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

A TWO-PART, PHASE 1A/B, OPEN-LABEL, MULTICENTER TRIAL EVALUATING PHARMACOKINETICS, SAFETY AND EFFICACY OF PF 07284890 (ARRY 461) IN PARTICIPANTS WITH BRAF V600 MUTANT SOLID TUMORS WITH AND WITHOUT BRAIN INVOLVEMENT

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.

Study Overview

• Status: Terminated
• Conditions: Carcinoma, Non-Small-Cell Lung; Brain Neoplasms; Malignant Melanoma; Brain Neoplasms, Primary; Malignant Neoplasms
• Intervention / Treatment: Drug: PF-07284890; Drug: Binimetinib; Drug: Midazolam

• Study Type: Interventional
• Enrollment (Actual): 65
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Cancer Centre
• Israel
  • ?eif?
    • Haifa, ?eif?, Israel, 3109601
      • Rambam Health Care Campus
  • Central District
    • Petah Tikva, Central District, Israel, 49100
      • Rabin Medical Center
    • Ramat Gan, Central District, Israel, 5262100
      • Sheba Medical Center
  • Jerusalem
    • Jerusalem, Jerusalem, Israel, 9112001
      • Hadassah Medical Center
  • TELL ABĪB
    • Tel Aviv, TELL ABĪB, Israel, 6423906
      • Sourasky Medical Center
• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope (City of Hope National Medical Center, City Of Hope Medical Center)
    • San Francisco, California, United States, 94143
      • UCSF Helen Diller Family Comprehensive Cancer Center
  • Florida
    • Orlando, Florida, United States, 32806
      • Orlando Health Cancer Institute
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center
    • Tampa, Florida, United States, 33612
      • Richard M Schulze Family Foundation Outpatient Center at McKinley Campus
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern Memorial Hospital
    • Chicago, Illinois, United States, 60611
      • Northwestern Medical Group
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Johns Hopkins University / Johns Hopkins Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02115
      • Brigham & Women's Hospital
    • Boston, Massachusetts, United States, 02114
      • Ophthalmic Consultants of Boston Inc (OCB)
    • Boston, Massachusetts, United States, 02115
      • Imaging: Brigham and Women's Hospital
    • Brookline, Massachusetts, United States, 02446
      • Imaging: Brigham and Women's Radiology, Coolidge Corner Imaging
    • Chestnut Hill, Massachusetts, United States, 02467
      • Imaging: Brigham and Women's Ambulatory Care
    • Foxborough, Massachusetts, United States, 02035
      • Imaging: Brigham and Women's Mass General Healthcare Center
    • Newton, Massachusetts, United States, 02459
      • Dana-Farber Cancer Institute - Chestnut Hill
  • Missouri
    • City of Saint Peters, Missouri, United States, 63376
      • Siteman Cancer Center - St Peters
    • Creve Coeur, Missouri, United States, 63141
      • Siteman Cancer Center - West County
    • Florissant, Missouri, United States, 63031
      • Siteman Cancer Center - North County
    • St Louis, Missouri, United States, 63110
      • Barnes-Jewish Hospital
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine
    • St Louis, Missouri, United States, 63129
      • Siteman Cancer Center - South County
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
    • Hackensack, New Jersey, United States, 07601
      • John Theurer Cancer Center at Hackensack University Medical Center
    • Middletown, New Jersey, United States, 07748
      • MSK Monmouth.
  • New York
    • Commack, New York, United States, 11725
      • MSK Commack
    • Harrison, New York, United States, 10604
      • MSKCC-Westchester (500 Westchester Ave.)
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10021
      • Memorial Sloan Kettering Cancer Center - David H. Koch Center for Cancer Care (74th Street).
    • New York, New York, United States, 10022
      • Rockefeller Outpatient Pavilion (53rd Street)
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • UNC Hospitals, The University of North Carolina at Chapel Hill
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Durham, North Carolina, United States, 27705
      • Duke Eye Center
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center, Investigational Chemotherapy Services
  • Tennessee
    • Franklin, Tennessee, United States, 37067
      • Tennessee Oncology PLLC
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology PLLC
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

