PF-07284892 in Participants With Advanced Solid Tumors

Study Overview
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Brief Summary
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The purpose of this first-in-patient, open label study is to determine the maximum tolerated dose and/or recommended dose for further study of PF-07284892 as a single agent and in combination with lorlatinib, encorafenib and cetuximab, or binimetinib and evaluate the pharmacokinetics, safety, and preliminary clinical activity of single agent and each combination therapy.

Official Title
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A PHASE 1, OPEN-LABEL, MULTI-CENTER, DOSE ESCALATION AND DOSE EXPANSION STUDY TO EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND PRELIMINARY EVIDENCE OF ANTI-TUMOR ACTIVITY OF PF-07284892 (ARRY-558) AS A SINGLE AGENT AND IN COMBINATION THERAPY IN PARTICIPANTS WITH ADVANCED SOLID TUMORS

Conditions
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Solid Tumor

Intervention / Treatment
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* Drug: PF-07284892
* Drug: lorlatinib
* Drug: binimetinib
* Biological: cetuximab
* Drug: encorafenib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years at the time of informed consent Histological or cytological diagnosis of ALK-positive advanced NSCLC, CRC with BRAF V600E mutation, or RAS- mutant, NF1-mutant or BRAF class 3 mutant solid tumor. Participants with ROS-positive NSCLC are also eligible for Part 1 and 2 (Other ROS1-positive solid tumors may be considered after discussion with the sponsor). Documentation evidence of biomarker mutation status Part 3: ALK-positive NSCLC with prior lorlatinib and no prior platinum-based chemotherapy (Cohort 1); with prior lorlatinib and prior platinum-based chemotherapy (Cohort 2); or with no prior lorlatinib (Cohort 3). BRAF V600E mutant CRC participants resistant to BRAFi plus EGFRi (Cohort 4 ); refractory to BRAFi plus EGFRi (Cohort 5); or BRAFi plus EGFRi naïve (Cohort 6). RAS- mutant, NF1-mutant or BRAF class 3 mutant solid tumors who have received prior SOC (Cohort 7). Exclusion Criteria: Brain metastasis larger than 4 cm Active malignancy within 3 years Systemic anti-cancer therapy or small molecule therapeutics within 2 weeks prior to start of study treatment. Antibody based agents within 4 weeks prior to start of study treatment. Mitomycin C or nitrosoureas within 6 weeks prior to start of study treatment. For participants who may get lorlatinib or encorafenib on study, history of interstitial lung disease For participants who may get binimetinib on study, history or current evidence of retinal vein occlusion (RVO) or concurrent neuromuscular disorder associated with elevated creatine kinase (CK)

