First-in-Man Phase I Trial of the Selective MET Inhibitor Tepotinib in Patients with Advanced Solid Tumors.

PurposeTepotinib is an oral, potent, highly selective MET inhibitor. This first-in-man phase I trial investigated the MTD of tepotinib to determine the recommended phase II dose (RP2D).Patients and methodsPatients received tepotinib orally according to one of three dose escalation regimens (R) on a 21-day cycle: R1, 30-400 mg once daily for 14 days; R2, 30-315 mg once daily 3 times/week; or R3, 300-1,400 mg once daily. After two cycles, treatment could continue in patients with stable disease until disease progression or unacceptable toxicity. The primary endpoint was incidence of dose-limiting toxicity (DLT) and treatment-emergent adverse events (TEAE). Secondary endpoints included safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor effects.ResultsOne hundred and forty-nine patients received tepotinib (R1: n = 42; R2: n = 45; R3: n = 62). Although six patients reported DLTs [one patient in R1 (115 mg), three patients in R2 (60, 100, 130 mg), two patients in R3 (1,000, 1,400 mg)], the MTD was not reached at the highest tested dose of 1,400 mg daily. The RP2D of tepotinib was established as 500 mg once daily, supported by translational modeling data as sufficient to achieve ≥95% MET inhibition in ≥90% of patients. Treatment-related TEAEs were mostly grade 1 or 2 fatigue, peripheral edema, decreased appetite, nausea, vomiting, and lipase increase. The best overall response in R3 was partial response in two patients, both with MET overexpression.ConclusionsTepotinib was well tolerated with clinical activity in MET-dysregulated tumors. The RP2D of tepotinib was established as 500 mg once daily. MET abnormalities can drive tumorigenesis. This first-in-man trial demonstrated that the potent, highly selective MET inhibitor tepotinib can reduce or stabilize tumor burden and is well tolerated at doses up to 1,400 mg once daily. An RP2D of 500 mg once daily, as determined from translational modeling and simulation integrating human population pharmacokinetic and pharmacodynamic data in tumor biopsies, is being used in ongoing clinical trials

Phosphate solubilizing and PGR activities of ericaceous shrubs microorganisms isolated from Mediterranean forest soil

Many soil microorganisms are able to transform insoluble forms of phosphorus into an accessible soluble form, thus contributing to plant nutrition through exhibiting other beneficial traits such as production of organic acids, siderophore indole acetic acid (IAA) and production of hydrogen cyanide (HCN). Achieving this purpose, ericoid fungi and actinobacteria were isolated from roots and rhizospheric soil of Calluna vulgaris L., belonging to the ericaceous family. All isolates were shown to be able to solubilize insoluble phosphate in liquid cultures and to produce transparent halos of solubilization on PVK solid medium. The actinobacteria isolate AH6 was the most efficient compared to others, producing 145.5 mg/L of phosphate and 141 mu g/L of IAA. However, fungi isolate S2 and S3 had high solubilization capacity and produced a high concentration of IAA in comparison with S1, which was a good siderophore producer. We applied a sequencing approach by amplifying the ITS region for fungi and 16S for actinobacteria. Most of the actinobacteria isolates belong to the Streptomyces genus while fungi were identified as related to ericoid mycorrhizal fungi. To evaluate the effectiveness of selected rhizobacteria and symbiotic fungi isolates and to confirm their role as biofertilizers, inoculation experimentations on plants are required

Activity of tepotinib in brain metastases (BM): Preclinical models and clinical data from patients (pts) with MET exon 14 (METex14) skipping NSCLC

