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Nice to see Happy happy. :)
Loving the higher lows. :)
Hi Doc Logic, Thanks. I hope you’re a well. It’s nice to see the same folks posting. Agree! It’s likely going to be a while before we get to hear all the intrigue details on the findings. Just hoping it shows positive combination effects with Avastin so that that rGBM patients (who either saved tissue or get second surgery) can get it too. best, RK
Just an FYI. NWBO can still chart 5 year post first injection with the locked data they have, especially since they data locked later than August. This trial enrolled 331 patients and majority (305) were enrolled prior to August 2015. This is what we know as fact. Only they have their exact enrollment dates. This is not something I have. But I suspect that most of the last 25 were enrolled in August and Sept 2015, given all 25 patients were somewhere within the screening spectrum with surgery all prior to screening closing. And only It could be that 99% percent of patients received their first dosage by Oct 2015. And only patient #331 received first dosage in Nov 2015. So yes they can still chart the 5 year post injection of all patients, with only a small number patient info at 4 years 10-11 months. What’s great news is they can plot a long tail of survival for this trial with the shortest patient just shy of 5 years post injection. :)
Go time!
I knew once they passed year 3 and didn’t lock they would proceed to get the long tail. Kept my word and have been silent. You’ll see they will have the long tail which makes me as quite accurate.
Hadn’t seen the news. When I say I’ve been patiently waiting, I do mean patiently. :) Will check my email now.
Hank. Come next month, the shortest duration of post first dosage that they will have on any patient for the OS KM will be 5 years. They already have 5 years post first GBM surgery as of August 2020, as remember they were not able to screen more patients after August 2015. If they did data lock OS inside they trial they will simply just chart the OS 5 year KM curve as 5 year post surgery in scientific journals once they do unblinded analysis on this study. Using post surgery is something they have done before with their other Phase trial analysis. All this said, they would have that blinded OS info to chart (as of August 2020 last data check (even if they didn’t data lock)) so they are in good shape with material to present at any upcoming virtual conference. My big thing that I truly believe is they want the long tail data, and I was exhausted with folks claiming the trial would end years ago when in my heart I knew it wouldn’t. The long tail is important to capture with biological immunotherapy trials. No skeptic can dispute long term survival that is not post hoc. They do have it as of August 2020. But as of November 2020 they will have the long tail as of post first dose initiation. It’s a small thing but they waited this long, why not get it.
:) hope all is well.
You’re welcome to disagree. And yes, true we all know survival data continues to agree once the study is done.
Glioblastoma: Is Survival Possible?
By Ben A. Williams Copyright, 2014
Glioblastoma multiforme are among the most deadly neoplasms and continue to be regarded as incurable and universally fatal. This reputation seems well deserved, at least as based on population-based outcome data over a twenty-year period from the Alberta Brain Tumor registry. Of 689 glioblastoma patients, only 2% survived three years or longer, and of these 15 patients only 4 were still alive at the time of the report (1).
Case series reports from major individual treatment centers are somewhat more positive but still dismal, Of a series of 449 patients treated over a 16-year period at UCSF, 22 (5%) survived five years or longer (2). Of these, ten were still alive at the time of last follow-up, with six showing no sign of progression after initial therapy.
A case series of 213 GBM patients from George Washington University and surrounding treatment centers (3) reported that 33 (15%) survived three years or longer, but survival at the 5-year mark was not reported.
A series of 766 GBM cases receiving treatment at Duke University included 32 patients (4%) who survived five years or longer, but this number was reduced to 17 patients upon further histological review (4). The most frequent basis of the change in diagnosis was an initial diagnosis of a lower-grade glioma that transformed into GBM. Survival time after the detection of the change to higher-grade tumor was not reported.
A case series of 352 GBM patients from the Memorial Sloan-Kettering database included 39 patients (11%) who survived three or more years (5). Median survival for this selected group was 9.15 years, and 23 patients were still alive at last follow-up. Twelve patients remained in continuous remission after a median follow-up of over five years.
Given that the great majority of patients now receive the “Stupp protocol” (radiation + low-dose temozolomide, followed by monthly temozolomide) as initial treatment, the most relevant data for the current patient generation are the long-term survival outcomes from the landmark European clinical trial that resulted in temozolomide’s FDA approval (6). Survival data for up to five years are now available (7). Of the 254 patients that received the now standard combined protocol, 16% were alive after three years, and 9.8% were still alive after five years.
The most recent follow-up report also included a survival analysis with respect to various prognostic variables. Five-year survival of patients under the age of 50 was 17%, compared to 6.4% for those over the age of 50. For patients with a methylated MGMT promoter gene, 5-year survival was 13.8%, compared to 8.3% for those with an unmethylated gene.
Although 5-year survival rate was approximately double that of previous patient series, Stupp et al. question whether a cure is really possible, because the survival curve showed no sign of a plateau, which suggests that the asymptotic level of survival will eventually reach zero.
A somewhat different perspective is provided by a Taiwanese study that examined the conditional probabilities of surviving an additional year given different lengths of prior survival time (8). The probabilities of surviving an additional year after 1, 2, 3, 4 and 5 years of prior survival were .65, .59, .86, .80,and .75. The increase in conditional survival rate after three years suggests that the probability of recurrence decreases the longer the survival. However, this patient series included only 69 patients. It is also important to recognize that a probability of .85 of surviving the next year implies that there is a .15 probability of death in the next year, which, when iterated over succeeding years, produces a cumulative probability of death that is increasingly high.
An additional conditional probability analysis of survival from a collection of six different clinical trials at UCSF (9) reported that the percentages of patients surviving one additional year after 1, 2, 3, 4, and 5 years of prior survival were 35, 49, 69, and 93%, respectively. The authors also noted that the data were better described by a Weibull probability function than by an exponential function.
The largest conditional probability analysis comes from the SEER database (10), which includes 28% of the population of the United States. Included were patients with a glioblastoma diagnosis from the years 1998 to 2008, a total of over 10,000 patients. The probabilities of surviving an additional year were 53% from the time of diagnosis, 38% after one year of prior survival, 55% after two years, 70% after three years, 82% after four years, and 78% after five years. They also noted that after five years of survival, the probability of surviving an additional five years was 45%. The percentage of patients surviving 5 years was 6.2%, which implies that the percentage surviving 10 years was approximately 3%.
A second very large data based came from all patients diagnosed with high-grade gliomas (Grades III and IV) from 1990 to 2000 in Los Angles County, California. (11). Collapsed over both tumor grades, median survival was only 6.6 months, and the probability of surviving at least one year was 31%, indicating much worse outcomes than those obtained when patients have participated in clinical trials. For GBM patients alone, the four-year survival rate was 3%. However, when a conditional probability analysis was performed, the probability of surviving one additional year (for GBM patients only) was .29, .55, .71, and .85, after one, two, three, four, and five years, respectively.
Of substantial interest from the conditional probability analysis is that variables that predict unconditional survival (tumor grade, patient age) lost their prognostic value after 3-4 years of prior survival. The implication of these survival analyses is that a small percentage of patients survive at least 5-10 years, raising the possibility that at least some patients are genuinely cured. But the further implication is that there continues to be a substantial rate of death even after extended survival, although the death rate substantially decreases the longer the prior survival.
Evidence that relapses frequently occur even for patients with extended long-term survival comes from a recent long-term follow-up of ten patients who had survived for five years at the time of their selection for further study (12). Survival analysis after a mean follow-up of 140 months revealed that only five of the original ten were alive, and one of these had a recurrence at 126 months and was still receiving treatment. Another had a relapse after 17 months and again after 28 months, but was still alive after 102 months. Two other patients had relapses after 118, and 124 months and were deceased. Of the three remaining patients with no relapse, ongoing survival time was 145, 134, and 123 months.
Although the late relapses seen in this study are consistent with the frequent statement that GBM is invariably fatal, the three patients with recurrence-free survival longer than ten years offer the possibility that at least a few patients are indeed true long-term survivors.
It is also important to recognize the possibility that some of the late “relapses” may not be recurrences of the original tumor but new disease induced by the radiation treatment. Experimental work with animal models supports the reality of this risk (13). Three-year- old normal rhesus monkeys were given whole brain radiation using a protocol similar to the common human radiation protocol and then followed for 2-9 years thereafter. A startling 82% of the monkeys developed glioblastoma tumors during that follow-up period.
Of major interest is whether long-term survival is due to the particular characteristics of the patients themselves or of the treatments they have received. The great majority of long-term survivors have had some form of systemic chemotherapy, although this may simply reflect the fact that chemotherapy has been part of the standard treatment. In fact there is one report of three long-term survivors (11, 16, and 18 years) of 71 patients receiving only brachytherapy (14).
Patient characteristics most common among long-term survivors are young age at the time of diagnosis, higher Karnosky performance status, methylation of the MGMT promoter gene, and a complete surgical resection. However, there are long-term survivors who are exceptions to each of these generalizations. Several other characteristics have also occasionally been reported, including female gender, the presence of giant cell histology (15), and lower rates of mutations of p53 and PTEN (16).
