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
    • Hamilton, Ontario, Canada, L8V5C2
      • Hamilton Health Sciences-Juravinski Cancer Centre
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Cancer Centre
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Research Institute
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • Jewish General Hospital
• Israel
  • ?eif?
    • Haifa, ?eif?, Israel, 3109601
      • Rambam Health Care Campus
  • Hamerkaz
    • Petah-Tikva, Hamerkaz, Israel, 49100
      • Rabin Medical Center
    • Ramat Gan, Hamerkaz, Israel, 5262100
      • Sheba Medical Center
  • Tell Abīb
    • Tel Aviv, Tell Abīb, Israel, 6423906
      • Sourasky Medical Center
  • Yerushalayim
    • Jerusalem, Yerushalayim, Israel, 9112001
      • Hadassah Medical Center
• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope (City of Hope National Medical Center, City of Hope Medical Center)
    • Duarte, California, United States, 91010
      • City of Hope Investigational Drug Services (IDS)
    • Los Angeles, California, United States, 90033
      • USC/Norris Comprehensive Cancer Center
    • Los Angeles, California, United States, 90033
      • Keck Hospital of Usc
    • Los Angeles, California, United States, 90033
      • LAC + USC Medical Center
    • Los Angeles, California, United States, 90033
      • Norris Healthcare Center 3 (HC3)
    • Los Angeles, California, United States, 90033
      • USC/Roski Eye Institute
    • Pasadena, California, United States, 91105
      • Keck Medical Center of USC Pasadena
    • San Francisco, California, United States, 94143
      • UCSF Helen Diller Family Comprehensive Cancer Center
    • San Francisco, California, United States, 94158
      • UCSF Medical 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
  • Indiana
    • Indianapolis, Indiana, United States, 46250
      • Community Health Network, Inc.
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Kansas
    • Fairway, Kansas, United States, 66205
      • The University of Kansas Clinical Research Center
    • Fairway, Kansas, United States, 66205
      • The University of Kansas Cancer Center - Investigational Drug Services
    • Kansas City, Kansas, United States, 66160
      • The University of Kansas Hospital
    • Westwood, Kansas, United States, 66205
      • The University of Kansas Cancer Center
  • 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
    • Foxboro, Massachusetts, United States, 02035
      • Imaging: Brigham and Women's Mass General Healthcare Center
    • Newton, Massachusetts, United States, 02459
      • Dana-Farber Cancer Institute - Chestnut Hill
  • Michigan
    • Farmington Hills, Michigan, United States, 48334
      • Michigan Health Professionals (PI Clinic)
    • Sterling Heights, Michigan, United States, 48314
      • Revive Research Institute
  • Minnesota
    • Saint Paul, Minnesota, United States, 55101
      • Regions Hospital Pharmacy
    • Saint Paul, Minnesota, United States, 55101
      • HealthPartners Cancer Center at Regions Hospital
  • Missouri
    • Creve Coeur, Missouri, United States, 63141
      • Siteman Cancer Center - West County
    • Florissant, Missouri, United States, 63031
      • Siteman Cancer Center - North County
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
    • Saint Louis, Missouri, United States, 63110
      • Barnes-Jewish Hospital
    • Saint Louis, Missouri, United States, 63129
      • Siteman Cancer Center - South County
    • Saint Louis, Missouri, United States, 63110
      • Washington University Infusion Center Pharmacy
    • Saint Peters, Missouri, United States, 63376
      • Siteman Cancer Center - St Peters
  • 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
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10016
      • NYU Langone Health
    • New York, New York, United States, 10016
      • Laura and Isaac Perlmutter Cancer Center
    • New York, New York, United States, 10016
      • NYU Langone Medical Center (Tisch Hospital)
    • New York, New York, United States, 10017
      • NYU Langone Radiology- ACC East 41st street
    • New York, New York, United States, 10022
      • Memorial Sloan Kettering Cancer Center Rockefeller Outpatient Pavilion
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • UNC Cancer Hospital Infusion Pharmacy
    • 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
