Dose-Escalation Study Of SB-485232 Administered As Daily Subcutaneous Injections In Adults With Solid Tumors

A Phase I, Dose Escalation Study to Assess the Safety and Pharmacokinetics of SB- 485232 Administered as Daily Subcutaneous Injections in Adult Patients With Solid Tumors

This is a phase I, open-label, dose-escalation study of SB-485232. Subjects will receive SB-485232 administered as subcutaneous injections daily for 14 days. Dose escalation (enrollment into the next cohort) cannot occur until all three subjects have completed the previous cohort; 5 doses will be tested. An additional dosing regimen has been added to evaluate higher doses given twice weekly for 7 weeks. Therefore, the full evaluation period for each patient will extend out to approximately eleven weeks after the first day of SB-485232 dosing.

Inclusion Criteria:

• Histologically or cytologically confirmed diagnosis of malignancy.
• Subjects with solid tumors must have locally advanced or metastatic disease at the time of enrollment.
• Measurable or evaluable disease that is refractory or resistant to standard therapy or for which there is no effective standard therapy.
• Predicted life expectancy of at least 12 weeks.
• Kinesin spindle protein (KPS) of greater than 70%.
• No chemotherapy, immunotherapy, hormonal therapy, or biological therapy for cancer, radiotherapy, or surgical procedures (except for minor surgical procedures) within 4 weeks before beginning treatment with SB-485232 (6 weeks for nitrosoureas and mitomycin C).
• Subjects must have recovered from toxicities (incurred as a result of previous therapy) sufficiently to be entered into a Phase I study.
• Provide written informed consent.
• Absence of anti-SB-485232 antibodies.
• Hemoglobin greater than or equal to 9 g/dL.
• Absolute neutrophil count greater than or equal to 1.5 X 109 /L.
• Platelet count greater than or equal to 100 X 109 /L.
• Partial thromboplastin time (PTT) and prothrombin time/international normalized ratio (PT/INR) within normal limits.
• Serum creatinine less than or equal to 1.5 mg/dL (135 µmol/L) or estimated creatinine clearance greater than 50 mL/min (calculated by the Cockcroft-Gault Formula).
• Total serum bilirubin less than or equal to 1.5 mg/dL.
• Aspartate transaminase (AST) and alanine transaminase (ALT) less than or equal to 3 X ULN.
• Sexually active males or females of reproductive capacity must use adequate contraception.
• For subjects with a history of coronary artery disease, stress test must be within normal limits.
• Subjects with a history of congestive heart failure, myocardial infarction or prior anthracycline chemotherapy must have a Multiple Gated Acquisition (MUGA) scan with a left ventricular ejection fraction of greater than 40%.

Exclusion Criteria:

• Women who are pregnant or are breast-feeding.
• Severe or uncontrolled infections requiring systemic antibiotic therapy.
• Any serious medical or psychiatric disorder that would interfere with subject safety or informed consent.
• Known leptomeningeal disease or evidence of prior or current metastatic brain disease.
• Receiving concurrent chemotherapy, immunotherapy, radiotherapy, or investigational therapy.
• Receiving concurrent systemic steroids.
• History of ventricular arrhythmias requiring drug or device therapy.
• Any severe concurrent disease or condition, including significant autoimmune diseases, which in the judgment of the principal investigator, would make the subject inappropriate for study participation.
• Any unresolved or unstable serious toxicity from prior administration of another investigational drug.
• Any investigational drug within 30 days or 5 half-lives (whichever is longer) preceding the first dose of SB-485232.
• Psychological, familial, sociological, or geographical conditions that do not permit compliance with the study.
• Received prior treatment with SB-485232.
• Poor venous access.