Crolibulin™

Description

Crolibulin™ is a novel small molecule vascular disruption agent and apoptosis inducer for the treatment of patients with advanced solid tumors. Crolibulin™ has shown promising vascular targeting activity with potent anti-tumor activity in pre-clinical in vitro and in vivo studies. The molecule has been shown to induce tumor cell apoptosis and selectively inhibit growth of proliferating cell lines, including multi-drug resistant cell lines. Murine models of human tumor xenografts demonstrated crolibulin™ inhibits growth of established tumors of a number of different cancer types. Two manuscripts on this compound were published in the November 2004 issue of Molecular Cancer Therapeutics.

Pre-clinical studies suggest that the anti-tumor effects of crolibulin™ may be the result of a dual mechanism, a direct effect on disruption of tumor vascular endothelial cells leading to hypoxia and central tumor necrosis, as observed with vascular disruption agents, and a second effect on tumor apoptosis.

In 2009, EpiCept announced that it had completed the first study in man for crolibulin™. EpiCept identified the maximum tolerated dose of crolibulin™ in the Phase I study after 1 hour and 4 hour infusions. Crolibulin™ was administered as a single agent in increasing doses to small cohorts of patients with advanced solid tumors. A total of 33 patients were enrolled in the study. The study provided evidence of clinical symptomatic activity and radiographic evidence of efficacy in end-stage cancer patients.

Stage of Development

In December 2010, the National Cancer Institute (NCI) initiated a Phase Ib/II, that assessed the drugs safety and efficacy in combination with cisplatin in patients with anaplastic thyroid cancer (ATC).  The primary objective of the first stage of the clinical trial was to assess the safety and tolerability of cisplatin and crolibulin™ given in 21-day treatment cycles. The study assessed the toxicities of crolibulin™ co-administered with cisplatin, evaluated dose-limiting toxicities (DLTs) and determined the maximum tolerated dose (MTD) for the combination.

In June 2013, the results from the Phase I portion of this clinical trial were preseented at the meeting of the American Society of Clinical Oncology (ASCO).  Twenty-one patients were enrolled and received cisplatin and crolibulin™ up to 100/20mg/m² of cisplatin/crolibulin™. The authors concluded that the combination of cisplatin plus crolibulin™ shows interesting results and deserves further evaluation as a regimen for ATC.  The MTD of cisplatin/crolibulin™ is 100mg/m² IV day 1 and 20mg/m² IV days 1,2,3 every 21 days.  This combination is well tolerated, with toxicity primarily related to cisplatin.  The most common grade 3 toxicities were lymphopenia (33%), hypertension during infusion (29%), hyponatremia (24%), anemia (19%) and hypophosphatemia (10%).

The primary objective in the second stage of the trial (Phase II) will be to compare the combination of crolibulin™ and cisplatin against cisplatin alone in adult ATC patients by assessing the duration of progression-free survival (PFS).  An important secondary objective is the comparison of the response rates evaluated by RECIST (Response Evaluation Criteria in Solid Tumors).  Up to 70 patients are planned to be enrolled in the trial.

ATC is an extremely aggressive cancer that has a median survival of four to five months from the time of diagnosis.  Few patients survive more than one year.  Treatment for most patients is generally palliative, indicating a profound unmet medical need.