Translational pharmacokinetic-pharmacodynamic modeling of preclinical and clinical data of the oral MET inhibitor tepotinib to determine the recommended phase II dose.

Tepotinib is a highly selective and potent MET inhibitor in development for the treatment of patients with solid tumors. Given the favorable tolerability and safety profiles up to the maximum tested dose in the first-in-human (FIH) trial, an efficacy-driven translational modeling approach was proposed to establish the recommended phase II dose (RP2D). To study the in vivo pharmacokinetics (PKs)/target inhibition/tumor growth inhibition relationship, a subcutaneous KP-4 pancreatic cell-line xenograft model in mice with sensitivity to MET pathway inhibition was selected as a surrogate tumor model.

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

Purpose: Tepotinib 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 Methods: Patients 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.

A phase I, dose-escalation study of the Eg5-inhibitor EMD 534085 in patients with advanced solid tumors or lymphoma.

Background: The kinesin spindle protein Eg5 is involved in mitosis, and its inhibition promotes mitotic arrest. EMD 534085, a potent, reversible Eg5 inhibitor, demonstrated significant preclinical antitumor activity.

Methods: This first-in-man, single-center, open-label, phase I dose-escalation study (3 + 3 design) investigated EMD 534085 safety, pharmacokinetics and antitumor activity in refractory solid tumors, Hodgkin's lymphoma, or non-Hodgkin's lymphoma.

Patterns of metastatic spread in early breast cancer.

Aims: The aim of this study was to prospectively investigate metastatic pathways of spread to lymph node versus bone marrow and identify biological characteristics that determine these patterns in early invasive breast cancer.

Patients And Methods: In all, 177 patients with early invasive breast cancer underwent surgical extirpation of the primary tumour with sentinel lymph node biopsy (SLNB). Bone marrow (BM) aspiration was performed to screen for cytokeratin-positive cells by immunocytochemistry.

Lymph node status and breast cancer-related lymphedema.

Objective: This study examines the association between nodal positivity and risk of developing breast cancer-related lymphedema (BCRL) in patients who underwent axillary lymph node dissection (ALND).

Summary Background Data: The pathophysiology of BCRL is poorly understood. It has been assumed that one of the factors predisposing to the development of BCRL is nodal positivity, although retrospective series have produced contradictory findings.