Sponsor: Pfizer (industry)
Phase: 1
Start date: Nov. 30, 2022
Planned enrollment: 124
PF-07799933, also known as ARRY-440, is an investigational oral selective ATP-competitive RAF kinase inhibitor developed by Pfizer. It is designed to target BRAF mutations, including Class I (V600), Class II, and Class III alterations, which are implicated in various advanced solid tumors. (ascopubs.org)
PF-07799933 inhibits BRAF signaling by suppressing both monomeric and dimeric forms of mutant BRAF proteins. Unlike approved BRAF inhibitors, it displays significantly less paradoxical activation of wild-type RAF and spares non-BRAF-containing RAF dimers, potentially reducing associated toxicities. Additionally, PF-07799933 is brain-penetrant, addressing a common site for metastases in BRAF-altered cancers. (ascopubs.org)
A Phase 1, open-label, dose escalation and dose expansion study (NCT05355701) is currently underway to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of PF-07799933 as a single agent and in combination with binimetinib or cetuximab in participants aged 16 years and older with advanced solid tumors harboring BRAF alterations. (ichgcp.net)
As of April 30, 2025, no published results from human clinical trials are available to assess the efficacy and safety of PF-07799933. The ongoing Phase 1 study aims to determine the maximum tolerated dose and recommended dose expansion for monotherapy and combination therapy, as well as to evaluate preliminary antitumor activity. (ascopubs.org)
Last updated: Apr 2025
PF-07799544, also known as ARRY-134, is an investigational, brain-penetrant MEK inhibitor developed by Pfizer. It is currently undergoing Phase 1 clinical trials to assess its safety, tolerability, pharmacokinetics, and antitumor activity in individuals aged 16 and older with advanced solid tumors. (ascopubs.org)
PF-07799544 selectively inhibits MEK1 and MEK2, key components of the MAPK signaling pathway. By targeting these kinases, the drug aims to reduce downstream ERK phosphorylation, thereby potentially decreasing tumor cell proliferation. Its ability to cross the blood-brain barrier addresses a significant challenge in treating brain metastases associated with MAPK pathway-driven cancers. (pfizeroncologydevelopment.com)
The ongoing Phase 1 study (NCT05538130) is designed in two parts:
Phase 1a: Evaluates PF-07799544 as a monotherapy in participants with advanced solid tumors who have progressed on standard treatments. The primary goal is to determine the maximum tolerated dose and recommended dose for expansion. (ascopubs.org)
Phase 1b: Assesses PF-07799544 in combination with PF-07799933, a next-generation BRAF dimer inhibitor, in participants with BRAF-mutated solid tumors, including those with brain metastases. This phase includes multiple sub-studies focusing on different BRAF mutation classes and tumor types. (ascopubs.org)
As of now, detailed efficacy and safety data from these trials have not been published. The trials are ongoing, and results are awaited to determine the clinical benefits and safety profile of PF-07799544.
Last updated: Apr 2025
Goal: To assess the safety, tolerability, pharmacokinetics, and preliminary efficacy of PF-07799544, a novel brain-penetrant MEK inhibitor, as monotherapy and in combination with other targeted agents in patients with advanced solid tumors, including subsets of patients with BRAF mutations.
Patients: Adults with advanced or metastatic solid tumors, including primary brain tumors, who have progressed on standard treatments or have no satisfactory alternative options. Specific expansion cohorts include patients with melanoma harboring BRAF V600 or non-V600 class II/III alterations, and other solid tumors with BRAF class II/III mutations.
Design: This is a non-randomized, open-label, multi-arm phase 1 trial with both dose escalation and expansion cohorts. Participants receive either PF-07799544 alone or in combination with other investigational agents, with allocation depending on tumor type and molecular alterations.
Treatments: The study evaluates PF-07799544, an oral, brain-penetrant MEK inhibitor with preclinical and early-phase evidence of activity against tumors with alterations in the RAS/RAF/MEK/ERK pathway. PF-07799544 specifically targets MEK and is administered as a tablet, initially twice daily. In combination arms, the study also investigates PF-07799933, a brain-penetrant, selective pan-mutant BRAF inhibitor with activity against all classes of BRAF mutations. No definitive human efficacy data for PF-07799544 exist yet, though its ability to penetrate the CNS is of particular interest, especially for tumors with brain involvement. Encorafenib, a standard oral BRAF inhibitor, is also used in certain arms, specifically in patients with melanoma.
