A multipronged attack on the tumor vasculature network is at the heart
of a recently launched clinical trial aimed at developing new therapeutic
options for women with advanced, recurrent, platinum-resistant ovarian cancer.
The novel agent fosbretabulin tromethamine is being combined with bevacizumab
(Avastin) and physician’s choice of either paclitaxel or pegylated
liposomal doxorubicin in the experimental arm of the phase II/III FOCUS
study (NCT02641639). The regimen will be compared with bevacizumab plus
chemotherapy, which is one option for this patient population.
Fosbretabulin and bevacizumab both target vascular signaling but in different
ways, said principal investigator Krishnansu S. Tewari, MD, 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
OncLive. “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
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
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.2 In contrast,
bevacizumab 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.3 It is categorized
as an antiangiogenic agent.
The rationale for combining the 2 vascular-targeting drugs was established
in the single-arm phase II GOG-01861 study, conducted in 107 patients
with recurrent or persistent epithelial ovarian, tubal, or peritoneal
carcinoma who had undergone ≤3 prior treatments.1 Participants were
randomized to receive bevacizumab (15 mg/kg) plus fosbretabulin (60 mg/m2)
intravenously once every 3 weeks versus bevacizumab alone.
The regimen demonstrated a median progression-free survival of 7.3 months
compared with 4.8 months for bevacizumab alone (HR, 0.69;
P = .05). The overall response rate among patients with measurable disease
as defined by RECIST criteria was 35.7% among participants treated with
the combination (n = 42) versus 28.2% among those who received bevacizumab
alone (n = 39).1
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 bevacizumab.
The FOCUS study will be conducted in 2 stages. In the first part, 80 patients
will be randomized to the experimental 3-drug regimen versus the control;
up to 4 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 (<3 vs 3-6 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 ≥1 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 1 randomized phase III 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 bevacizumab plus chemotherapy for this
"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 tumors5 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.