A FIH Study of PF-07284890 in Participants With BRAF V600 Mutant Solid Tumors With and Without Brain Involvement

NCT04543188 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: C44710012022-003184-23
• Study Type: interventional
• Target: 65
• Locations: 3 countries
• Sites: 45

Brief Summary

First-in-human study to assess safety, tolerability, PK, and preliminary activity of PF-07284890 as a single agent and in combination with binimetinib in participants with BRAF V600-mutated advanced solid tumor malignancies with and without brain involvement.

Conditions

Malignant Melanoma; Carcinoma, Non-Small-Cell Lung; Brain Neoplasms, Primary; Brain Neoplasms; Malignant Neoplasms

Keywords

Proto-Oncogene Proteins B-raf; Brain Neoplasms; Melanoma; Carcinoma, Non-Small-Cell Lung; Brain Diseases; Central Nervous System Neoplasms; Enzyme Inhibitors

Outcome Measures

Primary Outcomes (11)

• Number of Participants With Dose Limiting Toxicities (DLTs): Phase 1a

  DLT was defined as any adverse event (AE) or abnormal laboratory value which were related to study treatment and assessed as unrelated to disease (disease progression), occurring during the first 21 days of treatment that met at least 1 of the study specified criteria. DLTs were graded according to the National Cancer Institute- Common Terminology Criteria for Adverse Events (NCI-CTCAE), version (v) 5.0.

  Cycle 1 (21 Days)

• Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a

  An adverse event (AE) was any untoward medical occurrence in participant/ clinical study participant temporally associated with use of study intervention, whether/ not considered related to study intervention. TEAEs were defined as any AE that occurs during on-treatment period. The on-treatment period was defined as period that starts with first dose of study treatment and ends at last dose of study treatment +30 days, or start of new anti-cancer therapy \[- 1 day\], whichever occurred first. Serious TEAEs were any untoward medical occurrence at any dose that: suspected to cause death; life-threatening; required hospitalization; persistent/significant disability/incapacity and might caused congenital anomaly/birth defect. Serious treatment related TEAEs were related to study treatment and relatedness was judged by investigator. TEAEs were graded according to NCI-CTCAE v 5.0 (grade 3= severe, grade 4= life-threatening and grade 5= death related to AE). AEs included SAEs and all non-SAE.

  From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment or start of new anti-cancer therapy (-1 Day) whichever occurred first (maximum treatment exposure: 542 days; maximum follow-up: 572 days)

• Number of Participants With Hematology Laboratory Abnormalities of Any CTCAE Grade: Phase 1a

  The following hematology laboratory parameters were assessed: activated partial thromboplastin time prolonged, anemia, hemoglobin increased, international normalized ratio (INR) increased, leukocytosis, lymphocyte count decreased, lymphocyte count increased, neutrophil count decreased, platelet count decreased and white blood cell decreased. Laboratory abnormality events were graded according to NCI CTCAE v5.0; grade 1=mild, grade 2=moderate, grade 3=severe, grade 4=life-threatening consequences and grade 5=death. In this outcome measure, those number of participants are reported who had hematology laboratory abnormality in any parameter of any CTCAE Grades.

  From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment (maximum treatment exposure: 542 days; maximum follow-up: 572 days)

• Number of Participants With Chemistry Laboratory Abnormalities of Any CTCAE Grade: Phase 1a

  The following chemistry laboratory parameters were assessed: alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, blood bilirubin increased, creatine phosphokinase (CPK) increased, creatinine increased, hypercalcemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia and hyponatremia. Laboratory abnormality events were graded according to NCI CTCAE v5.0; grade 1=mild, grade 2=moderate, grade 3=severe, grade 4=life-threatening consequences and grade 5=death. In this outcome measure, those number of participants are reported who had chemistry laboratory abnormality in any parameter of any CTCAE Grades.

  From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment (maximum treatment exposure: 542 days; maximum follow-up: 572 days)

• Number of Participants With Dose Interruptions Due to TEAEs: Phase 1a

  Dose interruption was defined as a planned dosing day with 0 mg total dose administered. Dose interruptions were applicable to unexpected dose interruptions. In this outcome measure, dose interruptions for any drug were considered.

