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

Sponsor

Pfizer (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04543188

Collaborator

(none)

225

Enrollment

Locations

Arms

32.7

Anticipated Duration (Months)

7.8

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Malignant Melanoma Carcinoma, Non-Small-Cell Lung Brain Neoplasms, Primary Brain Neoplasms Malignant Neoplasms	Drug: PF-07284890 Drug: Binimetinib Drug: Midazolam	Phase 1

Study Design

Study Type:

Interventional

Anticipated Enrollment :

225 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Jan 8, 2021

Anticipated Primary Completion Date :

Sep 30, 2023

Anticipated Study Completion Date :

Sep 30, 2023

Arms and Interventions

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 or Non-Small Cell Lung Cancer (NSCLC), 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 or NSCLC, 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 or NSCLC, 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 or NSCLC, 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: Drug-Drug Interaction Substudy 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

Outcome Measures

Primary Outcome Measures

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
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)

Secondary Outcome Measures

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
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, 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
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope (City of Hope National Medical Center, City of Hope Medical Center)	Duarte	California	United States	91010
2	City of Hope Investigational Drug Services (IDS)	Duarte	California	United States	91010
3	UCSF Helen Diller Family Comprehensive Cancer Center	San Francisco	California	United States	94143
4	UCSF Medical Center	San Francisco	California	United States	94158
5	Emory University Hospital Midtown	Atlanta	Georgia	United States	30308
6	Emory University Hospital	Atlanta	Georgia	United States	30322
7	Investigational Drug Service	Atlanta	Georgia	United States	30322
8	The Emory Clinic	Atlanta	Georgia	United States	30322
9	Winship Cancer Institute Emory University	Atlanta	Georgia	United States	30322
10	University of Iowa Hospitals and Clinics	Iowa City	Iowa	United States	52242
11	Johns Hopkins University / Johns Hopkins Hospital	Baltimore	Maryland	United States	21231
12	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
13	Ophthalmic Consultants of Boston Inc (OCB)	Boston	Massachusetts	United States	02114
14	Siteman Cancer Center - West County	Creve Coeur	Missouri	United States	63141
15	Siteman Cancer Center - North County	Florissant	Missouri	United States	63031
16	Barnes-Jewish Hospital	Saint Louis	Missouri	United States	63110
17	Washington University Infusion Center Pharmacy	Saint Louis	Missouri	United States	63110
18	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
19	Siteman Cancer Center - South County	Saint Louis	Missouri	United States	63129
20	Siteman Cancer Center - St Peters	Saint Peters	Missouri	United States	63376
21	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
22	John Theurer Cancer Center at Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
23	Duke Eye Center	Durham	North Carolina	United States	27705
24	Duke University Medical Center, Investigational Chemotherapy Services	Durham	North Carolina	United States	27710
25	Duke University Medical Center	Durham	North Carolina	United States	27710
26	Tennessee Oncology PLLC	Franklin	Tennessee	United States	37067
27	Sarah Cannon Research Institute - Pharmacy	Nashville	Tennessee	United States	37203
28	Tennessee Oncology PLLC	Nashville	Tennessee	United States	37203
29	The University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030