Pyrr. Let's unravel your comments comparing Keytruda to Direct.

You state:-

''How do you think DCVax-Direct will stack up against Keytruda's stunning efficacy profile if both were on the market? Even if somehow NWBO manages to get Direct approved, do you think anyone would choose it over a CI like this?
What about for those who fail on CI therapy? Apparently they will not qualify for DCVax-Direct, as researchers do not think Direct will work in such cases:

Quote:
Exclusion Criteria:

• Prior active immunotherapy for cancer within the past 2 years. --DCVax-Direct P1 trial


So it seems all immunotherapy-refractory patients will not qualify to receive Direct. And so they would have to take it first. But why on earth would they? Not when CI are an option instead.''



Now, first of all, you are treating this as an either/or comparison.

Why?

LP has previously stated that she sees the synergistic possibilities, regarding Direct along with a checkpoint inhibitor.
Now, if you have read the latest update on Direct, you will have seen that 80% of evaluable Direct patients showed either a de novo or significantly increased expression of PD-L1.

Are you aware that PD-L1 expression is required for Keytruda to work?

From the Keytruda website:-

'• PD-L1 expression has been shown to be predictive of response to KEYTRUDA.'

So, Direct has the potential to allow Keytruda to work, where it would not otherwise.

THAT is why, Direct will be used either as a monotherapy, or PRIOR TO a checkpoint inhibitor such as Keytruda.

The majority of sufferers with cancers such as breast or pancreatic do not express PD-L1, so, in these cases, Keytruda will not work.

Therefore, Direct, in addition to its own efficacy, will have an important role in potentiating Keytruda efficacy.
The important thing to remember is Direct HAS to come first, where enhanced PD-L1 expression is required.

So, can you see, it is not either/or.

The fact that Direct Phase 1 precluded patients from the trial, who had received prior active immunotherapy has nothing to do with 'researchers do not think Direct will work in these cases' i.e. when prior CI therapy had been used. That is your invention.
I would imagine that it quite usual in an immunotherapy trial, to preclude patients who have had a prior immunotherapy.

That is not to mention the serious adverse events related to Keytruda.

The Keytruda website states that these occurred in 38% of recipients...
So, Direct, as well as its own huge promise, may well allow Keytruda to work, where it otherwise would not!

To conclude:-

-it is not an either/or
-Direct stands as an effective, safe therapy.
-For many patients, Keytruda will not work. Prior use of Direct may allow it to work. Keytruda's adverse effects in 38% of patients remain a concern.

Adam

Quote from your post:-

'This is a devastatingly negative analysis for anyone who cares to judge DCVax Direct objectively.'

You're right about the first bit: it is a devastatingly negative analysis.

However for 'anyone who cares to judge DCVax Direct objectively' it's an irrelevance.

You have clearly made a basic error in your calculations.
You estimate 93% Progressive Disease after 32 weeks.

This is patently incorrect, when you examine the latest table showing the long tail of durable responses. This already demonstrates a median OS, way in excess of what could be expected given the patient population, and indicates that this will improve further as the data matures.

Clearly, for many of the patients, it was a case of too little too late.
Their disease progressed in the early weeks of Direct regimen and so they were apparently given no further injections. Thus, Direct had little chance to work.

If you look at the patients who received 4 or more injections, you can see that approximately 90% were surviving at the time the table was produced, and all the patients who received 5 or 6 injections were still alive.
And, as you rightly point out, these are patients with an average of 3 tumors, with only one tumor being injected.

It is hardly surprising that given that all these patients are/were terminally ill, and had exhausted all SOC treatments, and would have had seriously compromised immune systems, that some would progress rapidly before treatment with Direct had a chance to work.

My conclusion is that Direct clearly works, with many terminally ill patients across a wide range of diverse cancers, and frankly, this is quite momentous!
With further treatment refinement i.e. multiple tumor injection, I think we can reasonably expect further enhanced efficacy.