  During study treatment (from first dose of study treatment [Day 1] up to last dose of study treatment [maximum treatment exposure: 542 days])

• Number of Participants With Dose Reduction Due to TEAEs: Phase 1a

  A dose reduction was defined as the day when the actual dose was less than the planned dose at enrollment and the actual dose was greater than 0 mg (ie, missed doses were not counted as a reduction). In this outcome measure, dose reductions for any drug were considered.

  During study treatment (from first dose of study treatment [Day 1] up to last dose of study treatment [maximum treatment exposure: 542 days])

• Number of Participants With Dose Discontinuations Due to TEAEs: Phase 1a

  In this outcome measure, dose discontinuations for any drug due to TEAEs were considered.

  During study treatment (from first dose of study treatment [Day 1] up to last dose of study treatment [maximum treatment exposure: 542 days])

• Extracranial Response Rate by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1: Phase 1b

  Extracranial response rate was defined as the percentage of participants with a best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR) in extracranial lesions by Investigator assessment per RECIST v1.1. CR: disappearance of all target and non-target lesions. Any pathological lymph nodes (non-target) must have reduction in short axis to less than (\<) 10 millimeter (mm). PR: at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

  From date of first dose until CR or PR (maximum treatment exposure: 400 days)

• Intracranial Response Rate by mRECISTv1.1: Phase 1b

  Intracranial response rate as assessed using modified RECIST (mRECIST) v 1.1., was defined as the percentage of participants with brain or central nervous system (CNS) involvement who achieved a CR or PR. CR: disappearance of all target and non-target lesions. For target lesions: Any pathological lymph nodes must be \<10 mm in the short axis. For non-target lesions: All lymph nodes identified as a site of disease at baseline must be non-pathological (eg, \<10 mm short axis). PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

  From date of first dose until CR or PR (maximum treatment exposure: 400 days)

• Overall Response Rate (ORR): Phase 1b

  ORR: percentage of participants with BOR of confirmed CR/PR by investigator assessment in intracranial metastasis (mRECISTv1.1) and extracranial lesions (RECISTv1.1). RECIST v1.1- CR: disappearance of all target and non-target lesions. Any pathological lymph node (non-target) must have reduction in short axis to \<10mm. PR: at least 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. mRECIST- CR: disappearance of all target and non-target lesion. For target lesion: Any pathological lymph nodes must be \<10 mm in short axis. For non-target lesion: All lymph nodes identified as site of disease at baseline must be non-pathological (eg, \<10 mm short axis). PR: at least 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters.

  From date of first dose until CR or PR (maximum treatment exposure: 400 days)

• Response Rate Using Response Assessment in Neuro-Oncology (RANO) for Primary Brain Tumors: Phase 1b

  RANO response rate was defined as the percentage of glioblastoma participants who achieved a CR or PR per RANO. CR was defined as complete disappearance of all enhancing measurable and non-measurable disease sustained for more than or equal to (\>=) 4 weeks; no new lesions; stable or improved non-enhancing (T2/ \[fluid attenuated inversion recovery\] FLAIR) lesions; off steroids and neurological condition stable or improved. PR was defined as \>=50% decrease compared to baseline in the sum of the perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks; no progression of non-measurable disease; no new lesions; stable or improved non enhancing (T2/FLAIR) lesions on the same or lower dose of corticosteroids compared with baseline scan; the corticosteroid dose at the time of the scan evaluation should be no greater than the dose at the time of the baseline scan and neurological condition stable or improved.

  From date of first dose until CR or PR (maximum treatment exposure: 400 days)

Secondary Outcomes (42)

• Maximum Observed Concentration (Cmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a

  Pre-dose,1, 2, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1 (C1D1); 24 hours was only for arms where study drug was administered as QD.

• Time for Cmax (Tmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a

  Pre-dose,1, 2, 4, 6, 8 and 24 hours post-dose on C1D1; 24 hours was only for arms where study drug was administered as QD.

