A Phase 1/2 Study of Safety and Tolerability of MT-125 With Chemoradiation in Patients With Newly Diagnosed MGMT Methylated Glioblastoma (NOVA-GBM)

A Phase 1/2 Dose Escalation and Randomized Expansion Study of Safety, Tolerability, and Pharmacokinetics of MT-125 Monotherapy With Chemoradiation in Patients With Newly Diagnosed MGMT Methylated Glioblastoma

This is a Phase 1, single-arm MT-125 dose escalation study followed by a Phase 2, randomized parallel design dose expansion phase, to determine the safety and tolerability of MT-125 administered 5 consecutive days a week with 2 days off for the 6 weeks of outpatient treatment of Radiotherapy (RT) plus TMZ. Participants with newly diagnosed histologically or molecularly confirmed IDH wild type and MGMT methylated GBM will be eligible to enroll. The dose-limiting toxicity (DLT) observation window will be 6 weeks, starting with the first dose of MT-125 administration and chemoradiation. A Bayesian Optimal Interval (BOIN) adaptive trial design will be used to efficiently evaluate up to four dose levels. Secondary endpoints for this Phase 1/2 study will include determination of the MTD, the systemic PK of MT-125, and the RP2D of MT-125. Once the MTD is defined, additional participants will be enrolled as part of an expansion cohort, with a randomized parallel design, which will include up to 2 dose levels which are expected to be MTD and one dose below the MTD. Up to 36 participants will be enrolled in the study (up to 24 participants in the dose escalation phase and up to a total of 12 participants maximum per dose level for the two expansion cohorts).

Study Overview

• Status: Not yet recruiting
• Conditions: Glioblastoma
• Intervention / Treatment: Drug: MT-125

Detailed Description

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 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.

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. The Sponsor is currently evaluating MT-125 as a monotherapy in a first-in-human (FIH) trial (STAR-GBM) with standard of care RT in newly diagnosed isocitrate dehydrogenase (IDH) wildtype / MGMT unmethylated GBM. Due to the poor response of MGMT unmethylated tumors to TMZ, the chemotherapeutic is excluded in the STAR-GBM trial. Here we will evaluate MT-125 as a monotherapy in a Phase 1/2 trial (NOVA-GBM) in newly diagnosed IDH wildtype / MGMT methylated GBM with standard of care RT and TMZ, following the standard chemoradiation treatment regimen.

In the pivotal 28-day nonclinical safety studies of MT-125, 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.

The goal of this Phase 1/2, MT-125 dose escalation and expansion 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 plus TMZ. Participants with newly diagnosed GBM with histologically or molecularly confirmed IDH wildtype and MGMT methylation will be eligible to enroll. 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 1/2 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.

• Study Type: Interventional
• Enrollment (Estimated): 36
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Hospital
      • Contact: Clinical Trials Referral Office; Phone Number: 855-776-0015; Email: mayocliniccancerstudies@mayo.edu
      • Principal Investigator: Shannon F Fortin-Ensign, MD, PhD
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Hospital
      • Contact: Clinical Trials Referral Office; Phone Number: 855-776-0015; Email: mayocliniccancerstudies@mayo.edu
      • Principal Investigator: Wendy J Sherman, MD
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Hospital
      • Contact: Clinical Trials Referral Office; Phone Number: 855-776-0015; Email: mayocliniccancerstudies@mayo.edu
      • Principal Investigator: Ugur Sener, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥18 years at the time of signing the informed consent form (ICF).
2. New Diagnosed with histologically or molecularly confirmed IDH wildtype and MGMT methylated GBM.
3. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1 or 2..

4. The following laboratory values obtained ≤15 days prior to registration:

   1. Hemoglobin ≥9.0 g/dL
   2. Absolute neutrophil count (ANC) ≥1500/mm3
   3. Platelet count ≥100,000/mm3
   4. Total bilirubin ≤1.5 x upper limit of normal (ULN)
   5. Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤3 x ULN (or ≤5 x ULN for participants with liver involvement)
   6. Prothrombin time (PT)/ International normalized ratio (INR)/ Activated partial thromboplastin time (aPTT) ≤1.5 x ULN OR if participant is receiving anticoagulant therapy and INR or aPTT is within target range of therapy
   7. Serum eGFR ≥60 ml/min
5. QTc 470 ms on triplicate 12 lead ECG ≤29 days prior to registration. NOTE: QTc intervals will be corrected using Fridericia's formula (Fridericia 1920)
6. Echocardiographic Assessment: Left Ventricular Ejection Fraction (LVEF) ≥ 55%.

