Description:
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.
Title
- Brief Title: A FIH Study of PF-07284890 in Participants With BRAF V600 Mutant Solid Tumors With and Without Brain Involvement
- Official Title: 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
Clinical Trial IDs
- ORG STUDY ID:
C4471001
- NCT ID:
NCT04543188
Conditions
- Malignant Melanoma
- Carcinoma, Non-Small-Cell Lung
- Brain Neoplasms, Primary
- Brain Neoplasms
- Malignant Neoplasms
Interventions
| Drug | Synonyms | Arms |
|---|
| PF-07284890 | ARRY-461 | Drug-Drug Interaction Substudy |
| Binimetinib | Mektovi | Drug-Drug Interaction Substudy |
| Midazolam | | Drug-Drug Interaction Substudy |
Purpose
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.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| PF-07284890 (Part A monotherapy) | Experimental | Monotherapy dose escalation of PF-07284890 | |
| PF-07284890+binimetinib (Part A combo-therapy) | Experimental | Combination dose escalation of PF-07284890 + binimetinib | |
| Expansion Phase (Part B, Cohort 1) | Experimental | PF-07284890 (at recommended dose from Part A) plus binimetinib in participants with BRAF V600 melanoma or Non-Small Cell Lung Cancer (NSCLC), with asymptomatic brain involvement, and no prior BRAF or MEK inhibitor utilization | |
| Expansion Phase (Part B, Cohort 2) | Experimental | PF-07284890 (at recommended dose from Part A) plus binimetinib in participants with BRAF V600 melanoma or NSCLC, with symptomatic brain involvement, and no prior BRAF or MEK inhibitor utilization | |
| Expansion Phase (Part B, Cohort 3) | Experimental | PF-07284890 (at recommended dose from Part A) plus binimetinib in participants with BRAF V600 melanoma or NSCLC, with asymptomatic brain involvement, and prior BRAF inhibitor utilization | |
| Expansion Phase (Part B, Cohort 4) | Experimental | PF-07284890 (at recommended dose from Part A) plus binimetinib in participants with BRAF V600 melanoma or NSCLC, with symptomatic brain involvement, and prior BRAF inhibitor utilization | |
| Expansion Phase (Part B Cohort 5) | Experimental | PF-07284890 (at recommended dose from Part A) plus binimetinib in participants with BRAF V600 solid tumor; history of or current leptomeningeal metastases; without disease in the brain; with disease in the brain that does not meet Cohorts 1-4; asymptomatic or symptomatic in the brain; primary brain tumors | |
| Drug-Drug Interaction Substudy | Experimental | PF-07284890 (at recommended dose from Part A) plus binimetinib plus midazolam in participants with BRAF V600 solid tumor | - PF-07284890
- Binimetinib
- Midazolam
|
Eligibility Criteria
Inclusion Criteria:
- Age ≥18 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 or NSCLC 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.
- Cohort 6 (DDI Sub-study): 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
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Phase 1a - Number of participants with dose limiting toxicities (DLTs) |
| Time Frame: | Cycle 1 (approximately 21 days / 3 weeks) |
| Safety Issue: | |
| Description: | 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 |
Secondary Outcome Measures
| Measure: | Phase 1a: Maximum plasma concentration of PF-07284890 and binimetinib |
| Time Frame: | 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) |
| Safety Issue: | |
| Description: | Single dose (Cmax) and multiple dose (assuming steady state is achieved; Css,max) pharmacokinetic (PK) parameters |
| Measure: | Phase 1a: Time to reach maximum plasma concentration of PF-07284890 and binimetinib |
| Time Frame: | 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 |
| Safety Issue: | |
| Description: | Single dose (Tmax) and multiple dose (assuming steady state is achieved; Tss,max) PK parameters |
| Measure: | 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 |
| Time Frame: | 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 |
| Safety Issue: | |
| Description: | Single dose PK parameter |
| Measure: | Phase 1a: Terminal half-life (t1/2) of PF-07284890 and binimetinib |
| Time Frame: | 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 |
| Safety Issue: | |
| Description: | Single dose and multiple dose (assuming steady state is achieved and data permit) PK parameter |
| Measure: | Phase 1a: Area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUCinf) of PF-07284890 and binimetinib |
| Time Frame: | 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 |
| Safety Issue: | |
| Description: | Single dose will be calculated as data permit PK parameter |
