Phase I Dose Escalation and Expansion of Oral BAY 1143269 in Combination With Intravenous Docetaxel

An Open-label, Non-randomized, Multicenter Phase I Study to Characterize the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Maximum Tolerated Dose of Oral MKNK1 Inhibitor BAY 1143269 Given Alone or in Combination With Intravenous Docetaxel in Subjects With Advanced Solid Tumors

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?

Inclusion Criteria:

• Male or female subjects aged > 18 years
• Subjects must have histologically or cytologically confirmed locally advanced or metastatic solid tumors and must be refractory to any standard therapy, or have no standard therapy available, or have actively refused any standard therapy or, in the investigator's opinion, experimental treatment in this study is clinically and ethically acceptable for the subject.
• Subjects must have at least 1 measurable or evaluable tumor lesion according to RECIST 1.1 (Response Evaluation Criteria in Solid Tumors, version 1.1)
• Subjects must have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Subjects must have a life expectancy of at least 12 weeks
• Subjects must have adequate bone marrow function as assessed by the following: hemoglobin >=9.0 g/dL or >=5.6 mmol/L, absolute neutrophil count (ANC) >=1.500/mm^3 or >=1.5 x 10^9/L (CTCAE Grade <=1), platelet count >= 100000/mm^3 or >=100 x 10^9/L
• Subjects must have adequate kidney function, as assessed by the estimated glomerular filtration rate (eGFR) >=60 mL/min per 1.73 m*2 [Common Terminology Criteria for Adverse Events(CTCAE Grade <=1)] calculated by the Modification of Diet in Renal Disease Study Group (MDRD) formula
• Subjects must have adequate liver function assessed by: total bilirubin <= 1.0 x upper limit of normal (ULN), aspartate aminotransferase (ALT) <= 3.0 x ULN (CTCAE Grade <=1) or, if receiving BAY1143269 in combination with IV docetaxel, AST and ALT <=1.5 x ULN if concomitant with alkaline phosphatase increase >2.5 x ULN
• Subjects must have adequate coagulation as assessed by: international normalized ratio (INR) or prothrombin time (PT) <=1.5 times ULN (CTCAE Grade <=1), partial thromboplastin time (PTT) <=1.5 x ULN (CTCAE Grade <=1)
• Women of reproductive potential must have a negative serum beta human chorionic gonadotropin (b-HCG) pregnancy test within 7 days before the first dose of study drug. Women of reproductive potential and men with female partners of childbearing potential must agree to consistently use highly effective contraception between signing the informed consent and 60 days after the last administration of study drug

Exclusion Criteria:

• Subjects who have a previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study, except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta and Tis) or any previous cancer curatively treated <3 years before the first dose of study drug
• Subjects who have a history of, or current evidence of bleeding disorder, i.e. any hemorrhage / bleeding event of CTCAE Grade >= 2 <4 weeks before the first dose of study drug.
• Subjects who have new or progressive brain or meningeal or spinal metastases
• Subjects who have a history of, or current evidence of uncontrolled cardiovascular disease or a left ventricular ejection fraction (LVEF) <50%
• Women who are pregnant or breast-feeding
• Subjects experiencing unresolved toxicity of previous antitumor therapy (excluding alopecia) which is CTCAE Grade >1 at screening
• Subjects who are current smokers or users of other tobacco products or have quit <90 days before first dose of study drug
• Subjects taking or likely to take strong and moderate CYP2D6 inhibitors, strong CYP1A1 inhibitors, and/or CYP1A1/CYP1A2 sensitive substrates or with narrow therapeutic index. Subjects receiving oral BAY1143269 and IV docetaxel must not take or be likely to take strong CYP3A1 inhibitors
• Subjects who have received systemic antitumor therapy within 4 weeks or radiotherapy to target lesions within 3 weeks before the first dose of study drug, which is longer
• Subjects who had received investigational drug treatment, including BAY1143269 and docetaxel, outside of this study within 4 weeks before the first dose of study drug, or for small molecules within the 5 half-lives of the agent before the first dose of study drug, whichever is longer