7. Negative serum pregnancy test done ≤7 days prior to first dose of MT-125 administration, for persons of childbearing potential only.

   a. If >7 days between last test and first dose of study treatment, the serum pregnancy test will be repeated.

8. Has provided written informed consent.
9. Ability to complete questionnaire(s) by themselves or with assistance.
10. Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).
11. On a stable dose of steroids for at least 2 weeks prior to enrollment

Exclusion Criteria:

1. Any of the following because this study involves an investigational agent, the genotoxic, mutagenic, and teratogenic effects of which on the developing fetus and newborn are unknown:

   1. Pregnant persons
   2. Nursing persons
   3. Persons of childbearing potential and persons able to father a child who are unwilling to employ adequate contraception (see Appendix 2 for highly effective forms of contraception)
2. Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the participant inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
3. Receiving any other investigational agent.
4. Any concomitant disease, condition, or treatment that could interfere with the conduct of the study, or that would, in the opinion of the Investigator or Sponsor, pose an unacceptable risk to the participant in the study or interfere with the interpretation of study data.
5. Other active malignancy requiring therapy such as RT, chemotherapy, or immunotherapy. Participants on hormonal therapy for treated breast or prostate cancer are permitted if they meet other eligibility criteria. NOTE: Participants with malignancies under active surveillance are still eligible.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MT-125 at 25 mg; Up to 6 participants will receive 25 mg of MT-125 for 5 days then off for 2 days for a total of 6 weeks in combination of RT plus TMZ	Drug: MT-125; This is an investigational new drug under IND 170975.
Experimental: MT-125 at 50 mg; Up to 6 participants will receive 50 mg of MT-125 for 5 days then off for 2 days for a total of 6 weeks in combination of RT plus TMZ	Drug: MT-125; This is an investigational new drug under IND 170975.
Experimental: MT-125 at 83.5 mg; Up to 6 participants will receive 83.5 mg of MT-125 for 5 days then off for 2 days for a total of 6 weeks in combination of RT plus TMZ	Drug: MT-125; This is an investigational new drug under IND 170975.
Experimental: MT-125 at 100 mg; Up to 6 participants will receive 100 mg of MT-125 for 5 days then off for 2 days for a total of 6 weeks in combination of RT plus TMZ	Drug: MT-125; This is an investigational new drug under IND 170975.
Experimental: MT-125 at MTD and one dose lower than MTD; Participants will be randomized to receive either MTD or one dose lower than MTD for 5 days, then off 2 days for a total of 6 weeks in combination with RT plus TMZ	Drug: MT-125; This is an investigational new drug under IND 170975.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose Limiting Toxicity Measurement	The dose escalation portion of this study will follow a BOIN design with cohorts containing a min of 3 DLT evaluable participants. If the observed DLT rate at the current dose is ≤0.236, then the decision will be to escalate the dose to the next higher dose level; if the observed DLT rate at the current dose is >0.359, then the decision will be to deescalate the dose to the next lower dose level; otherwise, the decision will be to stay at the current dose level.	Day 1 through 6 weeks of treatment
Incidence and Severity of AEs	Incidence and Severity, attribution, grade and type of AE will be assessed based on the NCI CTCAE v5.	Day 1 through 6 weeks of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerated Dose	To determine the maximum tolerated dose (MTD) of MT-125	Day 1 through Day 40
PK Parameters - T1/2	Time required for plasma concentrations of a drug to decrease by 50%	Completed on study days; Day 1, Day 2, Day 5, Day 19, Day 33 and Day 40
Determine the phase 2 dose	To determine the Recommended Phase 2 Dose (RP2D) of MT-125	Day 1 through 6 weeks of treatment
PK Parameters- Cmax	The time it takes for a drug to reach a maximum concentration after administration.	Completed on study days; Day 1, Day 2, Day 5, Day 19, Day 33 and Day 40
PK Parameters-AUC 0-24hr	Area under the plasma concentration-time curve over the last 24 hour dosing interval.	Completed on study days; Day 1, Day 2, Day 5, Day 19, Day 33 and Day 40
PK Parameters - CL	CL will quantify the body's efficiency in eliminating MT-125	Completed on study days; Day 1, Day 2, Day 5, Day 19, Day 33 and Day 40
PK Parameters - Vss	The steady state volume of distribution that describes how MT-125 distributes throughout the body once it has reached a state of equilibrium.	Completed on study days; Day 1, Day 2, Day 5, Day 19, Day 33 and Day 40

