Replies to post #41389 on Innovation Pharmaceuticals Inc (IPIX)

[Tails]

Seel,
Thank you. That is what I've been waiting to hear.

Is the fact that one patient was restaged twice significant?

[TheHound]

Thank you for your input. Highly respected.

[BonelessCat]

Thanks Seel. You are the best. you said what I wanted to but without the language and training had togo to the forest and tree metaphor instead.

[MinnieM]

Excellent post that looks like it came from your cell again. ;) I'll break it up for easier reading.

Thanks for taking the time to post. You should do so more often! ;)



In Reply to 'Seel' responding to post# 41065

"The fact that tumor growth resumed is a clear sign that response at these levels is extremely dubious at best."

Incorrect.

Tumor reduction necessitating restaging confirmed in 6 drug resistant patients, multiple solid tumor types using recist 1.1 revised criteria is a clear,positive response. Disease progression following stabilization could be related to different factors which your post ignores, though blatantly obvious reason is most likely the tiny dose.

We know these patients weren't near expected efficacious dose. Solid tumor reduction at known suboptimal dose is far from meaningless. It is, in fact, remarkably hopeful and unexpected.

The continued progression of treatment resistant cancers, on the other hand, is to be expected at subtherapeutic dose. You do remember that they were all end stage with drug resistant tumors, right? And yet you find the fact drug resistant/treatment resistant tumors in 6 patients did respond to markedly suboptimal dose of this novel drug to mean little...

And 'tumors can appear to stabilize on their own'???

Again - end stage, multidrug and drug resistant solid tumors here. Can you tell me what the incidence of 'tumors appearing to stabilize on their own' could be in this end stage population?

What is likelihood that 6 dying people had solid tumors that 'appeared to stabilize on their own'?

You state that " errors can be significant due to technological imaging limitations".

Are you aware of the machine used for this trial? It is the Aquilion One. If you are at all familiar with recent tomography technology then you know this machine and therefore know how off base your 'significant error' theory is.

This is world leading research team. If you don't think they calculate in an overly generous standard margin of error %age in every restaging then...once again...you show your lack of familiarity with this whole process. Best team, scanner with sci-fi imaging function, actual mathematical formula for calculating restaging which includes standard of error...

And of course they need to continue affirming p21 activation. They gained a slight effect at these low doses.

The company has written "p21 biomarker expression in patients:
Kevetrin activated p21 in 4 out of 5 patients treated with 20 or 30 mg/m2".

That is very significant. That is an increase. It is reportedly slight and it exists - or else it simply would not have shown. The procedure used at this early stage is relative quantification. They simply compared gene expression in untreated sample with expression in treated sample of same patient. Purely mathematical and quantification completely automated - though checked by the lab team.

Expression increased or it didn't - it's pretty black and white, even if increase is only slight. It suggests that since slight increase seen with 'slight' dose, sizable increase may be seen with sizable dose.

We will have to wait for that supposition to prove out, but the fact that we have to wait doesn't make the small measured expression in 4 out of 5 patients at still scant dose an insignificant event. We have learned that there is evidence of p21 activation. Very important news.

[TruongKy]

Post 41389 by Seel should be a sticky note

Outstanding explanation!

[TheProgressive]

Hands down the best K trial breakdown up to this point, by far. Having Seel here is an absolute gift for this forum.

Even for those that may have questions or even doubts regarding the P or B game plan, I urge you to read and reread this post by Seel on the implications of the latest news on the Kevetrin trial. We are all extremely fortunate to have someone with her clinical trial knowledge and background posting here.

Thank you Seel for sharing your knowledgable and credible insight!!

[TheDane]

Excellent information. Thanks.

[cabel]

Thanks Seel for sharing your knowledge and experience,.. nice seeing you on this board,... please visit more often!!

[macnqueso]

Outstanding post. Thank you for taking the time.

This post which is 41389

and the one from Pete's friend - 41034

will tell you what you need to know regarding this clinical trial...


We are still very, very early into the clinical process with K... could it yet be an abject failure... absolutely it could...

But if it is successful... it will truly be a game changer... myself, and several others on this board, have alluded to the fact that the numbers are so ridiculous regarding potential valuation that we would sound like extreme pumpers or crazy fools if we put them in print... PC_Cish is about all i will say at this time, but in truth i believe this very much undervalues the long-term value of K if successful... we are talking about the potential to treat roughly 50% of all human cancers through the mechanism of re-booting the human immune system with the reactivation of p53...

