LGG-22. SJ901: Phase I/II evaluation of single agent mirdametinib (PD-0325901), a brain-penetrant MEK1/2 inhibitor, for the treatment of children, adolescents, and young adults with low-grade glioma (LGG)

Abstract

BACKGROUND: MEK inhibitor trials in pediatric low-grade glioma (pLGG) have yielded promising results, but there remains room for improvement since objective responses are rarely complete and disease recurrence after completion of therapy is common. Mirdametinib (PD-0325901) is a highly selective MEK1/MEK2 inhibitor that, in preclinical studies, has been reported to have superior blood-brain-barrier penetration compared to other MEK inhibitors. As such, we recently launched the SJ901 clinical trial (NCT04923126) to determine the safety, recommended phase 2 dose, pharmacokinetics, and preliminary efficacy of mirdametinib in patients with pLGG when administered continuously. Here, we present preliminary phase 1 data. METHODS: SJ901 is a multi-arm phase I/II trial of mirdametinib in patients >2 and <25 years with LGG. Phase I requires participants to have no prior exposure to MEK inhibitors and recurrent/progressive disease with biopsy-proven evidence of MAPK pathway activation. Three escalating dose levels (2 mg/m2/dose BID, 2.5mg/m2/dose BID and 3mg/m2/dose BID) are planned using a rolling 6 design. RESULTS: Accrual began in June 2021. As of Jan 13, 2022, eleven patients enrolled: 5 on dose level 1 (DL1) and 6 on dose level 2 (DL2). Median age is 10 (3-21) years. Ten patients have somatic gene rearrangements (7 BRAF, 1 MYB, 1 RAF1, 1 FGFR1) and one has an NF1 germline mutation. Four have metastatic disease. No dose-limiting toxicities occurred for DL1 (whereas data are pending for DL2) and only grade 1/2 treatment-related adverse events have been observed. No MEK-related retinopathy or cardiopathy has been observed. Four of the six patients with at least one follow-up disease evaluation have a minor response (>25%-<50% decrease). Median time on therapy is 6.6 (2.2-7) months. No disease progressions have occurred. CONCLUSION: Thus far, mirdametinib is well-tolerated and clinically promising when dosed continuously in patients with recurrent/progressive pLGG. More information will be forthcoming.

Continuous response despite reduced dose of trametinib as single agent in an adolescent with a relapsed disseminated pediatric low-grade glioma KIAA1549-BRAF fusion positive: a case report and review of the literature

“…There are several phase I and II clinical trials involving MEK inhibitors for treating pLGG, including selumetinib ( 20 , 21 , 26 ), trametinib ( 15 – 19 , 23 ), cobimetinib ( 22 ), binimetinib ( 24 ), and mirdametinib ( 25 ). The two most researched about are selumetinib and trametinib.…”

Small Molecule Tyrosine Kinase Inhibitors (TKIs) for Glioblastoma Treatment

“…Mirdametinib 33 (Figure 9), also known as PD-0325901, is a selective MEK1/MEK2 inhibitor, characterized by an effective blood-brain barrier permeability, when compared to other MEK inhibitors. Clinical trial NCT04923126 (still in recruiting phase) was launched to evaluate its safety, preliminary efficacy and PK in patients suffering from pediatric low-grade glioma (pLGG) [168].…”

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“…In contrast, Nf1 mutant mice were in better clinical condition at the end of the trial compared to the placebo group and no T‐ALL development was seen during treatment 69 . In phase 1 clinical trials, mirdametinib appeared to be safe and well tolerated 70,71 . Phase 2 clinical trials in neurofibromatosis type 1 (NF1), gliomas and solid tumors are ongoing.…”

“…69 In phase 1 clinical trials, mirdametinib appeared to be safe and well tolerated. 70,71 Phase 2 clinical trials in neurofibromatosis type 1 (NF1), gliomas and solid tumors are ongoing.…”