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Do you mind if I ask whether you are a stock holder, and whether your investment strategy is long or short?
Still unclear what happens when a treatment arm patient 'crosses over'.
Do they 'reset the clock' or just continue dosing regimen? (I'm unclear). Do they employ placebo at all after crossover? I doubt it, but some have suggested they would.
Must be in the protocol somewhere, or the site investigators would be confused...
Not too much to lose when DcVax is added to SOC. Quite a bit to lose when DCVax becomes SOC.
Those with most to gain from being wrongly assessed as progressors.
That would be placebo arm patients.
Call me optimistic if you like, but when the investigation is concluded favourably, I expect good old Woody will re-open that expansive wallet.
He will do his DD again, and if he perceives that NWBO represents value, which of course it does, he will treat it like a fresh Day 1 investment. It's the logical thing to do.
He has more (financial) interest than most in ensuring NWBO's success, after all!
I just have a gut feeling that funding is already sorted for the interim, until that whopping great catalyst comes along...
I expect 1 year is more realistic for Sawston to come on stream.
Woody can always pop down and crack a few heads.
And in the meantime we have contracts with Kings and Frauhofer.
Always best to counterbalance negative spin.
I guess Sawston is being readied to meet demand, before Accelerated Approval is applied for.
No point in applying for AA until you have unequivocal evidence of efficacy and assured manufacturing capacity.
Obvious surrogate endpoint is tumor shrinkage/eradication based on MRI images. This might be 6-9 months after reactive inflammatory response (pseudo progression) with treatment arm. And perhaps 12 months after a placebo subject crosses over.
Tumor regression/eradication, decrease in tumor load would be reliable indicators of objective response and stable disease.
Such a surrogate endpoint would have to be clearly evident in a sufficient number of trial subjects, to make any other explanation virtually statistically impossible!
So, I guess it might be a few months yet, but in the scheme of things that's not long.
NWBO might also be actively pursuing an application to the MHRA for approval in the UK and the rest of the EU, which is something we tend to forget.
Oh yes, pseudo progression is an indicator of much enhanced median OS in GBM. One study recorded median OS of 34.7 months for pseudo progressors compared to 13.4 months for patients without pseudo progression!
This was on SOC, not immunotherapy. And, if you had MGMT promoter methylation status as well as pseudo-progression, median OS jumped to 54.1 months...
Much more effective than a certain other device touted on here!
Extract from this study.
Quote:-
Title
"Diagnosis of Pseudoprogression using MRI perfusion in patients with Glioblastoma Multiforme may predict improved survival."
Gahramanov et al.
"Aims
This retrospective study determined the survival of glioblastoma patients with or without pseudoprogression.
Methods
A total of 68 patients were included. Overall survival was compared between patients showing pseudoprogression (in most cases diagnosed using perfusion MRI with ferumoxytol) and in patients without pseudoprogession. MGMT methylation status was also analyzed in the pseudoprogression cases.
Results
Median survival in 24 (35.3%) patients with pseudoprogression was 34.7 months (95% CI: 20.3–54.1), and 13.4 months (95% CI: 11.1–19.5) in 44 (64.7%) patients without pseudoprogression (p < 0.0001). The longest survival was a median of 54.1 months in patients with combination of pseudoprogression and (MGMT) promoter methylation.
Conclusion
Pseudoprogression is associated with better outcome, especially if concurring with MGMT promoter methylation. Patients never diagnosed with pseudoprogression had poor survival. This study emphasizes the importance of differentiating tumor progression and pseudoprogression using perfusion MRI."
Quote
"One such alias was created under the name of Michonne. No doubt also intended to initiate intelligent conversation with us in an uncharged and respectful manner. Thank you for reminding us how pure his intentions have been over the years."
Errr. No.
I guess you'd rather not address the issues that I've raised then?
Do you have a reasoned response?
Well, I guess I'm curious about how further bias could have entered this study.