Make no mistake... those who understand this process, painstakingly slow though it may be... understand that the news regarding K at the R&R... is the best possible news we could have received at this point in the process...

Leo and Menon are correct not to overplay this news... in terms of scientific process it is still too soon to make too much of it... the news is good, very good, nonetheless...

[dmattingly62]

Seel, fantastic!, thank you eom

[Truthbythought]

Glad you are excited. Lots and lots of assumptions in your rebuttal but who am I to rain on your parade. Ok ok i will try. I still say not easy to measure tumor growth if it is growing slowly no matter how good your tech is and note Stage IV tumors can still grow SLOWLY. I also still say stabilization followed by disease progression raises significant doubt about whether apparent stabilization was due to the medication. You think the tumor responded and then stopped responding at these dosages? Maybe, but I still believe it is reasonable to conclude and more likely that stabilization itself was an error of the physician/technician as a result of difficulty of measuring precise changes of the size of the tumor. Specifically - doctor looked at scans and thought disease stabalized because he cannot detect the slight growth and then another month goes by and now the change is enough to detect. Measuring changes in tumor size has always been an issue in cancer trials and one of the reasons nobody is comfortable with open label cancer studies vs blinded because of physician bias and error to see stabilization.

The market seems to agree that things are not quite as good as you say they are - at least not yet.

[KMBJN]

Thanks for the post, but have some follow-up questions and comments about assessing tumor response. I'm hoping you can clear some things up for me.

First, where does it say there was tumor shrinkage? I only heard them say "stable" and some of these followed later by "progression." Stable means less than 20% growth of tumor by Recist 1.1 criteria, and progression means more than this.

Are you saying that "restaging" automatically implies tumor reduction?

Here is some good information about cancer staging:

http://www.cancer.org/treatment/understandingyourdiagnosis/staging

I think someone posted before the bit from the above about "restaging." Restaging I suppose means reassigning the stage, which means it could be worse and it could be better, correct?

Maybe someone had Stage IIIb breast cancer and it was restaged to Stage IIIc, or it could've been changed to IIIa, or IV, or II ...

There was nothing in the eligibility criteria for the Kevetrin trial about staging, just "Pathologically confirmed solid tumor which is locally advanced or metastatic, and either refractory after standard therapy for the disease, or for which no effective curative or surgical treatment options are available"

so I'm guessing most subjects were stage III or IV, but restaging doesn't automatically imply tumor shrinkage as far as I can tell.

And if there was tumor shrinkage, why not just come out and say it??? They must know the tumor response at 2 month follow-up imaging according to Recist 1.1 criteria for I imagine at least 10 of the subjects, so why not give us the information? The options are complete response, partial response, stable disease, or progressive disease.

I heard them say 6 with stable disease (at 2 months?), of which some of them then progressed. I didn't hear anything about complete or partial response = shrinkage.

All this talk about "efficacy" is great, but we really need to see the important numbers - tumor response according to RECIST 1.1 criteria, time to progression (PFS), and most importantly overall survival compared to historical cohorts for each type of cancer before we say there was efficacy.

So, some are saying that drug levels are expected to be too low to be efficacious, yet there is efficacy? Most PI trials are not even statistically powered to determine efficacy, so I think caution is prudent.

Some recommendations for improving RECIST 1.1 criteria using PET-CT:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2755245/

"The typical development pathway for cancer therapeutic drugs includes an evolution from phase I to phase II and to phase III clinical trials. In phase I trials, toxicity of the agent is typically assessed to determine what dose is appropriate for subsequent trials. Typically, the statistical power of phase I drug trials is inadequate to assess antitumor efficacy. In phase II trials, evidence of antitumor activity is obtained. Phase II trials can be done in several ways. One approach is to examine tumor response rate versus a historical control population treated with an established drug. New drugs with a low response rate are typically not moved forward to advanced clinical testing under such a paradigm. In such trials, tumor response has nearly always been determined anatomically. An alternative approach is to use a typically larger sample size and have a randomized phase II trial, in which the new treatment is given in one treatment arm and compared with a standard treatment (1–4). Once drug activity is shown—or suggested—in phase II, phase III trials are typically performed. Phase III trials are larger and typically have a control arm treated with a standard therapy. Not all phase III trials are successful, but all are costly."