Abstract 1286P Background BM occur in 20–40% of NSCLC harboring METex14 skipping. We investigated the activity of the MET inhibitor tepotinib in BM in preclinical models and in pts from the VISION study (NCT02864992). Methods Penetration of the blood–brain barrier was assessed in Wistar rats (n=3) at 3.66 mg/kg/h iv tepotinib by determining the unbound brain (fu br)-to-plasma (fu pl) concentration or exposure ratio (Kp u,u). Efficacy was assessed in two lung cancer patient-derived xenografts (PDX) from BM harboring high MET amplification (MET gain in copy number: LU5349 = 11, LU5406 = 24) grown in NOD-SCID mice. Subcutaneous PDX (n=5/group) or PDX orthotopically implanted into the brain (n=10/group) were treated with tepotinib 125 mg/kg or vehicle control orally once daily. Intracranial tumor growth was monitored by gadolinium-based MRI. In VISION Cohort A, pts with METex14 skipping NSCLC received tepotinib 500 mg once daily. Systemic objective response, as assessed per RECIST v1.1 by independent review committee (IRC) was a preplanned analysis in pts with baseline brain lesions identified by IRC (BM-IRC) or investigator assessment (BM-INV). Results Preclinical data indicated high binding of tepotinib in the brain, with unbound tepotinib in brain tissue lower than in plasma (fu br = 0.4%, fu pl = 4%). Concentrations of unbound tepotinib in the brain were 25% of plasma (Kp u,u = 0.25).Tepotinib treatment resulted in tumor regression in both PDX models (mean % tumor volume: –84% in LU5349, –63% in LU5406). As of 1 Jan 2020, 22/152 pts enrolled in Cohort A had baseline BM, with similar baseline pt characteristics and comparable systemic response data (Table) as the overall population. Table: 1286P BM-IRC BM-INV Number of patients with BM; n Non-target lesions 14 12 Target lesions 0 1 Objective response rate, % (95% CI) 57.1% (28.9, 82.3) 53.8% (25.1, 80.8) Best overall response; n Partial response 8 7 Stable disease 3 3 Conclusions Tepotinib administration resulted in tumor regression in MET-driven lung cancer BM PDX models. Clinical activity in pts with NSCLC harboring METex14 skipping with baseline BM was consistent with the overall population in VISION. Cohort C aims to assess intracranial response

First-in-Man Phase I Trial of the Selective MET Inhibitor Tepotinib in Patients with Advanced Solid Tumors.

PurposeTepotinib is an oral, potent, highly selective MET inhibitor. This first-in-man phase I trial investigated the MTD of tepotinib to determine the recommended phase II dose (RP2D).Patients and methodsPatients received tepotinib orally according to one of three dose escalation regimens (R) on a 21-day cycle: R1, 30-400 mg once daily for 14 days; R2, 30-315 mg once daily 3 times/week; or R3, 300-1,400 mg once daily. After two cycles, treatment could continue in patients with stable disease until disease progression or unacceptable toxicity. The primary endpoint was incidence of dose-limiting toxicity (DLT) and treatment-emergent adverse events (TEAE). Secondary endpoints included safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor effects.ResultsOne hundred and forty-nine patients received tepotinib (R1: n = 42; R2: n = 45; R3: n = 62). Although six patients reported DLTs [one patient in R1 (115 mg), three patients in R2 (60, 100, 130 mg), two patients in R3 (1,000, 1,400 mg)], the MTD was not reached at the highest tested dose of 1,400 mg daily. The RP2D of tepotinib was established as 500 mg once daily, supported by translational modeling data as sufficient to achieve ≥95% MET inhibition in ≥90% of patients. Treatment-related TEAEs were mostly grade 1 or 2 fatigue, peripheral edema, decreased appetite, nausea, vomiting, and lipase increase. The best overall response in R3 was partial response in two patients, both with MET overexpression.ConclusionsTepotinib was well tolerated with clinical activity in MET-dysregulated tumors. The RP2D of tepotinib was established as 500 mg once daily. MET abnormalities can drive tumorigenesis. This first-in-man trial demonstrated that the potent, highly selective MET inhibitor tepotinib can reduce or stabilize tumor burden and is well tolerated at doses up to 1,400 mg once daily. An RP2D of 500 mg once daily, as determined from translational modeling and simulation integrating human population pharmacokinetic and pharmacodynamic data in tumor biopsies, is being used in ongoing clinical trials