The German Glioma Network has been reported a molecular analysis of patients from a very large database (301 patients) (17). Multivariate analysis showed younger age, higher KPS scores, and use of temozolomide chemotherapy predicted longer survival, but the only molecular markers predictive of LTS were MGMT promoter methylation and mutations of the gene for isocitrate dehydrogenase (IDH). There were no significant differences for p53 mutations, EGFR, and allelic losses on chromosome arms 1p, 9p, 10q, and 19q.
A second extensive genomic analysis focused on the differences between tumors of long- term survivors (LTS) (greater than 3 years) vs. those of short-term survivors (less than 1.5 years) matched in age to the LTS patients (18). Predictive of short-term survival was loss of 6q and 10q, and gains of 19p, 19q and 20q. Combinations involving two or more of these mutations were more strongly predictive of short survival than were any one mutation in isolation. Also, loss of 19q occurred only in the long-term survivors.
The most extensive report of the characteristics of long-term survivors comes from the German Glioma Network, which compared 69 patients who survived more than 36 months with 257 patients who survived less than 36 months (19). LTS patients were younger but not significantly different with respect to KPS. They were also only marginally more likely to have complete resection at the time of initial surgery, but were significantly more likely to have two or more surgical interventions. The analysis of molecular markers showed that LTS patients were significantly more likely to have methylation of the MGMT promoter-gene, but less likely to have EGFR amplification. The difference in p53 mutations was not significant. The most consistent variable associated with LTS was IDH mutations, as 33% of LTS patients had the mutation, compared to only 4% for control patients. Presence of MGMT methylation and IDH mutations were highly correlated but still partially dissociable. Specifically, patients with IDH mutations but without MGMT methylation had the same prognosis as patients without IDH mutations. It is also noteworthy that there were a significant number of long-term survivors who had no IDH mutations.
Two case histories with very long survival have recently been reported. The first was a male patient diagnosed at the age of 25 with a tumor in the right frontal lobe, for which he received a subtotal resection (20). Following his participation in an 8-in-1 experimental chemotherapy protocol, he received standard focal fractionated radiotherapy with a 2-cm margin. The tumor recurred two years later, at which time he received a near total resection and the placement of gliadel wafers in the tumor bed. His condition remained stable for 18 years, at which time he suffered another recurrence involving two separate tumor masses, one of which was treated with a third resection and the other with stereotactic radiosurgery. He also received temozolomide chemotherapy. Soon after the 20-year anniversary of his diagnosis he suffered a multifocal recurrence that was rapidly progressive.
Molecular analysis of the tumor tissue taken at the time of the third surgery revealed that it was p53 positive, PTEN positive, and MGMT methylated. EGFR and protein kinase AKT were negative. The second recent report (21) involved a male patient diagnosed at age 24 with an occipital lobe tumor, who received a gross total resection and then received localized radiation and chemotherapy with nimustine and interferon-beta. Surgery was repeated three months later to treat a local recurrence, and the patient remained tumor free for 19 years, at which time he developed a cavernous angioma, which upon removal was found to be free of glioblastoma cells or radionecrosis. The patient remains tumor free two years later, 21 years after his initial diagnosis. Analysis of the initial tumor tissue showed it to be MGMT methylated.
The same report also described the case history of a third long-term survivor reported in a Turkish journal (22). This patient was diagnosed at age 16 with a tumor in his right frontal lobe. After a second surgery for an early recurrence, he was still alive at the time of the report twenty years after diagnosis. His tumor also was found to be MGMT methylated.
It is noteworthy but perhaps fortuitous that all three of these long-term survivors had early recurrences, for which they received a second resection, and then long periods of tumor remission. The fact that some GBM patients live 10-20+ years after diagnosis implies that posing the issue in terms of whether the disease can be cured is not the right question. Everyone eventually dies, and it is likely that anyone who has received the surgery, radiation, and chemotherapy associated with a “terminal” cancer diagnosis will have a shortened life span quite apart from dying directly from the disease. Certainly late recurrences do happen. But a meaningful number of people also live a large chunk of their life expectancy after receiving a GBM diagnosis. It is an awful disease, but one that has responded to treatment in a significant number of patients. As of now, we have only a minimal basis for predicting which patients will receive a significant benefit of treatment, and even less basis for choosing treatments that will be most successful.
References
1. Scott, J. N., Rewcastle, N.B., Brasher, P. M. A., et al. (1999). Which glioblastoma multiforme patient will become a long-term survivor? A Population-Based Study, Ann Neurol, 1999, 46: 183-188
2. Chandler, L., Prados, M. D., Malec, M., & Wilson, C. B. (1993). Long-term survival in patients with glioblastoma multiforme. Neurosurgery, 32(5): 716-720
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3. Salcman, M., Scholtz, H., Kaplan, R.S., & Kulik, S. (1994). Long-term survival in patients with malignant astrocytoma. Neurosurgery, 34(2): 213-220
4,McLendon, R. E., & Halperin, E. C. (2003). Is the long-term survival of patients with intracranial glioblasoma multiforme overstated? Cancer, 98(8): 1745-48
5. Hottinger, A. F., Yoon, H., DeAngelis, L.M., & Abrey, L. E. (2009). Neurological outcome of long-term glioblastomas survivors. 95 (3): 301-305
6. Stupp, R., Mason, W. P., van den Bent, M.J. et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. New England J. Med, (2005), 352 (22): 987-99
7.Stupp, R., Hegi, M.E, Mason, W. P., et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomized phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol., (2009), May;10(5):459-66. .
8. Lin, C. L., Lieu,A. S., Lee, K. S. et al. (2003). The conditional probabilities of survival in patients with anaplastic astrocytoma or glioblastoma multiforme. Surg Neurol, 60: 402-06
9. Polley, M.Y., Lamborn, K. R., Chang, S. M., Butoski, N., Clarke, J. L., & Prados, M (2011). Conditional probability of survival in newly diagnosed glioblastoma patients. J. Clin. Oncol., 2011, 29 (31), 4175-80
10. Johnson, D.R., Ma, D. J., Buckner, J. C., & Hammack, J. E. (2012). Conditional probability of long-term survival in glioblastoma. Cancer, Nov, 15, 118(22): 5609-13
11. Tsao-Wei, D.D., Hu, J., Groshen, S. G., & Chamberlain, M. C. (2012). Conditional survival of high-grade glioma in Los Angeles County during the year 1990-2000. Journal of Neurooncology, 110: 145-152
12. Bahr, O., Herrlinger, U., Willer, M., & Steinbach, J. P. (2009). Very late relapses in glioblastoma long-term survivors. Journal of Neurology, 256(10), 1756-58
13. Lonser, R. R., et al. Induction of glioblastoma multiforme in nonhuman primates after therapeutic doses of fractionated whole-brain radiation therapy. Journal of Neurosurgery, 2002, 97 (6), 1378-1389
14. Dehdashti, A. R., Sharma, S., Laperriere, N., & Bernstein, M. (2007). Coincidence vs Cause: Cure in three glioblastoma patients treated with brachytherapy. Can. J. Neurol Sci, 34: 339-342
15. Shinojima, N., Kochi, M., Hamada, J-I, et al. (2004). The influence of sex and the presence of giant cells on postoperative long-term survival in adult patients with supratentorial glioblastoma multiforme. J. Neurosurg, 101: 219-226
They still would have had 5 years of survival on patients to graph. Only the last few patients were enrolled in the final months of 2015. Waiting gives them 100% of patients passed 5 years.
Right now as statistic stands there are well less than 10% of patients who survive with a GBM diagnosis passed 5 years.
We already know that a large percentage of this study’s ITT population survived over 40 months, something like 30%. Now remember one third of this study got placebo upfront and only crossed over treatment upon progression. So that 30% is impressive. We will get to see what percentage of their study survives over 60 months (treatment and upon progression treatment) and my bet is it will be a significant improvement to the typical 5%.
Until they do the statistical analysis they won’t lock data on survival. They only locked progression free survival data with the most recent data lock. Do remember their are two data locks for two endpoints. Data on survival continues to accrue inside the study data (to which they can chart KM curve) once they officially end the study and do the statistical data analysis on both.
Stay well
Long term survival a decent percentages of patients :)
Not implying anything. I have no idea what they themselves are thinking when they draft notices. I’m saying it makes sense to data lock once they have 5 years data on all patients as they are an immunotherapy trial. Could they lock data with a few patients short of 5 years, yes. But I believe once they are so close to 5 years on all patients they won’t data lock on long term survival and officially end the study until they are there.
Yes, of course.
They have been keeping us updated. Every one of the steps take time. But yes I do believe they expect 5 year survival data on all patients.
Thanks. Hope all is well.
Hi Panlosrv,
They will have at least 5 years of survival data on every patient sometime shortly — last enrolled patient was Nov 2015. It didn’t make sense to me why they would data lock prior to then when they waited this long. Hope that helps. :) RK
Hi,
Yes. All is good. Hope you’re well too. I think they gave us the best case scenario and we won’t see data lock until 5 years are up for 95-98% of enrolled patients.
