Phase II open-label, safety, pharmacokinetic and efficacy study of 2-methoxyestradiol nanocrystal colloidal dispersion administered orally to patients with recurrent glioblastoma multiforme

Abstract

2065 Background: 2-methoxyestradiol (2ME2) inhibits tumor cell proliferation and induces apoptosis by inhibiting microtubule polymerization and increasing reactive oxygen species-induced cell damage. In addition, 2ME2 downregulates HIF-1a at the posttranscriptional level and inhibits HIF-1a-mediated VEGF expression. Preclinical studies confirm significant in vitro and in vivo anti-glioma activity including tumor regression in combination with temozolomide. We therefore performed a single-center, phase 2 study to evaluate 2ME2 in recurrent glioblastoma multiforme (GBM) patients. Methods: Key eligibility include: adults with GBM at first or second recurrence; measurable disease; Karnofsky performance status = 70% and adequate organ function. 2ME2 was given orally 4 times/day at a dose of 1000mg for the first 11 patients and then escalated to 1500 mg for remaining patients. Patients are evaluated after every 28-day cycle. The primary efficacy endpoint is 6-month progression-free survival. Results: Sixteen patients (14 male) have been enrolled, including 7 at first recurrence and 9 at second recurrence. The median age is 52 years (range, 32–64 years). Thirty-five cycles have been administered to date. Grade II-IV, attributable toxicities include transaminase elevation (grade 3, n=3; grade 2, n=1); hypophosphatemia (grade 3, n=1); anorexia (grade 2, n=1) and rash (grade 2, n=1). Six patients (38%) have achieved stable disease including one minor response. PK studies revealed similar 2ME2 exposures to those achieved among solid tumor patients treated at the same dose level and no differences between GBM patients on or not on CYP3A-inducing anti-epileptic agents. Further accrual and follow-up is ongoing. Conclusions: Continuous daily 2ME2 dosing, administered as a monotherapeutic, is well tolerated and is associated with modest anti-tumor activity among recurrent GBM patients. Combination studies with temozolomide are underway. No significant financial relationships to disclose.