Pseudo progression not only affects immunotherapies.
It is a phenomenon that is also exhibited in association with chemo/radio therapy.
A number of studies have shown that this phenomenon is apparently exhibited by 26-58% of GBM patients, who demonstrate apparent early progression.
Subsequent scans of said population who remained on treatment, demonstrated that 38% of these showed radiographic improvement or stabilisation and were deemed to have pseudo-progressed.
Now this has implications for lots of GBM studies.
Not least the Optune one. If progression was assessed in any way differently between the two arms, then it would render the data useless.
If it was the case that a patient in the control arm was more likely to have been deemed a progressor, as opposed to a pseudo progressor, then said patient would cease to receive chemotherapy (which might have continued to be effective) and then get the device (which might be mistakenly deemed to be the effective agent.)
This might at least partially explain the fact that the control arm received less cycles of chemo.
Bit of a minefield isn't it?
And that is without knowing whether any re-intervention or salvage therapies were employed with any of the patients.
So, Optune demonstrated a marginal benefit in a trial that, for me, has major question marks, in terms of possible bias.
I'd like to know why, and I don't think it's necessarily the reason your thinking of!
Did you notice that the Optune patients received much more chemotherapy
Median no. of TMZ cycles:-
Optune/TMZ: 6 cycles
TMZ only: 4 cycles
There was a lot of speculation on this site that existing OS figures were in fact out of date, due to the advances in imaging techniques that allow much more precise tumor removal. It's obviously a bit of a moving train and evidence from a recent trial suggests 'they're all living longer'!
I believe LL quoted a longer figure based on her clinical experience.
In recurrent GBM:-
Optune Median OS 6.6 months. Post hoc projected analysis changed this figure to 7.8 months.
'Best active chemotherapy'. Median OS 6.0 months
Pyrr
I see you have avoided mentioning Optune median OS in newly diagnosed GBM patients. It is 19.4 months...
I have often heard SOC median OS described as 18-24 months..
Some have argued that median OS for newly diagnosed GBM patients receiving SOC has already moved on from 18 months to nearer 2 years.
Clearly not the case going by the Optune trial data.
Optune represents a marginal benefit at best, with a median OS of of 19.4 months, and control arm median OS of 16.6 months, in their Phase 3 trial.
The majority of treatment participants were deceased at 2 years.
Optune has no systemic or curative effect.
It could be related to the Declaration of Helsinki and its statements about the use of placebos. Perhaps the European centres deemed it unethical to continue to enrol new patients who might receive placebo once L had demonstrated its efficacy.
There could be 101 reasons for the screening halt.
Perhaps one of them could be that the FDA thought it was unethical to enrol further patients on to the trial, knowing that a third of them would be denied treatment other than SOC, until their disease would inevitably progress. An interim analysis may already have demonstrated that L has unprecedented ability to engender stable disease.
The trial itself would continue to confirm the preliminary findings.
In what way has he done a 180?
He hasn't sold a share..
Interesting that Novocure chose PFS as the Primary endpoint in their Phase 3 trial, with OS as the secondary endpoint. Evidently the right choice for them, with no pseudo progression issues that can characterise immunotherapies.
I guess Optune could be adopted as part of SOC on the basis of significant but small improvements in PFS and OS (a few months).Though their trial wasn't blinded, which I guess should mean that their data should have been considered slightly less significant. No claims are made about Optune having any curative capacity, or the ability to engender stable disease.
I guess that's the nature of SOC. It remains the same until something superior comes along...
Thanks for response.
No, I'm not making that confusion. If there were flaws in the design and specified endpoints of the L trial, then that has happened. I trust that unprecedented OS will see us through in any event.
I'm more interested, on behalf of the company, that they get it right with Direct!
You will be aware that in Phase 1, patients who did not receive the full quota of injections deceased rapidly, whereas the majority of those who received the full quota remain alive today. I know you will say dead patients don't get injections, but if you look at the whole picture, you won't buy that.