To its detractors, notably yourself and AF who like to suggest it has no hope, I would suggest that, yes, it defies logic!

It works!

Adam,

We will have to add 'Direct is hocus pocus' to your list of infamous taglines.

You attempt to make a case that Direct cannot possibly work:-

'None of this is surprising because mechanistically, DCVax Direct is one of the most ludicrous ideas you can conjure in cancer immunotherapy. The idea that harvested dendritic cells, cultured and expanded ex vivo, and then injected back into the tumor will suddenly pick up antigens and promote a potent tumor-killing immune response is hocus pocus.'

Then at the end of your post, you state:-

'DCVax Direct defies logic'

Is that what you meant to say?!

A Freudian slip perhaps...

Direct's potential global applications (in both senses) is the one that gives Big Pharma the biggest headaches. One of them may be able to ride NWBO's coat-tails, if they have a checkpoint inhibitor that comes up to scratch.

Turtle.

This is not off topic.
Both are running Phase 3 GBM trials. For certain patients they have potentially competing therapies.
Both have been subjects of short attacks.
Both have been subject to misleading media coverage.

NB
Pyrr's recommendation of RUSL, however, is off topic.
And, with his track record, I'd leave that one well alone...

There is nothing logical about your post.

It is just a series of assertions, that don't stand up to the most elementary scrutiny.

You state:-

'None of the DCVax Direct patients responded to treatment. Zero. None.'

'The idea that harvested dendritic cells, cultured and expanded ex vivo, and then injected back into the tumor will suddenly pick up antigens and promote a potent tumor-killing immune response is hocus pocus.'

The long-tail of survivors strongly suggests stable disease. And what is another way of saying stable disease? Well, it sounds like PFS!

And long-tail survival, I would suggest is related to OS!

And how does the FDA measure efficacy?
Well, surprise, surprise PFS and OS.

Albeit on a small-scale study, NWBO report that:-

'Overall, both CD4+ helper T cells and CD8+ killer T cells increased materially from
baseline in at least 20 of 28 assessed patients (71%) in DCVax-Direct Phase 1.'

And in 80% of patients, PD-L1 Checkpoint expression was induced:-


• 20 of 25 evaluable patients (80%) in DCVax-Direct Phase I trial, showed either de novo or significantly increased expression of PD-L1 following DCVax-Direct treatment.

• At least in some types of cancers, PD-L1 expression is correlated with
(and may predict) patient responsiveness to checkpoint inhibitors
(e.g., gastric cancers)

Just in case you missed it, Direct is applicable to at least 13 non-operable solid cancers including:-

-Pancreas
-Sarcoma
-Bladder
-mCRC
-Melanoma
-Pancr Net
-Gall Bladder
-Lung
-Lung Net
-Ovarian
-Breast

Quite exciting really.

There seems to be a correlation between the degree of potential, and the degree of ridicule from yourself.
'

It's as well to remember when comparisons are made with CLDX, that their Phase 3 GBM trial was only open to patients with a documented EFGRvIII positive tumor status. This represents approximately 25% of the GBM population.

AF
If I may quote from your post:-

'I'm not under investigation of any kind. I don't know why you'd think i was under investigation, but I'm not.'

You seem to be stating this as fact.

How can you possibly know!

Adam.
How many times have you been told to stop telling stories?

RK.
Would you mind explaining what point you are trying to make, and what is its significance?

I'm afraid you've completely lost me.

The longer the screening halt goes on, the more I conclude that something unprecedented is happening behind the scenes. That is very different from saying that something 'major has gone awry'
Why connote it that way, when you do not have the evidence to support such a supposition?

Yes, of course we would like to see Direct Phase 2 under way by now.
Frankly, I doubt whether the financial resources are there right now.
The smooth 'runway' that Woodford envisaged has been compromised by the allegations in the PhaseV hit piece.

I am sure that he would see the logic in continuing investing right through to commercialisation, and I am sure that was/is his intention.
However, he cannot further his investment until NWBO receives a clean bill of health from the investigation.

