Ombrabulin Hydrochloride

Combination vascular-targeted therapies (VTTs) represent a promising approach for patients with platinum-resistant recurrent ovarian cancer (OC). VTTs include two mechanistically distinct classes of agents: anti-angiogenic agents (AAs) and vascular-disrupting agents (VDAs). AAs suppress growth of new tumor vasculature through inhibition of vascular endothelial growth factor (VEGF) and other pro-angiogenic molecules. Bevacizumab, a monoclonal antibody that binds to VEGF, has improved progression-free survival (PFS) when given with chemotherapy in patients with advanced OC. VDAs target the established tumor vascular network, inducing vessel occlusion, shutdown of circulation, and widespread necrosis within the tumor interior - a region often resistant to conventional chemotherapy and radiation. Tubulin-binding VDAs such as BNC105P, ombrabulin, and combretastatin A4-phosphate (CA4P) have been studied for the treatment of OC. These agents act by binding tubulin in the endothelial cells of tumor vessels, triggering cytoskeletal disruption, altering cellular shape, and destabilizing cell-cell junctions, which lead to increased vascular leakage and, ultimately, to disruption of blood flow. Fundamental differences between the vascular networks of tumors and those of normal tissues allow these agents to selectively reduce tumor circulation while having little effect on non-malignant tissues. Animal studies and clinical trials show enhanced efficacy when VDAs are combined with chemotherapy as well as AAs. The latter combination allows targeting of different aspects of the tumor vasculature, a strong rationale for combining these two drug classes into a single regimen. CA4P is the only VDA in active development for OC. In a phase II trial of patients with recurrent OC, CA4P added to bevacizumab improved PFS compared with bevacizumab alone. The phase II, placebo-controlled PAZOFOS trial (NCT02055690) is evaluating the effects of CA4P plus the anti-angiogenic agent pazopanib in recurrent OC. FOCUS, a phase II/III, placebo-controlled trial (NCT02641639), is currently evaluating CA4P plus bevacizumab and chemotherapy in platinum-resistant OC.

In clinical studies in Western countries, the recommended dose of combination ombrabulin a vascular disrupting agent, with cisplatin is 25 mg/m2 ombrabulin with 75 mg/m2 cisplatin every 3 weeks. Here, we report the first Phase 1 study of this treatment regimen in Japanese patients with advanced solid tumors.

This was an open-label, multicenter, sequential cohort, dose-escalation Phase 1 study of ombrabulin with cisplatin administered once every 3 weeks. The study used a 3 + 3 design without intrapatient dose escalation. The investigated dose levels of ombrabulin were 15.5 and 25 mg/m2 combined with cisplatin 75 mg/m2. The latter dose level was regarded as the maximum administered dose if more than one patient experienced dose-limiting toxicities.

Ten patients were treated, but no dose-limiting toxicity was observed at both dose levels. Ombrabulin 25 mg/m2 with cisplatin 75 mg/m2 was the maximum administered dose and regarded as the recommended dose in the combination regimen for Japanese patients with cancer. The most frequently reported drug-related adverse events were neutropenia, decreased appetite, constipation, nausea and fatigue. One partial response and five cases of stable disease were reported as the best overall responses. Pharmacokinetic parameters of ombrabulin and cisplatin were comparable with those in non-Japanese patients.

Ombrabulin 25 mg/m2 with cisplatin 75 mg/m2 once every 3 weeks was well tolerated and established as the recommended dose in Japanese patients with advanced solid tumors. The safety and pharmacokinetic profiles were comparable between Japanese and Caucasian patients.