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati Medical Center
    • Cincinnati, Ohio, United States, 45219
      • Carl & Edyth Lindner Center for Research & Education at TCH and TCH Cancer Center
    • West Chester, Ohio, United States, 45069
      • West Chester Hospital
  • Tennessee
    • Franklin, Tennessee, United States, 37067
      • Tennessee Oncology PLLC
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology PLLC
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute - Pharmacy
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas MD Anderson Cancer Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Hospitals and Clinics

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
Phase 1a - Number of participants with dose limiting toxicities (DLTs)	DLTs will be evaluated during the first cycle (21 days) as both a single agent or in combination with binimetinib. The number of DLTs will be used to determine the maximum tolerated dose (MTD)/recommended dose for further study	Cycle 1 (approximately 21 days / 3 weeks)
Phase 1a - Number of participants with treatment emergent adverse events (AEs)	AEs as characterized by type, frequency, severity, timing, seriousness, and relationship to study therapy	Baseline up to 30 days after last dose of study medication
Phase 1a - Number of participants with clinically significant change from baseline in laboratory abnormalities	Laboratory abnormalities as characterized by type, frequency, severity, and timing	Baseline up to follow up visit (30 days after last dose of study treatment)
Phase 1a - Number of dose interruptions, dose modifications, and discontinuations due to AEs	Incidence of dose interruptions, dose modifications, and discontinuations due to AEs	Baseline through approximately 12 months
Phase 1b - Overall response	Response will be evaluated via radiographical tumor assessments by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and intracranial response by modified RECIST version 1.1 (mRECIST v 1.1) or RANO for primary brain tumors	Baseline up to approximately 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1a: Maximum plasma concentration of PF-07284890 and binimetinib	Single dose (Cmax) and multiple dose (assuming steady state is achieved; Css,max) pharmacokinetic (PK) parameters	Cycle 1 Day 1 (predose, 1, 2, 4, 6, 8, and 24 hours (Day 2) post dose); Cycle 1 Day 15 (predose, 1, 2, 4, 6, and 8 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); End of Treatment (EOT)
Phase 1a: Time to reach maximum plasma concentration of PF-07284890 and binimetinib	Single dose (Tmax) and multiple dose (assuming steady state is achieved; Tss,max) PK parameters	Cycle 1 Day 1 (predose, 1, 2, 4, 6, 8, and 24 hours (Day 2) post dose); Cycle 1 Day 15 (predose, 1, 2, 4, 6, and 8 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); EOT
Phase 1a: Area under the plasma concentration-time curve from time 0 to the last time point of quantifiable concentration (AUClast) of PF-07284890 and binimetinib	Single dose PK parameter	Cycle 1 Day 1 (predose, 1, 2, 4, 6, 8, and 24 hours (Day 2) post dose); Cycle 1 Day 15 (predose, 1, 2, 4, 6, and 8 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); EOT
Phase 1a: Terminal half-life (t1/2) of PF-07284890 and binimetinib	Single dose and multiple dose (assuming steady state is achieved and data permit) PK parameter	Cycle 1 Day 1 (predose, 1, 2, 4, 6, 8, and 24 hours (Day 2) post dose); Cycle 1 Day 15 (predose, 1, 2, 4, 6, and 8 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); EOT
Phase 1a: Area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUCinf) of PF-07284890 and binimetinib	Single dose will be calculated as data permit PK parameter	Cycle 1 Day 1 (predose, 1, 2, 4, 6, 8, and 24 hours (Day 2) post dose); Cycle 1 Day 15 (predose, 1, 2, 4, 6, and 8 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); EOT
Phase 1a: Apparent oral clearance of PF-07284890 and binimetinib	Single dose (CL/F) and multiple dose (assuming steady state is achieved and as data permit; CLss/F) PK parameter	Cycle 1 Day 1 (predose, 1, 2, 4, 6, 8, and 24 hours (Day 2) post dose); Cycle 1 Day 15 (predose, 1, 2, 4, 6, and 8 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); EOT
Phase 1a: Volume of distribution of PF-07284890 and binimetinib	Single dose (Vz/F) and multiple dose (assuming steady state is achieved and as data permit; Vss/F) PK parameter	Cycle 1 Day 1 (predose, 1, 2, 4, 6, 8, and 24 hours (Day 2) post dose); Cycle 1 Day 15 (predose, 1, 2, 4, 6, and 8 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); EOT
