The novel agent plinabulin (under development by BeyondSpring) has not been approved by the Food and Drug Administration (FDA), as the agency announced Wednesday that more clinical data is need.
The company had applied for approval for use of plinabulin in combination with granulocyte colony-stimulating factor (G-CSF) for the prevention of chemotherapy-induced neutropenia (CIN).
The application was based on a single registrational trial (106 Phase 3).
In a complete response letter, the FDA said that the results were “not sufficiently robust to demonstrate benefit and that a second well-controlled trial would be required to satisfy the substantial evidence requirement to support the CIN indication.”
The company said that it “expects to work closely with the FDA to consider the possible future clinical pathway for CIN, which may include a second study.”
It also notes that plinabulin is the first drug candidate submitted for FDA approval that has the potential to work in the critical first week of chemotherapy treatment before G-CSF is effective, to prevent the onset and improve clinical outcomes of CIN.
Experts Had Doubts
Some of the details of the phase 3 trial that were submitted for approval were presented as a poster at last year’s San Antonio Breast Cancer Symposium (SABCS), as reported then by Medscape Medical News.
The phase 3 trial, known as PROTECTIVE-2, was conducted among 221 breast cancer patients being treated with docetaxel, doxorubicin, and cyclophosphamide. All study patients received pegfilgrastim, the standard of care for the prevention of neutropenia. They were also randomly assigned to receive either plinabulin (n = 111) or placebo (n = 110) on day 2 of the first treatment cycle.
The primary endpoint of the trial was the rate of prevention of grade 4 neutropenia, which was reported as occurring in 31.5% of patients who received the combination of plinabulin plus pegfilgrastim, vs 13.6% of those who received pegfilgrastim monotherapy (P = .0015).
In their poster at SABCS, the authors report that the plinabulin arm “was associated with a >40% reduced febrile neutropenia risk” compared with the placebo arm (19.7% vs 40.9%; odds ratio, 0.592).
In a company press release issued at the time, the combination of plinabulin with pegfilgrastim was described as “a major advancement in offering protection against CIN.”
However, experts contacted by Medscape Medical News at the time were not impressed.
Terry Ng, MD, medical oncologist, University of Ottawa, Ontario, Canada, said the results of the breast cancer study are not entirely clear, inasmuch as the endpoint ― the rate of prevention of grade 4 neutropenia ― is not easily understood and does not represent what is most clinically significant.
Charles Shapiro, MD, medical oncologist, Icahn School of Medicine at Mount Sinai, New York City, agreed, and said: “What counts most is neutrophils <500/µL and fever, or febrile neutropenia.”
Shapiro added that any would-be addition to pegfilgrastim should require strong supporting evidence, because alone, it is “already good at reducing the incidence and duration of febrile neutropenia and severe neutropenia.”
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