Exclusion Criteria:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

9

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PF-07284890 (Part A monotherapy); Monotherapy dose escalation of PF-07284890	Drug: PF-07284890; PF-07284890 will be administered orally, daily for 21 consecutive days (21-day cycle); Other Names: ARRY-461
Experimental: PF-07284890+binimetinib (Part A combo-therapy); Combination dose escalation of PF-07284890 + binimetinib	Drug: PF-07284890; PF-07284890 will be administered orally, daily for 21 consecutive days (21-day cycle); Other Names: ARRY-461; Drug: Binimetinib; Binimetinib will be administered together with PF-07284890 orally, 45mg twice daily; Other Names: Mektovi
Experimental: Expansion Phase (Part B, Cohort 1); 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; PF-07284890 will be administered orally, daily for 21 consecutive days (21-day cycle); Other Names: ARRY-461; Drug: Binimetinib; Binimetinib will be administered together with PF-07284890 orally, 45mg twice daily; Other Names: Mektovi
Experimental: Expansion Phase (Part B, Cohort 2); 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; PF-07284890 will be administered orally, daily for 21 consecutive days (21-day cycle); Other Names: ARRY-461; Drug: Binimetinib; Binimetinib will be administered together with PF-07284890 orally, 45mg twice daily; Other Names: Mektovi
Experimental: Expansion Phase (Part B, Cohort 3); 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; PF-07284890 will be administered orally, daily for 21 consecutive days (21-day cycle); Other Names: ARRY-461; Drug: Binimetinib; Binimetinib will be administered together with PF-07284890 orally, 45mg twice daily; Other Names: Mektovi
Experimental: Expansion Phase (Part B, Cohort 4); 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; PF-07284890 will be administered orally, daily for 21 consecutive days (21-day cycle); Other Names: ARRY-461; Drug: Binimetinib; Binimetinib will be administered together with PF-07284890 orally, 45mg twice daily; Other Names: Mektovi
Experimental: Expansion Phase (Part B Cohort 5); 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; PF-07284890 will be administered orally, daily for 21 consecutive days (21-day cycle); Other Names: ARRY-461; Drug: Binimetinib; Binimetinib will be administered together with PF-07284890 orally, 45mg twice daily; Other Names: Mektovi
Experimental: Expansion Phase Drug-Drug Interaction Substudy (Part B Optional Cohort 6); PF-07284890 (at recommended dose from Part A) plus binimetinib plus midazolam in participants with BRAF V600 solid tumor	Drug: PF-07284890; PF-07284890 will be administered orally, daily for 21 consecutive days (21-day cycle); Other Names: ARRY-461; Drug: Binimetinib; Binimetinib will be administered together with PF-07284890 orally, 45mg twice daily; Other Names: Mektovi; Drug: Midazolam; Midazolam will be administered 7 days before start of study drug, on Cycle 1 Day 1, and on Cycle 1 Day 15
Experimental: Expansion Phase (Part B Optional Cohort 7); PF-07284890 (at the recommended dose for expansion when administered with food) plus binimetinib in participants with BRAF V600 solid tumor	Drug: PF-07284890; PF-07284890 will be administered orally, daily for 21 consecutive days (21-day cycle); Other Names: ARRY-461; Drug: Binimetinib; Binimetinib will be administered together with PF-07284890 orally, 45mg twice daily; Other Names: Mektovi