| Measure: | Phase 1a: Apparent oral clearance of PF-07284890 and binimetinib |
| Time Frame: | 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 |
| Safety Issue: | |
| Description: | Single dose (CL/F) and multiple dose (assuming steady state is achieved and as data permit; CLss/F) PK parameter |
| Measure: | Phase 1a: Volume of distribution of PF-07284890 and binimetinib |
| Time Frame: | 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 |
| Safety Issue: | |
| Description: | Single dose (Vz/F) and multiple dose (assuming steady state is achieved and as data permit; Vss/F) PK parameter |
| Measure: | Phase 1a: Area under the plasma concentration-time curve over the dosing interval at steady state (AUCss,T) of PF-07284890 and binimetinib |
| Time Frame: | 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 |
| Safety Issue: | |
| Description: | Multiple dose (assuming steady state is achieved) PK parameter |
| Measure: | Phase 1a: Trough plasma concentration at steady state (Css,min) of PF-07284890 and binimetinib |
| Time Frame: | 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 |
| Safety Issue: | |
| Description: | Multiple dose (assuming steady state is achieved) PK parameter |
| Measure: | Phase 1a: Accumulation ratio (Rac) of PF-07284890 and binimetinib |
| Time Frame: | 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 |
| Safety Issue: | |
| Description: | Multiple dose (assuming steady state is achieved and as data permit) PK parameter |
| Measure: | Phase 1a: Overall response |
| Time Frame: | Baseline up to approximately 12 months |
| Safety Issue: | |
| Description: | Response will be evaluated via radiographical tumor assessments by RECIST v1.1 and intracranial response by mRECIST v 1.1 |
| Measure: | Phase 1b - Number of patients with treatment emergent AEs |
| Time Frame: | Baseline up to 30 days after last dose of study medication |
| Safety Issue: | |
| Description: | AEs as characterized by type, frequency, severity, timing, seriousness, and relationship to study therapy |
| Measure: | Phase 1b - Number of participants with clinically significant change from baseline in laboratory abnormalities |
| Time Frame: | Baseline up to follow up visit (30 days after last dose of study treatment) |
| Safety Issue: | |
| Description: | Laboratory abnormalities as characterized by type, frequency, severity, and timing |
| Measure: | Phase 1b - Number of dose interruptions, dose modifications, and discontinuations due to AEs |
| Time Frame: | Baseline through approximately 12 months |
| Safety Issue: | |
| Description: | Incidence of dose interruptions, dose modifications, and discontinuations due to AEs |
| Measure: | Phase 1b: Maximum plasma concentration of PF-07284890 and binimetinib |
| Time Frame: | 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 |
| Safety Issue: | |
| Description: | Single dose (Cmax) and multiple dose (assuming steady state is achieved; Css,max) PK parameter |
| Measure: | Phase 1b: Time to reach maximum plasma concentration of PF-07284890 and binimetinib |
| Time Frame: | 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 |
| Safety Issue: | |
| Description: | Single dose (Tmax) and multiple dose (assuming steady state is achieved; Tss,max) PK parameter |
| Measure: | 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 |
| Time Frame: | 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 |
| Safety Issue: | |
| Description: | Single dose PK parameter |
| Measure: | Phase 1b: Terminal half-life (t1/2) of PF-07284890 and binimetinib |
| Time Frame: | 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 |
| Safety Issue: | |
| Description: | Single dose and multiple dose (assuming steady state is achieved and data permit) PK parameter |
| Measure: | Phase 1b: Area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUCinf) of PF-07284890 and binimetinib |
| Time Frame: | 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 |
| Safety Issue: | |
| Description: | Single dose will be calculated as data permit PK parameter |
| Measure: | Phase 1b: Apparent oral clearance of PF-07284890 and binimetinib |
| Time Frame: | 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 |
| Safety Issue: | |
| Description: | Single dose (CL/F) and multiple dose (assuming steady state is achieved and as data permit; CLss/F) PK parameter |
| Measure: | Phase 1b: Volume of distribution of PF-07284890 and binimetinib |
| Time Frame: | 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 |