He likes to give all credit to RT/TMZ for most of 100 patients who haven’t seen a PFS event. This is impossible. The skeptics conveniently forgets that only 8% of the patients had good prognostic factors. Only 65% of the 108 had potential for RT/TMZ pseudoprogression. And simply having pseudoprogression doesn’t mean patients go on to non-event. But he sure would like to get folks to believe that survival in this trial isn’t impressive the same we he argued that pseudoprogression would cause PFS events.
“Unknown factors: sub-group with extended survival
Approximately 30% of the ITT population (n?=?100) showed particularly extended survival, with a KM derived mOS estimate of 40.5 months. This is not fully explained by known prognostic factors, as only some of these patients had positive prognostic factors: only 29% were younger than 50 years of age, 65.9% had methylated MGMT, 71% had a complete resection, and only 8% of these patients had all three positive prognostic factors. These patients will be the subject of extensive further analyses and research.” -—— JoTM May 2018 paper
Two things. Study design and immunotherapy mechanism of action. Linda Liau already told us that Trial design removed some of their best responders by first inclusion criteria. They also had a crossover arm, which means we will get to see whether this trial has “late effect” and can murky the statistical outcome. She also told us with immunotherapy it takes time to mount a substantial immune response. The effects of immunotherapy can be seen in Overall Survival. For GBM overall survival is the standard. They have waited this long to unblind, it makes sense to add OS as a primary endpoint, and adjust the SAP imho.
Off my Jan 27, 2017. Hope this helps to explain immune therapy mechanisms of action
He can cough all he wants and rewrite PFS history, using his eyesight to but he can't change the prior trial's OS. He can plant suggestions that investigator made mistakes in recording of prior events and study median but without proof it's just accusations and conjecture. He can talk all he wants about futility, but his low PFS theory is based on PsPD passing size perimeters, that means the therapy is working well. If it's working well they should see long-tail. And if the therapy were not working well we wouldn't be waiting for a primary endpoint update as Linda Powers told annual meeting shareholder attendees, scans need to read and tumors carefully measured. Well death requires no MRI reading.
But let's chat about changes in tumor size on an Immunotherapy and the clinical signals of ilpilumumab:
-- it demonstrated a relatively low conventional (shrinking of tumors) response rates: (10-15% in melanoma)
But then as they Investigators were going through their observations, efficacy was distinctively different:
-- they noticed survival improvement more than their 10-15% response rate initially was suggesting as.
That suggested that there must another benefit beyond the conventional response (same observation as other immunotherapies).
Case studies showed mixed examples of efficacy benefit. Axel Hoos described (verbatim):
1)Included conventional response patterns: after initial treatment: tumors shrink
2)included case patterns where after initial treatment: Tumors grow, and then subsequently shrink; predominantly because Lymphocytic infiltration into the tumor; makes the lesion larger, for the T cells can then acts against the tumor cells that leads to shrinkage
3) included case with patterns where the immune system is in some form of equilibrium state with the tumor; and leads to prolonged stabilization of disease. That may over time lead to a conventional response but it may take time to a year or more for that to happen.
4)included cases with patterns where actually new lesions appear while other lesions disappear or shrink. Those patterns are particularly interesting because suggest they that micro metastatic tumor cell deposits in different tissues that once detected by the immune system may actually lead to a visible lesion on a CAT scans, that previously did not exist, because T cells accumulate around the micro metastatic tumor cell and make that a visible lesion. Those lesion are usually small and they are transient. They go away with time, once the T cells do their job.
Conventional Responses is:
-- Tumor shrinkage
Immunotherapy benefit go above and beyond conventional responses of "shrinking" mass that might be there. To look only at conventional response rate is faulty as it doesn't give a true picture of response benefit.
"5. Delayed vaccine effect
As a consequence of their immunological mechanisms of action, cancer vaccines may require considerable time after administration to induce immunity. Therefore, tumors in subjects treated with cancer vaccines may show early progression followed by subsequent response. This potential phenomenon should be considered in the design of later phase clinical trials, particularly if nonclinical data or early phase clinical trials suggest that the phenomenon exists and time-to- event endpoints are used. Due to delayed effect of the vaccine, the endpoint curves may show no effect for the initial portion of the study. If the vaccine is effective, evidence of the effect may occur later in the study. This delay in the effect may lead to an average effect that is smaller than expected and thus may require both an increase in sample size to compensate for the delay and a careful assessment of trial maturity for the primary analysis. In addition, possible violation of the proportional hazards assumption should be considered when selecting a statistical method for the primary analysis. " -- FDA on vaccines
But trial was not enrolling the patients with established tumors. Not to mention this trial more than doubled the 110 events it initially was set to review in PFS, so they appear to cover the "sample size" to compensate for any potential delay effect. And so expected to see more cases of #3 and some cases of #4, when dormant cells wake up elsewhere.
3) included case with patterns where the immune system is in some form of equilibrium state with the tumor; and leads to prolonged stabilization of disease. That may over time lead to a conventional response but it may take time to a year or more for that to happen.
4)included cases with patterns where actually new lesions appear while other lesions disappear or shrink. Those patterns are particularly interesting because suggest they that micro metastatic tumor cell deposits in different tissues that once detected by the immune system may actually lead to a visible lesion on a CAT scans, that previously did not exist, because T cells accumulate around the micro metastatic tumor cell and make that a visible lesion. Those lesion are usually small and they are transient. They go away with time, once the T cells do their job.
Remember with DCVax-L Phase III there shouldn't be established tumors, as it's an intent for gross total resection patients that they remove. This trial was designed to remove ALL EVIDENCE OF DISEASE PROGRESSION at baseline. And this study design was to find patients who qualify for a GTR. It doesn't mean they will always get it, but with state of the article surgical equipment, the rates of GTR should be high. Tumor debunking is known to decrease immunosuppressive cytokines such as TGFB. As such, this study will more than likely experience a higher disease stabilization as it WILL not be enrolling the type of patients that the ilpilumumab trial enrolled --melanoma patients with established tumor mass. And so there shouldn't be a need to "shrink" tumors and cause immune "swelling" first effect like the DCVax-Direct trial encounter leading to possible "false" progression. The PsPD in thar made it passed main trial screening should not have tumors. They have Blood Brain Barrier (BBB) enhancements, of a therapy working well, which isn't the same thing as a TUMOR that is growing. And PsPD after enrollment can be determined by other imaging modalities, which this trial uses. It is a "enhancement" condition that clears itself in time. It is not disease progression.
Here is an example of what we should expect to see as far as MRI imaging on disease progression. This is a recurrent DC enrolled study. The patients that had lower disease tumor volume had significantly longer PFS and OS. The recurrent trial OS median was at 8 months (range: 5–107 mo). IF a KM Curve for all patients were created, there would be a long-tail response for a nice percentage of the GBM patients, as the median OS doesn’t tell the story. Had KM curve of all survival those who lived longer would represent the 35% of long tail survival curve (OS times of the 15 patients (7 of which had signs of disease progression at first vaccination).