http://www.ncbi.nlm.nih.gov/pubmed/23971174

http://www.ncbi.nlm.nih.gov/pubmed/19380403

some problems with CT imaging:

"Although response assessment on CT has been refined over many years, fundamental limitations remain. Interobserver variability in tumor size measurements is still high because of difficulties in delineating tumor tissue from secondary changes in the surrounding tissues. Furthermore, CT is inaccurate in differentiating viable tumor from necrotic or fibrotic tissue. Consequently, the degree of response may be underestimated on CT. Conversely, if tumor shrinkage is short lived and followed by rapid tumor regrowth, CT may overestimate the beneficial effects of a treatment. Finally, CT is limited in characterizing responses in tumors that do not change in size during therapy. Because the growth rate of untreated human tumors varies tremendously, an unchanged tumor size after some weeks of therapy may represent a drug effect but may also indicate a slowly growing tumor that was not affected by the applied therapy."

The odds that some of the tumors are stable on their own after 2 months is probably not that low, depending on the median progression free survival of that particular cancer.

It's very hard to say anything about efficacy without knowing RECIST tumor response category for each type of cancer, and having such small numbers of a heterogenous group of solid tumor cancers.

It seems like a better way to measure tumor growth is to look at the tumor growth rate before and after treatment. It doesn't always correlate with RECIST 1.1 criteria:

http://www.ncbi.nlm.nih.gov/pubmed/21763126

[redwing992006]

Seel - are you a radiologist ?

[tootalljones]

thought to bump this old up,(as well as this thread of posts) in lieu of the JP Morgan conference which is less than a month away.

[Tails]

One of my favorite posts from Seel from the past:


"The fact that tumor growth resumed is a clear sign that response at these levels is extremely dubious at best." Incorrect. Tumor reduction necessitating restaging confirmed in 6 drug resistant patients, multiple solid tumor types using recist 1.1 revised criteria is a clear,positive response. Disease progression following stabilization could be related to different factors which your post ignores, though blatantly obvious reason is most likely the tiny dose. We know these patients weren't near expected efficacious dose. Solid tumor reduction at known suboptimal dose is far from meaningless. It is, in fact, remarkably hopeful and unexpected. The continued progression of treatment resistant cancers, on the other hand, is to be expected at subtherapeutic dose. You do remember that they were all end stage with drug resistant tumors, right? And yet you find the fact drug resistant/treatment resistant tumors in 6 patients did respond to markedly suboptimal dose of this novel drug to mean little...
And 'tumors can appear to stabilize on their own'??? Again - end stage, multidrug and drug resistant solid tumors here. Can you tell me what the incidence of 'tumors appearing to stabilize on their own' could be in this end stage population? What is likelihood that 6 dying people had solid tumors that 'appeared to stabilize on their own'? You state that " errors can be significant due to technological imaging limitations". Are you aware of the machine used for this trial? It is the Aquilion One. If you are at all familiar with recent tomography technology then you know this machine and therefore know how off base your 'significant error' theory is. This is world leading research team. If you don't think they calculate in an overly generous standard margin of error %age in every restaging then...once again...you show your lack of familiarity with this whole process. Best team, scanner with sci-fi imaging function, actual mathematical formula for calculating restaging which includes standard of error...
And of course they need to continue affirming p21 activation. They gained a slight effect at these low doses. The company has written "p21 biomarker expression in patients:
Kevetrin activated p21 in 4 out of 5 patients treated with 20 or 30 mg/m2". That is very significant. That is an increase. It is reportedly slight and it exists - or else it simply would not have shown. The procedure used at this early stage is relative quantification. They simply compared gene expression in untreated sample with expression in treated sample of same patient. Purely mathematical and quantification completely automated - though checked by the lab team. Expression increased or it didn't - it's pretty black and white, even if increase is only slight. It suggests that since slight increase seen with 'slight' dose, sizable increase may be seen with sizable dose. We will have to wait for that supposition to prove out, but the fact that we have to wait doesn't make the small measured expression in 4 out of 5 patients at still scant dose an insignificant event. We have learned that there is evidence of p21 activation. Very important news.