Determine the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics (PK), and/or recommended Phase II dose (RP2D) of oral BAY 1143269 given alone or in combination with intravenous (IV) docetaxel in subjects with advanced solid tumors.
BAY 1143269 is a potent and selective, orally administered novel inhibitor of mitogen-activated protein kinase interacting serine/threonine-protein kinase 1 (MKNK1). MKNK1 activity is essential for the phosphorylation of eukaryotic translation initiation factor 4E (eIF4E), which promotes the synthesis of oncogenic proteins, inhibits apoptosis, and helps tumor cells survive under stress. Increased p-EIF4E levels were found in tumor tissues from cancer patients. MKNK also functions as a mediator of pro-inflammatory cytokine production. Established anti-mitotic drugs such as vinca alkaloids, taxanes, or epothilones activate the spindle assembly checkpoint (SAC), a key surveillance mechanism that monitors the attachment of spindle microtubules to the kinetochores of the chromosomes during pro-metaphase and halts the transitions to anaphase until all chromosomes are bi-oriented, fully attached, and correctly tensed at the metaphase plate. These antimitotic drugs destabilize or stabilize the spindle microtubules and cause mitotic arrest. Prolonged arrest in mitosis forces a cell either into a mitotic exit without cytokinesis or into a mitotic catastrophe leading to cell death. MKNK1 inhibitors allow cell apoptosis and increase tumor death. The combination of taxane and MKNK1 inhibitor can ultimately delay tumor progression and may provide a useful anticancer therapeutic approach. This study will attempt to answer the following questions: * What is the maximum tolerated dose (MTD) of BAY 1143269 when given alone or in combination with docetaxel? * What is the safety profile and pharmacokinetics of BAY1143269 when given at the MTD? * What are the adverse events of BAY 1161909 when given at different dose levels with docetaxel?
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
15
BAY 1143269 5 mg or 25 mg tablet. Each treatment cycle will last 21 days.
Unnamed facility
Dallas, Texas, United States
Unnamed facility
Houston, Texas, United States
Unnamed facility
San Antonio, Texas, United States
Unnamed facility
Sutton, Surrey, United Kingdom
Maximum Tolerated Dose (MTD) of Oral BAY1143269 Alone and in Combination With Intravenous Docetaxel
The MTD of oral BAY1143269 given alone was defined as the maximum dose at which the predicted incidence of dose-limiting toxicities (DLTs) during Cycle 1 is below 30 percent (%).
Time frame: Up to 2 years
Maximum Observed Drug Concentration (Cmax) in Plasma After Single and Multiple Dose Administration of BAY1143269
Maximum observed concentration of BAY1143269 in plasma after single dose and multiple dose administration was measured.
Time frame: Cycle 1, 2 Day 1: Pre-dose to 24 hours post-dose
Area Under the Concentration-time Curve From Time Zero to 24 Hours [AUC(0-24)] After Single and Multiple Dose Administration of BAY1143269
Area under the concentration-time curve from zero to 24 hours after single dose and multiple dose administration of BAY1143269 in plasma was measured.
Time frame: Cycle 1, 2 Day 1: Pre-dose to 24 hours post-dose
Tumor response
Tumor response was assessed by Response Evaluation Criteria in Solid Tumors(RECIST V1.1). Evaluation of target lesions included CR(Disappearance of all target lesions),PR(at least a 30% decrease in sum of diameters of target lesions),PD:at least a 20% increase in sum of diameters of target lesions, taking smallest sum recorded as reference since treatment started or appearance of one or more new lesions) and Stable disease(SD:neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD).Evaluation of non-target lesions included CR(disappearance of all non-target lesions and normalization of tumor marker level),Non-CR/PD(Persistence of 1 or more non target lesions and/or maintenance of tumor marker level above normal limits) and PD(Appearance of 1 or more new lesions and/or unequivocal progression of existing non target lesions).
Time frame: Baseline; end of Cycle 2
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