A Phase 1/2 Study of the Safety and Tolerability of MT-125 in GBM Patients

MT-125 is a potent, selective, and central nervous system (CNS) permeable dual small molecule inhibitor of the non-muscle myosin II (NMII) paralogs, IIA and IIB. MT-125 is being developed by Myosin Therapeutics Inc. as a potential treatment for glioblastoma (GBM). NMIIs are molecular motor ATPases that act directly on actin to regulate the cytoskeleton's control of cellular processes such as movement, division, signaling and mitochondrial biology. As a result, simultaneous inhibition of NMIIA and IIB with MT-125 interferes with tumor cell proliferation, invasion and metastasis, while also generating reactive oxygen species (ROS) in tumor cells. The latter is due to the role of NMII in mitochondrial quality control and underlies the synergistic survival benefit observed in preclinical studies when MT-125 and radiation therapy (RT) are combined. Additionally, NMIIA is upregulated in several types of cancer, including GBM, speaking to its importance in cancer physiology and making these tumor cells highly sensitive to its inhibition. The focus of this first-in-human (FIH) clinical study is GBM. Patients with GBM have a poor prognosis, and there have been no new Food and Drug Administration (FDA) approved drugs for these patients since 2008, when bevacizumab was approved. The current well-known standard of care for newly diagnosed GBM is maximal safe surgical resection followed by concurrent RT with temozolomide (TMZ). O6-methylguanine- DNA methyltransferase (MGMT) promoter methylation status is the most predictive biomarker for TMZ responsiveness, where patients with unmethylated MGMT do not respond to TMZ. There is, therefore, an urgent unmet need for effective systemic therapy in patients with unmethylated MGMT. MT-125 significantly prolongs survival as a monotherapy in animal models and is synergistic with both RT and with FDA-approved oncogenic kinase inhibitors to further enhance survival. In order to develop highly effective combinations of MT-125 with other pharmacologic therapies, we will start with an evaluation of MT-125 as a monotherapy in a first-in-human (FIH) Phase 1 trial with RT in newly diagnosed isocitrate dehydrogenase (IDH) wild type / MGMT unmethylated GBM. In the pivotal 28-day nonclinical safety studies, no dose-limiting toxicities (DLT) or adverse effects (AE) were noted in any of the parameters evaluated (clinical observations, functional endpoints, clinical pathology, macroscopic and histologic tissue assessments) at doses up to the NOAELs, 20 mg/kg/day and 30 mg/kg/day in dogs and rats, respectively, which yielded systemic MT-125 exposures 10- to 16-fold greater than efficacious exposures in pharmacodynamic in vivo models. As the NOAELs in both studies were below the STD10 (rats) and HNSTD (dogs), the calculated safety margins are conservative. Here we will perform a FIH monotherapy trial in newly diagnosed IDH wild type/ MGMT unmethylated GBM with RT. The goal of this FIH, Phase 1, single arm MT-125 dose escalation study is to evaluate the safety and tolerability of MT-125 administered 5 consecutive days per week with 2 days off for the 6 weeks of outpatient RT. Participants with newly diagnosed GBM with histologically or molecularly confirmed IDH wild type and MGMT unmethylated will be eligible to enroll. We have chosen this subpopulation of patients, as they do not historically benefit from TMZ therapy, which justifies not including treatment with this alkylator in the clinical trial. The DLT observation window will be 6 weeks following first treatment administration, and a Bayesian Optimal Interval (BOIN) trial design will be used to efficiently evaluate up to four dose levels. Secondary endpoints for this Phase 1 study will include determining the maximum tolerated dose (MTD), which will contribute to the selection of the recommended phase 2 dose (RP2D) and evaluating the systemic pharmacokinetics (PK) of MT-125. Once the MTD is determined, additional participants will be enrolled into a randomized, parallel dose expansion cohort, consisting of up to 2 potential doses of MT-125. The dose levels for the expansion cohort will be selected as the MTD and the dose below the MTD. Overall response rate (ORR) in those participants with measurable disease, progression-free survival (PFS6) in all participants, and Overall Survival (OS) in all participants are included as exploratory endpoints. If no MTD is identified within the initially defined dose range and all tested doses are deemed well-tolerated based on the observed DLTs, the study may be paused temporarily to allow consideration of dose levels beyond those originally planned.