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	AUClast was determined using the linear/log trapezoidal method.	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	T1/2 was calculated as loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.	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	AUCinf was calculated as AUClast + (Clast/kel), where Clast is the predicted plasma concentration at the last quantifiable time point from the log-linear regression analysis. Those outcome measures are either due to either patient(s) has insufficient sample(s) (e.g., sampling only through Tmax or 1 sample after) for analyses or t1/2 could not be determined	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.
Apparent Oral Clearance (CL/F) of PF-07284890 and Binimetinib for Single Dose: Phase 1a	CL/F was calculated as Dose/AUCinf.	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.
Apparent Volume of Distribution (Vz/F) of PF-07284890 and Binimetinib for Single Dose: Phase 1a	Vz/F was calculated as Dose/(AUCinf * kel) where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.	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.
Cmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a		Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15
Tmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a		Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15
Area Under the Plasma Concentration Time Curve Over the Dosing Interval (AUCtau) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a		Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15
Lowest Concentration Observed During the Dosing Interval (Cmin) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a		Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15
CL/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a	CL/F was calculated as Dose/AUCinf.	Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15
Vz/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a	Vz/F was calculated as Dose/(AUCinf * kel) where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.	Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15
t½ of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a	T1/2 was calculated as loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. In the determination of the t1/2, steady-state was assumed and the pre-dose value was used for the 24-hour post-dose value, which could have enabled the reporting of the t1/2 value higher than 8 hours.	Pre-dose (24 hours post-dose concentration), 1, 2, 4, 6 and 8 hours post dose on C1D15
Accumulation Ratio (Rac) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a	Rac was defined as area under the plasma concentration-time curve over the dosing interval at steady state (AUCss,τ) divided by area under the plasma concentration-time curve over the dosing interval from a single dose (AUCsd,τ).	Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D1 and C1D15
Extracranial Response Rate by RECISTv1.1: Phase 1a	Extracranial response rate was defined as the percentage of participants with a BOR of CR or confirmed 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 < 10 mm. 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: 542 days)
Intracranial Response Rate by mRECISTv1.1: Phase 1a	Intracranial response rate as assessed using modified mRECIST v 1.1., was defined as the percentage of participants with brain or 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: 542 days)
ORR by RECISTv1.1: Phase 1a	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: 542 days)
Overall Response Rate as Per RANO for Brain Tumours: Phase 1a	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 >= 4 weeks; no new lesions; stable or improved non-enhancing (T2/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; 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: 542 days)
Number of Participants With TEAEs, Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1b	An 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/start of new anti-cancer therapy (-1 Day) whichever occurred first (maximum treatment exposure: 400 days, maximum follow up: 430 days)
Number of Participants With Hematology Laboratory Abnormalities: Phase 1b	The following hematology laboratory parameters were assessed: activated partial thromboplastin time prolonged, anemia, hemoglobin increased, 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: 400 days, maximum follow up: 430 days)
Number of Participants With Chemistry Laboratory Abnormalities: Phase 1b	The following chemistry laboratory parameters were assessed: alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, blood bilirubin increased, 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: 400 days, maximum follow up: 430 days)
Number of Participants With Dose Interruptions Due to TEAEs: Phase 1b	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: 400 days])
Number of Participants With Dose Reduction Due to TEAEs: Phase 1b	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: 400 days])
Number of Participants With Dose Discontinuations Due to TEAEs: Phase 1b	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: 400 days])
Cmax of PF-07284890 and Binimetinib for Single Dose: Phase 1b		Pre-dose,1, 2, 4, 6, 8 and 24 hours post-dose on C1D1
Tmax of PF-07284890 and Binimetinib for Single Dose: Phase 1b		Pre-dose,1, 2, 4, 6, 8 and 24 hours post-dose on C1D1
AUClast of PF-07284890 and Binimetinib for Single Dose: Phase 1b	AUClast was determined using the linear/log trapezoidal method.	Pre-dose,1, 2, 4, 6, 8 and 24 hours post-dose on C1D1
Cmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b		Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15
Tmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b		Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15
AUCtau of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b		Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15
Cmin of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b		Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15
CL/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b	CL/F was calculated as Dose/AUCinf.	Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15
Intracranial Disease Control Rate (DCR) Per mRECIST v1.1: Phase1b	DCR: percentage of participants with BOR of CR, PR/ SD, Non-CR/Non-PD by Investigator assessment. CR: disappearance of all target and non-target lesions. For target lesions: Any pathological lymph nodes must be <10 mm in short axis. For non-target lesions: All lymph nodes identified as site of disease at baseline must be non-pathological. PR: At least 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive disease (PD). PD: for target lesions- At least 20% increase in sum of diameters of target lesions, taking as reference smallest sum of diameters recorded since treatment started. In addition, sum must have an absolute increase of at least 5 mm. PD for non-target lesions- unequivocal progression of existing non-target lesions. Non-CR/Non-PD: persistence of 1/ more non-target lesion(s) identified as site of disease.	From date of first dose until CR or PR or SD (maximum treatment exposure: 400 days)
Overall Disease Control Rate (DCR) Per RECIST v1.1: Phase1b	DCR: percentage of participants with BOR of CR, PR or SD, Non-CR/Non-PD by Investigator assessment. CR: disappearance of all target & non-target lesions. For target lesions: Any pathological lymph nodes must be <10 mm in short axis. For non-target lesions: All lymph nodes identified as site of disease at baseline must be non-pathological. PR: At least 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PD: for target lesions- At least 20% increase in sum of diameters of target lesions, taking as reference smallest sum of diameters recorded since treatment started. In addition, sum must have an absolute increase of at least 5 mm. PD for non-target lesions- unequivocal progression of existing non-target lesions. Non-CR/Non-PD: persistence of 1/ more non-target lesion(s) identified as site of disease.	From date of first dose until CR or PR or SD (maximum treatment exposure: 400 days)
Intracranial Progression Free Survival (PFS) by mRECISTv1.1: Phase1b	PFS was defined as the time from date of the first dose of study treatment to the earliest documented disease progression by Investigator assessment, or death due to any cause, whichever occurred first. PD: for target lesions- At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters recorded since the treatment started . In addition, the sum must have an absolute increase of at least 5 mm. PD for non-target lesions- unequivocal progression of existing non-target lesions. If a participant had not had a PFS event at the time of the analysis cutoff or at the start of any new anticancer therapy, PFS was censored at the date of last adequate tumor assessment. Analysis was performed using Kaplan-Meier method.	From date of first dose of study treatment until first documentation of PD or death due to any cause or censoring date whichever occurred first (maximum treatment exposure: 400 days)
Overall Progression Free Survival (PFS): Phase1b	PFS was defined as the time from date of the first dose of study treatment to the earliest documented disease progression by Investigator assessment, or death due to any cause, whichever occurred first. PD: for target lesions- at least 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study (this includes baseline sum if that is smallest on study). In addition to the relative increase of 20%, sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered a sign of progression. PD for non-target lesions- unequivocal progression of existing non-target lesion. If a participant had not had a PFS event at the time of the analysis cutoff or at the start of any new anticancer therapy, PFS was censored at the date of last adequate tumor assessment. Overall PFS included evaluation for brain metastasis and extracranial lesions. Analysis was performed using Kaplan-Meier method.	From start of study treatment until first documentation of PD or death due to any cause or censoring date (maximum treatment exposure: 400 days)
Overall Survival (OS): Phase1b	Overall survival was defined as the time from the date of first study treatment to the date of death due to any cause. Participants who were still alive at the end of the study or lost to follow-up were censored at the last date they were known to be alive. Analysis was performed using Kaplan-Meier method.	From start of study treatment until death due to any cause or censoring date (maximum treatment exposure: 400 days)
Intracranial Duration of Response (DOR) by mRECIST v1.1: Phase1b	DOR was defined as the time from date of the first radiographic response (CR or PR) to the earliest documented PD or death due to any cause. 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. PD: for target lesions- At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters recorded since the treatment started. In addition, the sum must have an absolute increase of at least 5 mm. PD for non-target lesions- unequivocal progression of existing non target lesions.	From CR or PR until first documented PD or death due to any cause (maximum treatment exposure: 400 days)
Overall DOR by RECIST v1.1: Phase1b	DOR: time from date of first radiographic response (CR/PR) to earliest documented PD/ death due to any cause.CR: disappearance of all target and non-target lesions. Any pathological lymph nodes (non-target) must have reduction in short axis to < 10 mm. PR: at least a 30 % decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD: for target lesions- At least 20% increase in sum of diameters of target lesions, taking as reference smallest sum of diameters recorded since treatment started. PD for non-target lesions- unequivocal progression of existing non-target lesions.	From CR or PR until first documented PD or death due to any cause (maximum treatment exposure: 400 days)
Intracranial Time to Response (TTR) by mRECIST v1.1: Phase1b	Time to response is the time from treatment start to date of first documentation of objective response (PR or CR). 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 TTR by RECIST v1.1: Phase1b	Time to response is the time from treatment start to date of first documentation of objective response (PR or CR). CR: disappearance of all target and non-target lesions. Any pathological lymph nodes (non-target) must have reduction in short axis to < 10 mm. PR: at least a 30 % decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Response evaluable population.	From date of first dose until CR or PR (maximum treatment exposure: 400 days)