I'm reasonably sure that Direct has/will experience the tumor swell/necrosis, pseudo-progression phenomenon, before stable disease ensues, if injections continue...
I'm very encouraged to hear that Phase 1 results will be interpreted by irRC as well as well as RECIST. If that is the case, it shows that NWBO are on the ball.
I am not aware of any 2nd or 3rd or 4th line treatments that could be, or were offered to Direct subjects, who have inoperable cancer and have exhausted SOC.
Now I agree with you regarding Phase 1 data. I think the company could tell us more. Whilst most communications, particularly around L are embargoed, I see no reason why they could not tell us more about Direct patients, especially if there are patients who have stable disease, years down the line, and living full lives.
They are missing a trick.
NWBO , are you listening!
I don't know your professional background, but you clearly have extensive knowledge re. clinical trials, and if you are that rare phenomenon, a DCVax agnostic, then one should take note of your insights!
As you say, ASCO may reveal more.
In the case of DCVax which has been proven safe in both L and Direct, this is not a problem, in fact it is a definite plus for terminally ill patients who have no alternatives.
They will be able to continue to receive injections after apparent progression as measured by the old RECIST criteria, instead of having treatment withdrawn with the inevitable final consequence.
The FDA have stated the very important provisos that apply here as detailed in my post 54311.
If I was in that position as a terminally ill cancer sufferer, I wouldn't want it any other way...
Take another look at Direct Phase 1 data and compare median OS for patients who received 4 or more injections, and those who received less.
Did I read you right, or were you actually make the opposite point?
Thankyou for that.
I am gratified that you agree that Phase 1 demonstrated that Direct is safe.
That in itself, marks DCVax apart from many, if not most, immunotherapies that exhibit serious adverse side-effects in a significant
proportion of recipients.
Although Phase 1 long tail survival suggests, in my opinion, that something unprecedented and momentous is going on here,
you state that using RECIST criteria, Direct Phase 1 did not demonstrate efficacy through ORR.
So, would you agree that Phase 2 should be all about unequivocally demonstrating efficacy? And that the irRC method of assessing
'total tumor load' instead of the simplistic RECIST method of a longitudinal measurement of the primary tumor,should be employed
when considering if 'disease progression' has occurred?
And the irRC of course, has the built-in 2 month re-assessment to recognise pseudo-progression as opposed to 'real' progression.
And would you agree that it would be sensible for NWBO to build in
to the protocol, the stipulation that treatment continues, after apparent or even real progression, having regard for the provisos
listed by FDA.
And if the Phase 2 was not designed as a 'pivotal' trial or a registrational trial, what other suggestions would you make, in terms
of trial size, number of centres etc. to make the trial efficient and data rich?
Thankyou.
AV11. Contradictory Statements?
I am still hypothesising about the necessary elements for a fruitful Direct Phase 2 trial.
You stated:-
Quote.
"It would make no sense to run another single arm trial capturing Response Rate as the primary. If you believe the stuff works and you want to prove it via its effect on patients living longer (or living longer w/o progression) that can only be measured via a randomized trial."
and then you stated:-
"The FDA will, of course, allow them to run a single arm trial measuring Response Rate and/or PFS and/or OS, but the results would not support licensing DCVax. It might even be a good idea to run such a trial prior to a registrational trial."
Can you clarify?
Thanks for that.
Very important section from FDA's "Guidance for Industry. Clinical Considerations for Therapeutic Cancer Vaccines"
" 'Disease progression/recurrence immediately or shortly after the initial administration of cancer vaccines.'
In oncologic practice, investigational and approved treatments are generally discontinued when patients experience
disease progression. Because of the time required for the host (patient) to elicit or amplify an immune response to a cancer vaccine (i.e., tumor-specific immune response), the vaccine may have a delayed effect in the study subjects. In this situation, clinical progression may occur before the
vaccine has had sufficient time to be effective. Therefore, clinical progression that is asymptomatic and/or is not likely to
result in life-threatening complications with further progression (e.g., Central Nervous System (CNS) metastases or impending fractures from bony metastases) may not be sufficient reason for discontinuation of administration of a cancer vaccine.
