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

A Phase 1/2 Single-Arm Dose Escalation Study of the Safety, Tolerability, and Pharmacokinetics of MT-125 Monotherapy With Radiation in Newly Diagnosed Glioblastoma

The purpose of the study is to determine the recommended dose and further understand the safety of MT-125 in participants who have been diagnosed with glioblastoma, a primary brain tumor, when administered in combination with your standard of care treatment.

Initially, participants with newly diagnosed glioblastoma will be given different doses of MT-125 in combination with radiotherapy (RT) with the goal of identifying the highest tolerated dose.

Up to 36 people with glioblastoma who are at least18 years old are being invited to join this study. MT-125 is a type of study treatment which acts on cancer cells in the brain to destroy them. It will be administered on the same day as your standard of care radiotherapy because it is also designed to help radiotherapy work better. However, this is the first time MT-125 will be studied in humans. Therefore, the use is considered investigational. If you would like more details about MT-125 in glioblastoma participants, please ask the Study Doctor.

You will be among the first participants with glioblastoma to receive this study treatment. Its safety and effectiveness have not yet been established in humans. Thus, we do not know whether it will work for you. Your condition may improve, may get worse, or there may be no change.

The selected participant population-individuals newly diagnosed with histologically and/or molecularly confirmed IDH wild-type, MGMT-unmethylated glioblastoma-represents those least likely to experience safety concerns or adverse events related to the study treatment, and most likely to derive therapeutic benefit.

There are certain tests/questions you must complete to find out if you meet the requirements to be in the study. If you do not meet these requirements, you cannot take part in the study. If this happens, you can talk to your Study Doctor about other options.

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.

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 wild type and MGMT unmethylated 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.

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.