Ombrabulin Hydrochloride

The combination use of the vascular disrupting agent ombrabulin with chemotherapeutic agents was previously shown to be highly synergistic in preclinical models.

In this dose-escalation study of ombrabulin (15.5-35 mg/m2) in combination with docetaxel (60 or 75 mg/m2) and cisplatin (75 mg/m2), agents were administered 24 h apart every 3 weeks to Japanese patients with advanced solid tumors. The study was designed and conducted in a 3 + 3 manner. Safety, tumor response and pharmacokinetics were evaluated.

Eleven patients with non small cell lung cancer as the primary tumor were treated. Two patients out of five had dose limiting toxicities (DLTs) in Cycle 1 at the starting doses of ombrabulin 15.5 mg/m2, docetaxel 60 mg/m2 and cisplatin 75 mg/m2. Thus, dose escalation was terminated. The first dose level was re-evaluated in six patients who received prophylactic granulocyte-colony stimulating factor (G-CSF). However, because of the occurrence of DLTs in Cycle 1 in two patients out of six, the study was led to the premature termination without pursued upper dose level. Partial response was observed in four patients out of 11. Pharmacokinetic parameters of ombrabulin and cisplatin were not altered in this combination treatment, while docetaxel clearance decreased by ~40% compared to that observed with docetaxel monotherapy at the same dose (60 mg/m2).

A combination regimen of ombrabulin with cisplatin and docetaxel was not feasible for Japanese patients owing to the occurrence of hematological and non-hematological DLTs at the initial dose level.

ClinicalTrials.gov number, NCT01095302.

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.