Replies to post #104321 on NorthWest Biotherapeutics Inc (NWBO)

[Rkmatters]

AVII marks up Brad’s scan taking 2 weeks after initial treatment, and suggest that they are progression. Somehow he has convinced you that taking sporadic scan at various times to check for response is not acceptable. He has also convince you that Macdonald criteria does not adapt when measuring response. According to AVII, the first sign of any change from Post RT MRI, the patient is out. The way he imagines it, there is no time to measure response to and progression on a newly imposed treatment therapy. And he has you convinced and confused because the protocol does not tell you what counts as response.

Meanwhile UCLA actually looked for these kind of responses that he likes to call straight out of the bat progression:

“In addition, we utilized gene expression profiling to identify a group of patients with a particular gene expression signature (mesenchymal glioblastoma) that had longer survival following dendritic cell vaccination, compared with contemporary/historic control patients of the same gene expression subgroup, who did not receive vaccination. This signature was associated with inflammatory transcripts and enhanced tumor-infiltrating T lymphocytes. Thus, these results suggest that gene expression signatures may be able to identify an immunogenic subgroup of glioblastoma that could be more responsive to immune-based therapies.— DCVax-L Phase I/II paper

“Secondary objectives were to assess this vaccination strategy for its ability to stimulate systemic anti tumor CTL responses and to investigate whether induction of such responses correlated with intracranial T-cell infiltration and/or clinical survival.” — DCVax-L Phase I

With regards to the Phase III exclusion criteria, AVII ignores that response to RT/TMZ had not been measured yet. Another scan was needed to confirm progression of those excluded patients. And with regards to both Brad and the Phase III main enrollment, AVII ignored that DCVax-L therapy has not been measured yet. The month 2 scan is the first scan in the trial to measure response. I have told him many times that response to therapy can not be measured before a patient is even on therapy. Even old MacDonald criteria wants to make sure the psuedoprogression patients are accounted for with regards to treatment response. And so, a subsequent scan would automatically be needed after Month 2.

Meanwhile, Linda Liau tells you that the Indeterminate patients who are psPD and who are alive have not seen a progression event; and that the excluded patients were unfortunately removed from the trial due to the exclusion criteria. He sees that they were confirmed progression event patients. Meanwhile, they were not. Similar to MacDonald criteria, all those excluded patients required a follow-up scan to confirm progression. Do note that ANY change from a gross total resection patients in T1 enhancement automatically qualifies as a possible progression event. Possible does not mean that it is ruled an automatic progression event; instead patient follow-up must be done. But if you don't believe that see the last linked study below, which partially explains why RANO was incorporated; and how pseudoprogression decision trees are necessary in all trials.

As for the proof you need to feel comfortable that what I tell you is accurate, here is the proof of the Macdonald 1990 criteria paper below.

“Tumor progression is defined by increasing tumor size, new areas of tumor, or unequivocal neurologic deterioration. Provided the investigator carefully excludes nontumor-related causes of clinical or radiologic worsening (ie, pseudoprogression), either is evidence of treatment failure. “ — Macdonald 1990 criteria

And it is as I stated, the first scan that shows possible progression, MUST be sustained for the patient to be called progression.

“Response in this scheme demands a sustained (ie, > 1 month) and significant (ie, > 50%) reduction in the size of the enhancing tumor on CT or MRI scans.” — MacDonald 1990 criteria.

Patients can not be removed prior to measuring for response to therapy. The first scan after initiation of therapy where possible progressive disease shows up is not enough. Patient require a follow-up scan to confirm that what was seen on the first scan is progression. And so, if progression is suspected on the Month 2 fist scan but psuedoprogression can't be ruled out, then according to old MacDonald, another scan is needed.

“When is response assessed, how is its duration measured, and when can treatment failure be declared? In our experience, CR can occur within 2 months, and time to maximum response can be as long as 6 to 12 months. Murovic et al reported that time to CR may range from 9 to 151 weeks.8 We suggest that patients be assessed for response after two courses of treatment, that responding and stable patients continue treatment, that duration of response be the interval between the start of treatment and the first clinical or radio- logic sign of tumor progression, and that tumor progression be declared no sooner than 1 month after the first course of treatment.” — Macdonald 1990 criteria.

