Phase I Study to Determine the Maximum Tolerable Dose of BAY94-9343 in Patients With Advanced Solid Tumors.

Inclusion Criteria:

• All subjects must be ≥ 18 years at the first screening examination / visit
• Eastern Cooperative Oncology Group Performance Status of 0 - 2
• Life expectancy of at least 12 weeks
• Subjects with advanced, histologically or cytologically confirmed solid tumors, refractory to any standard therapy or with no standard therapy available
• Radiographically or clinically evaluable tumor

• Adequate bone marrow, liver, and renal function as assessed by the following laboratory requirements to be conducted within 14 days prior to start of first dose:

  • Hemoglobin ≥ 9.0 g/dL
  • Absolute neutrophil count (ANC) ≥ 1500/mm3
  • Platelet count ≥ 100,000 /mm3
  • Total bilirubin ≤ 1.5 times the upper limit of normal
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normal (ULN) (≤ 5 x upper limit of normal for subjects with liver involvement)
• International normalized ratio (INR) and partial thromboplastin time (PTT) ≤ 1.5 x ULN for subjects not undergoing anticoagulative treatment. Subjects undergoing anticoagulative treatment with eg. warfarin or heparin, which was initiated at least 4 weeks prior to the planned start of treatment in this study and which is well controlled with INR and PTT in therapeutic ranges, are eligible
• Serum creatinine ≤ 1.5 times ULN and glomerular filtration rate (GFR) ≥ 30 ml/min/1.73 m2, according to the MDRD (Modified Diet in Renal Disease) abbreviated formula

Exclusion Criteria:

• Impaired cardiac function or clinically significant cardiac disease (ie, congestive heart failure (CHF), New York Heart Association (NYHA) Class III or IV)
• Myocardial infarction or onset of unstable angina < 3 months prior to screening
• Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin
• Left ventricular ejection fraction (LVEF) <40% (as measured at screening by multiple gated acquisition scan (MUGA) or echocardiogram)
• Uncontrolled hypertension defined as systolic blood pressure > 150 mm Hg and/or diastolic blood pressure > 90 mmHg, despite optimal medical management
• History of symptomatic metastatic brain or meningeal tumors unless the subject is > 3 months from definitive therapy
• Subjects with severe renal impairment or on dialysis
• Human immunodeficiency virus (HIV) infection or subjects with an active hepatitis B or C infection necessitating treatment. Subjects with chronic hepatitis B or C are eligible
• Active clinically serious infections > National Cancer Institute Common Terminology Criteria Adverse Events (NCI CTCAE) Grade 2
• Serious, non-healing wound, ulcer, or bone fracture
• Known or suspected allergy or intolerance to any agent given in the course of this trial
• Substance abuse, medical, psychological or social conditions that may interfere with the subject's participation in the study or evaluation of the study result
• Major surgery, open biopsy, or significant trauma within 2 weeks prior to the planned start of study treatment
• Anticancer chemotherapy, experimental cancer therapy, or immunotherapy within 2 weeks of start of first dose. Anticancer therapy is defined as any agent or combination of agents with clinically proven anti tumor activity administered by any route with the purpose of affecting the malignancy, either directly or indirectly, including palliative and therapeutic endpoints. Toxic effects of previous anticancer chemotherapy, experimental cancer therapy, or immunotherapy have to be normalized completely (excluding alopecia)
• Toxic effects considered as chronic, such as chemotherapy induced neuropathy of NCI CTC AE grade ≤ 2, where anymore resolution is not expected, does not prevent subjects from participation in the trial
• Radiotherapy to the target lesions within 3 weeks prior to Day 1, Cycle 1 (first dose of study drug). Radiotherapy to the target lesions during study will be regarded as progressive disease