Further Direct trials must take in to account the rapid advances in genetic research in the last couple of years, particularly in the area of antigen expression. And the trial must design this in, with the use of genetic predictive markers to maximise response rates, and the selective employment of other adjunctive inputs such as Decitabine.
In other words, they've got to get it right from the outset!

Perhaps we should remind ourselves of the updated data presented by LP at Phacilitate on Jan 26th.
Excellent long tail survival in L info arm.
And again, quite amazing long tail survival from Direct, treating a diverse range of solid cancers, in a small study.

Due to Nwbo's radio silence, AF has had precious little to negatively spin, until the forum brought LL's video to our attention.

Unfortunately, we did a lot of the legwork for him. He sat back and allowed the board to dissect its meaning and value, and then it was half an hours work in between craft beers for him to come up with his spin.

It is particularly unfair on LL, who is undoubtedly a very dedicated and expert clinician and researcher.

I would imagine that, in the case of GBM, the FDA would have a strategy for all relevant clinical trials in the event of disease progression, given that, until the genesis of DCVaxL, such a diagnosis was effectively a death sentence.
Any trial with a placebo arm must surely have built in provision for a crossover, or subject departure from trial. Anything else would be unethical.
The fact that the crossover on our trial means every participant will have the chance to benefit from DCVaxL, I take as a tacit sign that the FDA already recognises DCVax as the safest and most promising therapy.
Would you go on a CLDX trial if you knew you might be receiving a placebo without being afforded the opportunity to 'cross over'
If the CLDX trial is comparing SOC with SOC plus CLDX drug, then, in those circumstances a cross over may not be essential.

RK

Quote:-

'Debate the point, not the pointer is how I will continue to post. Your choice of course to do what you want. Leave me out of any "pointer topic" discussions going forward please. Thank you.'

Would you care to review your posts in response to Sentiment Stocks?

There would appear to be some inconsistency....

Austin

Why do you think UCLA hung up on him and Les refused to comment?
That was the obvious and only sensible thing to do!

Why did AF fail to mention that LL demonstrated that DCVax L appears to be a complete cure for the mesenchymal subgroup?

Doesn't exactly meet his agenda, does it?

There will be 100 plus mesenchymal patients in the trial, and the data will continue to mature, and become more and more impressive.

By accident or design, the trial will also provide an additional data stream-
i.e. differences in DCVaxL efficacy depending on early or delayed administration.
Useful for when L becomes an established part of SOC.

Yes, be confident that FDA required crossover.
This was clearly stated by LL.

Adam is just attempting to negative spin. Having a crossover was clearly the only ethical way forward, and affords placebo patients a viable treatment after progression.

Strange that Adam should neglect to mention that LL's video, clearly demonstrates that DCVax L represents a likely complete cure for mesenchymal subgroup. This is truly revolutionary.
Again, it would be unethical to have OS as primary endpoint, without a crossover for placebo patients on progression.

Are the CLDX and BMY trials that you mention, double blind with a placebo arm? If so, what happens to placebo patients when they progress?
The only ethical thing to do would be to treat them with DCVax L...

If OS was primary endpoint for DCVax, the trial might have to run
for decades!

I'm sorry Evaluate, but that just does not work.


You say:-

'..because they KNOW that they will be receiving real vaccine and not need to wonder whether they are receiving placebo vaccine anymore.'


Then you say:-

'Not sure whether it is unethical to have possibility of placebo after crossover (ie .... after their real vaccine runs out after crossover)'

It surely is unethical to make this statement to trial patients in the guidance at outset, that if they crossover:-

' .. you will definitely be having the vaccine from then on.'

when, if you are correct, the patient could conceivably receive several doses of placebo spread over years, so as to maintain the blind element.

The only alternative to this would be up to a total of 19 doses of L spread over perhaps 5 years, with crossover falling in the middle.
This is untested in pre-trial models, so would surely not be employed, and, in any event, it is doubtful that many subjects would have sufficient lysate.

