Because there are cases of delayed pseudo who fail to be removed at baseline visit. Those patients end up in the main arm of studies. Some will have ended up in this Phase III no doubt. If they are receiving vaccine, same as Brad did, what happens is some Mesenchymal patients can appear like progression patients but they are not, and the condition only shows up a few months into the study. Brad's pseudo condition cleared up, and so in the Ph i/II he was not classified as a progression patient at any point. There is concern in this study that the definition for progression will not allow this study much leeway in terms of ruling out progression in these hard to determine late stage pseudo cases. But this study does have a Central Review team in place to confirm progression. Sites may suggest it is progression, but patients are not removed until the Central Review (xxx) evaluates the radiographic scans to determine patient response, and that to me means they're potentially trying to determine if there is a causation. They will try to keep pseudos in the main arm and not rule them as progression for as long as possibly. But they won't know who is on treatment or not. And, it may boil down to sticking to old definition of progression, which depends on tumor burden size.
"XXX an imaging core laboratory, will evaluate radiographic
scans to determine patient eligibility, response, and tumor progression for all study sites."
The issue is no one knows how much wiggle room there is on central views discretion on "unequivocal" progression. But over at IV, they are convinced pseudo within the main arm (the Brad's of the study) will be termed as progression patients based on tumor burden.
"14.2. DEFINITION OF PROGRESSION AFTER ENROLLMENT
Progression, calculated from the nadir tumor burden (i.e. post operative, Baseline, or
Baseline 2), is defined as one of the following:
• In the case of complete resection during primary therapy: a new measurable tumor
at the site of the resected tumor, defined as a mass with a longest diameter equal to
or greater than 1 cm in at least one dimension. If progression is not defined by these
studies, treatment may proceed and determinations made at the next scheduled
MRI.
• In the case of incomplete resection during primary therapy: a 25% increase or
greater in the residual tumor if the recurrent portion of the tumor is at least 1 cm or
greater in its longest diameter, measured by MRI and confirmed by scans above as
attributable to tumor growth;
• If resection is indicated for recurrent disease, while radiographic criteria for
progression have not been met: surgical resection, subsequently confirmed as
progressive GBM by Pathology at the clinical site and to be confirmed by
independent pathology;
• Appearance of any new lesion/site at least 1 cm in at least one dimension or greater
measured by MRI and confirmed by scans above;
• Unequivocal progression of non-measurable disease (either non-enhancing disease seen only on T2/FLAIR images or enhancing disease not meeting size criteria for measurability), such that there is confidence that tumor growth has occurred;4
4 Radbruch et al. 2010: Neuro Oncol. 2011 Dec 6.
• Death: all deaths are counted as events for the primary endpoint.
Radiographic evidence of disease progression will be evaluated and corroborated by
independent radiology review to determine disease progression for purpose of this trial.
MRIs to assess disease progression are done every 2 months. Unscheduled MRIs or
other testing will be recorded in eCRFs. If, during unscheduled procedures, there is
evidence of disease progression, it must be confirmed through independent review as
described above.
14.3. TIME TO TUMOR PROGRESSION
Time to tumor progression is assessed from nadir tumor burden (post operative,
Baseline, or Baseline 2) to the date of the first observation of objective disease
progression measured by MRI and confirmed if necessary by scans as described above
in section 14.2.
Patients who have not progressed by the end of the study will continue to be followed
for tumor progression or tumor recurrence, for survival (Section 14.5) and for their
medical history."
And you may have late pseudo condition patients who are removed as PFS patients but then crossover to open label and continue to receive vaccine. OS doesn't change for these patient, but where one records progression on disease may change. And that then brings the issue that patients who may not have progressed (in blinded vaccine arm) are restarting their vaccine schedule from zero. And then that opens up looking at how treatment schedules actually may be affecting the trial (blind vaccine to open vaccine schedule). And then top it all off, you also have placebo patients who are eventing later (including these delayed pseudos on placebo) and crossing over to open label. Well those patients are living beyond the 17 months the study planned. And that is why all these OS crossover open label patients are starting to resemble each other. All patients are living longer. The vaccine may not ward of PFS by the months and months they were expecting, but yet OS is trending well for this trial. But it presents a challenge if PFS is not statistically significant. And so yes, pseudos wreak havoc on trials.
