NorthWest Biotherapeutics Inc (NWBO)

[biosectinvestor]

Note: I whipped this post up in a few minutes, so please excuse any typos...

First of all, the combination trial is a Phase 1 trial, so your notions and ideas are nonsensical. The measure is whether Keytruda helps these patients, not DCVax-L. DCVax-L is effectively the placebo in this trial.

So what they are measuring here is quite complex and doesn't fit your description, but more importantly, they'd not be able to get a measure without waiting 5 years for the last patient to get it if it was purely OS, and again, this is a Phase I combination trial to measure the impact of Keytruda as an additional drug. This is for recurrent patients and they have effectively already shown that for recurrent patients, DCVax-L has a significant impact on OS by itself.

They have numerous measures, all listed, not just one, and they will look at the range of different biomarkers and measures. The primary measure is NOT PFS, nor is it OS.

The SECONDARY measures are OS and PFS, with PFS at 6 months, measured very carefully by a newer standard to avoid the problems they encountered previously. Moreover, there are numerous other measures. Presumably DCVax-L will be already approved when that study is fully evaluated for the effects of the combination, based on a wide range of measures, including biomarkers, that were not fully understood or available on the DCVax-L Phase 3 when it started. Indeed, the primary measures appear to be biomarker measures.

Additionally, since the start of the Phase 3 trial, they have worked on identifying pseudoprogression and have protocols for avoiding what happened there at the start of the trial because they had no way to distinguish what was an unknown complexity introduced by immunotherapies, which trigger immune reactions such as inflation, that can be misidentified by doctors not aware of the disease process with DCVax-L

It's really a silly comment.

Brief Summary:
This phase I trial studies the side effects and how well of pembrolizumab and a vaccine therapy (ATL-DC vaccine) work in treating patients with glioblastoma that has come back (recurrent) and can be removed by surgery (surgically accessible). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Vaccines, such as ATL-DC vaccine, may help the body build an effective immune response to kill tumor cells. Giving pembrolizumab and ATL-DC vaccine may work better in treating patients with glioblastoma compared to ATL-DC alone.

Also, DCVax-L is the placebo arm in this trial effectively. So the measures are to measure how Keytruda impacts these things, when given in combination with DCVax-L, which is the baseline treatment (standard of care in this trial) for these recurrent patients, in this trial. Also something your point, HyGro, ignores. It's quite critical to understanding what's actually going on here. Additionally, the Principal Investigator is Timothy F Cloughesy. Just FYI.

Primary Outcome Measures:
Cell cycle-related signature [ Time Frame: Up to 6 years ]
Expansion of T cell receptor (TCR) clones [ Time Frame: Up to 6 years ]
Two-sample T-test with Bonferroni adjustment will be used to compare the increase number of expanded TCR clones after dendritic cell (DC) vaccination with PD-1 blockade in Group A versus (vs) DC vaccination with a placebo in Group B.

Incidence of adverse events (AEs) [ Time Frame: Up to 30 days post treatment ]
Adverse events will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. All patients who receive any amount of pembrolizumab/placebo or ATL-DC vaccination will be evaluable for toxicity, serious adverse events (SAEs), and events of clinical interest (ECIs).

Secondary Outcome Measures:
6 month progression-free survival (PFS6) [ Time Frame: At 6 months ] Efficacy will be measured by percent PFS6 as defined by Response Assessment in Neuro-Oncology (RANO) criteria. Kaplan-Meier (KM) curves and median estimates from the KM curves will be provided as appropriate. Percent PFS6 will be estimated from the KM curves and compared to historical controls.

Overall survival (OS) [ Time Frame: Up to 6 years ]
OS will be compared using log rank test.


Other Outcome Measures:
Biomarker analysis [ Time Frame: Up to 6 years ]
The association between biomarkers and clinical outcomes (PFS and OS) will be evaluated using Cox regression. Changes in markers pre- and post- treatment will be assessed using paired t-tests.

TIL (tumor infiltrating lymphocyte) density and TCR (T cell receptor) Clonality in the tumor quantitatively measured by next generation TCR sequencing [ Time Frame: from baseline to surgery ]
The differences of TIL density and TCR Clonality between the archival tumor (pre-treatment) and protocol tumor (post-neoadjuvant treatment) will be assessed using paired T-test, and the association between the changes in TIL density and TCR Clonality and clinical outcome (PFS and OS) will be evaluated using Cox regression.

TIL density and TCR Clonality in the peripheral blood quantitatively measured by next generation TCR sequencing [ Time Frame: from baseline to surgery and post surgery treatment period, up to 24 months ]
The changes of TIL density and TCR Clonality in the peripheral blood from samples collected prior to neoadjuvant treatment and samples collected post-neoadjuvant treatment at each MRI visit will be assessed using paired T-test, and the association between the changes in TIL density and TCR Clonality and clinical outcome (PFS and OS) will be evaluated using Cox regression.

gene expression signature and somatic mutations in the tumor measured by RNA Seq and nano string IO360 [ Time Frame: from baseline to surgery ]
The differences of gene expression signature and somatic mutations between the archival tumor (collected pre-treatment) and protocol tumor (collected post-neoadjuvant treatment) will be assessed using paired T-test, and the association between the changes in the cell cycle related gene expression signature and clinical outcome (PFS and OS) will be evaluated using Cox regression.

gene expression signature from peripheral blood measured by RNA seq and nano string IO360 [ Time Frame: from baseline to surgery and post surgery treatment period, up to 24 months ]
The changes of gene expression signature in the peripheral blood from samples collected prior to neoadjuvant treatment and samples collected post-neoadjuvant treatment at each MRI visit will be assessed using paired T-test, and the association between the changes in gene expression signature and clinical outcome (PFS and OS) will be evaluated using Cox regression.