Ages Eligible for Study
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Minimum Age: 18 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-07284892 monotherapy<br>Monotherapy dose escalation of PF-07284892 in participants with ALK- or ROS1-positive non-small cell lung cancer (NSCLC), B-type Raf proto-oncogene V600E mutation colorectal cancer (CRC), or RAS- mutant, NF1-mutant or BRAF class 3-mutant solid tumors | Drug: PF-07284892<br>* PF-07284892<br>* Other names: ARRY-558;|
| Experimental: PF-07284892 in combination with lorlatinib (Part 2)<br>Combination dose escalation of PF-07284892 in combination with lorlatinib in participants with ALK- or ROS1-positive NSCLC | Drug: PF-07284892<br>* PF-07284892<br>* Other names: ARRY-558;Drug: lorlatinib<br>* lorlatinib<br>* Other names: Lorbrena; PF-06463922, Lorviqua;|
| Experimental: Expansion Phase (Cohort 1)<br>PF-07284892 + lorlatinib in participants with ALK+ NSCLC with prior lorlatinib | Drug: PF-07284892<br>* PF-07284892<br>* Other names: ARRY-558;Drug: lorlatinib<br>* lorlatinib<br>* Other names: Lorbrena; PF-06463922, Lorviqua;|
| Experimental: Expansion Phase (Cohort 2)<br>PF-07284892 + lorlatinib in participants with ALK+ NSCLC with no prior lorlatinib | Drug: PF-07284892<br>* PF-07284892<br>* Other names: ARRY-558;Drug: lorlatinib<br>* lorlatinib<br>* Other names: Lorbrena; PF-06463922, Lorviqua;|
| Experimental: Expansion Phase (Cohort 3)<br>PF-07284892 + encorafenib + cetuximab in participants with BRAF V600E mutant CRC with prior BRAF inhibitor (BRAFi) plus epidermal growth factor receptor inhibitor (EGFRi) | Drug: PF-07284892<br>* PF-07284892<br>* Other names: ARRY-558;Biological: cetuximab<br>* cetuximab<br>* Other names: Erbitux;Drug: encorafenib<br>* encorafenib<br>* Other names: Braftovi, PF-07263896, LGX818;|
| Experimental: Expansion Phase (Cohort 4)<br>PF-07284892 + encorafenib + cetuximab in participants with BRAF V600E mutant CRC with no prior BRAFi plus EGFRi | Drug: PF-07284892<br>* PF-07284892<br>* Other names: ARRY-558;Biological: cetuximab<br>* cetuximab<br>* Other names: Erbitux;Drug: encorafenib<br>* encorafenib<br>* Other names: Braftovi, PF-07263896, LGX818;|
| Experimental: Expansion Phase (Cohort 5)<br>PF-07284892 + binimetinib in participants with RAS- mutant, NF1-mutant or BRAF class 3 mutant solid tumors who have received prior standard of care (SOC) | Drug: PF-07284892<br>* PF-07284892<br>* Other names: ARRY-558;Drug: binimetinib<br>* binimetinib<br>* Other names: Mektovi, PF-06811462, MEK162;|
| Experimental: PF-07284892 in combination with encorafenib and cetuximab (Part 2)<br>Combination dose escalation of PF-07284892 in combination with encorafenib and cetuximab in participants with BRAF V600E mutant CRC | Drug: PF-07284892<br>* PF-07284892<br>* Other names: ARRY-558;Biological: cetuximab<br>* cetuximab<br>* Other names: Erbitux;Drug: encorafenib<br>* encorafenib<br>* Other names: Braftovi, PF-07263896, LGX818;|
| Experimental: PF-07284892 in combination with binimetinib (Part 2)<br>Combination dose escalation of PF-07284892 in combination with binimetinib in participants with Ras-mutant, NF-1 mutant or BRAF class 3 -mutant solid tumors | Drug: PF-07284892<br>* PF-07284892<br>* Other names: ARRY-558;Drug: binimetinib<br>* binimetinib<br>* Other names: Mektovi, PF-06811462, MEK162;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 and Part 2- 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 lorlatinib, encorafenib + cetuximab, or binimetinib. The number of DLTs will be used to determine the maximum tolerated dose (MTD)/recommended dose for further study | Cycle 1 (21 days) | 
| Part 1 and Part 2- 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 | 
| Part 1 and Part 2 - 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 30 days after last dose of study treatment | 
| Part 1 and Part 2 - Number of dose interruptions, dose modifications, and discontinuations due to AEs | Incidence of dose interruptions, dose modifications, and discontinuations due to AEs | Baseline up to 30 days after the last dose of study medication | 
| Part 3- Overall response | Response will be evaluated via radiographical tumor assessments by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) | Baseline to up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 and Part 2- Maximum plasma concentration (Cmax) of PF-07284892 and metabolite | 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 hours postdose); Cycle 1 Day 18 (predose, 1, 2, 4, 6, 8, 24, and 48 hours postdose); Cycle 2-6 Day 1 (predose and 2 hours postdose); Cycle 7-12 Day 1 predose; end of treatment (EOT) | 
| Part 1 and Part 2- Time to reach maximum plasma concentration (Tmax) of PF-07284892 and metabolite | Single dose (Tmax) and multiple dose (assuming steady state is achieved; Tss,max) pharmacokinetic parameters | Cycle 1 Day 1 (predose, 1, 2, 4, 6, 8 hours postdose); Cycle 1 Day 18 (predose, 1, 2, 4, 6, 8, 24, and 48 hours postdose); Cycle 2-6 Day 1 (predose and 2 hours postdose); Cycle 7-12 Day 1 predose; EOT | 
| Part 1 and Part 2- Area under the plasma concentration-time curve from time 0 to the last time point of quantifiable concentration (AUClast) of PF-07284892 and metabolite | Single dose PK parameter | Cycle 1 Day 1 (predose, 1, 2, 4, 6, 8 hours postdose); Cycle 1 Day 18 (predose, 1, 2, 4, 6, 8, 24, and 48 hours postdose); Cycle 2-6 Day 1 (predose and 2 hours postdose); Cycle 7-12 Day 1 predose; EOT | 
| Part 1 and Part 2- Area under the plasma concentration-time curve from time 0 to extrapolated to infinity (AUCinf) of PF-07284892 and metabolite | Single dose and multiple dose (assuming steady state is achieved) PK parameter | Cycle 1 Day 1 (predose, 1, 2, 4, 6, 8 hours postdose); Cycle 1 Day 18 (predose, 1, 2, 4, 6, 8, 24, and 48 hours postdose); Cycle 2-6 Day 1 (predose and 2 hours postdose); Cycle 7-12 Day 1 predose; EOT | 
| Part 1 and Part 2- Metabolite ratio of PF-07284892 and metabolite | Single dose PK parameter | Cycle 1 Day 1 (predose, 1, 2, 4, 6, 8 hours postdose); Cycle 1 Day 18 (predose, 1, 2, 4, 6, 8, 24, and 48 hours postdose); Cycle 2-6 Day 1 (predose and 2 hours postdose); Cycle 7-12 Day 1 predose; EOT | 
| Part 1 and Part 2- Area under the plasma concentration-time curve from 0 to 24 (AUC24) or 48 hours (AUC48) of PF-07284892 and metabolite | Multiple dose (assuming steady state is achieved) PK parameter | Cycle 1 Day 1 (predose, 1, 2, 4, 6, 8 hours postdose); Cycle 1 Day 18 (predose, 1, 2, 4, 6, 8, 24, and 48 hours postdose); Cycle 2-6 Day 1 (predose and 2 hours postdose); Cycle 7-12 Day 1 predose; EOT | 
| Part 1 and Part 2- Overall response | Response will be evaluated via radiographical tumor assessments by RECIST v1.1 | Baseline to up to 2 years | 
| Part 2- Duration of Response (DOR) | Time from the first documentation of objective response to the first documentation of objective progressive disease, relapse or to death due to any cause | Baseline to up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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colorectal cancer, non-small cell lung cancer, B-type Raf proto-oncogene (BRAF) mutation, Ras mutation, anaplastic lymphoma kinase (ALK)-positive, neurofibromatosis type 1 (NF1), ROS1