Project Grant R44CA278293

PHASE 0/I DOSE ESCALATION TRIAL OF MT-125 MONOTHERAPY IN RECURRENT HIGH-GRADE GLIOMAS - PROJECT SUMMARY AN AREA OF SIGNIFICANT UNMET NEED IS THE TREATMENT OF GLIOBLASTOMA (GBM), AN AGGRESSIVE, FAST-GROWING AND LETHAL BRAIN CANCER THAT REPRESENTS HALF OF ALL MALIGNANT BRAIN TUMORS. UNTREATED, GBM IS FATAL WITHIN THREE MONTHS, AND DUE TO ITS HIGH RATE OF RECURRENCE AND INVASIVE NATURE, THE CURRENT STANDARD OF CARE, CONSISTING OF SAFE MAXIMAL TUMOR RESECTION, RADIATION THERAPY AND CHEMOTHERAPY, ONLY EXTENDS SURVIVAL FOLLOWING INITIAL DIAGNOSIS TO ONE YEAR. INVASION AND PROLIFERATION ARE DEFINING PHENOTYPES OF GBM, AND GBM CELLS DO ONLY ONE OR THE OTHER. HOWEVER, BLOCKING INVASION STIMULATES PROLIFERATION AND VICE VERSA, IMPLYING THAT AN IDEAL THERAPEUTIC NEEDS TO BLOCK BOTH PROCESSES SIMULTANEOUSLY. GENETIC INTERVENTIONS HAVE SHOWN THAT SIMULTANEOUS DISRUPTION OF TWO NON-MUSCLE MYOSIN II MOLECULAR MOTORS (NMIIA AND IIB) MEET THESE CRITERIA. HOWEVER, THE TRANSLATIONAL POTENTIAL OF THIS RESEARCH HAS BEEN LIMITED BY THE LACK OF A CLINICALLY SAFE, CNS- PENETRANT NMII SMALL MOLECULE INHIBITOR. FOLLOWING EXTENSIVE MEDICINAL CHEMISTRY EFFORTS TO OPTIMIZE SELECTIVITY, SAFETY, AND TOLERABILITY, MT-125 WAS IDENTIFIED. MT-125 IS A WELL-TOLERATED, DUAL SMALL MOLECULE INHIBITOR OF NMIIA AND IIB WITH A HIGH DEGREE OF BRAIN PENETRANCE, A REQUIREMENT FOR AN EFFECTIVE GBM THERAPEUTIC. PRECLINICAL IN VITRO AND IN VIVO STUDIES SHOW THAT MT-125 BLOCKS BOTH INVASION AND PROLIFERATION AND EXTENDS SURVIVAL. DUE TO ITS UNIQUE MODE OF ACTION, MT-125 SYNERGIZES WITH FDA APPROVED, CNS PERMEANT KINASE INHIBITORS AND WITH RADIOTHERAPY TO DRAMATICALLY EXTEND SURVIVAL IN BOTH GENETICALLY ENGINEERED AND PATIENT- DERIVED MOUSE XENOGRAFT MODELS OF GBM. MT-125 IS ACTIVE AGAINST IDH WT/MGMT UNMETHYLATED GBMS, WHICH RESIST ALL CURRENT MEDICAL THERAPIES. MYOSIN RECENTLY RECEIVED ORPHAN DRUG DESIGNATION FROM THE FDA FOR THE TREATMENT OF MALIGNANT GLIOMAS WITH MT-125 AFTER AN IN-DEPTH REVIEW OF THE COMPANY'S DATA PACKAGE AND WE RECEIVED SUPPORTIVE PRE-IND FEEDBACK FROM THE FDA DIVISION OF ONCOLOGY 2. THE GOAL OF THIS SBIR PHASE IIB BRIDGE APPLICATION, WHICH BUILDS ON THE COMPANY'S CURRENTLY FUNDED NCI FAST TRACK STTR WITH DR. ROSENFELD (MAYO CLINIC), IS TO PERFORM A PHASE 0/1B CLINICAL TRIAL WITH MT-125. THE PRIMARY ENDPOINTS WILL BE TO DETERMINE THE OPTIMAL BIOLOGOCIAL DOSE (OBD) OF MT-125 AND ASSESS DRUG DISTRIBUTION WITHIN TUMOR TISSUES. SYSTEMIC PHARMACOKINETICS WILL BE EVALUATED AS A SECONDARY ENDPOINT. BASED ON TRANSLATION TO HUMAN DOSE EQUIVALENTS, OUR EFFICACY AND TOXICITY TESTING IN TWO SPECIES TO DATE INDICATE THAT THE PROPOSED STARTING DOSE IS POTENTIALLY THERAPEUTIC. THEREFORE, SECONDARY ENDPOINTS WILL ALSO GATHER PRELIMINARY DATA ON EFFICACY THROUGH MEASURES OF RESPONSE RATE, PROGRESSION FREE SURVIVAL, AND OVERALL SURVIVAL. DUE TO MT-125'S ABILITY TO BLOCK PROLIFERATION THROUGH INHIBITED CYTOKINESIS, THE COMPOUND INCREASES THE NUMBER OF MULTI-NUCLEATED CELLS WITHIN TUMORS. THIS REPRESENTS A POTENTIAL MEASURE OF TARGET ENGAGEMENT, AND WE WILL, THEREFORE, ASSESS THE PRESENCE OF MULTI-NUCLEATION WITHIN RESECTED TUMORS IN PHASE 0.