Collaborators and Investigators

• Sponsor: Pfizer
• Investigators: Study Director: Pfizer CT.gov Call Center, Pfizer

Publications and helpful links

General Publications

• 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.

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): January 8, 2021
• Primary Completion (Actual): March 20, 2024
• Study Completion (Actual): March 20, 2024

Study Registration Dates

• First Submitted: September 2, 2020
• First Submitted That Met QC Criteria: September 2, 2020
• First Posted (Actual): September 10, 2020

Study Record Updates

• Last Update Posted (Estimated): October 23, 2025
• Last Update Submitted That Met QC Criteria: October 7, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Keywords: Melanoma; Enzyme Inhibitors; Carcinoma, Non-Small-Cell Lung; Brain Diseases; Brain Neoplasms; Central Nervous System Neoplasms; Proto-Oncogene Proteins B-raf
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Site; Respiratory Tract Diseases; Neoplasms by Histologic Type; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Skin Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Nervous System Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Skin and Connective Tissue Diseases; Neoplasms; Carcinoma, Non-Small-Cell Lung; Melanoma; Brain Neoplasms; Brain Diseases; Central Nervous System Neoplasms; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Benzazepines; Benzodiazepines; Midazolam; binimetinib; PF-07284890
• Other Study ID Numbers: C4471001; 2022-003184-23 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No