One potential approach to this situation would be for the study protocol to clearly define the extent and location of clinical disease progression for which continued vaccination will be continued. The following are potential clinical situations in which sponsors may wish to consider providing provisions in the protocol for continued vaccination despite evidence of disease progression:
o Subjects continue to meet all other study protocol eligibility criteria.
o No dose limiting toxicity (DLT) has been observed, and all toxicities
resolved to the baseline level, consistent with the study eligibility criteria.
o No deterioration of subject performance status.
o No curative salvage therapy exists for the indication (e.g. resection of pulmonary metastases in osteosarcoma patients).
o Does not delay imminent intervention to prevent serious complications of disease progression (e.g., CNS metastases).
o Clinical evidence from early phase clinical trials suggests delayed effects."
So, in brief, it must be written in to the protocol that progression (which is likely to be pseudo progression) will not lead to
ceasing of further injections, as long as the above conditions in the Guidance continue to be met.
Essential that this is written in to Direct Phase 2 protocol.
Journal of the National Cancer Institute.
Yes indeed, RECIST is only really adequate for assessing
chemotherapy, and does not represent the best efficacy test
for immunotherapies. Hence the importance of the new efficacy
criteria known as irRC.
Just one of the potential applications for Direct:-
The American Cancer Society;
Projected estimate of deaths from Lung Cancer in the US in 2016
is 158,080.
Very thought-provoking post.
Can I add a suggestion to your Direct Phase 2 trial design proposals.
Build in the use of irRC response criteria:-
Quote from JNCI
"For decades, investigators have relied on modified WHO criteria or, more recently, RECIST to assess clinical activity of anticancer agents. These standard criteria were designed to capture effects of cytotoxic agents and depend on tumor shrinkage to demonstrate activity. However, the response patterns seen with immunotherapeutic agents extend beyond those of cytotoxic agents and can manifest, for example, after a period of “stable disease” in which there is no tumor shrinkage or after initial tumor burden increase or appearance of new lesions (eg, tumor infiltrating lymphocytes).
This potential delayed detection of clinical activity on radiographic assessment may reflect the dynamics of the immune system — the time required for T-cell expansion followed by infiltration of the tumor—and a subsequent measurable antitumor effect. For example, some reported clinical experiences with cancer vaccines demonstrated that patients with stable disease or progressive disease may have subsequent tumor regression, whereas others may show initial mixed responses, with regression in some lesions while other lesions remain stable, progress, or first appear. In these studies, patients with measurable tumor burden decrease had more responses that did not fit currently accepted response criteria than conventional responses. Such patterns have been noted by many investigators; however, they were inconsistently included in publications or were not systematically captured because of the absence of suitable response criteria, which, in turn, did not allow for their clinical significance to be adequately studied. It has become evident that RECIST or WHO criteria may not offer a complete description of the response to immunotherapeutic agents, and either adjusted or new criteria are needed."
Otherwise, very solid proposals, which should allow Direct efficacy to be optimally demonstrated, and, who knows, lay the way open for a successful application for Accelerated Approval.
The Role of irRC in assessing response rates in Immunotherapy.
From what I understand from reading, it is now being increasingly recognised that RECIST is not the most appropriate criteria to use in respect of measuring outcome in Immunotherapy trials, and that immune-related Response Criteria (irRC) is now increasingly finding favour.
I can see that use of irRC in respect of DCVax trials will prove the superior assessment tool.