• Area Under the Plasma Concentration Time Curve From Time Zero to the Last Time Point of Quantifiable Concentration (AUClast) of PF-07284890 and Binimetinib for Single Dose: Phase 1a

  Pre-dose,1, 2, 4, 6, 8 and 24 hours post-dose on C1D1; 24 hours was only for arms where study drug was administered as QD.

• Terminal Elimination Half Life (t½) of PF-07284890 and Binimetinib for Single Dose: Phase 1a

  Pre-dose,1, 2, 4, 6, 8 and 24 hours post-dose on C1D1; 24 hours was only for arms where study drug was administered as QD.

• Area Under the Plasma Concentration Time Curve From Time Zero Extrapolated to Infinity (AUCinf) of PF-07284890 and Binimetinib for Single Dose: Phase 1a

  Pre-dose,1, 2, 4, 6, 8 and 24 hours post-dose on C1D1; 24 hours was only for arms where study drug was administered as QD.

Study Arms (9)

PF-07284890 (Part A monotherapy)

EXPERIMENTAL

Monotherapy dose escalation of PF-07284890

Drug: PF-07284890

PF-07284890+binimetinib (Part A combo-therapy)

EXPERIMENTAL

Combination dose escalation of PF-07284890 + binimetinib

Drug: PF-07284890; Drug: Binimetinib

Expansion Phase (Part B, Cohort 1)

EXPERIMENTAL

PF-07284890 (at recommended dose from Part A) plus binimetinib in participants with BRAF V600 melanoma, with asymptomatic brain involvement, and no prior BRAF or MEK inhibitor utilization

Drug: PF-07284890; Drug: Binimetinib

Expansion Phase (Part B, Cohort 2)

EXPERIMENTAL

PF-07284890 (at recommended dose from Part A) plus binimetinib in participants with BRAF V600 melanoma, with symptomatic brain involvement, and no prior BRAF or MEK inhibitor utilization

Drug: PF-07284890; Drug: Binimetinib

Expansion Phase (Part B, Cohort 3)

EXPERIMENTAL

PF-07284890 (at recommended dose from Part A) plus binimetinib in participants with BRAF V600 melanoma, with asymptomatic brain involvement, and prior BRAF inhibitor utilization

Drug: PF-07284890; Drug: Binimetinib

Expansion Phase (Part B, Cohort 4)

EXPERIMENTAL

PF-07284890 (at recommended dose from Part A) plus binimetinib in participants with BRAF V600 melanoma, with symptomatic brain involvement, and prior BRAF inhibitor utilization

Drug: PF-07284890; Drug: Binimetinib

Expansion Phase (Part B Cohort 5)

EXPERIMENTAL

PF-07284890 (at recommended dose from Part A) plus binimetinib in participants with BRAF V600 solid tumor; history of or current leptomeningeal metastases; without disease in the brain; with disease in the brain that does not meet Cohorts 1-4; asymptomatic or symptomatic in the brain; primary brain tumors

Drug: PF-07284890; Drug: Binimetinib

Expansion Phase Drug-Drug Interaction Substudy (Part B Optional Cohort 6)

EXPERIMENTAL

PF-07284890 (at recommended dose from Part A) plus binimetinib plus midazolam in participants with BRAF V600 solid tumor

Drug: PF-07284890; Drug: Binimetinib; Drug: Midazolam

Expansion Phase (Part B Optional Cohort 7)

EXPERIMENTAL

PF-07284890 (at the recommended dose for expansion when administered with food) plus binimetinib in participants with BRAF V600 solid tumor

Drug: PF-07284890; Drug: Binimetinib

Interventions

PF-07284890 DRUG

PF-07284890 will be administered orally, daily for 21 consecutive days (21-day cycle)

Also known as: ARRY-461

Expansion Phase (Part B Cohort 5); Expansion Phase (Part B Optional Cohort 7); Expansion Phase (Part B, Cohort 1); Expansion Phase (Part B, Cohort 2); Expansion Phase (Part B, Cohort 3); Expansion Phase (Part B, Cohort 4); Expansion Phase Drug-Drug Interaction Substudy (Part B Optional Cohort 6); PF-07284890 (Part A monotherapy); PF-07284890+binimetinib (Part A combo-therapy)