The natural killer cell response and tumor debulking ARE associated with prolonged survival in recurrent glioblastoma patients receiving dendritic cells loaded?with autologous tumor lysates
Recurrent glioblastomas (GBs) are highly aggressive tumors associated with a 6–8 mo survival rate. In this study, we evaluated the possible benefits of an immunotherapeutic strategy based on mature dendritic cells (Dcs) loaded with autologous tumor-cell lysates in 15 patients affected by recurrent GB. The median progression-free survival (PFS) of this patient cohort was 4.4 mo, and the median overall survival (OS) was 8.0 mo. patients with small tumors at the time of the first vaccination (< 20 cm3; n = 8) had significantly longer PFS and OS than the other patients (6.0 vs. 3.0 mo, p = 0.01; and 16.5 vs. 7.0 mo, p = 0.003, respectively). cD8+ T cells, cD56+ natural killer (NK) cells and other immune parameters, such as the levels of transforming growth factor ß, vascular endothelial growth factor, interleukin-12 and interferon ? (IFN?), were measured in the peripheral blood and serum of patients before and after immunization, which enabled us to obtain a vaccination/baseline ratio (V/B ratio). an increased V/B ratio for NK cells, but not cD8+ T cells, was significantly associated with prolonged PFS and OS. Patients exhibiting NK-cell responses were characterized by high levels of circulating IFN? and e4Bp4, an NK-cell transcription factor. Furthermore, the NK cell V/B ratio was inversely correlated with the TGFß2 and VeGF V/B ratios. These results suggest that tumor-loaded DCs may increase the survival rate of patients with recurrent GB after effective tumor debulking, and emphasize the role of the NK-cell response in this therapeutic setting.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3661164/pdf/onci-2-e23401.pdf
Several lines of evidence indicate that the immune system is capable of interacting with cancer cells to prevent their growth as well as to destroy established tumors.2 However, attempts at utilizing the immune system to treat established tumors are confronted with consistent limitations, largely due to the immunosuppressive environment generated by malignant cells.3 The induction of anti-GB immunity has been documented in vitro as well as in animal models.4 Results from several early clinical trials using dendritic cell (DC) vaccines to initiate antitumor immune responses were promising,5 indicating that antitumor immunity was induced in a fraction of patients and that immunological responders exhibited a prolonged survival rate as compared with control patients. Furthermore, increased levels of interferon ? (IFN?) in the peripheral blood as well as in peripheral blood mononuclear cells (PBMCs) of GB patients have been associated with prolonged survival, and tumor debulking is known to decrease the expression of immunosuppressive cytokines such as transforming growth factor ß (TGFß).6,7 Severe side effects have never been associated with DC-based vaccines, and the quality of life of patients treated with this immunotherapeutic intervention has been deemed acceptable.8
Although several GB-associated antigens have been identified, it is possible that the use of whole tumor-cell products as antigens (i.e., lysates, tumor-eluted peptides or fusion products between DCs and GB cells) may reduce the risk of tumor escape due to antigen-loss variants. An example of such escape has been provided by the recent results of a clinical trial targeting a tumor-associated antigen created by a large deletion of the epidermal growth factor receptor (EGFR)-coding gene (EGFRvIII), which is expressed by 25–30% of GB patients. Vaccinated patients demonstrated an increased survival rate that was correlated with increased anti- EGFRvIII antibody titers. Notably, recurrent tumors were devoid of GB cells expressing EGFRvIII, due to tumor immunoediting.9
Most clinical studies have emphasized the role of CD8+ T cells in antitumor immune responses as elicited by DC-based immu- notherapy.6,10 Although it has been suggested that CD56+ natural killer (NK) cells play a role in such responses,11 the capacity of these cells in exerting bene cial effects against gliomas (and possibly other tumors) has not been fully evaluated. NK cells are large, granular lymphocytes belonging to the innate immune system. Unlike T or B lymphocytes, NK cells do not possess rear- ranged T-cell receptors or immunoglobulin genes and instead kill target cells based on the absent expression of MHC Class I molecules.12 DCs have been recognized as major players in the regulation/initiation of both innate and adaptive immunity.13,14 Moreover, resting NK cells can be primed by the production and trans-presentation of interleukin (IL)-15 by DCs.15
In this study, we report the results obtained with 15 patients affected by recurrent GB receiving a DC-based vaccine and stress the relevance of NK cells in inhibiting tumor growth in the con- text of DC-based immunotherapy.
The clinical features of the patients are summarized in Table 1, and their main genetic features are summarized in Table S1. The median age at the time of vaccination was 46 years (range: 16–64), and the median KPS was 70 (range: 30–90). DC immunotherapy started after the third surgery in 4 patients, after the second surgery in 10 patients and at the time of MRI relapse in 1 patient (patient 6). After the first histological diagnosis of GB (according to WHO criteria), all patients received standard therapy, which consisted of conventional radiotherapy (standard dose 60 Gy) and chemotherapy (temozolomide according to Stupp’s protocol or nitrosoureas), followed by second- or third-line treatments (fotemustine, mito- xantrone, enzastaurine, diphtheria toxin). Within 72 h after the surgery, all patients were subjected to MRI examination with contrast enhancement. The exam showed residual tumors in 14/15 patients. Leukapheresis was performed within 4 weeks of the surgery. During this time, patients received a maintenance dose of glucocorticoids (4 to 12 mg of dexamethasone) and anti- epileptic treatments.
BUT THIS IS AN IMPORTANT POINT showing that theories about MRI size for non-progression patients (even in recurrence, typically do not increase above progression thresholds unless it’s PROGRESSION; Magnetic resonance imaging (MRI). MRI was scheduled within two days before the first vaccination, every 2 mo thereafter or when clinical conditions were worsening.
Two months after the first vaccination, a clear increase in tumor volume (ranging from 180% to 620%) was observed in patients manifesting disease progression, whereas a slight increase in tumor volume (ranging from to 2.3% to 23%) occurred in most of the remaining patients. For the latter group, because the increase in tumor volume was < 25%, the disease was defined as stable according to the MacDonald criteria.
Nine months after the first vaccination, an MRI performed on patient 3 showed a 187% increase in tumor volume, indicating disease progression. Although the neurological condition of the patient was unchanged, she received two further vaccinations. Without changing the steroid dosage, 5 mo later, the tumor volume had decreased by 58% and remained unchanged for the following 30 mo.
PATIENT #9, only received SoC (S, R, C (per Stupp) prior to recurrence. And with surgery, and no residual tumor (a.k.a, this Phase III nGBM intent to treat population) witnessed a response to DC vaccination, a total of 7 injections (though dosage changes, per the study: Patients 7–15 were scheduled to receive seven vaccinations. Vaccinations 1–4 were given at 2-week intervals followed by two monthly vaccinations and a nal vaccination 2 mo after the sixth vaccination. The first, fifth, sixth and seventh vaccines contained 10 × 106 DCs, while the other courses contained 5 × 106 DCs. ) Patient #9 PFS2 (recurrent progression) was 14 months PFS from debulking recurrent surgery. Patient #9 OS was 17.5 months, calculated from second surgery. PFS was calculated from the last surgery until disease progression and death/last follow-up, if censored. OS was calculated from the last surgery to death/last follow-up, if censored. This is a patient who failed newly diagnosed Standard of Care, and did not record a progression with NO RESIDUAL TUMOR, while on a DC therapy.
Table 2. Outcomes of dendritic cell-based immunotherapy in RECURRENT GBM PATIENTS. DC immunotherapy started after the third surgery in 4 patients, after the second surgery in 10 patients and at the time of MRI relapse in 1 patient (patient 6). After the first histological diagnosis of GB (according to WHO criteria), all patients received standard therapy, which consisted of conventional radiotherapy (standard dose 60 Gy) and chemotherapy (temozolomide according to Stupp’s protocol or nitrosoureas), followed by second- or third-line treatments (fotemustine, mito- xantrone, enzastaurine, diphtheria toxin). Within 72 h after the surgery, all patients were subjected to MRI examination with contrast enhancement. The exam showed residual tumors in 14/15 patients.
Patient No. of vaccinations Amount of DCs (× 106) PFS (mts) OS (mts)
1 3 vaccines 40 (× 106) 3 PFS 7.5 OS
2 3 vaccines 40 (× 106) 8 PFS 12.5 OS
3 5 vaccines 60 (× 106) 7 PFS 51 OS
4 3 vaccines 40 (× 106) 4.5 PFS 7 OS
5 6 vaccines 60 (× 106) 4 PFS 11.5 OS
6 5 vaccines 60 (× 106) 22 PFS 25 OS (died of heart failure) — DC therapy started at MRI first progression
7 4 vaccines 25 (× 106) 5 PFS 16.5 OS
8 4 vaccines 25 (× 106) 1 PFS 5 OS
9 7 vaccines 55 (× 106) 14 PFS 17.5 OS — THE ONLY PATIENT WITH NO RESIDUAL TUMOR at first injection
10 5 vaccines 35 (× 106) 12 PFS 16.5 OS
11 5 vaccines 35 (× 106) 2 PFS 7 OS
12 5 vaccines 35 (× 106) 2 PFS 7 OS
13 4 vaccines 25 (× 106) 3 PFS 6 OS
14 6 vaccines 45 (× 106) 4 PFS 7 OS
15 4 vaccines 25 (× 106) 5 PFS 8 OS
Patients 1, 2, 3, 4 and 6 received three biweekly intradermal injections of 20 × 106 (first vaccination) and 10 × 106 DCs (second and third vaccinations). Patient 3 was treated with two further monthly injections (with 10 × 106 DCs each) 9 mo after the third vaccination. Patient 6 also received one further injection of 10 × 106 DCs at progression, which was 9 mo after the third vaccination. Patient 5, who was 17 years old at the time of recurrence, was treated at the Pediatric Hemato-oncology and Neuro-oncology University Hospital Gasthuisberg and received four weekly injections (with 10 × 106 DCs each) followed by two monthly vaccinations (with 10 × 106 DCs each).
Patients 7–15 were scheduled to receive seven vaccinations. Vaccinations 1–4 were given at 2-week intervals followed by two monthly vaccinations and a final vaccination 2 mo after the sixth vaccination. The first, fifth, sixth and seventh vaccines contained 10 × 106 DCs, while the other courses contained 5 × 106 DCs.
PFS and OS were not affected by the following clinical parameters: age > 40 y; age > 60 y; immunotherapy schedule; steroid dosage at the rst vaccination and the presence of progres- sion at the first vaccination (5.7 ± 4.1 mg vs. 0.5 ± 0.9 mg; p = 0.0036). Furthermore, patients with a tumor volume < 20 cm3 (PFS: p = 0.01; OS: p = 0.003) and a Karnofsky Performance Score (KPS) > 70 (PFS: p = 0.005; OS: p = 0.4,) survived longer than the rest of the patient cohort (Fig. 1B and C).