This is leaving aside the further issue of pseudo-progression.

So, I'm afraid this remains a muddle and a conundrum for the trial, and one that they WILL have come across, in the case of a minority of patients. AND, may have been the cause of, or contributed to the need for a lengthy screening hold.

Still long, but needed to flag this up, as it seems to have been missed or ignored by most.

Then we are in a muddle.

RK maintains that it goes open label at this point, whereas you suggest blinding is maintained.

After cross over from treatment, what you are suggesting is that a patient may go from gradually increasing intervals between L injections as per dosing protocol, and then return on a fresh regimen to the early closely spaced injections. L was never designed to be given it that way i.e. start giving more frequent injections halfway through a carefully planned dosing regimen.

I wonder if this board's confusion is mirroring what actually happened, or is happening in the actual trial.

I maintain that any use of placebo after crossover is in practice unethical, even if it that issue wasn't obvious at the time of trial design. I also doubt that administering more than 10 doses of L would be done, as to the best of my knowledge, they never planned for that.

I do believe that the only way that they could proceed in this set of circumstances would be to not vary the L administration after crossover i.e. not going back to the start.

Sorry Outside Lane. Not trying to score points, but I don't think the following part of your post can be right.

To quote you:-

'To account for the fact that a patient on DCVAX-L might progress and therefore 'crossover', the protocol starts the treatment from the beginning. If the vaccine was partially consumed, the patient gets placebo after crossover. If the vaccine was fully consumed, the patient gets placebo. The giving of placebo is only a function of the fact that the treatment is not unlimited. All patients who elect to crossover starts the DCVAX-L regimen from day 0, as if they had nothing before, even if they were already getting DCVAX-L.'

I still need to clarify this as I think it is important.

If a patient from the treatment cohort progresses, they will, to use a wholly unsuitable term, 'cross over' Then they will continue receiving L injections at the prescribed intervals just as before, until they have received all ten injections or run out of lysate, regardless of how many or few of those injections were before progression and crossover. And then finish active participation in the trial.
So they have only 'crossed over' in a technical sense. The treatment they receive will not change.

The above must hold true.

The only other way of doing things would be to use placebo after 'cross over' to maintain a facade.
Clearly unethical.

If they did not realise this at the time of trial design, then surely they have now realised.

Thus the statement from the patient information is innaccurate:-
'If you go into the crossover option, you still won’t know which treatment you’d been having up until then. But you will definitely be having the vaccine from then on.'

So if you crossover from treatment, you do not commence a programme of 10 injections. You just have the remaining number that you require to reach 10 in total.

So blinding ends at crossover, either explicitly or implicitly.

Please tell me I have got this right!!!

Sorry for previous mentions of 12 injections. Should have said 10.

Maybe it became realised that you could only ethically maintain a double blind trial UP UNTIL CROSSOVER. If you attempted to keep it blind after crossover, patients and doctors would realise by subsequent injection schedule what cohort they started out on.
The only way to maintain it blind would be to give placebo after a treatment patient had had 12 injections of L, some before and some after crossover.
Another possible reason for screening halt?
Unblinding at crossover, it seems to me, is the only way to continue ethically, and the only way to maintain data integrity.

So if you 'crossover' from treatment arm after 11 injections, you do not start a new regimen of 12 injections. You just wait up to six months for your last injection of L and then finish trial treatment?
You would then know by deduction that you started out on L and not placebo.

That's the bit that doesn't sit right. If you 'crossover' due to progression after 10 of 12 injections, you will then start another 12 injections, only the first two of which will be L, and then for the next 2 to 3 years you will be getting placebo!
That clearly seems unethical, and it would appear that the only ethical way around this would be to unblind to patient and doctor at crossover, so that a patient could elect to leave the trial rather than continue with years of placebo.

