Methods
NSCLC, abnormal urinary function or outflow obstruction, tumor, bleeding, epilepsy, toxicity, malignancy, METex14-positive NSCLC, diabetes mellitus, uveitis, ocular toxicity, hematological toxicity, thrombocytopenia, PD, nausea/vomiting/diarrhea, Cancer
ADVERSE EVENT, TUMOR, BLEEDING, FEBRILE NEUTROPENIA, EPILEPSY, ADVERSE EVENTS, THROMBOCYTOPENIA, DIABETES MELLITUS, SOLID TUMORS, VIRAL INFECTION, UVEITIS, MALIGNANCIES, NSCLC, CNS METASTASES, ONCOLOGY, EVENTS, CANCER
This study was part of a modular, first-in-patient, openlabel multicenter study of OMO-1, administered orally, mono-therapy, and in combination with EGFR-TKI, in patients with locally advanced, unresectable, or metastatic solid malignancies (study protocol can be). OMO-1 is a small molecule inhibitor of MET. Module 1 (OMO-1 monotherapy) consisted of Part A (dose escalation) and Part B (expansion cohorts). Part A assessed the safety and tolerability of ascending doses of OMO-1 given as monotherapy in unselected patients with locally advanced, unresectable, or metastatic malignancies and determined the recommended phase 2 dose (RP2D). Part B assessed the preliminary efficacy of the RP2D of OMO-1 in patients with METex14-positive NSCLC (cohort 1) and patients with MET amplified NSCLC or patients with other MET positive solid tumors, either METex14 or MET amplification (MET basket; cohort 2). The MET status of the tumor was assessed locally by site-specific guidelines. For MET exon 14 skipping mutations next generation sequencing (NGS) was used and for MET amplifications either NGS or fluorescence in situ hybridization (The primary objective of the study was to determine the safety and tolerability of OMO-1 when given orally to patients with locally advanced, unresectable, or metastatic solid malignancies and to define the dose and schedule for further clinical evaluation. Secondary objectives were to assess the preliminary efficacy of OMO-1 by response evaluation criteria in solid tumors (RECIST) v 1.1 and to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of OMO-1, following a single dose and/or at steady state after multiple dosing, when given orally as monotherapy or in combination with epidermal growth factor receptor (EGFR)-tyrosine kinases inhibitor (TKI).Eligible patients were aged ≥18 years with Eastern Cooperative Oncology Group (ECOG) performance score 0-1, adequate organ function, histological, or cytological confirmation of locally advanced, unresectable, or metastatic solid malignancy refractory to conventional treatment. Exclusion criteria included a diagnosis of diabetes mellitus or current use of metformin (OMO-1 might increase exposure to metformin because metformin is secreted by OCT-2), prior splenectomy, active illness or viral infection, symptomatic CNS metastases, a history of epilepsy or uveitis, abnormal urinary function or outflow obstruction, and previous bone marrow transplant or recent surgery.OMO-1 was administered orally, twice daily (BID) with a minimal interval of 4-5 h with food in a continuous 21 day/cycle regimen until clinical progression or emergence of significant toxicity. The starting dose was 100 mg BID. The dose was escalated sequentially in cohorts of at least 3 patients using a standard 3 + 3 dose escalation design. Dose-escalation stopped when significant safety or tolerability concerns were observed in 2 or more patients and where the non-optimal long-term exposure dose (OLED) was exceeded. The RP2D was defined as the maximum dose whereby the safety or tolerability findings did not exceed 1 out of 6 patients. Computed tomography (CT) based tumor assessments were conducted according to RECISTv1.1 at screening and every 6 weeks once study treatment had commenced. Safety assessments were continually assessed and based on all adverse events (AEs; graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0, 2009 (NCI-CTCAE v 4.0)), clinical laboratory data, and physical examinations. In view of the association between MET inhibition and ocular toxicity, ophthalmological examination was conducted at baseline.The dose-limiting toxicity (DLT) evaluation period was within the first cycle of treatment; although all events beyond this point were also reviewed at the time of dose escalation to ensure an OLED was chosen as RP2D. A DLT was defined as any of the following occurring during the DLT-evaluation period: grade 3 or 4 non-hematological toxicity (excluding nausea/vomiting/diarrhea that responded to standard medical treatment), grade 4 hematological toxicity, febrile neutropenia, grade 3 thrombocytopenia with bleeding, QTc prolongation (>500 ms, or 60 ms above baseline), any toxicity related to OMO-1 that was clinically significant or unacceptable or unresolved after a treatment delay of >14 days and any toxicity clinically significant and/or unacceptable, greater than that at baseline and judged to be a DLT by the SRC.