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

Abstract

Lessons learned: SCB01A is a novel microtubule inhibitor with vascular disrupting activity. This first-in-human study demonstrated SCB01A safety, pharmacokinetics, and preliminary antitumor activity. SCB01A is safe and well tolerated in patients with advanced solid malignancies with manageable neurotoxicity.

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/m2 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/m2 cohort; grade 3 gastric hemorrhage in the 6.5 mg/m2 cohort; grade 2 thromboembolic event in the 24 mg/m2 cohort; and grade 3 peripheral sensorimotor neuropathy, grade 3 elevated aspartate aminotransferase, and grade 3 hypertension in the 32 mg/m2 cohort. The MTD was 24 mg/m2 , and average half-life was ~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/m2 every 21 days; it is safe and tolerable in patients with solid tumors.

Trial registration: ClinicalTrials.gov NCT01151930 NCT01159522.

Keywords: Microtubule inhibitor; SCB01A; Solid tumor.

© AlphaMed Press; the data published online to support this summary are the property of the authors.

Figures

Figure 1

Duration of progression‐free survival stratified by tumor assessments of study subjects at the end of study.Abbreviation: PFS, progression‐free survival.

Figure 2

Best overall response (change in target lesion from baseline) of study subjects.Note: Target lesion for one subject was not measurable.

Figure 3

PK profile of SCB01A. (A): Plasma concentration‐time profiles of SCB01A. (B): Maximum plasma concentration of SCB01A. (C): Area under the curve of SCB01A.Abbreviations: AUC, area under the curve; Cmax, maximum plasma concentration.

Figure 4

Response of dorsal root ganglion cells at different treatment concentrations and exposure durations of SCB01A.