DC immunotherapy leads to NK-cell responses in a fraction of patients. The first vaccination led to an increase in the frequency of circulating NK cells in patients 2, 3, 6, 9, 10 and 14 (Fig. 2A), which further augmented after the second vaccination. The peripheral blood lymphocytes (PBLs) of these patients exhibited increased expression levels of E4BP4 and interferon ? (IFN?), as measured by real-time PCR (Fig. 2B and C).
This Figure 2. patients with increased frequencies of natural killer (NK) cells showed an increased expression of e4Bp4 and interferon ?. (A) The time course of NK-cell frequency evaluated by flow cytometry shows a significant increase in some patients (n = 6, blue line) but not in others (n = 8, red line).(B and C) The time course of e4Bp4 and interferon ? (IFN?) expression levels as evaluated by real-time pcR shows a signi cant increase in patients with increased NK-cell frequency (n = 3, blue line) but not in others (n = 6, red line) (*p < 0.01, **p < 0.001, ***p < 0.0001 vs. first vaccination). (D and E) Flow cytometry histograms of IFN? production by cD3+cD8+ T cells and cD3-cD56+ NK cells from patient 9 and patient 11.
Our study also reported a significant, positive influence of NK-cell responses (i.e., high V/B NK cell ratio) on survival, particularly PFS, which is an interesting observation given that OS may be influenced by subsequent treatments, notably the anti-VEGF antibody bevacizumab. The patients who survived longer (patients 3 and 8), however, did show signs of CD8+ T cells responses. This intriguing finding suggests that CD8+ T cells may be involved in DC-mediated anti-glioma responses. The mechanisms that favored CD8+ T cell responses in these two patients remain unclear. Furthermore, recent data suggest that the genetic signature of GB may influence the outcome of DC immunotherapy,43 and systems biology tools may increase our understanding of the interactions between tumor cells and immune system, as recently reported.44 In particular, it is likely that systems vaccinology, which combines transcriptional profiling with flow cytometry, proteomics and transcriptomics, may allow for the identification of appropriate biomarkers that are associated with therapeutic immune responses.45,46
Encouraging data have emerged regarding the possibility that the combination of immunotherapy and chemotherapy might result in optimal antitumor responses, particularly T cell-based responses.47 In GB, the potential efficacy of combining immuno- therapy with the anti-VEGF antibody bevacizumab, which has previously been shown to exert signi cant effects on recurrent GB,48 was highlighted by the observation that VEGF inhibits DC maturation and tumor-infiltration by lymphocytes.49,50 The anti- CTLA4 antibody ipilimumab may also result in increased T-cell responses when used in association with DC immunotherapy, as recent data provided indirect evidence that ipilimumab may permeate the blood brain barrier and have an effect on melanoma brain metastases.51
Furthermore, DC immunotherapy combined with temozolomide-based chemotherapy has provided promising results in the clinical setting. Temozolomide is already a part of the standard treatment for GB,52 and both preclinical observations and preliminary clinical data suggest that the combination of temozolomide with immunotherapy may result in the development of antitumor T cell responses.53,54
The tumor volume at the time of vaccination, as measured in T1-weighted images after contrast enhancement, was correlated with survival rates. As expected, patients with larger tumors required more dexamethasone during the first cycle of vaccination, which presumably had a negative impact on DC maturation and activity.23 The negative, dose-dependent influence of bulky GBs has previously been reported during DC immunotherapy.24 Moreover, antitumor immunity may develop more effectively in the presence of small tumors, a theory that has been mathematically modeled in the case of adoptive immunotherapy for GB.25
And as we also know the Indeterminate PsPDs that were removed at baseline (prior to disease confirmation) using post surgical scan "enhancement" changes and remain alive in the Indeterminate Arm have not had a PFS event. The SIZE clock was then reset for all main arm study patients to baseline.
The "baseline" scan is where all randomized study arm patients are being measured for PFS events in this trial. And so any patient that didn't fail prior baseline, well their tumor size growth measure is reset to nadir of baseline scan, not the post surgical scan. PsPD scans tend to stabilize after the initial "enhancement". And most PsPD do not pass size limits.
Fact is that Brad (phase III patients GBM 1-3) was not removed for his PsPD size changes from his Phase I/II baseline scan of his therapy working well. If he had been classified to have a "false progression" event his DCVax-L therapy would have stopped. Here in this trial it would not.
The 10 Indeterminate patients who remain alive scans did not grow > 1 cm after the BBB distribution, when measured from baseline to month 2 scan, after being evaluated by the same Central Review Imaging then no reason to believe that PsPDs who do not have true progression will be wrongful removed for progression. Patients are removed for "unequivocal" progression after enrollment or if a new lesion shows up (size matters their too). Prior to enrollment they were removed for both "equivocal" (PsPD) and "unequivocal" progression. And as Linda Liau said, some PsPDs were excluded from main enrollment and the study design. She felt that they should have been enrolled, as they could possibly make the difference on PFS medians, but post surgical scan to baseline scan, the Central Review blinded removed simple based on size change at a time where they easily get mixed in with rapid progression. There are no rapid progression patients scans in the main arm at baseline. And again they will have baseline Nadir (lowest size point at baseline) from which to base tumor progression changes. Patients will have already gone through 6 weeks of Chemoradation to capture BBB enhancement at baseline scan. They didn't have those difference at post surgical scan and that was why many false progression patients were excluded from the main trial.
Assuming the vaccine works, even if there are "false positive" progression determination after main trial enrollment that doesn't mean patients go on to have a real event. The skeptics fail to recognize that long tail survivor in Phase I/II were all Mesenchymal. That gene group makes up a large percentage of GBM. And that gene type has historically bad OS on standard of care. The nomograms can give patient life expectations, but knowing the gene type picture helps with accuracy.
I imagine that there will be a provable statistical relevance overall survival difference between percentage of Mesenchymal patients randomized to the vaccine and the placebo regardless of crossover or not. Remember Linda Liau mentioned that Mesenchymal standard of care Chemo responsive patients, like Brad Silver (patient GBM 1-3) are expected to live around 16 months. The Phase I/II was able to show statistical significance for that Gene Type without a randomized control and many skeptics felt that was not a true significance. This Phase III study could blow Mesenchymal's historical survival data out of the water. This Phase III has a placebo control and even with crossover design, the Mesenchymal who are treated early on in the study at a time with no evidence of disease can do better then those treated after disease progression. It won't even matter if the vaccine at crossover improved the Mesenchymal in the overall placebo cohort overall survival, there should still be a statistical difference between that gene type given that fact that 47% of the placebo group did not crossover. That can be a straight vaccine verses placebo comparison that regulators can look at.
There will be placebo patients who won't crossover who fall in that Mesenchymal gene type group. Those patients will represent standard of care Mesenchymal's. If the Mesenchymal randomized to vaccine patients live years longer than may be all the study needs to show statistical significance. Now imagine the placebo Mesenchymal's crossover lives 3 years, that to me would make a strong case for approval even stronger. Those who bet against the company and the company stock may try to get investors to believe that the Mesenchymal data will simply be perceived as post hoc. And those who short the stock certainly want investors to believe that Linda Liau is wrong and that historical and placebo control Mesenchymal data both within and outside the study won't count. Meanwhile I perceive that if this study repeats both what is known about Mesenchymal's historical survival data (by way of the placebo non-crossover arm) and what is known about Mesenchymal's DCVax-L historical (by those patients in the treatment cohort) that it will be approved for at least that gene type subgroup. But hey, I like survival facts, as does the regulators as they speak for themselves. :)
If memory serves, its enhancement she is showing. Essentially inflammation of area. Not tumor. A good percentage of patients has no tumor left, so the scans you would see would be after gross total resection. How long it takes to disappear depends on patient response to treatment.
From the recent analysis.
For patients with gross total surgical resection (n?=?209), mOS was 25.4 months from surgery (95% CI 21.8–28.2), with 2 and 3-year survival rates of 51.2%, and 29.9%, respectively. For patients with only partial surgical resection (n?=?122), mOS from surgery was 21.1 months (95% CI 19.1–23.1), with 2 and 3-year survival rates of 37.7%, and 18.0%, respectively (Table 2).
In patients with both MGMT methylation and gross total resection (n?=?83), the mOS was 36.5 months (95% CI 31.5–46.5)—1.8 months longer than the mOS of patients with MGMT methylation and only partial resection (n?=?48). In patients with unmethylated MGMT, there was no statistically significant survival advantage with gross total resection compared to only partial resection.
This it what I wrote July 1, 2017 on one of my debates with Koman about AvII’s posts about this Phase III trial — which in his opinion would have a high PFS early event rate. We now know he’s wrong. But yes, simply by using the interdertimate data years ago, I knew he was WRONG.
Here is the July 1, 2017 post.
