, Therapy

Safety Lead-In:
- To determine the safety and tolerability of EC + mFOLFOX6 and EC + FOLFIRI

Phase 3:
- To compare the efficacy of EC + mFOLFOX6 (Arm B) vs SOC (Control Arm [Arm C]) as measured by PFS and by ORR

Cohort 3:
- To compare the efficacy of EC + FOLFIRI (Arm D) vs FOLFIRI with or without bevacizumab (Control Arm [Arm E]) as measured by ORR

Secondary objectives 12

1. Safety Lead-In: - Assess the overall safety and tolerability of EC + mFOLFOX6 and EC +FOLFIRI
2. Safety Lead-In:- Estimate the efficacy of EC + mFOLFOX6 and EC + FOLFIRI
3. Safety Lead-In:- Compare the efficacy of EC + mFOLFOX6 and EC + FOLFIRI
4. Safety Lead-In:- Characterize the PK of encorafenib, irinotecan, oxaliplatin and relevant metabolite
5. Safety Lead-In:- Assess drug-drug interaction of encorafenib with irinotecan or oxaliplatin
6. Ph3 - Further compare the efficacy of Arm B vs the Control Arm as measured by OS
7. Ph 3: - To further evaluate the efficacy of Arm B vs the Control Arm as measured by ORR, DOR, PFS, progression after next line of therapy (PFS2) and TTR
8. Ph 3: - Evaluate efficacy of EC (Arm A) vs the Control Arm as measured by ORR, DOR, PFS, PFS2, TTR and OS
9. Ph 3:- Evaluate efficacy of Arm A vs Arm B as measured by OS, PFS, PFS2, ORR, DOR and TTR
10. Ph 3: - Determine the safety and tolerability of EC
11. Ph 3: - Determine the safety and tolerability of EC + mFOLFOX6
12. Cohort 3: Further compare the efficacy of Arm D vs Arm E as measured by PFS

Conditions and MedDRA coding

Colorectal cancer (BRAF V600E-mutant mCRC)

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

Yes

IPD plan description

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. 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.
2. 2. Body weight ≥40 kg.
3. 3. Participants with histologically or cytologically confirmed colorectal adenocarcinoma.
4. 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.
5. 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.
6. 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).
7. 7. Participants who have met all Molecular Prescreening inclusion criteria.
8. 8. Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.
9. 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. 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.

Exclusion criteria 14

1. 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. 2. Presence of acute or chronic pancreatitis.
3. 3. Leptomeningeal disease.
4. 4. History of chronic inflammatory bowel disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤12 months prior to randomization.
5. 5. Known DPD deficiency; refer to local fluorouracil or capecitabine label or local clinical guidances, for DPD status recommendation prior to starting treatment.
6. 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).
7. 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. 8. Colorectal adenocarcinoma that is RAS mutant or for which RAS mutation status is unknown.
9. 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.
10. 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. 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.
12. 12. Evidence of active noninfectious pneumonitis.
13. 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.
14. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Safety Lead-In: Incidence of dose-limiting toxicities (DLTs)
2. 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
3. Cohort 3: • ORR by BICR

Secondary endpoints 35

1. 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)
2. Safety Lead-In: Incidence of dose interruptions, dose modifications and discontinuations due to AEs
3. 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
4. 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
5. 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
6. 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
7. Safety Lead-In: Overall survival (OS) defined as the time from the first dose to death due to any cause
8. Safety Lead-In: PK parameters of encorafenib, irinotecan, oxaliplatin and relevant metabolites
9. 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)
10. Safety Lead-In: Changes in exposures of oxaliplatin on Cycle 1 Day 15 compared to Cycle 1 Day 1 in Cohort 2 (EC + mFOLFOX6)
11. Phase 3: - OS, defined as the time from the date of randomization to death due to any cause
12. Phase 3: - ORR by Investigator
13. Phase 3: - ORR by BICR (Arm A vs Control Arm, Arm A vs Arm B)
14. Phase 3: - DOR by BICR and by Investigator
15. Phase 3: - PFS by BICR (Arm A vs Control Arm, Arm A vs Arm B)
16. Phase 3: - OS (Arm A vs Control Arm, Arm A vs Arm B)
17. Phase 3: - 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
18. 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
19. 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
20. 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).
21. Phase 3:- Trough plasma concentrations of encorafenib and the metabolite LHY746 in Arm A and Arm B
22. Phase 3: - PK parameters of encorafenib and its metabolite LHY746
23. Phase 3:- Summarize MSI-status as determined by retrospective central testing of baseline tumor tissue
24. Phase 3: - ctDNA levels and BRAF V600 variant allele fraction (VAF) from ctDNA analysis of plasma samples collected at baseline and on treatment
25. 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
26. Cohort 3: -ORR by Investigator
27. 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
28. 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
29. Cohort 3:--OS, defined as the time from the date of randomization to death due to any cause
30. 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
31. 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
32. Cohort 3:- PRO scores as measured by the EORTC QLQ-C30, EQ-5D-5L, and anchoring instruments PGIS and PGIC
33. Cohort 3:Trough plasma concentrations of encorafenib and the metabolite LHY746 in Cohort 3 Arm D
34. Cohort 3:- Summarize MSI-status as determined by retrospective central testing of baseline tumor tissue
35. Cohort 3:- ctDNA levels and BRAF V600 VAF from ctDNA analysis of plasma samples collected at baseline and on treatment

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Comparator 16

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Pfizer Inc.

Sponsor organisation

Pfizer Inc.

Address

66 Hudson Boulevard East

City

New York

Postcode

10001-2189

Country

United States

Scientific contact point

Organisation

Pfizer Inc.

Contact name

Adam Schayowitz

Public contact point

Organisation

Pfizer Inc.

Contact name

Adam Schayowitz

Third parties 10

Locations

13 EU/EEA countries · 70 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 1 · Art. 52 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 161 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

19 submissions — initial application plus substantial / non-substantial modifications