A FIH Study of PF-07284890 in Participants With BRAF V600 Mutant Solid Tumors With and Without Brain Involvement
- Conditions
- Brain Neoplasms, PrimaryMalignant NeoplasmsMalignant MelanomaBrain NeoplasmsCarcinoma, Non-Small-Cell Lung
- Interventions
- Registration Number
- NCT04543188
- Lead Sponsor
- Pfizer
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 66
-
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
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description PF-07284890 (Part A monotherapy) PF-07284890 Monotherapy dose escalation of PF-07284890 Expansion Phase (Part B, Cohort 1) PF-07284890 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 Expansion Phase (Part B, Cohort 4) Binimetinib 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 Expansion Phase (Part B Cohort 5) PF-07284890 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 Expansion Phase (Part B Optional Cohort 7) Binimetinib PF-07284890 (at the recommended dose for expansion when administered with food) plus binimetinib in participants with BRAF V600 solid tumor Expansion Phase (Part B, Cohort 2) PF-07284890 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 Expansion Phase (Part B, Cohort 2) Binimetinib 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 Expansion Phase (Part B, Cohort 3) PF-07284890 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 Expansion Phase (Part B, Cohort 3) Binimetinib 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 Expansion Phase (Part B, Cohort 4) PF-07284890 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 Expansion Phase (Part B Optional Cohort 7) PF-07284890 PF-07284890 (at the recommended dose for expansion when administered with food) plus binimetinib in participants with BRAF V600 solid tumor PF-07284890+binimetinib (Part A combo-therapy) PF-07284890 Combination dose escalation of PF-07284890 + binimetinib Expansion Phase Drug-Drug Interaction Substudy (Part B Optional Cohort 6) PF-07284890 PF-07284890 (at recommended dose from Part A) plus binimetinib plus midazolam in participants with BRAF V600 solid tumor PF-07284890+binimetinib (Part A combo-therapy) Binimetinib Combination dose escalation of PF-07284890 + binimetinib Expansion Phase (Part B, Cohort 1) Binimetinib 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 Expansion Phase (Part B Cohort 5) Binimetinib 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 Expansion Phase Drug-Drug Interaction Substudy (Part B Optional Cohort 6) Binimetinib PF-07284890 (at recommended dose from Part A) plus binimetinib plus midazolam in participants with BRAF V600 solid tumor Expansion Phase Drug-Drug Interaction Substudy (Part B Optional Cohort 6) Midazolam PF-07284890 (at recommended dose from Part A) plus binimetinib plus midazolam in participants with BRAF V600 solid tumor
- Primary Outcome Measures
Name Time Method Phase 1a - Number of participants with clinically significant change from baseline in laboratory abnormalities Baseline up to follow up visit (30 days after last dose of study treatment) Laboratory abnormalities as characterized by type, frequency, severity, and timing
Phase 1a - Number of dose interruptions, dose modifications, and discontinuations due to AEs Baseline through approximately 12 months Incidence of dose interruptions, dose modifications, and discontinuations due to AEs
Phase 1b - Overall response Baseline up to approximately 12 months 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
Phase 1a - Number of participants with dose limiting toxicities (DLTs) Cycle 1 (approximately 21 days / 3 weeks) 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
Phase 1a - Number of participants with treatment emergent adverse events (AEs) Baseline up to 30 days after last dose of study medication AEs as characterized by type, frequency, severity, timing, seriousness, and relationship to study therapy
- Secondary Outcome Measures
Name Time Method Phase 1a: Volume of distribution (Vz/F) of CYP3A4 probe substrate midazolam Day -7 (Lead-in); Cycle 1 Day 1 and Day 15 (predose, 0.5, 1, 2, 4, and 8 hours post dose) PK parameter as data permit
Phase 1a: Maximum plasma concentration of PF-07284890 and binimetinib 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) Single dose (Cmax) and multiple dose (assuming steady state is achieved; Css,max) pharmacokinetic (PK) parameters
Phase 1a: Time to reach maximum plasma concentration of PF-07284890 and binimetinib 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 Single dose (Tmax) and multiple dose (assuming steady state is achieved; Tss,max) PK parameters
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 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 Single dose PK parameter
Phase 1a: Terminal half-life (t1/2) of PF-07284890 and binimetinib 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 Single dose and multiple dose (assuming steady state is achieved and data permit) PK parameter
Phase 1a: Area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUCinf) of PF-07284890 and binimetinib 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 Single dose will be calculated as data permit PK parameter
Phase 1a: Apparent oral clearance of PF-07284890 and binimetinib 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 Single dose (CL/F) and multiple dose (assuming steady state is achieved and as data permit; CLss/F) PK parameter
Phase 1a: Volume of distribution of PF-07284890 and binimetinib 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 Single dose (Vz/F) and multiple dose (assuming steady state is achieved and as data permit; Vss/F) PK parameter
Phase 1a: Area under the plasma concentration-time curve over the dosing interval at steady state (AUCss,T) of PF-07284890 and binimetinib 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 Multiple dose (assuming steady state is achieved) PK parameter
Phase 1a: Trough plasma concentration at steady state (Css,min) of PF-07284890 and binimetinib 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 Multiple dose (assuming steady state is achieved) PK parameter