Phase 1a: Area under the plasma concentration-time curve over the dosing interval at steady state (AUCss,T) of PF-07284890 and binimetinib	Multiple dose (assuming steady state is achieved) PK parameter	Cycle 1 Day 1 (predose, 1, 2, 4, 6, 8, and 24 hours (Day 2) post dose); Cycle 1 Day 15 (predose, 1, 2, 4, 6, and 8 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); EOT
Phase 1a: Trough plasma concentration at steady state (Css,min) of PF-07284890 and binimetinib	Multiple dose (assuming steady state is achieved) PK parameter	Cycle 1 Day 1 (predose, 1, 2, 4, 6, 8, and 24 hours (Day 2) post dose); Cycle 1 Day 15 (predose, 1, 2, 4, 6, and 8 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); EOT
Phase 1a: Accumulation ratio (Rac) of PF-07284890 and binimetinib	Multiple dose (assuming steady state is achieved and as data permit) PK parameter	Cycle 1 Day 1 (predose, 1, 2, 4, 6, 8, and 24 hours (Day 2) post dose); Cycle 1 Day 15 (predose, 1, 2, 4, 6, and 8 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); EOT
Phase 1a: Overall response	Response will be evaluated via radiographical tumor assessments by RECIST v1.1 and intracranial response by mRECIST v 1.1 or RANO for primary brain tumors	Baseline up to approximately 12 months
Phase 1b - Number of patients with treatment emergent AEs	AEs as characterized by type, frequency, severity, timing, seriousness, and relationship to study therapy	Baseline up to 30 days after last dose of study medication
Phase 1b - Number of participants with clinically significant change from baseline in laboratory abnormalities	Laboratory abnormalities as characterized by type, frequency, severity, and timing	Baseline up to follow up visit (30 days after last dose of study treatment)
Phase 1b - Number of dose interruptions, dose modifications, and discontinuations due to AEs	Incidence of dose interruptions, dose modifications, and discontinuations due to AEs	Baseline through approximately 12 months
Phase 1b: Maximum plasma concentration of PF-07284890 and binimetinib	Single dose (Cmax) and multiple dose (assuming steady state is achieved; Css,max) PK parameter	Cycle 1 Day 1 and 15 (predose, 1, 2, and 4 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); EOT
Phase 1b: Time to reach maximum plasma concentration of PF-07284890 and binimetinib	Single dose (Tmax) and multiple dose (assuming steady state is achieved; Tss,max) PK parameter	Cycle 1 Day 1 and 15 (predose, 1, 2, and 4 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); EOT
Phase 1b: Area under the plasma concentration-time curve from time 0 to the last time point of quantifiable concentration (AUClast) of PF-07284890 and binimetinib	Single dose PK parameter	Cycle 1 Day 1 and 15 (predose, 1, 2, and 4 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); EOT
Phase 1b: Terminal half-life (t1/2) of PF-07284890 and binimetinib	Single dose and multiple dose (assuming steady state is achieved and data permit) PK parameter	Cycle 1 Day 1 and 15 (predose, 1, 2, and 4 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); EOT
Phase 1b: Area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUCinf) of PF-07284890 and binimetinib	Single dose will be calculated as data permit PK parameter	Cycle 1 Day 1 and 15 (predose, 1, 2, and 4 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); EOT
Phase 1b: Apparent oral clearance of PF-07284890 and binimetinib	Single dose (CL/F) and multiple dose (assuming steady state is achieved and as data permit; CLss/F) PK parameter	Cycle 1 Day 1 and 15 (predose, 1, 2, and 4 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); EOT
Phase 1b: Volume of distribution of PF-07284890 and binimetinib	Single dose (Vz/F) and multiple dose (assuming steady state is achieved and as data permit; Vss/F) PK parameter	Cycle 1 Day 1 and 15 (predose, 1, 2, and 4 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); EOT
Phase 1b: Area under the plasma concentration-time curve over the dosing interval at steady state (AUCss,T) of PF-07284890 and binimetinib	Multiple dose (assuming steady state is achieved) PK parameter	Cycle 1 Day 1 and 15 (predose, 1, 2, and 4 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); EOT