http://ascopubs.org/doi/pdf/10.1200/JCO.1990.8.7.1277


So AVII telling marking up Brad’s scan taken 2 weeks after initiating therapy and telling you that it qualifies as a progression event is wrong. It qualifies as response that should be measured with follow-up scan(s). If that follow-up scan(s) got clinically worse then UCLA would have had no choice but to remove Brad, regardless that he was responding. But that didn't happen. He got progressively better instead, we just don't see all those scans. They only shared the scan of the complete disappearance. It should be understood that a rapid progression patient can not hide behind pseudoprogesssion scan for long. If Brad had been a rapid progression patient then his scans would have gotten worse. There is no reliable method that can look at first scans and determine whether they are seeing tumor progression or response. Understand that when there is no tumor to start with the mere “ enhancement” showing up automatically fits the > 25% showing up. AUTOMATICALLY. But even under old MacDonald criteria, they allowed to see a sustained change. I know AVII does not believe that RANO is incorporated into this trial because the “does not equal progression” is not spelled out in the protocol. I’m telling you that it does not need to be because the first SCAN after therapy falls 10 weeks after chemoradiation ends, and that first scan by default can not be used to eliminate patients. THAT first scan will determine whether they want patients to come back 2 months later to test again, or back in sooner than that. As you know this trial allowed for other imaging modalities, and so if they suspect the first scan is possible progression, they will test patients patients much sooner than 2 months to rule the event as progression.

Investigational imaging techniques for distinguishing progression from treatment effects:

* There is not yet a validated imaging technique that distinguishes treatment effect from true treatment failure, and clinical follow-up and/or pathologic confirmation are currently utilized to distinguish these processes. Several currently available imaging techniques may potentially be helpful, but rigorous evaluation testing the clinical usefulness has not occurred.
* Alternative MRI sequences
* – Dynamic contrast imaging takes advantage of increased vascularity of the tumor compared with the normal or necrotic tissue. The amount of contrast flowing through a given volume is measured by assessment of T2* alteration, and higher flow of contrast through the tissue is indicative of more vascularization. This method may be more sensitive and specific that delayed contrast enhancement imaging alone.
* – Diffusion weighted imaging is a reflection of the local motion of water molecules in the microenvironment. The more restricted the motion of water molecules, the higher signal obtained on diffusion weighted images. In general, cancer cells are tightly packed with high nucleolus to cytoplasm ratios, hence, more restricted environment and higher signal.
* – Spectroscopy can yield valuable information regarding the composition of major metabolites within the tissue. Choline has been shown to increase in cases of tumor progression while decreasing in radiation-induced necrosis. The downside of spectroscopy is long acquisitions and volume averaging.
* PET and single-photon emission computed tomography are based on metabolic activity of the tissue and rate of uptake of the radiopharmaceutical. While currently not the mainstream modalities to differentiate tumor progression versus postradiation changes – mainly marred by low specificity and low special resolution – they hold a promising future, given ongoing development of tumor-specific radiotracers and molecular imaging.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4325371/

And here is an example using chemoradiation (PP — means Pseduoprugression below) using good old MacDonald criteria:

Assessment of Response
Standard MacDonald criteria were used to determine response to chemoradiation.13 The definition of PP was defined as (1) an initial assessment of progression using standard MacDonald criteria 1 to 3 months after completion of treatment, and (2) either subsequent MRIs showed stability or improvement for at least 2 months without alteration of corticosteroid dose or a change in therapy or a subsequent resection showed RT effects without evidence of viable tumor.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2860441/

See this Brandes paper and FIGURE 1 which explains the pseduoprugression decision tree. This describes standard of care patient, and the Phase III trial exclusion criteria, as well as the Pseudo cohort. None of the psuedoprogression patients that were removed at the Post RT MRI scan recorded a progression event. Instead, according to Macdonald criteria, the suspected progression patients all came back for their next scan and that is where they were divided between rapid and pseudoprogression. AVII continued to ignore this FIGURE 1 image, but that doesn't mean that you should. The Indeterminate patients as you know may be a mix of psPd and rapids, and so the psPD are of patients best describe the PsPD progression cohort. This FIGURE 1 however should make it clear to you that none of the exclusion criteria patients had confirmed progression at Post RT MRI. It is as the CUA 46 abstract describes as needing to confirm progression on a follow-up scan, which as you know fell at Month 2 MRI scan. ALL the Indeterminate patients did not have progression at Month 2 follow-up scan. And again, all the remaining Indeterminate and Pseudo patients are well beyond the period of a progression event that Brandes study recorded. Lastly, note that the non-progression patients group describe this Phase III main enrollment.

