Phase I Dose-Escalation Study of SCB01A, a Microtubule Inhibitor with Vascular Disrupting Activity, in Patients with Advanced Solid Tumors

Background. SCB01A, a novel microtubule inhibitor, has vascular disrupting activity. Methods. In this phase I dose-escalation and extension study, patients with advanced solid tumors were administered intravenous SCB01A infusions for 3 hours once every 21 days. Rapid titration and a 3 + 3 design escalated the dose from 2 mg/m(2) to the maximum tolerated dose (MTD) based on dose-limiting toxicity (DLT). SCB01A-induced cellular neurotoxicity was evaluated in dorsal root ganglion cells. The primary endpoint was MTD. Safety, pharmacokinetics (PK), and tumor response were secondary endpoints. Results. Treatment-related adverse events included anemia, nausea, vomiting, fatigue, fever, and peripheral sensorimotor neuropathy. DLTs included grade 4 elevated creatine phosphokinase (CPK) in the 4 mg/m(2) cohort; grade 3 gastric hemorrhage in the 6.5 mg/m(2) cohort; grade 2 thromboembolic event in the 24 mg/m(2) cohort; and grade 3 peripheral sensorimotor neuropathy, grade 3 elevated aspartate aminotransferase, and grade 3 hypertension in the 32 mg/m(2) cohort. The MTD was 24 mg/m(2), and average half-life was similar to 2.5 hours. The area under the curve-dose response relationship was linear. Nineteen subjects were stable after two cycles. The longest treatment lasted 24 cycles. SCB01A-induced neurotoxicity was reversible in vitro. Conclusion. The MTD of SCB01A was 24 mg/m(2) every 21 days; it is safe and tolerable in patients with solid tumors.