I believe that irRC provides at least a partial solution to the problems thrown up by pseudo-progression.
iiRC allows for the fact that some patients experience progression before they respond to therapy, as well as other advantages:-
"Responses to immunotherapeutic agents can differ from those observed with conventional chemotherapy. For example, some patients can experience disease progression before they respond to therapy, and others can develop new lesions at the same time that their index lesions are shrinking. As a result, modified response criteria were proposed for use when assessing the response to ipilimumab: the immune-related response criteria (irRC). The irRC were developed from the existing World Heath Organisation (WHO) criteria and Response Evaluation Criteria in Solid Tumours (RECIST), but with some important modifications. For example, patients with new or progressing lesions can be defined as having a PR if there is an overall decrease in tumour burden of ≥50% (i.e. it is not based on the increasing size of index lesions, or the presence or absence of new lesions). The irRC also define progressive disease differently, so that patients who have progressive disease using the existing RECIST/WHO criteria may remain on therapy." My emphasis.
From Wolchok in Annals of Oncology.
I understand that irRC was used in the assessment criteria leading to approval of ipilimumab (Yervoy)
Could it be that by applying iiRC instead of WHO/RECIST response criteria, L results are surpassing expectations in a positive way?
Koman
Quote from your post:-
"The confusion seems to be yours and not due to AVII's explanation. In your example, if the efficacy shown by looking at the OS endpoint doubles that of the expectation, then my question would be: Why would the company seek AA when they can get a halt for efficacy for REGULAR APPROVAL. You don't seem to understand that a regular approval is BETTER than AA. Also, you don't seem to understand why AA was designed in the first place- mainly to get a very promising therapy to the patients faster than the regular pathway- something that NWBO failed to do so far by continuing to delay their own AA pathway thru continued enhancements to their initial p2 AA trial. Now why would the company delay their own trial from finishing? No need to answer this rhetorical question."
Could it be that they are aiming for Regular Approval, which you describe as 'better'and they are not aiming for AA...
Av1177
Do you mind clarifying your response.
You stated:-
"PFS (and OS )can only be assessed in randomized trials (those with a control arm)"
How so, you can measure these in a single arm. And you can compare them with historical norms.
And you stated:-
"The FDA will, of course, allow them to run a single arm trial measuring Response Rate and/or PFS and/or OS, but the results would not support licensing DCVax."
This appears to conflict with the FDA guidance that I quoted:-
" FDA staff advised the ODAC and sponsors that single-arm, phase II studies are interpretable only for the purposes of AA applications in the setting of refractory disease."
So, if your data is good enough and you can demonstrate significant clinical benefit for terminally ill patients, then you can apply for AA and it can be granted, purely from a single arm Phase 2 Study.
Do you agree?
Direct Phase 2 without Control arm?
Referring back to part of an FDA document that Flipper quoted:-
"The FDA advised sponsors that future AA applications should preferentially be based on interim analyses of phase III (rather than phase II) trials, thus obviating the need for recruitment to additional confirmatory phase III trials.6–8 Also, FDA staff advised the ODAC and sponsors that single-arm, phase II studies are interpretable only for the purposes of AA applications in the setting of refractory disease. In contrast, interim analyses of phase III trials could support AA in a broad range of settings, and additional follow-up of these trials could provide evidence of clinical benefit."
Well, maybe Direct Phase 2 doesn't require a control arm.
The refractory disease requirement would be met.
So, you could design Phase 2 to purely prove efficacy in a single arm. You would not necessarily plan to gain approval from the Phase 2, but you would know that if your data does as well as you secretly hoped, you could apply for Accelerated Approval based solely on Phase 2 data.
You would start out with sensible expectations and endpoints (not like Phase 1) and choose, maybe 2 or 3 indications. Breast and Lung seem suitable candidates. Large patient availability and unlikely to respond to Keytruda due to lack of PD-L1 expression, so patients would not have to choose between an approved therapy and a trial therapy.
Sensible endpoints?
Primary Endpoint. Maybe Stable Disease (call it PFS if you have to) at 6 months.
Secondary endpoints could be Response Duration and Overall Survival.
