A Study to Learn About the Study Medicine Called PF-07799933 in People With Advanced Solid Tumors.

Study Overview
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Brief Summary
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The purpose of this clinical trial is to learn about the safety and effects of the study medicine (called PF-07799933) administered as a single agent and in combination with other study medicines (called binimetinib and cetuximab) in people with solid tumors. This study is seeking participants who have an advanced solid tumor with a certain type of abnormal gene called BRAF and available treatments are no longer effective in controlling their cancer. All participants in this study will receive PF-07799933. PF-07799933 comes as a tablet to take by mouth, 1 or 2 times a day. Depending on the part of the study, participants may also receive another study medicine: People with melanoma or other solid tumors may also receive binimetinib. Binimetinib comes as a tablet to take by mouth, 2 times a day. People with colorectal cancer may also receive cetuximab. Cetuximab will be given weekly (or every two weeks) in the clinic as a shot given in the vein or port (intravenous, IV). Participants may receive the study medicines for about 2 years. The study team will monitor how each participant is doing with the study treatment during regular visits at the study clinic.

Official Title
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A PHASE 1, OPEN-LABEL, DOSE ESCALATION AND DOSE EXPANSION STUDY TO EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND ANTI TUMOR ACTIVITY OF PF-07799933 (ARRY-440) AS A SINGLE AGENT AND IN COMBINATION THERAPY IN PARTICIPANTS 16 YEARS AND OLDER WITH ADVANCED SOLID TUMORS WITH BRAF ALTERATIONS

Conditions
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Melanoma, Colorectal Cancer, Non-Small-Cell Lung Cancer, Thyroid Cancer, Glioma

Intervention / Treatment
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* Drug: PF-07799933
* Drug: binimetinib
* Biological: cetuximab