Koman, thanks for transcribing. I had my own copy, but do appreciate it. Mutual respect. Before I begin, I want to paste it again:
Minute 34: Slide Speaking about Trial Design Lesson
"Post Radiation MRI scan, if the patients had progressive tumor they were put in this separate information arm. And the thought about that and what we saw from prior Phase I/II trial is that if patients had bulky disease; or actually not even bulky disease, progressive disease, those patients didn't respond as well. Because if your tumor is growing exponentially, you don't have enough time to mount an immune response to the tumor. And those patients at least what we saw did not derive much benefit. So that was the rationale, for EXCLUDING what we call "early progressors". Unfortunately what we have learned over the years is that determination of "early progressors" is difficult because of the issue of "pseudoprogression". So there may have been some patients who should not have been excluded or vice versa. "-- Linda Liau
Her comments above around PSEUDOPROGRESSION had to do with the trial design randomization "exclusion" flaw.
Do you not agree?
Koman, you said: So LLiau CLEARLY states that these PROGRESSIVE patients are removed at the baseline MRI which is determined by an INDEPENDENT CENTRALIZED LAB as my other transcript suggested. There was no clinical determination at that baseline scan as far as I can tell and it was purely done by reading a MRI scan to avoid bias.
I say: LLiau states that both true progression and some pseudoprogression patients were removed at baseline which was determined by an Independent Centralized Lab.
When I read her comments I interpret them as the inclusion/exclusion criteria:
Due to the trial design rationale, they sought to specifically remove rapid progression patients, BEFORE THEY ATTEMPTED RANDOMIZATION. Unfortunately in the process they EXCLUDED some psuedoprogression patients (INDETERMINATES) who should have been randomized in the trial.
The determination of "early progressors" is difficult to make "early on" in the study, as they can tell which is which. In the Compassionate Use Information Arm they needed subsequent scan to tell if the patients had progressive disease. We would later learn many did NOT have progressive disease, as Linda Liau noted, when referring to the failed enrollment patients:
"THERE MAY HAVE BEEN SOME PATIENT WHO SHOULD NOT HAVE BEEN EXCLUDED and vice versa".
Those are her words in "quotes", not mine. And is quite clear that removing rapids caused them to lose patients who did not have progressive disease. And in an effort to keep the pseudoprogression in the main trial, they may have let some possible rapids progressions in the trial (whose tumors didn't cross that size barrier). The exclusion criteria was based on size, a strong line in the sand to avoid selection bias. That we agree on.
You are calling those patients who failed main trial enrollment as recurrence (PROGRESSION). BUT the reality is that they were EXCLUDED because of actual or apparent early progression. Again her comments were specifically about Central Review unbiased removal of possibly "true and false" Progression based on Tumor Progression changes after surgery (A new lesion ≥ 1 cm or tumor growth ≥25% after post-surgery MRI) when compared to 6 weeks later after Chemo Radiation scan. Using that baseline scan as the cut-off EXCLUDED both rapid progression and pseudoprogression. LLiau's comments were regarding the attrition of patients at Post Radiation Baseline MRI scan. Meanwhile they only ever meant to remove true progression of disease prior to 2012. Again she said the trial design, “there may have been some patients who should not have been excluded” and by excluded, she means from the main trial enrollment. She did not ever say that psuedoprogression patients were removed due to progression in the trial. It was before enrollment that she pointed to and referenced.
OFF the 55 Compassionate Use Arm abstract confirms her suggestion:
We treated 55 rGBM patients with autologous dendritic cells pulsed with autologous tumor cell lysate (DCVax®-L) in an “Information Arm” outside of our Phase III clinical trial. 51 of these 55 patients were not eligible for the trial because they had actual or apparent early progression (recurrence) at a Baseline Visit at the end of 6 weeks of daily radiotherapy and chemotherapy after surgical resection of their brain tumor. 4 of the patients were not eligible for the trial for other reasons (e.g., insufficient doses of DCVax-L).
The changes from after surgery MRI to Post Radiation Baseline MRI does not capture TRUE progression. It only captures patients who MIGHT have progressive disease. It didn’t matter if the 55 Patients were Recurrent Patients or not. Those patients were removed, because of trial's design exclusion criteria in an effort to enroll patients who fit this:
"The primary objective of this study is to compare progression free survival (PFS) between patients in the DCVax-L cohort and patients in the placebo cohort in patients with no evidence of disease progression at baseline." -- protocol
You calling the scans official "Progression", does not make it so. Again, these 55 were eliminated because between Surgery Scan and Post Radiation Scan (Baseline) the INDEPENDENT CENTRAL REVIEW IMAGING TEAM failed some Patients AT BASELINE VISIT based simply on SIZE. The size criteria was the evidence of possible disease progression:
• A new lesion ≥ 1 cm or tumor growth ≥25% at Baseline scan 6 weeks after Surgery Scan
As I mentioned before, in an effort to enroll patients with "no progressive disease" at baseline, they eliminated pseudoprogression (not real progression) while the protocol called for SPECIFICALLY looking for early progression patients. Progression of disease always needs to be confirmed by a confirmation scan; and because patients didn’t really have a starting one after chemoradiation treatment, the BASELINE scan is the ONLY one that can confirm PROGRESSION STATE. IT IS THE ONLY SCAN USED IN THIS TRIAL TO CONFIRM PROGRESSION. Incidentally, the Compassionate Use, Informational Arm abstract confirms this.
As AVII is aware, Psuedoprogression is not true progressive disease, instead it is true responsiveness to therapy. They eventually understood that might be removing some Psuedoprogression patients, and it is why they opened the pseudoprogression enrollment in 2012 to capture progression on some of those screening excluded patients. It is understood they EXCLUDED some patients due the evidence progression at baseline, they still needed to confirm whether the patients had progression or not.
Again from the 55 Compassionate Use Informational Arm abstract, what we know as fact:
Patients re-imaged at Month 2 after Baseline Visit to confirm either actual disease progression or pseudo-progression (patients categorized by independent medical imaging company)
Methods: Disease progression (recurrence) was determined through MRI imaging at the Baseline Visit and at Month 2 thereafter. All images were reviewed and analyzed by an independent specialized medical imaging company. Each image was reviewed separately by two independent reviewers, and any material differences were resolved by a third independent reviewer. Reviews were conducted using both RANO and McDonald criteria. OS data is available for all 51 patients. Baseline and Month 2 images are available so far for 46 of the 51 patients.
Based on comparison of the Baseline and Month 2 images, the independent medical imaging company classified the 46 patients into the following 3 groups. The other 5 patients were unclassified, due to lack of available images.
* 20 Rapid-Progressor Patients: A new lesion ≥ 1 cm or tumor growth ≥25% at Baseline and at Month 2
* 25 Indeterminate Patients: Stable disease, modest progression and/or regression, or measurements still unclear
* 1 Pseudo-Progressor: Month 2 image showed resolution of most of the prior appearance of tumor growth
http://www.nwbio.com/NWBT_ITOC_poster_3-25-15.pdf
The psuedosprogressions were not wreaking havoc on the study the way that AVII suggested. INSTEAD AS LINDA LIAU SUGGESTS, SOME WERE EXCLUDED FROM THE STUDY AND SOME WERE NOT. UNDERSTAND THAT LLIAU TOLD US THAT THERE WERE PSUEDO WHO CENTRAL REVIEW DETERMINED THAT >25% TUMOR GROWTH ON THEIR BASELINE SCAN (WHEN COMPARED TO POST SURGICAL SCAN) AND THEY WERE EXCLUDED FROM MAIN ENROLLMENT. AND WE ALL AGREE THAT THERE WILL BE PSUEDOS WHO HAD < 25% TUMOR GROWTH ON THEIR BASELINE SCAN (WHEN COMPARED TO POST SURGICAL SCAN).
IT IS THE POST SURGICAL SCAN THAT IS USED FOR TRIAL DESIGN EXCLUSION CRITERIA STARTING BASELINE. IT IS THE POST RADIATION BASELINE SCAN THAT IT IS COMPARED TO IN ORDER TO MAKE THAT IN-OR-OUT OF THE MAIN ENROLLMENT DETERMINATION. BUT WHEN IT COMES TO THE PSUEDOPROGRESSION PATIENTS PROGRESSION TEST, IT IS THE BASELINE VISIT SCAN THAT USED AS A STARTING MEASURE FOR THE PROGRESSION DETERMINATION. THE BASELINE VISIT SCAN IS WHERE TREATMENT OR PLACEBO CHANGES BEGIN TO BE MEASURED. AND I REPEAT, NOT ONE INDETERMINATE BASELINE VISIT SCAN WAS LABELED AS A TRUE PROGRESSIVE STATE AT MONTH 2 COMPARISON.