No blinding, so you can see how you are doing.
I really don't think it is strategically sensible to even consider CI partnership in Phase 2. Phase 2 should be all about confirming and improving Direct efficacy on its own .
Patient eligibility. Expected survival of at least 6 months. Same requirement for high tumor load and inoperable status.
Less conservative dosing regime. All tumors injected.
Multi-centre. Yes
International. Yes. Go for US, UK, Germany where you can get maximum exposure to regulatory authorities, you have local manufacturing, and you already have links with trial sites and trial investigators.
Trial size. Small enough for economy reasons, large enough for statistical significance. Maybe 50 patients per indication.
Recruitment. Ensure it is fast
No delay between recruitment and commencement of treatment. You cannot afford this to happen, as it did in Phase 1.
Right that's all done and sorted.
I'll fire this off to NWBO straight away.
Only joking...
But would welcome any suggestions about the best design for Direct Phase 2, as I really don't know much about Trial Protocol.
What I do know is that it is critical for NWBO to get it right.
Very impressive.
I expected some end of day profit taking.
Must be new retail longs, or longs topping up
on awareness of fundamentals, rather than day traders.
Perhaps a bit of new institutional buying?
Lack of sellers, thats for sure, given the rise that persisted
throughout the day.
More the same tomorrow on no news?
Now I thought that the FDA required the L trial crossover on ethical grounds.
I could perfectly understand that.
Otherwise, a patient with this fatal disease would have a 1 in 3 chance of receiving no treatment at all, other than previously received SOC. I really think you would have major difficulties recruiting on to the trial in those circumstances.
Having the crossover to treatment is clearly why 'everyone is living longer' Not a problem if median OS vastly exceeds historical norm.
This issue also has relevance to the design of Direct Phase 2, when presumably there will be a control arm. Again there would be the issue of the control arm receiving no treatment. Surely unethical in the case of patients with very limited life expectancy.
Would a crossover again be required, and how would you trigger the crossover, given all the issues of around pseudo progression,
when a tumor is simplistically measured for size.
Just thinking out loud.
Any thoughts on this?
Electroporated DC's!
Sounds wonderful.
But they're at the pre-clinical stage, and the DC's don't migrate....
So it doesn't work?
Still, never mind, it's a wonderful name and they should get credit for that.
Agreed.
Very interesting, but how the hell did it get worldwide headlines?
Still, in the scheme of things, it broadens public consciousness of the whole immunotherapy field, which is no bad thing for NWBO.
And no reason why NWBO won't be getting that level of coverage
before long.
Actually, well worth checking out the BBC news section on their website.
They show this mornings headlines in various national dailies.
Then go to Health news, where there is a more in depth article and a video interview with Dr Alan Worsley from Cancer Research UK:-
Dr Alan Worsley, from Cancer Research UK, said that while the field was incredibly exciting, "this is a baby step".
He told the BBC: "We've been working for a while using this type of technology, genetically engineering cells. So far it's really shown some promise in this type of blood cancer.
"We should say that in most cases standard treatment for blood cancer is quite effective, so this is for those rare patients where that hasn't worked.
"The real challenge now is how do we get this to work for other cancers, how do we get it to work for what's known as solid cancers, cancers in the tissue?"
Good relevant interview, but a bit galling that he makes no reference to NWBO!
I've already commented on this, this morning, and answered some but not all of your questions.
See 54036 and 54040.
As the Brits on the board will know, the Mods and Rockers were rival youth cultures back in the sixties. The Mods used to ride scooters and wear parkas and the Rockers used to wear leather and ride proper motorbikes.
And every Bank Holiday weekend, they all used to descend down to seaside resorts like Brighton and have an almighty ruck on the beach, frightening the lives out of the locals.
So when I noticed we had a new Mod who is a bit of a rocker, I couldn't resist making the reference!
Yeah yeah off-topic I know...
I'll get my coat.