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

Официальное название

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

Обзор

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).

Подробное описание

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.

Вмешательства

• Препарат MT-125
  This is an investigational new drug under IND 170975.

Первичные конечные точки

• Dose Limiting Toxicity Measurement [Срок оценки: Day 1 through 6 weeks of treatment]
• Incidence and Severity of AEs [Срок оценки: Day 1 through 6 weeks of treatment]

Вторичные конечные точки (7)

• Maximum Tolerated Dose [Срок оценки: Day 1 through Day 40]
• PK Parameters- Cmax [Срок оценки: Completed on study days; Day 1, Day 2, Day 5, Day 19, Day 33 and Day 40]
• PK Parameters-AUC 0-24hr [Срок оценки: Completed on study days; Day 1, Day 2, Day 5, Day 19, Day 33 and Day 40]
• PK Parameters - T1/2 [Срок оценки: Completed on study days; Day 1, Day 2, Day 5, Day 19, Day 33 and Day 40]
• PK Parameters - CL [Срок оценки: Completed on study days; Day 1, Day 2, Day 5, Day 19, Day 33 and Day 40]
• PK Parameters - Vss [Срок оценки: Completed on study days; Day 1, Day 2, Day 5, Day 19, Day 33 and Day 40]
• Determine the phase 2 dose [Срок оценки: Day 1 through 6 weeks of treatment]

Критерии участия

Критерии включения

• Age ≥18 years at the time of signing the informed consent form (ICF).
• New Diagnosed with histologically or molecularly confirmed IDH wildtype and MGMT methylated GBM.
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1 or 2..
• The following laboratory values obtained ≤15 days prior to registration:

• Hemoglobin ≥9.0 g/dL
• Absolute neutrophil count (ANC) ≥1500/mm3
• Platelet count ≥100,000/mm3
• Total bilirubin ≤1.5 x upper limit of normal (ULN)
• Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤3 x ULN (or ≤5 x ULN for participants with liver involvement)
• 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
• Serum eGFR ≥60 ml/min
• 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)
• Echocardiographic Assessment: Left Ventricular Ejection Fraction (LVEF) ≥ 55%.
• 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.

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

Критерии исключения

• 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:

• Pregnant persons
• Nursing persons
• 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)
• 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.
• Receiving any other investigational agent.
• 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.
• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 3 центра

• Mayo Clinic Hospital — Phoenix
• Mayo Clinic Hospital — Jacksonville
• Mayo Clinic Hospital — Rochester

Публикации

• 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. . : . .
• 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. PMID 27407096
• 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. PMID 40499543
• 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. PMID 35641844
• 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. PMID 15758010
• 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. PMID 30514777
• 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 PMID 15758009
• 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.200 PMID 20231676

Идентификаторы

NCT: NCT07604285 · MT-125-GBM-201 · 26C19

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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