Novel Agent Moves Into Ovarian Cancer Combinations

A recently launched clinical trial is exploring a new agent to treat patients with advanced, recurrent, platinum-resistant ovarian cancer. 
A clinical trial is looking to develop new therapeutic options for women with advanced, recurrent, platinum-resistant ovarian cancer by using a multipronged attack on the tumor vasculature network.

The novel agent fosbretabulin tromethamine is being combined with Avastin (bevacizumab) and physician’s choice of either paclitaxel or pegylated liposomal doxorubicin in the experimental arm of the phase 2/3 FOCUS study (NCT02641639). The regimen will be compared with Avastin plus chemotherapy, which is one option for this patient population.

Fosbretabulin and Avastin both target vascular signaling but in different ways, said principal investigator Krishnansu S. Tewari, M.D., a full professor and director of research in the Division of Gynecologic Oncology at the University of California, Irvine and director of the Gynecologic Oncology Program at the Center for Cancer Prevention and Treatment at St. Joseph's Hospital in Orange, California.

“Bevacizumab prevents the formation of new blood vessels whereas fosbretabulin targets existing vasculature,” Tewari said in an interview with CURE. “The central part of the tumor undergoes necrosis because the existing vasculature is targeted. Meanwhile, out on the periphery or the rim of the tumor, bevacizumab is working to prevent new blood vessels from forming. So it’s a double attack on vasculature. Hence the terminology, vascular-targeting therapy."

That dual attack will be combined with chemotherapy, which is aimed at direct killing of cancer cells. “Hopefully, the regimen will be one concerted effort to target the cancer and therefore limit the toxicity to the patient,” said Tewari.

Rationale for Combination

Fosbretabulin is a small molecule derived from combretastatin A4 phosphate (CA4P), originally isolated from the African bush willow Combretum caffrum.

Specifically, fosbretabulin is classified as a vascular disrupting agent that selectively binds to β-tubulin and changes the shape of recently formed endothelial cells without affecting more mature cells. In contrast, Avastin is a humanized monoclonal antibody that binds to vascular endothelial growth factor (VEGF), preventing it from interacting with VEGF receptors on the surface of endothelial cells.It is categorized as an antiangiogenic agent.

The rationale for combining the two vascular-targeting drugs was established in the single-arm phase 2 GOG-01861 study, conducted in 107 patients with recurrent or persistent epithelial ovarian, tubal or peritoneal carcinoma who had undergone three or fewer prior treatments. Participants were randomized to receive Avastin (15 mg/kg) plus fosbretabulin (60 mg/m2) intravenously once every three weeks versus Avastin alone.

The regimen demonstrated a median progression-free survival of 7.3 months compared with 4.8 months for Avastin alone. The overall response rate among patients with measurable disease as defined by RECIST criteria was 35.7 percent among participants treated with the combination (42 patients) versus 28.2 percent among those who received Avastin alone (39 patients).

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