| Safety Issue: | |
| Description: | Single dose (Vz/F) and multiple dose (assuming steady state is achieved and as data permit; Vss/F) PK parameter |
| Measure: | Phase 1b: Area under the plasma concentration-time curve over the dosing interval at steady state (AUCss,T) of PF-07284890 and binimetinib |
| Time Frame: | 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 |
| Safety Issue: | |
| Description: | Multiple dose (assuming steady state is achieved) PK parameter |
| Measure: | Phase 1b: Trough plasma concentration at steady state (Css,min) of PF-07284890 and binimetinib |
| Time Frame: | 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 |
| Safety Issue: | |
| Description: | Multiple dose (assuming steady state is achieved) PK parameter |
| Measure: | Phase 1b: Accumulation ration (Rac) of PF-07284890 and binimetinib |
| Time Frame: | 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 |
| Safety Issue: | |
| Description: | Multiple dose (assuming steady state is achieved and as data permit) PK parameter |
| Measure: | Phase 1b: Disease Control Rate (DCR) |
| Time Frame: | Every 6 weeks from time of enrollment up to 1 year, then every 12 weeks thereafter |
| Safety Issue: | |
| Description: | 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, at 6 weeks for both overall and intracranial |
| Measure: | Phase 1b: Progression Free Survival (PFS) |
| Time Frame: | Baseline to measured progressive disease (up to 12 months) |
| Safety Issue: | |
| Description: | The period from study entry until disease progression, death or date of last contact for both overall and intracranial. |
| Measure: | Phase 1b: Overall Survival (OS) |
| Time Frame: | Baseline to date of death from any cause (up to 12 months) |
| Safety Issue: | |
| Description: | Overall survival was the duration from enrollment to death. For participants who are alive, overall survival was censored at the last contact. |
| Measure: | Phase 1b: Duration of Response (DoR) |
| Time Frame: | Baseline, every 6 weeks until disease progression or unacceptable toxicity up to 1 year, then every 12 weeks thereafter |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Phase 1b: Time to Tumor Response (TTR) |
| Time Frame: | Every 6 weeks from the time of enrollment up to 12 months |
| Safety Issue: | |
| Description: | 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 |
| Measure: | Phase 1b: Maximum plasma concentration (Cmax) of CYP34A probe substrate midazolam |
| Time Frame: | Day -7 (Lead-in); Cycle 1 Day 1 and Day 15 (predose, 0.5, 1, 2, 4, and 8 hours post dose) |
| Safety Issue: | |
| Description: | PK parameter |
| Measure: | Phase 1b: Time to reach maximum plasma concentration (Tmax) of CYP3A4 probe substrate midazolam |
| Time Frame: | Day -7 (Lead-in); Cycle 1 Day 1 and Day 15 (predose, 0.5, 1, 2, 4, and 8 hours post dose) |
| Safety Issue: | |
| Description: | PK parameter |
| Measure: | 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 |
| Time Frame: | Day -7 (Lead-in); Cycle 1 Day 1 and Day 15 (predose, 0.5, 1, 2, 4, and 8 hours post dose) |
| Safety Issue: | |
| Description: | PK parameter |
| Measure: | Phase 1b: Terminal half-life (t1/2) of CYP3A4 probe substrate midazolam |
| Time Frame: | Day -7 (Lead-in); Cycle 1 Day 1 and Day 15 (predose, 0.5, 1, 2, 4, and 8 hours post dose) |
| Safety Issue: | |
| Description: | PK parameter as data permit |
| Measure: | Phase 1b: Area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUCinf) of CYP3A4 probe substrate midazolam |
| Time Frame: | Day -7 (Lead-in); Cycle 1 Day 1 and Day 15 (predose, 0.5, 1, 2, 4, and 8 hours post dose) |
| Safety Issue: | |
| Description: | PK parameter as data permit |
| Measure: | Phase 1a: Apparent oral clearance (CL/F) of CYP3A4 probe substrate midazolam |
| Time Frame: | Day -7 (Lead-in); Cycle 1 Day 1 and Day 15 (predose, 0.5, 1, 2, 4, and 8 hours post dose) |
| Safety Issue: | |
| Description: | PK parameter as data permit |
| Measure: | Phase 1a: Volume of distribution (Vz/F) of CYP3A4 probe substrate midazolam |
| Time Frame: | Day -7 (Lead-in); Cycle 1 Day 1 and Day 15 (predose, 0.5, 1, 2, 4, and 8 hours post dose) |
| Safety Issue: | |
| Description: | PK parameter as data permit |
Details
| Phase: | Phase 1 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | Pfizer |
Trial Keywords
- Proto-Oncogene Proteins B-raf
- Brain Neoplasms
- Melanoma
- Carcinoma, Non-Small-Cell Lung
- Brain Diseases
- Central Nervous System Neoplasms
- Lung Neoplasms
- Lung Diseases
- Enzyme Inhibitors
Last Updated
May 28, 2021