Binimetinib DRUG

Binimetinib will be administered together with PF-07284890 orally, 45mg twice daily

Also known as: Mektovi

Expansion Phase (Part B Cohort 5); Expansion Phase (Part B Optional Cohort 7); Expansion Phase (Part B, Cohort 1); Expansion Phase (Part B, Cohort 2); Expansion Phase (Part B, Cohort 3); Expansion Phase (Part B, Cohort 4); Expansion Phase Drug-Drug Interaction Substudy (Part B Optional Cohort 6); PF-07284890+binimetinib (Part A combo-therapy)

Midazolam DRUG

Midazolam will be administered 7 days before start of study drug, on Cycle 1 Day 1, and on Cycle 1 Day 15

Expansion Phase Drug-Drug Interaction Substudy (Part B Optional Cohort 6)

Eligibility Criteria

• Age: 16 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥16 years at the time of consent
• Histologically confirmed diagnosis of advanced/metastatic solid tumor including primary brain tumor
• Documented evidence of a BRAF V600 mutation in tumor tissue or blood
• Confirmation of availability of adequate tumor tissue for submission to the sponsor/central laboratory
• Presence or absence of brain involvement unless specified below
• Dose Expansion (Part B)
• Cohort 1, 2, 3, 4: melanoma with at least 1 parenchymal brain lesion
• Cohort 1,3: asymptomatic in the brain for at least 14 days prior to start of study treatment
• Cohort 2,4: symptomatic in the brain within 14 days prior to the start of study treatment
• Cohort 5: any solid tumor that does not meet requirements for Cohorts 1-4, history of or current leptomeningeal metastases.
• Optional Cohort 6 (DDI Sub-study) and 7 (Food-Effect): if brain involvement present, must be asymptomatic
• Disease progression despite prior treatment and no acceptable alternative treatment options available unless specified below
• Dose Expansion (Part B)
• Cohort 1, 2: No prior BRAF inhibitor in the metastatic setting or in the adjuvant setting within 6 months of study treatment
• Cohort 3, 4: Required prior BRAF inhibitor in the metastatic setting or in the adjuvant setting within 6 months of treatment

You may not qualify if:

• Brain metastasis/primary brain tumor requiring immediate local intervention
• History of or current leptomeningeal metastases
• Any other active malignancy within 2 years prior to enrollment
• Radiation therapy to visceral metastases within 14 days prior to study treatment. WBRT within 28 days prior to study treatment.
• Systemic anti-cancer therapy or small-molecular therapeutic(s) within 2 weeks prior to start of study treatment; Antibody based agents within 4 weeks prior to start of study treatment.
• History or current evidence of RVO or current risk factors for RVO; History of retinal degenerative disease

Sponsors & Collaborators

• Pfizer: lead

Study Sites (45)

City of Hope (City of Hope National Medical Center, City of Hope Medical Center)

Duarte, California, 91010, United States

Location

UCSF Helen Diller Family Comprehensive Cancer Center

San Francisco, California, 94143, United States

Location

Orlando Health Cancer Institute

Orlando, Florida, 32806, United States

Location

Moffitt Cancer Center

Tampa, Florida, 33612, United States

Location

Richard M Schulze Family Foundation Outpatient Center at McKinley Campus

Tampa, Florida, 33612, United States

Location

Northwestern Medical Group

Chicago, Illinois, 60611, United States

Location

Northwestern Memorial Hospital

Chicago, Illinois, 60611, United States

Location

University of Iowa Hospitals and Clinics

Iowa City, Iowa, 52242, United States

Location

Johns Hopkins University / Johns Hopkins Hospital

Baltimore, Maryland, 21231, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Ophthalmic Consultants of Boston Inc (OCB)

