Abstract P6-11-10: IBL2001: Phase I/II study of a novel dose-dense schedule of oral indibulin for the treatment of metastastic breast cancer.
Authors: Traina TA , Hudis C , Seidman A , Gajria D , Gonzalez J , Anthony SP , Smith DA , Chandler JC , Jac J , Youssoufian H , Korth CC , Barrett JA , Sun L , Norton L 
Published: August 2014

Abstract
Background: Indibulin (ZI0-301) is a novel, oral, synthetic small molecule microtubule inhibitor which binds tubulin at a different site than taxanes and vinca alkaloids. Preclinical data demonstrate indibulin does not interact with acetylated (neuronal) tubulins and in clinical studies has not exhibited the neurotoxicity associated with other tubulin binders. Indibulin has potent antitumor activity in human cancer cell lines, including multidrug-, taxane-, and vinblastine-resistant. Norton-Simon modeling based on cell line data suggested that dose dense (dd) administration could optimize efficacy while limiting toxicity.
Methods: Eligible patients (pts) have metastatic or unresectable locally advanced breast cancer, ECOG performance status ≤ 2, adequate organ function, measurable or nonmeasurable disease and any number of prior therapies. Uncontrolled gastrointestinal malabsorption syndrome and grade 2 or higher peripheral neuropathy are the principal exclusions. Adverse events (AEs) are graded by CTCAE v. 4.0. Objective disease status is evaluated according to RECIST 1.1. The primary objective of the phase (Ph) I portion of the study is to determine the maximum tolerated dose (MTD) of indibulin when given in dd fashion 5 days treatment, 9 days rest using standard 3+3 dose escalation schema.

The secondary objectives are to evaluate safety profile at various dosing levels, pharmacokinetics (PK) and preliminary activity of indibulin. Once the MTD is defined, a food effect cross- over group (N = 12) will be enrolled. Two groups of 6 pts each will be treated in either the fed or fasted state during the first cycle. A subgroup of 13 pts consisting of 12 pts from the food effect group plus the last pt from the MTD cohort will be evaluated for PFS at 4 months and will serve as the population for the first stage of a Simon two-stage design. If 4 or more out of 13 pts do not progress at 4 months, the Ph II portion of the study will be opened.
Results: Twenty one pts (20 F, 1 M) have been enrolled to cohorts 1 through 6 and the dose escalation is ongoing. Preliminary safety and efficacy data have been analyzed for 18 pts treated in cohorts 1 through 5 and are presented henceforth. No DLT has been observed and no MTD has been reached. Median age 58 years (32–81). PS 0=4, 1=12, 2=2. Median number of prior therapies 5 (1–12). Most frequent treatment-emergent AEs were: anorexia, constipation, cough, nausea (each in 39% pts); dyspnea (33%); fatigue, vomiting (each 28%). There were no related grade 3–4 AEs. PK analysis revealed that indibulin plasma exposures increased approximately dose proportionally from 25 to 200 mg with Cmax of 165 ± 89 ng/mL and AUC0-24 of 1411 ± 111 ng·h/mL at 200 mg. There were no objective responses. Stable disease was seen in 1 pt in the 150 mg cohort. Longest duration on-study was 4 months.
Conclusions: Oral indibulin was well tolerated in the doses up to 200 mg and the dose-proportional PK with lack of DLTs allows for further dose-escalation. Stable disease observed at sub-MTD dose may be a sign of activity in this heavily pre-treated population.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-11-10.