Or what about the patient where there is only sufficient lysate for, say, 5 injections of L. What if that patient is deemed to have progressed shortly after their fifth injection. They would then presumably 'crossover' and commence a regimen of 12 injections of placebo, over a protracted period of time. Not good!: whether it was real or pseudo progression.

This clearly states that both patient and doctor will NOT know after crossover what cohort he/she started out in. So, not Open Label?

If, for example, a member of treatment cohort has 6 injections of L and then progresses, then they will cross over, and start 10 injections, the first 4 of which will be L and then 6 of placebo.
I can understand how this keeps it blinded, but it could be considered unethical if the patient continues to progress, during the 6 placebo injections, as presumably they could not move on to different treatment or a different trial....?

Can you explain to me why that would be rare?

Are you assuming that a subject from the treatment cohort is very unlikely to progress?

I didn't realise you had that degree of faith in DCVaxL, though I am very glad to hear it.

What if a trial subject has already received their requisite number of L immunisations and eventually progresses. How does he /she 'crossover'?
Such a subject would just continue the existing regimen.

For sure, there is a long way to go.

But the unequivocal data on mesenchymal patients from 2011 is surely cause for joy, wouldn't you say?

RK

I expect you're right. I expect placebo patients are taking a few months longer to event than their original estimate, for reasons I've already stated, even though we have chosen a placebo that, as far as we know, is genuinely inert.

But, like you say, does it really matter?

Linda L does go on to say that it is turning in to a comparison between early and late treatment with DCVax. That implies to me that many subjects have crossed over, albeit a few months later than might have been predicted.They're 'all living longer.'

I take this to mean they're all eventing later, placebo and treatment.
Yes that could have some implications for eventual trial outcome, if median OS with DCvax is only a few months longer than SOC. But all the indications are that with treatment, median OS will be increased by 100% plus.

LL's earlier study demonstrated that for mesenchymal subgroup, DCVaxL leads to long-term remission, effectively a cure. the statistical likelihood is that 30-50% of trial participants are in that group.
The most important piece of data is what happens after commencement of treatment with DCVaxL.

It just means that it will take a few months longer to establish statistical significance.
The treatment cohort will then be compared with SOC in terms of disease progression and OS, rather than compared with a placebo group, who will all have crossed over!

With hindsight, this was almost bound to happen.

So the FDA's insistence on a crossover arm, on understandable ethical grounds, means there is less urgency for the DMC to recommend a halt for efficacy, as there are no subjects being left on placebo beyond first progression.

One trusts that the statistician on the DMC will know just as soon as the data is statistically sound.

Anyone good on 'P' values?

A selective quote from the FDA's Guidance on the establishment and operation of DMC's which may be of interest.

Quote:-

4.4. Potential DMC Responsibilities

4.4.1. Interim Monitoring
Most experience with DMCs has been in the setting of studies that address major outcomes such as mortality or serious irreversible morbidity. Although many such studies focus on short-term endpoints such as 30-day survival, other studies often use endpoints that require a substantial duration of follow-up after the intervention delivery has been completed. The need for monitoring in such studies often extends beyond the time when individuals are treated, since trends in survival or other serious outcomes may not become evident until some time during the follow-up period. Thus, the DMC’s responsibility to monitor the study generally continues until the planned completion of follow-up, regardless of the duration of treatment.

4.4.1.1. Monitoring for Effectiveness
In studies with serious outcomes, all parties would wish that any major treatment advance be identified and made available as soon as possible. It is critical, however, that the study yield a valid and definitive result. Thus, tensions between ethical and scientific considerations may arise. Consider, for example, a placebo-controlled trial of a new product for a serious illness or condition for which there is no standard treatment. If the emerging data suggest that those receiving the treatment are doing better, one might expect that a DMC would consider whether the study should be terminated earlier than planned. Estimates of treatment effect, however, will be unstable at early points in a study, and the chance is substantial of observing a nominally statistically significant benefit (e.g., p<0.05) at one of multiple interim analyses during a study of an ineffective product (see Section 4.4.2). A DMC, guided by a pre-specified statistical monitoring plan acceptable to both the DMC and the study leadership, will generally be charged with recommending early termination on the basis of a positive result only when the data are truly compelling and the risk of a false positive conclusion is acceptably low.