T cell subset and activation markers within peripheral blood measured by flow cytometry [ Time Frame: from baseline to surgery and post surgery treatment period, up to 24 months ]
The changes of T cell subset and activation markers in the peripheral blood from samples collected prior to neoadjuvant treatment and samples collected post-neoadjuvant treatment at each MRI visit will be assessed using paired T-test, and the association between the changes in T cell subset/activation markers and clinical outcome (PFS and OS) will be evaluated using Cox regression.

TIL quantification including tumor quantification of PD-1, PD-L1, CD3, CD4, CD8, Iba-I, Ki-67 measured by immunohistochemistry of FFPE tissue [ Time Frame: from baseline to surgery ]
The differences of PD-1, PD-L1, CD3, CD4, CD8, Iba-I, Ki-67 protein expression level between the archival tumor (collected pre-treatment) and protocol tumor (collected post-neoadjuvant treatment) will be assessed using paired T-test, and the association between the changes in the protein expression level and clinical outcome (PFS and OS) will be evaluated using Cox regression.

More on measuring to avoid pseudoprogression:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499019/

Among the challenges to use of earlier response criteria include lack of guidance on pseudoprogression, pseudoresponse and nonenhancing tumor progression. Historical challenges in the field have also been concerned around appropriate surrogates of response and endpoints [6]. RANO working groups was established to address some of these issues and provide guidance on assessment of response and endpoints in neuro-oncology clinical trials. Although the work of RANO initially focused on gliomas, its work has extended to many other areas of neuro-oncology including brain metastases (BM), meningioma, pediatric tumors, spinal metastases and leptomeningeal disease.

This review will discuss the recommendations of the various RANO working groups. Although the primary focus of the RANO effort is to improve the conduct of clinical trials, some of the recommendations may be useful in the routine care of brain tumor patients.

Another problem with some drugs is that using the old standards for measurement, they reduced inflammation, without extending survival, and this came to be known as "pseudoresponse", meaning false response. The FDA is also concerned with this for some of the other drugs that were approved based on PFS and other proxy measures for survival, on an accelerated basis, but then those drugs did not extend survival. Keytruda and Opdivo were re-evaluated because of this just last year.

With development and growing use of anti-angiogenic agents that affect vascular permeability and contrast enhancement, the limitations and shortcomings of response criteria, such as RECIST and MacDonald, has become more apparent and necessitated changes to these criteria [12]. Similar to RECIST, difficulty in measurement of irregular borders is not overcome by MacDonald. Agents such as bevacizumab and other anti-angiogenic drugs in its class are known to reduce contrast enhancement, contributing to high response rates and prolonged progression-free survival; however, without impact in extending overall survival [11]. This is now known as ‘pseudoresponse,’ where the decrease in contrast enhancement is secondary to changes to vascular permeability, rather than a direct reduction in tumor size [13]. To address this issue, the RANO-HGG criteria requires that responses should be relatively durable and confirmed by a repeat MRI at least 4 weeks later [3].

The use of agents such as bevacizumab that reduce vascular permeability also introduced the problem of nonenhancing tumor progression that confounds the interpretation of PD. In up to 40% of patients treated with bevacizumab, the contrast-enhancing disease may appear stable but there is increase in nonenhancing disease captured on T2/FLAIR sequences indicating disease progression [14]. The MacDonald criteria focus solely on contrast-enhancing disease and does not consider nonenhancing disease progression. The RANO-HGG criteria attempts to address this issue by including increase in nonenhancing disease in the definition of progression (Table 2) [3]. Because of the difficulties in quantifying nonenhancing disease progression, the RANO-HGG criteria suggests that any qualitative increase in nonenhancing disease constitutes progression. This lack of a quantifiable measure of nonenhancing progression is a limitation of the current RANO-HGG criteria. In addition, there is debate regarding the usefulness of evaluating nonenhancing disease in trials involving agents that do not affect vascular permeability. Evaluation of nonenhancing disease is also problematic in immunotherapy trials since these agents are likely to increase peritumoral edema which cannot be easily differentiated from nonenhancing disease progression. As a result this component of the RANO-HGG criteria is often omitted from immunotherapy trials.

The RANO-HGG criteria also attempts to address the phenomenon of pseudoprogression, characterized by an increase in contrast enhancement in the absence of true disease progression, typically following concurrent chemoradiation (Figures 1 & 2) [15]. Some studies suggest that this occurs more frequently in tumors in which there is methylation of the DNA repair enzyme, O6-methylguanine-DNA methyltransferase (MGMT) [16], although other studies have not confirmed this [17]. The changes of pseudoprogression are expected to improve with time, whereas true disease progression will continue to increase. In the absence of tissue confirmation, there is no available imaging modality which reliably distinguishes true from pseudoprogression, although perfusion imaging may occasionally be helpful [18,19]. The RANO-HGG criteria suggests that within the first 3 months after completion of chemoradiation, even if the MRI shows increase enhancement patients should not be considered to have progressed and be eligible for clinical trials for recurrent disease because of the difficulty in differentiating pseudoprogression from true progression. The exceptions are patients who develop new areas of enhancement outside of the radiation field (beyond the high-dose region or 80% iso-dose line) or if there is unequivocal evidence of viable tumor on histopathologic sampling. Because of the difficulty in differentiating pseudoprogression from true progression there is the suggestion that the first postradiation MRI, rather than the postoperative MRI, should be used as the baseline scan [18].