Phase 1b: Trough plasma concentration at steady state (Css,min) of PF-07284890 and binimetinib	Multiple dose (assuming steady state is achieved) PK parameter	Cycle 1 Day 1 and 15 (predose, 1, 2, and 4 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); EOT
Phase 1b: Accumulation ration (Rac) of PF-07284890 and binimetinib	Multiple dose (assuming steady state is achieved and as data permit) PK parameter	Cycle 1 Day 1 and 15 (predose, 1, 2, and 4 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); EOT
Phase 1b: Disease Control Rate (DCR)	DCR is defined as the percent of participants with a confirmed complete response (CR), partial response (PR) or stable disease (SD) according to RECIST 1.1/RANO, at 6 weeks for both overall and intracranial	Every 6 weeks from time of enrollment up to 1 year, then every 12 weeks thereafter
Phase 1b: Progression Free Survival (PFS)	The period from study entry until disease progression, death or date of last contact for both overall and intracranial.	Baseline to measured progressive disease (up to 12 months)
Phase 1b: Overall Survival (OS)	Overall survival was the duration from enrollment to death. For participants who are alive, overall survival was censored at the last contact.	Baseline to date of death from any cause (up to 12 months)
Phase 1b: Duration of Response (DoR)	Duration of response (DR) defined as time from start of first documented objective tumor response [Complete Response (CR) or Partial Response (PR)] to first documented objective tumor progression or death due to any cause, whichever occurs first.	Baseline, every 6 weeks until disease progression or unacceptable toxicity up to 1 year, then every 12 weeks thereafter
Phase 1b: Time to Tumor Response (TTR)	TTR is defined as the time from first dose to first documentation of objective tumor response (CR or PR). For participants whose objective response (OR) proceeds from PR to CR, the onset of PR is taken as the onset of response. TTR will only be calculated for the subgroup of participants with a confirmed objective tumor response for both overall and intracranial	Every 6 weeks from the time of enrollment up to 12 months
Phase 1b: Maximum plasma concentration (Cmax) of CYP34A probe substrate midazolam	PK parameter	Day -7 (Lead-in); Cycle 1 Day 1 and Day 15 (predose, 0.5, 1, 2, 4, and 8 hours post dose)
Phase 1b: Time to reach maximum plasma concentration (Tmax) of CYP3A4 probe substrate midazolam	PK parameter	Day -7 (Lead-in); Cycle 1 Day 1 and Day 15 (predose, 0.5, 1, 2, 4, and 8 hours post dose)
Phase 1b: Area under the plasma concentration-time curve from time 0 to the last time point of quantifiable concentration (AUClast) of CYP3A4 probe substrate midazolam	PK parameter	Day -7 (Lead-in); Cycle 1 Day 1 and Day 15 (predose, 0.5, 1, 2, 4, and 8 hours post dose)
Phase 1b: Terminal half-life (t1/2) of CYP3A4 probe substrate midazolam	PK parameter as data permit	Day -7 (Lead-in); Cycle 1 Day 1 and Day 15 (predose, 0.5, 1, 2, 4, and 8 hours post dose)
Phase 1b: Area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUCinf) of CYP3A4 probe substrate midazolam	PK parameter as data permit	Day -7 (Lead-in); Cycle 1 Day 1 and Day 15 (predose, 0.5, 1, 2, 4, and 8 hours post dose)
Phase 1a: Apparent oral clearance (CL/F) of CYP3A4 probe substrate midazolam	PK parameter as data permit	Day -7 (Lead-in); Cycle 1 Day 1 and Day 15 (predose, 0.5, 1, 2, 4, and 8 hours post dose)
Phase 1a: Volume of distribution (Vz/F) of CYP3A4 probe substrate midazolam	PK parameter as data permit	Day -7 (Lead-in); Cycle 1 Day 1 and Day 15 (predose, 0.5, 1, 2, 4, and 8 hours post dose)

Collaborators and Investigators

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

Publications and helpful links

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 (Actual): April 3, 2024
• Last Update Submitted That Met QC Criteria: April 1, 2024
• Last Verified: April 1, 2024

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: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Skin Diseases; Respiratory Tract Diseases; Neoplasms by Histologic Type; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Central Nervous System Neoplasms; Nervous System Neoplasms; Lung Neoplasms; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Neoplasms; Carcinoma, Non-Small-Cell Lung; Brain Neoplasms; Melanoma; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Midazolam
• 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