A second type of consideration is whether the hypothesized benefit is likely ultimately to be achieved. If the interim data suggest that the new product is of no benefit—that is, there is no trend indicating superiority of the new product—or that accrual rates are too low or noncompliance too great to provide adequate power for identifying the specified benefit, a DMC may consider whether continuation of the study is futile and may recommend early termination on this basis. In this case, false negative conclusions are of concern; statistical procedures are available to guide such determinations (see Section 4.3.2).


Hopefully, the last para doesn't apply.

So while we wait, we can at least assume that the data is becoming more statistically significant. Perhaps a doubling of Stupp Median OS will do it.

Question.

Does anybody know whether the GBM subgroup of trial participants would have been identified at the time of trial entry?

Because if the mesenchymal group within the treatment arm of the trial, are doing as well as the mesenchymal group within LL's prior study, and if the DMC is able to interpret data with knowledge of subgroup, then it would be their duty to report as much to the FDA, and perhaps recommend a halt for unprecedented efficacy.

Of course, with every passing month the data will continue to mature, and have more statistical validity.

Yes, Evaluate

I concur with all of that,
.

At the end of the day, until we have some incontrovertible data, we can only hypothesise what is going on with the trial.

My hypothesis is that placebo subjects probably are going a few months longer than statistically predicted, before progression.
After all, many of the trial sites will be top-notch teaching hospitals with the best surgeons, the best imaging equipment etc.

So that would lead to a small delay in the event count.
Plus, as a voluntary trial subject, when you are told that you will receive a very promising treatment, either straight away or after placebo/progression, you're going to have a lot of hope, and you're going to hang on in there. You will very probably do your own research into DCVax, even if you agree to not publically divulge what trial you are on.

You certainly won't be electing to exercise any right to assisted suicide, or anything of that nature.

So yes, I think the majority of trial participants, whether placebo or L are taking longer to event, than could have reasonably predicted.
I honestly don't think we can draw precise, conclusive meaning from LL's statements. After all, she is firstly a clinician, and if she only realised how much her comments would be dissected, she probably wouldn't have said anything at all!

I'm quite clear however that median OS is proving to be much, much longer than could have been predicted:- 'they're all living much longer'
Not much doubt about that.And of course that is a massive indirect compliment to L., which we have quite rightly picked up on.
So, it might take quite a bit longer for the requisite number of events to automatically trigger the interim review.

My hypothesis is that this started to become apparent to the DMC, back in the early summer, and at this point the FDA invited NWBO to have discussions about the most logical way forward, and that the screening hold was then agreed. In what way, they collectively decided to reshape the trial, well that would be a guess in the dark.

We need to take into account that Dr Pazdur is now an active advocator of faster approval in the cancer field, and he is prepared to vary rigid protocol, if the circumstances call for it. And Linda tells us how communication with FDA is very good.

So I remain super confident about ultimate trial outcome, even if we have to wait another six months for news, though I think it will be quicker than that.

And then the world will get hold of this revolutionary advance, and NWBO will no longer be the tiny, anonymous little biotech company that it is today...
Then watch the investors jump on board.

Hang on in there Linda (and us diehard longs!)

It is not off topic to make reference to a different stock in a similar sector. That other stock may be developing a competing or complimentary therapy. Or experiencing a short attack.
That is highly relevant to NWBO investors, who need to keep abreast of the wider biotech space.

Correct!
So that, in a nutshell, is why he decided to join the board..

I guess on that basis, that AF, as a public figure, can also be openly maligned/impugned/called a crook, within the TOS.

His public profile, I would suggest, is considerably higher than LP's.

Would you agree?