Abstract CT314: Interim results from a phase I/II trial of TPI 287, a novel brain penetrable antimicrotubule agent, in combination with bevacizumab for the treatment of recurrent glioblastoma
Authors: Silberman Sandra L. , Goldlust Samuel , Nabors L. Burt , Duic J Paul , Benkers Tara , Mohile Nimish , Picker Donald , Singer Samuel , Farmer George 
Published: August 2015

Background: TPI 287 is a novel anti-microtubule agent designed to evade inactivation and efflux by multiple drug resistance pathways, which enables meaningful penetration of the blood-brain barrier. Preclinical results demonstrate CNS accumulation at pharmacologically relevant concentrations and significant anti-neoplastic activity in a murine model of brain metastases (Fitzgerald, et al Mol Can Ther 2012 11:1959-67). Safety data from clinical trials enrolling over 200 cancer patients have shown TPI 287 to be well tolerated. Based on these data, a dose-escalation phase I/II trial was designed to determine the maximum tolerated dose (MTD) and efficacy of TPI 287 for recurrent glioblastoma (GBM) in combination with the angiogenesis inhibitor bevacizumab. Interim results from the dose escalation portion of this trial are reported.

Methods: GBM patients at first or second relapse after failure of standard chemoradiation and without prior exposure to angiogenesis inhibitors are eligible. Standard-of-care bevacizumab is administered at 10 mg/kg as an IV infusion once every 2 weeks. TPI 287 is administered as an IV infusion every 3 weeks. Employing a 3+3 design, dose escalation of TPI 287 is ongoing until determination of MTD, followed by transition to the randomized phase II stage of the trial. MRIs are obtained every six-weeks with response assessment via RANO criteria.

Results: As of December 2014, 16 subjects have been enrolled in the first 5 TPI dose-escalation cohorts (140-180 mg/m2). No dose-limiting toxicities have been observed to date. Of 12 patients evaluable for safety, myelosuppression has been the only Grade 3 adverse event attributed to treatment (2 patients). Among the 13 patients evaluable for efficacy, there were 5 confirmed objective responses (1 CR; 4 PR) and 2 responses awaiting confirmation (1 CR; 1 PR). Durability of the confirmed responses has ranged from 5.5 to 8.2+ months.

Conclusions: These interim results demonstrate that TPI 287 in combination with bevacizumab is well tolerated. Moreover, efficacy data is promising, with a high rate of durable responses achieved below the MTD. This study also highlights the power of translational studies for evaluating effective cancer therapy. Evolving safety and efficacy results will be presented.

Citation Format: Sandra L. Silberman, Samuel Goldlust, L. Burt Nabors, J Paul Duic, Tara Benkers, Nimish Mohile, Donald Picker, Samuel Singer, George Farmer. Interim results from a phase I/II trial of TPI 287, a novel brain penetrable antimicrotubule agent, in combination with bevacizumab for the treatment of recurrent glioblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT314. doi:10.1158/1538-7445.AM2015-CT314