Evaluation at First MRI After Concomitant Radiochemotherapy and Correlation With Mgmt Status

At the first MRI scan, performed 1 month after concurrent RT/ TMZ, lesion enlargement was recorded in 50 patients (48.5%), while 53 patients were non-PD. The findings were psPDs in 32 (64%) of 50 patients and ePDs in 18 (36%) of 50 patients. MGMT promoter was methylated in 21 (66%) of the 32 psPD patients and in two (11%) of the 18 ePD patients (P .0002). Thirteen (25%) of the 53 non-PD patients had MGMT promoter methylated and the other 40 patients had MGMT promoter unmethylated status (Fig 1). A significant difference was found between the non-PD and the psPD group (P .0002), but not between non-PD and ePD groups (P .23), for MGMT promoter status. Clinical deterioration was found in 21 (42%) of 50 patients with enlarged lesion images, being present in 10 (55.6%) of 18 with ePD, and in 11 (34%) of 32 patients with psPD (P .14). All patients with psPD and clinical deterioration had a recovery of clinical function at a median time of 7 months (range 1.2 to 18 months). MGMT promoter status predicted psPD in 91.3% of meth- ylated cases (95% CI, 72% to 99%), but predicted ePD in only 59% of unmethylated cases (95% CI, 38% to 76%).

http://ascopubs.org/doi/pdf/10.1200/JCO.2007.14.8163

And this paper describes how RANO should be incorporated into surgical clinical trials, as even the smallest change after GTR (after follow-up scans, of course) could accidentally remove patients. As we know Brad's scan did not get progressively worse, but that doesn't mean other Phase I/II patients would not have benefited from the 12 week rule. Because this study treatment initiation starts later, the 12 week progression rule isn't a necessity, old MacDonald which requires confirmation of response covers DCVax-L patients too.

Nevertheless, to date, the only available way of distinguishing between psPD and PD by conducting a follow-up on patients with early enlarged images, as standard MRI is not sufficient, nor have alternative neuroradiological techniques been validated in prospective trials. Furthermore, the real impact of this entity has not yet been established due to the absence of prospective studies on large series consisting exclusively of patients who have been treated with concomitant radio-chemotherapy. The findings made in the present study show, for the first time, that the real incidence of psPD in GBM patients treated with concomitant TMZ and RT is 30%. Moreover, in approximately 50% of patients, the first MRI scan images after com- bined RT/TMZ were doubtful for progression, but only 36% of these patients were subsequently evaluated as true ePD; the other 64% had a psPD. Therefore, the next step for clinical research should be a priori identification of patients with psPD. We found that there is a 91.3% (95% CI, 72% to 99%) probability of psPDs in patients with methyl- ated MGMT promoter tumors and a 59% (95% CI, 38% to 76%) probability of early PD in unmethylated MGMT promoter tumors. If the probability of methylated MGMT promoter patients having psPD is high, it is almost equally probable that unmethylated MGMT promoter patients will have psPD or ePD if the first MRI images reveal lesion enlargement. New prospective studies testing new neuroradiological techniques on larger patient populations are therefore required in order to obtain sounder findings, and to study alternative psPD predictors. The higher rates of methylated MGMT promoter found in patients with psPD is probably correlated with the efficacy of concurrent RT/TMZ treatment on the residual tumor burden; in this setting the neuroradiological image of psPD may represent not only a treatment-induced blood brain barrier disruption, but also reflect the efficacy of therapy, since the OS of patients with, was significantly higher than in those without psPD.

http://ascopubs.org/doi/pdf/10.1200/JCO.2007.14.8163

[antihama]

Senti, doesn't the following address your concern? Per the protocol

Two weeks after completion of radiation and concurrent chemotherapy treatment, subjects will undergo the Baseline Visit, during which the final tests to determine eligibility are performed. Patients who do not have obvious evidence of progressive disease at the Baseline Visit (as determined by MRI) are enrolled in the main arm of the study (intent to treat), and are randomized…

Patients who do not have unequivocal progressive disease but who otherwise have evidence of disease progression (possible pseudoprogression) will initiate adjuvant temozolomide chemotherapy per standard of care, and will be scheduled to return to the clinic at 10 weeks post completion of initial radiation and concurrent chemotherapy treatment to undergo a repeat baseline visit, i.e. Baseline 2 Visit. Patients who do not have progressive disease at the Baseline 2 Visit (as determined by central review of their MRI) are enrolled into the study (intent to treat), and are randomized…

Edit - I realize this is for entering the trial but if this is a concern at the beginning of a trial wouldn't it logically stand to reason that it would be a concern later in the trial. PS I couldn't find your reference to "cite the 2010 paper in a footnote." but what comes to mind is procedures which reference other procedures in an analytical method. The 1st procedure assumes you are an expert in the more basic method.