Boston, Massachusetts, 02114, United States

Location

Brigham & Women's Hospital

Boston, Massachusetts, 02115, United States

Location

Imaging: Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Imaging: Brigham and Women's Radiology, Coolidge Corner Imaging

Brookline, Massachusetts, 02446, United States

Location

Imaging: Brigham and Women's Ambulatory Care

Chestnut Hill, Massachusetts, 02467, United States

Location

Imaging: Brigham and Women's Mass General Healthcare Center

Foxborough, Massachusetts, 02035, United States

Location

Dana-Farber Cancer Institute - Chestnut Hill

Newton, Massachusetts, 02459, United States

Location

Siteman Cancer Center - St Peters

City of Saint Peters, Missouri, 63376, United States

Location

Siteman Cancer Center - West County

Creve Coeur, Missouri, 63141, United States

Location

Siteman Cancer Center - North County

Florissant, Missouri, 63031, United States

Location

Barnes-Jewish Hospital

St Louis, Missouri, 63110, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Siteman Cancer Center - South County

St Louis, Missouri, 63129, United States

Location

Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

John Theurer Cancer Center at Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

MSK Monmouth.

Middletown, New Jersey, 07748, United States

Location

MSK Commack

Commack, New York, 11725, United States

Location

MSKCC-Westchester (500 Westchester Ave.)

Harrison, New York, 10604, United States

Location

Memorial Sloan Kettering Cancer Center - David H. Koch Center for Cancer Care (74th Street).

New York, New York, 10021, United States

Location

Rockefeller Outpatient Pavilion (53rd Street)

New York, New York, 10022, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

UNC Hospitals, The University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, 27514, United States

Location

Duke Eye Center

Durham, North Carolina, 27705, United States

Location

Duke University Medical Center, Investigational Chemotherapy Services

Durham, North Carolina, 27710, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Tennessee Oncology PLLC

Franklin, Tennessee, 37067, United States

Location

Tennessee Oncology PLLC

Nashville, Tennessee, 37203, United States

Location

The University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Princess Margaret Cancer Centre

Toronto, Ontario, M5G 2M9, Canada

Location

Rambam Health Care Campus

Haifa, ?eif?, 3109601, Israel

Location

Rabin Medical Center

Petah Tikva, Central District, 49100, Israel

Location

Sheba Medical Center

Ramat Gan, Central District, 5262100, Israel

Location

Hadassah Medical Center

Jerusalem, Jerusalem, 9112001, Israel

Location

Sourasky Medical Center

Tel Aviv, TELL ABĪB, 6423906, Israel

Location

Related Publications (1)

• Ren L, Moreno D, Baer BR, Barbour P, Bettendorf T, Bouhana K, Brown K, Brown SA, Fell JB, Hartley DP, Hicken EJ, Laird ER, Lee P, McCown J, Otten JN, Prigaro B, Wallace R, Kahn D. Identification of the Clinical Candidate PF-07284890 (ARRY-461), a Highly Potent and Brain Penetrant BRAF Inhibitor for the Treatment of Cancer. J Med Chem. 2024 Aug 8;67(15):13019-13032. doi: 10.1021/acs.jmedchem.4c00998. Epub 2024 Jul 30.

  PMID: 39077892 DERIVED

Related Links

• To obtain contact information for a study center near you, click here.

MeSH Terms

Conditions

Melanoma; Carcinoma, Non-Small-Cell Lung; Brain Neoplasms; Neoplasms; Brain Diseases; Central Nervous System Neoplasms

Interventions

PF-07284890; binimetinib; Midazolam

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases; Nervous System Neoplasms; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Pfizer ClinicalTrials.gov Call Center
• Organization: Pfizer Inc.

ClinicalTrials.gov_Inquiries@pfizer.com

1-800-718-1021

Study Officials

• Pfizer CT.gov Call Center

  Pfizer

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 2, 2020
• First Posted: September 10, 2020
• Study Start: January 8, 2021
• Primary Completion: March 20, 2024
• Study Completion: March 20, 2024
• Last Updated: October 23, 2025
• Results First Posted: October 23, 2025

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (39); CA (1); IL (5)