Participation Criteria
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Eligibility Criteria
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This study is seeking participants who meet the following eligibility criteria: Inclusion Criteria: Diagnosis of advanced/metastatic solid tumor including primary brain tumor. Qualifying BRAF alteration (V600 or non-V600 Class II/Class III BRAF alteration), in tumor tissue and/or blood (ie circulating tumor deoxyribonucleic acid [DNA], or ctDNA). Disease progressed during/following last prior treatment and no satisfactory alternative treatment options (Part 1 and Part 2). Tumor specific cohorts (melanoma, colorectal cancer) must have received specific prior approved therapies Exclusion Criteria: Brain metastasis larger than 4 cm Systemic anti-cancer therapy or small molecule therapeutics ongoing at the start of study treatment. 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: 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: Monotherapy dose escalation (Part 1)<br>Participants will receive PF-07799933 | Drug: PF-07799933<br>* Tablet<br>* Other names: ARRY-440;|
| Experimental: Combination dose escalation (Part 2)<br>Participants will receive PF-07799933 in combination with binimetinib or cetuximab | Drug: PF-07799933<br>* Tablet<br>* Other names: ARRY-440;Drug: binimetinib<br>* Tablet<br>* Other names: Mektovi, PF-06811462, MEK162;Biological: cetuximab<br>* Injection for intravenous use<br>* Other names: Erbitux;|
| Experimental: Dose expansion (Part 3) - Tumor and mutation specific Cohort 1<br>Participants will receive PF-07799933 | Drug: PF-07799933<br>* Tablet<br>* Other names: ARRY-440;|
| Experimental: Dose expansion (Part 3) - Tumor and mutation specific Cohort 2<br>Participants will receive PF-07799933 in combination with binimetinib | Drug: PF-07799933<br>* Tablet<br>* Other names: ARRY-440;Drug: binimetinib<br>* Tablet<br>* Other names: Mektovi, PF-06811462, MEK162;|
| Experimental: Dose expansion (Part 3) - Tumor and mutation specific Cohort 3<br>Participants will receive PF-07799933 | Drug: PF-07799933<br>* Tablet<br>* Other names: ARRY-440;|
| Experimental: Dose expansion (Part 3) - Tumor and mutation specific Cohort 4<br>Participants will receive PF-07799933 in combination with cetuximab | Drug: PF-07799933<br>* Tablet<br>* Other names: ARRY-440;Biological: cetuximab<br>* Injection for intravenous use<br>* Other names: Erbitux;|
| Experimental: Dose expansion (Part 3) - Tumor and mutation specific Cohort 5<br>Participants will receive PF-07799933 in combination with cetuximab | Drug: PF-07799933<br>* Tablet<br>* Other names: ARRY-440;Biological: cetuximab<br>* Injection for intravenous use<br>* Other names: Erbitux;|
| Experimental: Dose expansion (Part 3) - Basket Cohort 6<br>Participants will receive PF-07799933 in combination with binimetinib or cetuximab | Drug: PF-07799933<br>* Tablet<br>* Other names: ARRY-440;Drug: binimetinib<br>* Tablet<br>* Other names: Mektovi, PF-06811462, MEK162;Biological: cetuximab<br>* Injection for intravenous use<br>* Other names: Erbitux;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with dose limiting toxicities (DLTs) (Part 1 and Part 2) | DLTs will be evaluated during the first cycle (21 days) as both a single agent or in combination with binimetinib or cetuximab | Cycle 1 (21 days) | 
| Number of participants with treatment-emergent adverse events (AEs) (Part 1 and Part 2) | AEs as characterized by type, frequency, severity, timing, seriousness, and relationship to study therapy | Baseline to 28 days after last dose of study medication | 
| Number of participants with clinically significant change from baseline in laboratory abnormalities (Part 1 and Part 2) | Laboratory abnormalities as characterized by type, frequency, severity, and timing | Baseline to 28 days after last dose of study treatment | 
| Number of participants with clinically significant change from baseline in vital sign abnormalities (Part 1 and Part 2) | Vital sign abnormalities as characterized by type, frequency, severity, and timing | Baseline to 28 days after last dose of study treatment | 
| Dose interruptions due to AEs (Part 1 and Part 2) | Incidence of dose interruptions due to AEs | Baseline to 2 years | 
| Dose dose modifications due to AEs (Part 1 and Part 2) | Incidence of dose modifications due to AEs | Baseline to 2 years | 
| Discontinuations due to AEs (Part 1 and Part 2) | Incidence of discontinuations due to AEs | Baseline to 2 years | 
| MTD (Part 1 and Part 2) | Maximum tolerated dose (MTD) | Cycle 1 (21 days) | 
| RDE (Part 1 and Part 2) | Recommended dose for expansion (RDE) | Cycle 1 (21 days) | 
| Overall response rate (ORR) (Part 3) | Response will be evaluated via radiographical tumor assessments by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) | Baseline to 2 years | 
| Number of participants with clinically significant physical exam abnormalities (Part 1 and Part 2) | Physical exam abnormalities as as graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 | Baseline to 28 days after last dose of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 and Part 2: ORR | ORR as assessed using the RECIST version 1.1. | Baseline to 2 years | 
| Part 1/2/3: Intracranial response | Intracranial response by RECIST version 1.1 (for brain metastases) & Response Assessment in Neuro-Oncology (RANO) - for primary brain tumors). | Baseline to 2 years | 
| Part 1 and Part 2: Duration of response | Duration of response | Baseline to 2 years | 
| Part 3: Number of participants with treatment-emergent adverse events (AEs) | AEs as characterized by type, frequency, severity, timing, seriousness, and relationship to study therapy | Baseline to 2 years | 
