Novel Agent Moves Into Ovarian Cancer Combinations

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).

In terms of adverse events, the combination did not result in any unexpected signals, Tewari said. Grade 3 hypertension was observed more in the combination arm.

Tewari stressed that investigators would be watching carefully for cardiovascular side effects including hypertension and sinus tachycardia among patients who receive both vascular-targeting drugs. He said they have developed algorithms to address potential cardiovascular side effects.

Hypertension also is a concern with Avastin.

The FOCUS study will be conducted in two stages. In the first part, 80 patients will be randomized to the experimental three-drug regimen versus the control; up to four interim analyses will be conducted so that researchers can determine the safety and efficacy of the novel strategy. The second part of the study will randomize approximately 350 patients to the same treatment arms.

Participants will be stratified by the type of chemotherapy they receive, the duration of platinum-free interval (less than three vs three to six months) before enrolling in the trial, and the line of therapy (2nd vs 3rd).

The trial is open to women aged 18 years and older with confirmed platinum-resistant epithelial ovarian, fallopian tube or primary peritoneal cancer who have received at least one prior platinum-based regimens and have measurable disease. Participants receiving doxorubicin must have left ventricular ejection fraction ≥45% at baseline assessment.

Tewari said the triplet regimen is "very promising" for patients who are particularly in need of new therapies. He noted that thus far, only one randomized phase 3 clinical trial in the platinum-resistant ovarian cancer space has met its primary endpoint. Specifically, the AURELIA study led to the FDA's approval of Avastin plus chemotherapy for this patient population.

"In FOCUS, we are taking two of the winners of AURELIA — weekly paclitaxel plus bevacizumab and pegylated liposomal doxorubicin plus bevacizumab — and studying each doublet with and without fosbretabulin," said Tewari. "Therefore, with triplet therapy, we have a real opportunity to build on the success of AURELIA with chemotherapy directly killing the cancer cells, fosbretabulin attacking the central core of exisiting tumor vasculature, and bevacizumab preventing vessel regrowth at the periphery of the tumor through angiogenesis blockade."

At the same time, Tewari said the fosbretabulin strategy also may work in patients with bulky tumors as well as in individuals with platinum- sensitive recurrent disease.

Mateon Therapeutics, which is sponsoring the FOCUS trial, also is studying the drug in combination with pazopanib in ovarian cancer that is recurrent after platinum-containing therapy.