Outcomes: Primary endpoints include assessment of dose-limiting toxicities, adverse events (AEs), laboratory and vital sign abnormalities, and overall response rate (ORR, by RECIST v1.1) in dose expansion cohorts. Secondary endpoints include PK parameters for both PF-07799544 and PF-07799933, further safety measures, duration of response (including intracranial responses), and progression-free survival.
Burden on patient: Patient burden is expected to be high, typical for a phase 1 trial. Participants will undergo frequent clinic visits for safety assessments, laboratory tests, pharmacokinetic blood sampling, and radiographic tumor evaluations. Participation may also require tumor biopsies for molecular characterization or response assessment. The necessity for protocol-specific PK sampling and possibly additional scans, particularly for assessment of brain metastases, increases visit frequency and blood loss compared to standard care.
Inclusion Criteria:
* Diagnosis of advanced/metastatic solid tumor including primary brain tumor for monotherapy phase 1a dose escalation
* Disease progressed during/following last prior treatment and no satisfactory alternative treatment options for monotherapy phase 1a dose escalation
* For Substudy B, histological or cytological diagnosis of advanced/metastatic melanoma
* For Substudy C, unresectable or adv/metastatic solid tumor progressed on, or with demonstrated intolerance to SOC, excluding melanoma,
* For Substudy B and C, measurable disease by RECIST version 1.1
* For Substudy B, evidence of a BRAF V600 mutation or BRAF Class II/III alteration in tumor tissue and/or blood
* For Substudy C, evidence of a BRAF founder alteration (non-V600 Class II/III BRAF alteration)
Exclusion Criteria:
* Brain metastasis larger than 4 cm
* History or current evidence of retinal vein occlusion (RVO) or concurrent neuromuscular disorder associated with elevated creatine kinase (CK)
Edmonton, Alberta, T6G 1Z2, Canada
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Ottawa, Ontario, K1H 8L6, Canada
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Toronto, Ontario, M4N 3M5, Canada
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Toronto, Ontario, M5G 2M9, Canada
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Montreal, Quebec, H3T 1E2, Canada
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Quebec City, Quebec, G1J 1Z4, Canada
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Montréal, Quebec, H4A 3J1, Canada
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Beer-Sheva, Hadarom, 8410101, Israel
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Ramat Gan, Hamerkaz, 5265601, Israel
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Petah Tikva, Hamerkaz, 4941492, Israel
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Tel Aviv, Tell Abīb, 6423906, Israel
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Jerusalem, Yerushalayim, 9112001, Israel
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Fayetteville, Arkansas, 72703, United States
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Rogers, Arkansas, 72758, United States
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Springdale, Arkansas, 72762, United States
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Los Angeles, California, 90025, United States
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Santa Monica, California, 90404, United States
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Tampa, Florida, 33612, United States
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Tampa, Florida, 33612, United States
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Tampa, Florida, 33612, United States
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Boston, Massachusetts, 02215, United States
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Boston, Massachusetts, 02215, United States
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Boston, Massachusetts, 02115, United States
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Detroit, Michigan, 48202, United States
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Detroit, Michigan, 48202, United States
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Basking Ridge, New Jersey, 07920, United States
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Middletown, New Jersey, 07748, United States
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Montvale, New Jersey, 07645, United States
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New York, New York, 10032, United States
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New York, New York, 10032, United States
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New York, New York, 10032, United States
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New York, New York, 10065, United States
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Richmond Hill, New York, 11418, United States
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Uniondale, New York, 11553, United States
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Westbury, New York, 11590, United States
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New York, New York, 10022, United States
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Harrison, New York, 10604, United States
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Commack, New York, 11725, United States
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Brewster, New York, 10509, United States
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Cleveland, Ohio, 44106, United States
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Cleveland, Ohio, 44195, United States
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Portland, Oregon, 97213, United States
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Portland, Oregon, 97213, United States
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Nashville, Tennessee, 37203, United States
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Nashville, Tennessee, 37203, United States
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Houston, Texas, 77030, United States
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Seattle, Washington, 98195, United States
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Seattle, Washington, 98109, United States
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