Phase 1a: Accumulation ratio (Rac) of PF-07284890 and binimetinib 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 Multiple dose (assuming steady state is achieved and as data permit) PK parameter
Phase 1a: Overall response Baseline up to approximately 12 months 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
Phase 1b - Number of patients with treatment emergent AEs Baseline up to 30 days after last dose of study medication AEs as characterized by type, frequency, severity, timing, seriousness, and relationship to study therapy
Phase 1b - Number of participants with clinically significant change from baseline in laboratory abnormalities Baseline up to follow up visit (30 days after last dose of study treatment) Laboratory abnormalities as characterized by type, frequency, severity, and timing
Phase 1b - Number of dose interruptions, dose modifications, and discontinuations due to AEs Baseline through approximately 12 months Incidence of dose interruptions, dose modifications, and discontinuations due to AEs
Phase 1b: Maximum plasma concentration of PF-07284890 and binimetinib 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 Single dose (Cmax) and multiple dose (assuming steady state is achieved; Css,max) PK parameter
Phase 1b: Time to reach maximum plasma concentration of PF-07284890 and binimetinib 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 Single dose (Tmax) and multiple dose (assuming steady state is achieved; Tss,max) PK parameter
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 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 Single dose PK parameter
Phase 1b: Terminal half-life (t1/2) of PF-07284890 and binimetinib 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 Single dose and multiple dose (assuming steady state is achieved and data permit) PK parameter
Phase 1b: Area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUCinf) of PF-07284890 and binimetinib 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 Single dose will be calculated as data permit PK parameter
Phase 1b: Apparent oral clearance of PF-07284890 and binimetinib 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 Single dose (CL/F) and multiple dose (assuming steady state is achieved and as data permit; CLss/F) PK parameter
Phase 1b: Volume of distribution of PF-07284890 and binimetinib 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 Single dose (Vz/F) and multiple dose (assuming steady state is achieved and as data permit; Vss/F) PK parameter
Phase 1b: Area under the plasma concentration-time curve over the dosing interval at steady state (AUCss,T) of PF-07284890 and binimetinib 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 Multiple dose (assuming steady state is achieved) PK parameter
Phase 1b: Trough plasma concentration at steady state (Css,min) of PF-07284890 and binimetinib 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 Multiple dose (assuming steady state is achieved) PK parameter
Phase 1b: Accumulation ration (Rac) of PF-07284890 and binimetinib 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 Multiple dose (assuming steady state is achieved and as data permit) PK parameter
Phase 1b: Disease Control Rate (DCR) Every 6 weeks from time of enrollment up to 1 year, then every 12 weeks thereafter 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
Phase 1b: Progression Free Survival (PFS) Baseline to measured progressive disease (up to 12 months) The period from study entry until disease progression, death or date of last contact for both overall and intracranial.
Phase 1b: Overall Survival (OS) Baseline to date of death from any cause (up to 12 months) Overall survival was the duration from enrollment to death. For participants who are alive, overall survival was censored at the last contact.
Phase 1b: Duration of Response (DoR) Baseline, every 6 weeks until disease progression or unacceptable toxicity up to 1 year, then every 12 weeks thereafter 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.
Phase 1b: Time to Tumor Response (TTR) Every 6 weeks from the time of enrollment up to 12 months 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
Phase 1b: Maximum plasma concentration (Cmax) of CYP34A probe substrate midazolam Day -7 (Lead-in); Cycle 1 Day 1 and Day 15 (predose, 0.5, 1, 2, 4, and 8 hours post dose) PK parameter
Phase 1b: Time to reach maximum plasma concentration (Tmax) of CYP3A4 probe substrate midazolam Day -7 (Lead-in); Cycle 1 Day 1 and Day 15 (predose, 0.5, 1, 2, 4, and 8 hours post dose) PK parameter
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 Day -7 (Lead-in); Cycle 1 Day 1 and Day 15 (predose, 0.5, 1, 2, 4, and 8 hours post dose) PK parameter
Phase 1b: Terminal half-life (t1/2) of CYP3A4 probe substrate midazolam Day -7 (Lead-in); Cycle 1 Day 1 and Day 15 (predose, 0.5, 1, 2, 4, and 8 hours post dose) PK parameter as data permit
Phase 1b: Area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUCinf) of CYP3A4 probe substrate midazolam Day -7 (Lead-in); Cycle 1 Day 1 and Day 15 (predose, 0.5, 1, 2, 4, and 8 hours post dose) PK parameter as data permit
Phase 1a: Apparent oral clearance (CL/F) of CYP3A4 probe substrate midazolam Day -7 (Lead-in); Cycle 1 Day 1 and Day 15 (predose, 0.5, 1, 2, 4, and 8 hours post dose) PK parameter as data permit
Trial Locations
- Locations (76)
City of Hope (City of Hope National Medical Center, City of Hope Medical Center)
🇺🇸Duarte, California, United States
City of Hope Investigational Drug Services (IDS)
🇺🇸Duarte, California, United States
Keck Hospital of USC
🇺🇸Los Angeles, California, United States
LAC + USC Medical Center
🇺🇸Los Angeles, California, United States
Norris Healthcare Center 3 (HC3)
🇺🇸Los Angeles, California, United States
USC/Norris Comprehensive Cancer Center
🇺🇸Los Angeles, California, United States
USC/Roski Eye Institute
🇺🇸Los Angeles, California, United States
Keck Medical Center of USC Pasadena
🇺🇸Pasadena, California, United States
UCSF Helen Diller Family Comprehensive Cancer Center
🇺🇸San Francisco, California, United States
UCSF Medical Center
🇺🇸San Francisco, California, United States
Scroll for more (66 remaining)City of Hope (City of Hope National Medical Center, City of Hope Medical Center)🇺🇸Duarte, California, United States