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

Study Overview
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Brief Summary
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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.

Official Title
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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

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

Intervention / Treatment
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* Drug: PF-07284890
* Drug: Binimetinib
* Drug: Midazolam


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Proto-Oncogene Proteins B-raf, Brain Neoplasms, Melanoma, Carcinoma, Non-Small-Cell Lung, Brain Diseases, Central Nervous System Neoplasms, Enzyme Inhibitors