| Part 3: Number of participants with clinically significant change from baseline in laboratory abnormalities | Laboratory abnormalities as characterized by type, frequency, severity, and timing | Baseline to 2 years | 
| Part 3: Number of participants with clinically significant change from baseline in vital sign abnormalities | Vital sign abnormalities as characterized by type, frequency, severity, and timing | Baseline to 2 years | 
| Part 3: Dose interruptions due to AEs | Incidence of dose interruptions due to AEs | Baseline to 2 years | 
| Part 3: Dose dose modifications due to AEs | Incidence of dose modifications due to AEs | Baseline to 2 years | 
| Part 3: Discontinuations due to AEs | Incidence of discontinuations due to AEs | Baseline to 2 years | 
| Part 3: Time to event endpoints in each combination | Time to event endpoints in each combination | Baseline to 2 years | 
| Part 3: Disease Control Rate (DCR) | DCR | Baseline to 2 years | 
| Part 1/2/3: PK parameters of PF-07799933, Single dose, maximum observed concentration (Cmax) | PK parameters of PF-07799933, Single dose, Cmax | Baseline to 2 years | 
| Part 1/2/3: PK parameters of PF-07799933, Single dose, time to maximum plasma concentration (Tmax) | PK parameters of PF-07799933, Single dose, Tmax | Baseline to 2 years | 
| Part 1/2/3: PK parameters of PF-07799933, Single dose, area under the plasma concentration-time curve from time 0 to the last time point of quantifiable concentration (AUClast) | PK parameters of PF-07799933, Single dose, AUClast | Baseline to 2 years | 
| Part 1/2/3: PK parameters of PF-07799933, Single dose, area under plasma concentration-time curve over 24 hours (AUC24) | PK parameters of PF-07799933, Single dose, AUC24 | Baseline to 2 years | 
| Part 1/2/3: PK parameters of PF-07799933, Single dose, area under plasma concentration-time curve over 48 hours (AUC48) | PK parameters of PF-07799933, Single dose, AUC48 | Baseline to 2 years | 
| Part 1/2/3: PK parameters of PF-07799933, Single dose, terminal elimination half life (t½) | PK parameters of PF-07799933, Single dose, t½ | Baseline to 2 years | 
| Part 1/2/3: PK parameters of PF-07799933, Single dose, area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUCinf) | PK parameters of PF-07799933, Single dose, AUCinf | Baseline to 2 years | 
| Part 1/2/3: PK parameters of PF-07799933, Single dose, apparent oral clearance (CL/F) | PK parameters of PF-07799933, Single dose, CL/F | Baseline to 2 years | 
| Part 1/2/3: PK parameters of PF-07799933, Single dose, apparent volume of distribution (Vz/F) | PK parameters of PF-07799933, Single dose, Vz/F | Baseline to 2 years | 
| Part 1/2/3: PK parameters of PF-07799933, Multiple dose, maximum observed concentration (Cmax) | PK parameters of PF-07799933, Multiple dose, Cmax | Baseline to 2 years | 
| Part 1/2/3: PK parameters of PF-07799933, Multiple dose, trough plasma or serum concentration (Ctrough) | PK parameters of PF-07799933, Multiple dose, Ctrough | Baseline to 2 years | 
| Part 1/2/3: PK parameters of PF-07799933, Multiple dose, time to maximum plasma concentration (Tmax) | PK parameters of PF-07799933, Multiple dose, Tmax | Baseline to 2 years | 
| Part 1/2/3: PK parameters of PF-07799933, Multiple dose, area under the plasma concentration-time curve over the dosing interval (AUCτ) | PK parameters of PF-07799933, Multiple dose, AUCτ | Baseline to 2 years | 
| Part 1/2/3: PK parameters of PF-07799933, Multiple dose, CL/F | PK parameters of PF-07799933, Multiple dose, CL/F | Baseline to 2 years | 
| Part 1/2/3: PK parameters of PF-07799933, Multiple dose, average plasma concentration (Cav) | PK parameters of PF-07799933, Multiple dose, Cav | Baseline to 2 years | 
| Part 1/2/3: PK parameters of PF-07799933, Multiple dose, peak-to-trough ratio (PTR) | PK parameters of PF-07799933, Multiple dose, PTR | Baseline to 2 years | 
| Part 1/2/3: PK parameters of PF-07799933, Multiple dose, accumulation ratio (Rac) | PK parameters of PF-07799933, Multiple dose, Rac (AUCτ /AUCsd,τ) | Baseline to 2 years | 
| Part 1/2/3: PK parameters of PF-07799933, Multiple dose, t1/2 | PK parameters of PF-07799933, Multiple dose, t1/2 | Baseline to 2 years | 
| Part 1/2/3: PK parameters of PF-07799933, Multiple dose, Vz/F | PK parameters of PF-07799933, Multiple dose, Vz/F | Baseline to 2 years | 
| Part 3: PK parameters of cytochrome P450 (CYP)3A4 probe substrate midazolam, Cmax | PK parameters of CYP3A4 probe substrate midazolam, Cmax | Baseline to 2 years | 
| Part 3: PK parameters of CYP3A4 probe substrate midazolam, Tmax | PK parameters of CYP3A4 probe substrate midazolam, Tmax | Baseline to 2 years | 
| Part 3: PK parameters of CYP3A4 probe substrate midazolam, AUClast | PK parameters of CYP3A4 probe substrate midazolam, AUClast | Baseline to 2 years | 
| Part 3: PK parameters of CYP3A4 probe substrate midazolam, t½ | PK parameters of CYP3A4 probe substrate midazolam, t½ | Baseline to 2 years | 
| Part 3: PK parameters of CYP3A4 probe substrate midazolam, AUCinf | PK parameters of CYP3A4 probe substrate midazolam, AUCinf | Baseline to 2 years | 
| Part 3: PK parameters of CYP3A4 probe substrate midazolam, CL/F | PK parameters of CYP3A4 probe substrate midazolam, CL/F | Baseline to 2 years | 
| Part 3: PK parameters of CYP3A4 probe substrate midazolam, Vz/F | PK parameters of CYP3A4 probe substrate midazolam, Vz/F | Baseline to 2 years | 
| Part 3: TTR | Time to response (TTR) | Baseline to 2 years | 
| Part 3: DOR | Duration of response (DOR) | Baseline to 2 years | 
| Part 3: PFS | Progression-free survival (PFS) | Baseline to 2 years | 
| Part 3: OS | Overall survival (OS) | Baseline to 2 years | 
| Number of participants with clinically significant physical exam abnormalities (Part 3) | Physical exam abnormalities as as graded by NCI CTCAE version 5.0 | Baseline to 28 days after last dose of study medication |