A Phase 1/2 Study of Safety and Tolerability of MT-125 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).

Sex

All

Minimum age

18 Years

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.

• BACKGROUNDLiu 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. . : . .
• BACKGROUNDYuan 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. PMID 27407096
• BACKGROUNDKenchappa 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. PMID 40499543
• BACKGROUNDMelhem 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. PMID 35641844
• BACKGROUNDHegi 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. PMID 15758010
• BACKGROUNDHegi 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. PMID 30514777
• BACKGROUNDStupp 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.