THE PSUEDO THAT PASSED MAIN TRIAL INCLUSION/EXCLUSION CRITERIA (< 25% TUMOR GROWTH PRIOR TO ENROLLMENT) would have been randomized fairly 2:1 (randomization occurs based on MGMT promoter status). We both know Central Review REMOVED patients on SIZE CHANGES BEFORE ENROLLMENT (measured from Post Surgical Scan to Post Radiation MRI Baseline Scan). We both know that they will continue to do unbiased assessment based on SIZE CHANGES AFTER ENROLLMENT (tumor growth measurement to begin from Baseline Visit Scan). AND I REPEAT WHEN CENTRAL REVIEW LOOKED AT THE 55 FAIL SCREENED PATIENTS AND USED BASELINE SCAN AS THE STARTING POINT, THE INDETERMINATES (LIKELY PsPDs) DID NOT HAVE.
--- A new lesion ≥ 1 cm or tumor growth ≥25% at Baseline and at Month 2
INSTEAD, WHEN MEASURED FROM BASELINE VISIT SCAN, 25 Indeterminate Patients READINGS WERE: Stable disease, modest progression and/or regression, or measurements still unclear.
AND I ARGUED REPEATEDLY that just like their 25 Indeterminate peers -- whose disease either shrunk, grew a little (not enough for progression) or were stable disease -- the randomized main arm PsPD would experience the same PSPD non-progression baseline scan comparison outcome.
So yes, it is exactly like I interpreted it. And I stated, the “likely PsPD” in the Indeterminate cohort (outside the study) who were on vaccine were confirmed as NON-PROGRESSION patients by Month 2 scan. None of the 25 INDETERMINATE patients tumors grew to a officially be called PROGRESSION. NOT ONE. The "likely psPDs" who were excluded from enrollment were officially cleared of their POSSIBLE PROGRESSION STATE and called INDETERMINATES. NO PROGRESSIVE DISEASE WAS DETERMINED BY MONTH 2 IN ANY OF THOSE 25 INDETERMINATE PATIENTS. They couldn’t be confirmed “officially” PsPD because patients were put on vaccine therapy that confounded the baseline scan data. And so Linda Liau likes to call them “likely” PsPDs.
IT IS VERY EASY TO PROVE THAT IF ANY OF THOSE "likely PsPD” INDETERMINATE COMPASSIONATE USE ARM patients had been enrolled and randomized IN THE MAIN ARM many would be without a progression event. WHAT WE KNOW FOR A FACT IS not a single one would have been removed for “PROGRESSION” at month 2 (MEASURED FROM BASELINE). Some would become progression patients on follow-up scans. BUT, the fact remains that the patients who are PsPD and who are living 3+ years, she stated that many of those patients have not seen a PROGRESSION EVENT -- according to LLIAU. THAT ALONE TO ME PROVES THAT AVII IS WRONG. HAD HE BEEN CORRECT, then the VERY BEST RESPONDERS PSPDS IN THAT ARM (LONG TAIL SURVIVORS LIKE BRAD) would have CENTRAL REVIEW CONFIRM THEM AS PROGRESSION AT ONE POINT OR ANOTHER. YET THAT DID NOT OCCUR. LINDA LIAU KNOWS MORE THAN AVII, AND SHE SAID THEY HAVE NOT HAD A PROGRESSION EVENT. SHE CAN'T BE CALLED BIASED, AS SHE IS NOT THE ONE MAKING THE "NO PROGRESSION" DETERMINATION. SIMPLY LOOK AT THE INFORMATIONAL DATA AND YOU WILL SEE, the Indeterminate patients were removed for mimicking signs of progression disease but not for actually having confirmed disease progression. WE DO NOT HAVE THE PROGRESSION MONTH FOR THE INDETERMINATE PATIENTS THAT PASSED. BUT WE CERTAINLY HAVE CONFIRMATION THAT THE ONES THAT ARE ALIVE HAVE NOT SEEN A PROGRESSION EVENT. CLEARLY Psuedoprogression is not confirmed progression. WHETHER INSIDE OR OUTSIDE OF TRIAL ENROLLMENT, the PsPD patients will need to have Progression of Disease from their BASELINE VIST SCAN, and if that didn’t happen to the very responsive PsPDs in the INDETERMINATE ARM (AT MONTH TWO SCAN) it certainly will be difficult to prove it will happen to the possible psPD randomized patients. As for psPD wreaking havoc after enrollment, it’s just biased interpretation of LLiau’s words (BOSCH'S TOO) and conjecture on skeptics part. CONJECTURE AND NO PROOF, IMHO.
What she stated proved what I debated on this iHub, they don’t rule early signs of pseudoprogression as a progression event. They wait to see whether the next scan is stable, better or worse before determining if the patient had a true progression event. :)
Pseudoprogression
Shortly after completion of RT, patients with high-grade brain tumors can present with an increase in contrast-enhancing lesion size, followed by subsequent improvement or stabilization without any further treatment (Fig 1).8,9 This occurrence, which mimics tumor progression, is termed “pseudoprogression.” Pseudoprogression is a subacute treatment-related reaction with or without clinical deterioration. However, in most patients, the increase in radiologic abnormalities is clinically asymptomatic. Pseudoprogression is most likely induced by a pronounced local tissue reaction with an inflammatory component, edema, and abnormal vessel permeability causing new or increased contrast enhancement on MR imaging examinations. Most important, some studies have found an association between the incidence of pseudoprogression and increased survival; perhaps pseudoprogression represents an active “inflammatory” response against the tumor.9
Currently, the only method of distinguishing pseudoprogression and early progression of disease is to perform follow-up examinations of the patients because conventional MR imaging is unable to differentiate the 2 and alternative techniques have not yet been validated in prospective trials.9,11 Analysis with follow-up conventional MR imaging examinations allows such a distinction because the changes related to pseudoprogression decrease in size. The development and validation of new methods to evaluate true brain tumor response—as opposed to inflammatory change—would be very helpful in the assessment of treatment efficacy.
Every trial is different. Ebery disease is different. And every company is different. It is unique to Phase iii trial in GBM that had progression as it primary endpoint (which would require review of scans to be included in the analyze and not just a pulse) it would take much longer. And because this one does and is considered large (when one considers the number of places the study recruited) it would also mean a much busier travel schedule with more stops. And because they are a small biotech, it will likely mean they only hired the bear minimum of a team to perform such function. And so yes, I do see this as s multi-month process. Again, depends on how many they are able to close out a week /a month.
They have two CROs. One for international and one for the US. And then Marnix is on point to review data at his discretion. We don’t know how many people from each CRO agency is on NWBio acct. But whatever it is I imagine it’s not many full time. They have to go to every single clinical site in the trial and there are over 80 clinical sites in four counties. They will need to make sure scans are in for every patient. And what they have to review is substantial considering most patients have lived 2 years or more and the study duration started with possible as much as 11 years of MRI data on some patients (if we make an assumption that some of the 2008 -2010 patients are still alive. This isn’t Stupp, where a handful of sites recruited majority patients. Well over 1000 people were recruited. No site in this trial has more than UCLA targeted 28 patients. They have to make sure they have all the immune testing data on each patient. Go over crossover data. Lots of material. And again it’s not straight survival they will need to review is eCFs. And so yeah, I see it as s cumbersome timely collection process.
Off the protocol:
Parexel International, a contract research organization, will assist the sponsor in
performing the sponsor responsibilities in the EU (site selection, clinical
monitoring, pharmacovigilance, submissions to the ethics committees, and
clinical data management) noted in the regulations.
.Synteract, Inc., a contract
research organization, will assist the sponsor in performing the sponsor
responsibilities in the U.S. (site selection, clinical monitoring, pharmacovigilance,
regulatory submissions, and clinical data management) noted in the regulations.
PFS data won’t change from Nov until now. The data at this point can’t get better or worse. It was probably couldn’t get better or worse once they passed approx 2 years on last patient enrolled. It’s just a question of getting a confirmed PFS event on each patient. That I gather they are still in the process of doing. Not important that they data locked that endpoint as again it couldn’t change. They haven’t data locked OS.
For GBM, using OS is the standard. The fact that this trial has 3 years of survival data on every patient it would serve the trial well to have a co-primary endpoint. That the board discussed a while ago and unanimously agreed. Maybe they read this board and considered it, but just so at a junction near the end of the trial. If they haven’t done any analysis then it’s just a matter of wait time trying to get it through. The time it takes to go to all sites to verify PFS data and close out clinical sites may end up lining up well to get the 4 regulatory bodies to approve an updated SAP. I don’t see it as an issue. It makes sense to me that they pursue changing the SAP simultaneous as they close out sites. In my view it’s a smart strategy to update since they have at least 3 years of survival data on every last patient.
I honestly depends on how long it takes them to go through PFS data and lock down all clinical sites.