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
To obtain preliminary data on clinical efficacy measurements such as ORR	Overall Response Rate in those with Measurable disease	Day 1 though on average one year following completion of treatment
Exploratory Analysis to obtain preliminary data on clinical efficacy	6 month Progression Free survival (PFS6) based on MRI imaging	Up to 1 year following completion of treatment
To obtain preliminary data on clinical efficacy	Overall Survival (OS)	Day 1 though on average one year following completion of treatment.

Collaborators and Investigators

• Sponsor: Myosin Therapeutics Inc.
• Collaborators: Mayo Clinic

Publications and helpful links

General Publications

• Yuan Y, Hess KR, Hilsenbeck SG, Gilbert MR. Bayesian Optimal Interval Design: A Simple and Well-Performing Design for Phase I Oncology Trials. Clin Cancer Res. 2016 Sep 1;22(17):4291-301. doi: 10.1158/1078-0432.CCR-16-0592. Epub 2016 Jul 12.
• Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96. doi: 10.1056/NEJMoa043330.
• Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, Degroot J, Wick W, Gilbert MR, Lassman AB, Tsien C, Mikkelsen T, Wong ET, Chamberlain MC, Stupp R, Lamborn KR, Vogelbaum MA, van den Bent MJ, Chang SM. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol. 2010 Apr 10;28(11):1963-72. doi: 10.1200/JCO.2009.26.3541. Epub 2010 Mar 15.
• Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005 Mar 10;352(10):997-1003. doi: 10.1056/NEJMoa043331.
• Hegi ME, Genbrugge E, Gorlia T, Stupp R, Gilbert MR, Chinot OL, Nabors LB, Jones G, Van Criekinge W, Straub J, Weller M. MGMT Promoter Methylation Cutoff with Safety Margin for Selecting Glioblastoma Patients into Trials Omitting Temozolomide: A Pooled Analysis of Four Clinical Trials. Clin Cancer Res. 2019 Mar 15;25(6):1809-1816. doi: 10.1158/1078-0432.CCR-18-3181. Epub 2018 Dec 4.
• Melhem JM, Detsky J, Lim-Fat MJ, Perry JR. Updates in IDH-Wildtype Glioblastoma. Neurotherapeutics. 2022 Oct;19(6):1705-1723. doi: 10.1007/s13311-022-01251-6. Epub 2022 May 31.
• Kenchappa RS, Radnai L, Young EJ, Zarco N, Lin L, Dovas A, Meyer CT, Haddock A, Hall A, Toth K, Canoll P, Nagaiah NKH, Rumbaugh G, Cameron MD, Kamenecka TM, Griffin PR, Miller CA, Rosenfeld SS. MT-125 inhibits non-muscle myosin IIA and IIB and prolongs survival in glioblastoma. Cell. 2025 Aug 21;188(17):4622-4639.e19. doi: 10.1016/j.cell.2025.05.019. Epub 2025 Jun 10.
• Liu S, Yuan Y. Bayesian optimal interval designs for phase I clinical trials. Journal of the Royal Statistical Society: Series C (Applied Statistics). 2015;64(3):507-23. . : . .

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): March 1, 2027

Study Registration Dates

• First Submitted: May 18, 2026
• First Submitted That Met QC Criteria: May 18, 2026
• First Posted (Actual): May 22, 2026

Study Record Updates

• Last Update Posted (Actual): May 22, 2026
• Last Update Submitted That Met QC Criteria: May 18, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: GBM; Glioblastoma; newly diagnosed; IDH wild type; small molecule; MT-125; O6-methylguanine- DNA methyltransferase; isocitrate dehydrogenase (IDH) wild type; non-muscle myosin II; MGMT methylated GBM
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma
• Other Study ID Numbers: MT-125-GBM-201; 26C19 (Other Grant/Funding Number: Florida Cancer Innovation Fund)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No