I don't think this was shared before...
There are lots of clouds around this and "scealed evidences"... Why?
https://www.karger.com/Article/Fulltext/505379
We next examine the late-stage failure of bavituximab, which can be attributed to poor quality phase II data as well as difficult strategic and commercial factors that are not uncommon for smaller, early-stage companies.
The only phase III trial of bavituximab to date is the SUNRISE trial, which compared the efficacy of docetaxel plus bavituximab or placebo in patients with NSCLC [62]. The primary endpoint was OS [62]. At the first planned interim analysis, however, an independent data monitoring committee recommended early stopping due to futility [62]. At the time, median OS in the docetaxel/bavituximab arm was 10.5 months, worse than the 10.9 month median OS seen in the docetaxel/placebo arm (HR 1.06; 95% CI 0.88–1.29; p = 0.533) [62]. There was also no significant difference seen in progression-free survival (PFS), one of the trial’s secondary endpoints (HR 1.00; 95% CI 0.82–1.22; p = 0.99) [62].
What can account for such disappointing results?
Poor Quality Data from a Botched Phase II Trial
The late-stage failure of bavituximab can be traced in part to problems originating in the preceding phase II NSCLC study. That study was designed as a 3-arm study, with patients randomized to receive docetaxel plus placebo, docetaxel plus lower dose bavituximab (1 mg/kg), or docetaxel plus higher dose bavituximab (3 mg/kg) [63]. The primary endpoint was overall response rate (ORR), and secondary endpoints included OS and PFS [63]. Due to a labeling discrepancy, some patients in the placebo arm received doses of bavituximab 1 mg/kg, and some patients in the bavituximab 1 mg/kg arm received doses of placebo [63]. Patients in the bavituximab 3 mg/kg arm were not affected by the labeling error [63]. Data from the placebo and bavituximab 1 mg/kg arms were pooled into a “combined control group,” and the efficacy analyses were reported as “exploratory” [63].
As the labeling discrepancy did not impact the bavituximab 3 mg/kg arm, ORR in this treatment group could be considered a true standalone data point. Unfortunately, the observed 17.1% ORR (95% CI 5.6–28.6%, p = 0.37) fell short of the prespecified ORR of 26% required to achieve the primary endpoint [63]. As for the secondary endpoints, comparison of bavituximab 3 mg/kg against the combined control group was obviously problematic due to lack of a true control; nevertheless, significant differences in PFS and OS were not achieved. Median PFS was 4.5 and 3.3 months in the bavituximab 3 mg/kg and combined control group, respectively (HR 0.74, 95% CI 0.45–1.21, p = 0.24) [63]. Similarly, OS was 11.7 and 7.3 months in the bavituximab 3 mg/kg and combined control group, respectively (HR 0.55, 95% CI 0.40–1.10, p = 0.11) [63].
Certainly, advancing into phase III based on a phase II trial in which the primary endpoint was not met and “exploratory” secondary endpoints showed only nonsignificant trends was asking for trouble. The trial investigators themselves admitted that it was “not possible to draw firm conclusions” from the phase II trial [63], and yet the “go” to phase III decision was made.
One possible reason is that the phase II NSCLC study results were the best data they had. As discussed above, in addition to NSCLC, Peregrine tested bavituximab in numerous phase II trials across a variety of potential indications, including prostate cancer, pancreatic cancer, breast cancer, advanced hepatocellular carcinoma, and hepatitis C. As it happens, none of those study results were published, but while publication bias is a reality, negative results should not automatically be inferred from unpublished studies. In this case, however, the unpublished phase II studies, combined with the fact that phase III testing was not pursued in any disease state other than NSCLC, are somewhat more telling. The SUNRISE trial in NSCLC is the only phase III trial of bavituximab to date, and it may have been initiated because the botched phase II study produced the most positive data for bavituximab across all potential indications.
From CC
Sept 10 Dr. Garnick:
Thanks, Joe. As you have just heard from Joe, the data we announced last week has far exceeded our expectations. And I hope that you're as excited as I am with bavituximab's potential. I feel strongly that Peregrine should be recognized for having the corporate courage to conduct the rigorous, randomized placebo-controlled Phase II trial that provided these robust data and that provide the basis for us to plan for a pivotal Phase III program. We took extraordinary amount of care in developing this Phase II trial design and conferred with clinical experts and regulatory agencies, including the FDA, in design of this rigorous clinical trial. Peregrine chose to conduct this trial to definitively establish the proof of concept of bavituximab and now plan to potentially include this data as part of a registrational package.
Having personally been involved in the evaluation of over 30 Phase II trials over my career, none of which ever achieved statistical significance, including many of today's blockbuster biotech products, I am personally extremely pleased with the quality of this data and the clarity with respect to advancing bavituximab in Phase III trials, which it provides.
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