I’m of the opinion that they started this site visit PFS data lock process years ago (as reported in 2017) and visited closed clinical sites that only had follow-up period to do on patients — meaning sites like NYU that enrolled all their patients early on and did not have any more patients in the “active” phase of the study. These would be sites that enrolled patients prior to 2014 (ended enrollment 3 years or more). Patients that remained alive in any site would still be subject to their 3 month follow up OS calls and every 3 month scans (I don’t believe they are 2 mints at that point). But the Company had to stop visiting closed sites when they ran low on funds. Let’s say they visited 20 in the past. They would have to go back to those. They would just have to complete the process on the other 60 or so clinical sites. Now this process of visiting clinical sites (to close out the PFS patient data) resumed in the New Year (2019). We don’t know how many they have left to do but I suspect it’s more than half of the enrolled clinical sites. Depending on how many patients would be recruited at the sites will determine how long it takes to lock the PFS data for that clinical site. OS data would remain open on however many patients are alive and they would still be doing 3 follow-up calls and OS continue to mature until they are ready to do officially end the trial. Only difference is they would be recording that survival update every 3 months, up until the end, depending on when patients were enrolled. Once they complete all the PFS data lock on all the clinical sites, they are ready to do their final wave of OS calls. That would occur just after PFS data lock. It shouldn’t take more than a few days to reach the patients that remain alive. But they definitely won’t want to lose patients to follow-up so if they can’t get the patient we may have to wait for them to exhaust the follow up process before they data lock OS data and do analysis on both. We would only hear report of PFS data lock once. And SAP should take place shortly thereafter, but only once they lock OS data.
Flip feels reporting by Sept is more than reasonable time frame to data lock PFS data, data lock OS and do the SAP. Without knowing how many sites they completed in 2015 it’s really hard for me to say whether they’ll be done by then. But I do think 8 months should be sufficient to visit 40-60 sites (between 1 to 3 a week, depending on location). I won’t be surprised if we are waiting into Sept. Feel if they are not going fast on site visits we will end up getting 4 years of OS data from surgery on all patients and they may be purposely going slow to age the OS data.
Days (best scenario) after data lock.
This was covered a long time ago. It’s a once and done approach they plan to pursue because patient white blood cell counts can obscure the data. Plus If did the SAP the moment they crossed the PFS endpoint then most of Germany and Canada’s data wouldn’t have been included as Germany didn’t start enrolling until late 2014 and Canada didn’t start until 2015. Remember a good 50% of patients were not enrolled until sometime after May of 2014. You don’t want to do the analysis on a subset of data, which is what they would have done if they unblinded at first chance. It’s best to do it when you have all the data on all the patients as you get the worse of the data to affect the placebo arm (under the assumption the vaccine is an effective product). This is especially important to delay looking at OS this trial under enrolled — meaning it didn’t go to 348 patients as planned — it makes sense to capture all PFS and OS data on the full 331 patients. Waiting until the end of the trial ensures they get all the worst PFS data from every site is included. Remember it’s four countries data they would be looking at. And it’s about separation between the placebo and vaccine arms (1:2 randomization). If they did PFS analysis once they passed 248 events they would only capture all the worst 248 progression data from 248 patients of 331 enrolled patients. Now we know they will be capturing the worse 248 progression events from up to 331 patient events and then unblinking. It is quite possible have the best shot on reaching significance as there is a large pool of patients to look at the 1:2 difference of the worst 248 progression events. They obviously are trying to get the best out of the full patient data pool. That I support.
I’ll try to answer when anyone reaches out. I don’t read the board regularly but I did glance at some of days posts before seeing what Pablo was chatting about before responding.
Ps. I have not bought or sold any shares. Content with my NWBO holding. Still patiently waiting on results.
Hope all is well with you. :)
They reported days later. They had no funds to do the complete data lock. Now they do. Patiently waiting and while I’m not happy that it likely won’t happen by March, I get that a financially strapped company delays things.
I hear you. The idea that data lock can be dragged out beyond August is super frustrating. If we get to August that will mean 4 years since every single patient entered the screening process. I’m not holding my breath for ASCO but I’m optimistic we will know results by SNO.
The % of patients alive bodes well for the long term follow-up on patients. To deflate the good news, the skeptics are making some hefty assumptions that every single failed screen patients is dead. We don’t know how many are alive from that failed the main arm of the trial, but we do know that number is not ZERO. Consider that we know the compassionate use arm had approximately 10 patients who also remained alive (they are part of the failed screened group). We also know that among the failed screen group includes the Psuedo arm (the patients who historically show the greatest signs of Radiation and Temodar working well) which have a high likelihood of having long term survival (regardless of which cohort they would be: vaccine or placebo). Therefore to have the skeptics make the assumption that the long term survival percentage wouldn’t improve by a decent percentage outside the main arm is at best a faulty one. They can’t stop hanging around and trying to diminishing the main arm survival. And they do so by pretending there is no long term survival outside the main arm, which just isn’t true.
Hi Pablosrv,
There are no SAP issues.
They are in the follow-up period. Once they complete visiting all the sites they will data lock and report final analysis. A) The last patient was enrolled in Nov 2015. B) They only closed on the loan in December 2018 and site visits take time. C) Follow-up period for all blinded patients falls on a a 3 month cycle. D) they are a small maned company. In my opinion given A, B, C, and D that means reporting data lock has the potential to fall on any of the following follow-up months: May 2019; August 2019; Nov 2019; and so on. (I left out Feb 2019 as again they only closed on funds which they need to do site visits in December). If they data lock at end of the month near holidays, we should hear results no later then early the next month. I think Flip’s prediction of Sept gives the company plenty of time to complete data lock.
Hope that helps,
Regina
Goes through, not sure where or how “three” came through instead. Ahhh
Yes.
Also think this latest PR is just generally saying they will have the funds shortly (once the sale officially goes three) to complete the final data collection multi-month (many months) process to end the trial — investors have patience, no more raises, trial starts and trial ends are both going to happen.
It must be within 3 months according to the protocol. Typically once a patient progresses, 5-7 months later they die. Sadly, there isn’t any approved treatment that extends survival after progression. Anyway, they need to administer while a patient is healthy enough to receive the injections.
From the protocol:
Treatment Schedule after Confirmed Progression and Crossover
• Patients will receive up to 10 DCVax-L injections at days 0, 10, 20, and months 2,
4, 8, 12, 18, 24 and 30. Day 0 is the date of the first immunization and must occur
within 3 months of crossover (date of confirmation of disease progression). For
the immunizations at days 10 and 20, the variance may be ±2 days but the
minimum interval between injections must be at least 9 days. For the
immunizations at months 2, 4, 8, 12, 18, 24, and 30 the variance can be ±1 week
with a minimum interval of 6 weeks between injections.
It will not be less than LP will have us believe. I’m of the opinion they have to still go to most of the “last in” clinical sites in the trial. Has to be at least dozen or more sites that joined in late 2014 to early 2015 that finished recruitment in summer 2015. It’s the sites that recruited the last of the 26 last enrolled patients that might be spread out. But Canada was only supposed to have 21 patients. Germany was supposed to have 87 patients. Some of both those regions clinical sites should be closed out relatively quickly — days to a week — not weeks. Whereas, the UK data primary data is probably already closed out. They should have been done recruiting back in 2014. Most, but not all, of the US would have been done by now. Maybe 10 -15 left from those. But those sites too likely won’t have as many patients as NYU or UCLA did so it should be they can knock those out quickly too. None of us know where they enrolled last but I suspect those last in patients were at a mix of sites. Anyway, I’m guessing at least a few months is still accurate to data lock.jmo.
Hypoxia significantly inhibits the infiltration of immune cells into tumor tissue. Bevacizumab is believed to normalize tumor vasculature and decrease tumor hypoxic area. Mesenchymal patients have varying degrees of Tumor infiltrating lymphocytes (TIL) before therapy. The vaccine is said to increase TIL afterwards. The combinations of these two therapies could be enhance immune response infiltrated into tumor. They already have historical data on how long patients survive with salvage therapies after progression. I have no doubts whatever that the two in combination will be better than Avastin alone. None.
It goes back to their 2017 PR about in order to data lock, they need to visit every one of the Phase III clinical sites.
“In this process, all data from all of the treatment visits and follow up visits for all 331 patients in the Trial, must be subjected to quality control checking. The process involves in-person monitoring visits to all of the 80-plus sites in four countries to review the files onsite, as well as other documentary confirmation and checking of all MRI images. As such, it is a multi-month process. While this process is under way, OS and PFS events will continue to accumulate.” — Feb 2017 NWBIo PR
Most of us believe they started the data lock process of reviewing data at clinical sites back in early 2017, as reported. Each clinical site had s specific patient recruitment count target. Once that target was hit, recruitment closed. Once recruitment closed at a site (every site would be different) it would be 3 years after last enrolled patient that they could scrub the primary endpoint data at the clinical sites. As an example, UCLA began recruitment once the trial resumed in the summer of 2011. Since UCLA was one of the earliest clinical sites within the trial they likely reached their 28 patient enrollment target in 2014. That would be one of the sites they easily could have visited in 2017 and completed the primary endpoint quality control checking. NYU was another site that closed recruitment years ago. The list of opened then verified closed sites is long. As such, it may only the last in sites that we have to wait for them to visit now. Hopefully they never stopped this quality control checking as our wait is dependent on that.